CA3004951A1 - Control of cellular redox levels - Google Patents

Abstract

Disclosed herein are compositions and methods for regulating redox status and/of reducing oxidative stress in a subject, the methods and compositions comprising TLR agonists comprising bacterial lysates and/or lysate fractions. Also disclosed are compositions and methods comprising bacterial lysates and/or lysate fractions formulated or administered in combination with one or more other therapeutic or pharmaceutical agents.

Description

CONTROL OF CELLULAR REDOX LEVELS
CROSS-REFERENCE TO RELATED APPLICATIONS
10001j This application claims the benefit of U.S. Provisional Application No.
62/253,542, filed November 10,2015. This application is also a continuation-in-part of U.S.
Application No. 14/640.075,11ed March 6. 2015, which is a continuation oftl:S.
Application No. 14/034,044, filed September 23. 2013, which claims the benefit of U.S.
Provisional Application No: 61/704,090, filed September 21, 2012. This application is also a continuation-in-part of U. S Application No. 13/743,194, filed January 1.6..
2013, which claims the benefit of US. Provisional Application No. 611586;975, filed January 16,2012 All of the above-identified applications are hereby incorporated by reference in their entireties.
BACKGROUND
100021 The innate immune response is one of the pathways that regulates inflammation.
Inflammation is stimulated by chemical factors released by injured cells and serves to establish a physical barrier against the spread of infection, and to promote healing of any damaged tissue following the clearance of pathogens. The process of acute inflammation is initiated by cells already present in all tissues, mainly resident macrophages, dendritic cells, histiocyws,:Kupffer cells, and mastocytes. These cells present receptors, contained on the.
surface or within the cell, named pattern recognition receptors (PRRs), which recognize molecular patterns that are broadly shared by pathogens but are distinguishable from those of the host. These molecular patterns are collectively referred to as pathogen-associated molecular patterns (PAMPs). Immune cells undergo activation when one of their Pints recognizes a PAMP and. in response release inflammatory mediators.
100031 PAMPs are thus structures associated with groups of pathogens that are recognized by cells of the innate immune system. A vast array of different chemical types can serve as PAMPs, including glycans and glyeoconjutrates. These structures can also be referred to as small molecular motifs which are conserved within a class of microbes. They are recognized by Toll-like receptors (TI-Rs) and other PRRs in both plants and animals.
100041 TI.Rs are conserved receptors that recognize structures from bacteria, fungi, protozoa, and viruses. Although the MR receptor is located on the surface of the plasma membrane, binding to the receptor is transmitted transmembrane and results in an intercellular signaling response. TLR signaling ultimately leads to the induction or - I -suppression of genes that orchestrate the inflammatory response. Activation of a particular TLR, for example, initiates a series of intracellular events resulting in an immune response characterized by the production of pm-inflammatory cytokines. TLR signaling originates from the cytoplasmic Toll-interleukin 1 (TIR) domain, conserved among all ILRs. The adapter molecule MyD88, containing both a T. domain and a death domain, associates with the-T1R domain of TLRs and .1PAK.proteins. Phosphorylation of IRAK leads to association with TRAF6 and subsequent activation of Wadi and secretion of pro-inflammatory cytOkincs. A52R, an immunoregulatory protein from the vaccinia virus, has previously been shown to be an intracellular inhibitor of TER-lependent signaling. When expressed in FIEK293:cells,A52R. was shown to inhibit. NF-tcB activation in response to stimulation by a variety of TLIZs, including TLR4. TLR5, and the combination of TLR2 and 6, and TLR2 and 1. In addition, A52R inhibited NF-dit activation in response to Poly (1:0), a synthetic ligand tbr ILR3. TLR3 has-been implicated in anaiiti-viral innate immune response.
pool One of the primary responses of activation is to Shift the redox status of a cell, Reactive oxygen species (ROS) MO be produced for defensive purposes. The very presence of ROS consumes antioxidants (reductants) and results in a more oxidative redox status. Not only can ROS and oxidative conditions result in cellular damage with concomitant activation of genes, redox status itself controls gene expression. For example, when conditions become more oxidative, easily oxidized chemical groups such as sulthydryl groups on certain proteins become oxidized. The oxidized state of these proteins is then recognized, leading to activation of specific genes, such as genes controlling redox status and promoting controlling inflammation, or genes producing aberrant or disease-promoting proteins.
100061 Inflammation is part of the complex biological response of body tissues to harmful stimuli, such As pathogens, damaged cells, or irritants. Inflammation can also result from autoimmune disorders (Where body tissues are incorrectly recognized as being foreign).
Inflammation initially serves as a protective response that involves immune cells, blood vessels, and molecular mediators. One 'purpose of inflammation is to eliminate the initial cause of cell injury, clear out necrotic cells.and tissues damaged from the original insult and the inflammatory process, and to initiate tissue repair. It is useful to differentiate inflammation from infection conceptually, as there are many pathological situations where inflammation is not driven by microbial invasion or infection, for example, atherosclerosis, type HI hypersensitivity, trauma, and ischetnia. There are also pathological situations Where microbial invasion does not result in classic inflammatory response, for example, as in eosinophilia. Whereas too little inflammation could lead to progressive tissue destruction by

- 2 -the hattnfill "invaders" (e.g. batteria, virus and mutated cells) and compromise the survival of the organism, too much inflammation (as in the case of chronic inflammation) may lead to-a host of diseases, such as hay fever, periodontitis, atherosclerosis, rhetunatoid arthritis, and even cancer (e.g.., gallbladder carcinoma).
100071 The initiation of a redox change and the resulting inflammatory response to pathogens is a critical component of the innate immune response designed to control infection. Because the sustained production of inflammatoty mediators can lead to chronic inflammation, tissue damage and disease development, inflammation is normally closely regulated. The signaling cascade initiated by PAMP/TLR interactions and culminating in gene activation has been associated with many disease states, including sepsis, autoinuntine diseases, asthma, heart disease and cancer. For example, it is hypothesized that sepsis occurs when bacteria and their products activate an uncontrolled network of host-derived mediators, such as pro-inflammatory cytokines which can lead to multi-organ failure, cardiovascular collapse and death. An abnormal TLR signaling response could lead to exaggerated cell-activation responses contributing to sepsis.
100081 Inflammation (whether chronic or acute) results from and leads to the increased production and release of free radicals and other ROS from damaged and/or inflamed tissues and as a result contributes to or causes oxidative stress. At the same time, inflammation can result from oxidative stress when ROS damage tissues. As such, inflammation and the various conditions associated with it can also be regarded as an "oxidative stress-related disease or condition." Other stresses such as psychological stress can also lead to Shifts in redox level and resulting oxidative stress and even inflammation. With such a positive feedback loop when the redox status induces a state of oxidative stress, that state may become self-perpetuating. Oxidative redox status and oxidative stress is 'supposed to occur in a defined locus and for a limited time. When the locus of the oxidative oldox status is inappropriate and/or continues for too long, a pathological or disease state exists. A wide range of pathological or disease states are potentiated by inappropriate redox state or oxidative stress brought on by chronic or acute inflammation or vice versa.
100091 Oxidative stress is a pathological form of an oxidative redox state involving the damaging action of abnormally increased amounts of ROS including free radicals. Free radicals are single atoms or molecules having at least one external electron orbital "occupied"
by a single electron ("unpaired") instead of two electrons ("paired"). The existence of an unpaired electron makes free radical compounds exceptionally reactive. They may spontaneously react with, and thereby damage, a large variety of key cellular molecules. A

- 3 -certain number of ROS including free radicals are naturally produced by the body due to cell metabolism. For instance, the synthesis of some hormones involves the generation of free radicals while polymorphonnelear leukocytes use the production of free radicals as a form of "chemical warfare" to kill bacteria, thereby guarding the body against infections. Other free radicals, such as Nitric Oxide (NO) are fundamental for the homeostasis of the body, because they act as chemical messengers to modulate important functions, including vascular tone, platelet aggregation, cell adhesion, and so on.
100101 Free radicals are potentially dangerous because they spontaneously tend to fill their unfilled external orbital with a second electron. The presence of two electrons in the same orbital is the condition of maximal stability¨minimum energy. Therefore, when a free radical collides with a "target molecule", having one or more "available"
electrons, such as the molecule of an unsaturated fatty acid (e.g., arachidonic acid), it immediately "extracts" an electron from the tartlet molecule. Due to this effect "oxidation" the original free radical loses its potential dangerousness whilst the newly generated Molecule is "oxidized" and, in turn, may become a new free radical, thus perpetuating the reaction, if no antioxidants are available to damp it. The reaction can continue to other molecules, including carbohydrates, lipids, amino acids, peptides, proteins, nucleotides, nucleic acids and so on ("chain reaction effect"). Such action by free radicals can result in vatyinedegrees of tissue damage and can cause (or conversely result from) inflammatory responses. An initial or primary site of ROS
release may be an appropriate response to an invading microorganism, but the invader is not destroyed or if redox homeostasis is not restored following destruction of the invader, the redox state may spread and the continuing secondary oxidative redox state may result in a chronic, damaging pathology with collateral tissue damage. An example would be traumatic brain injury (TBI) which leads to localized inflammation and oxidative redox status in the brain. If homeostasis is not reestablished, chronic oxidative redox status may result leading to long term tissue damage and chronic traumatic encephalopathy 100111 There thus exists a need in the art for compositions and methods for controlling cellular redox SUMMARY
100121 The methods and compositions disclosed herein are not limited to specific advantages or functionality.
100131 In one aspect, the disclosure provides toll-like receptor (TLR) agonist compositions for regulating redox status in a subject, the composition comprising: (a) a 'MR

-4-agonist comprising at least one lysate and/or lysate .fraction of a bacterium, wherein the TLR
agonist activates at least one or more Tilts or 'NL,Rs; (b) an optional promoter for enhancing absorption of the composition; and (c) an optional carrier for increasing a volume of the composition, wherein administration of an effective amount of the composition to the subject measurably reduces oxidative stress levels in the subject.
100141 in another aspect, the disclosure provides methods of regulating redox status in a subject, the method comprising administering a therapeutically effective amount of a lysate composition according to the disclosure to a subject in need thereof In some embodiments, redox status regulation is assessed by measuring changes in isoprostane concentration in the subject.
[001,51 In another aspect, the disclosure provides methods of regulating redox status in a subject, the method comprising the steps of: (a) repeatedly administering to .a subject in need thereof doses spaced. apart in time and consisting of a composition comprising: (i) a toll-like receptor (TLR) agonist comprising at least one lysate and/or lysate fraction of a bacterium wherein the agonist activates at least one or more different TLRs or NL,Rs;
(ii) an optional promoter for enhancing absorption of the composition; and (iii)-an optional carrier for increasing a volume of the composition; and (b) making measurements of a bodily fluid of the subject to detect changes in oxidative stress levels.
100161 in another aspect, the disclosure provides methods of decreasing the amount of isoprostane in the urine or blood of a subject, the method comprising the steps of (a) determining the level Of isoprostane in the urine or blood of the subject; (b) administering to the subject an effective amount of a composition comprising: (i) a toll-like receptor (TLR) agonist comprising at least one bacterial lysate and/or lysate fraction from a bacterium, wherein the TLR agonist activates at least one or more different Mks or NLRs;
and (it) an optional promoter for enhancing absorption of the composition; and (c) continuing administration of the composition until the level of isoprostane in the urine or blood of the subject is decreased.
100171 in another aspect, the disclosure provides compositions comprising:
(a) a bacterial lysate and/or lysate fraction capable of activating at least one or more toll-like receptors (TLRs) or Nod-like receptors (NLRS); (h) an optional promoter for enhancing absorption of the composition; and (c) an optional carrier for increasing a volume of the composition.
100181 In another aspect, the disclosure provides pharmaceutical formulations comprising lysate compositions according to the disclosure, wherein the pharmaceutical formulation is

- 5 -formulated for buccal or sublingual administration. In some embodiments, the pharmaceutical formulations are formulated to dissolve in not less than I minute after administration.
100191 In another aspect, the disclosure provides methods of producing a bacterial lysate comprising the steps of: (a) fermenting a bacterium in a growth medium to the stationary growth phase to produce a fermentation broth; (b) harvesting bacteria from the fermentation broth; (c) pasteurizing the harvested bacteria; and (d) lysing the pasteurized bacteria with a lysozyme to produce a bacterial lysate. In some embodiments, the bacteria are harvested in the mid-logarithmic phase, the late-logarithmic phase, the early stationary phase, the mid-stationary phase, or the late stationary phase.
100201 In another aspect, the disclosure provides bacterial lysates produced according to methods comprising the steps of: (a) .fermenting a bacterium in a growth medium to the stationary growth phase to produce a fermentation broth; (Li) harvesting bacteria from the fermentation broth; (0) pasteurizing the harvested bacteria; and. (d) lysing the pasteurized bacteria with a lysozyme to produce a bacterial lysate; In some embodiments, the bacteria are harvested in the mid-logarithmic phase, the late-logarithmic phase, the early stationary phase, the mid-stationary phase, or the late stationary phase.
pan In another aspect, the disclosure provides methods for alleviating one or more oxidative stress-related side effects associated with administration of a pharmaceutical agent, the method comprising administering in combination with the pharmaceutical agent a therapeutically effective amount. of a lysate composition comprising: (a) a lysate and/or lysate *action fa bacterium;. (b) an optional promoter for enhancing absorption of the composition; and (c) an optional, carrier for increasing a volume of the composition; wherein the pharmaceutical agent and lysate composition are administered simultaneously or in any order, and through the same or different routes of administration.
100221 In another aspect, the disclosure provide.s methods-for treating oxidative stress-related diseases or conditions in a subject, the method comprising administering to the subject a therapeutically effective amount of a composition comprising: (a) a bacterial lysate and/or lysate fraction capable of activating at least one or more toll-like receptors CrtRs) or Nod-like receptors (NLIts); (b) an optional promoter for enhancing absorption of the composition;
and (c) an optional carrier for increasing a volume of the composition.
100231 In.another aspect, the disclosure provides methods forreducing oxidative stress in a subject, the method comprising: (a) determining the level of oxidative stress in the subject by measuring the amount of isoprostane in the urine or blood, of the subject;
(0) administering to the subject an effective =taunt of a composition comprising: (i) a toll-like receptor (TLR)

- 6 -agonist comprising at least one lysate and/or lysate fraction from a bacterium, wherein the TLR agonist activates at least one or more TL.Rs or NLIts; and (ii) an optional promoter for enhancing absorption of the composition; and (c) continuing administration of the composition until the level of oxidative stress is reduced, as determined by a decreased amount of isoprostane in the urine of the subject 1100241 In .another aspect, the disclosure provides therapeutic combinations comprising:
(a) a lysate composition comprising (i) a bacterial lysate and/or lysate fraction capable of activating at least oneor more toll-like receptors (ThRs) or Nod-like receptors (NLIts); (ii) an optional promoter for enhancing absorption of the composition; and (iii) an-Optional carrier for increasing a volume of the composition; and (b) one or more pharmaceutical agents; wherein the lysate composition and the one or more pharmaceutical agents are administered simultaneously or in any order, and wherein the lysate composition and the one or more pharmaceutical agents are administered via the same or different routes-of administration, 100251 In another aspect, the disclosure provides pharmaceutical formulations comprising the combination of (a) a lysate composition comprising (1) a bacterial lysate and/or lysate fraction capable of activating at least one or more toll-like receptors (ThRs) or Nod-like receptors (NRs); (ii) an. optional. promoter for enhancing absorption of the composition; and (iii) an optional carrier for increasing a volume of the composition; and (b) one or more pharmaceutical agents. In some embodiments, the one or more pharmaceutical agents are selected from the group consisting Of an antispasmodic, a motility stimulant, an H2-Receptor antagonist, antimuscarinic; a chelate, a prostaglandin analog, an aminosalicylate, corticosteroid, an drug affecting immune response, a stimulant laxative, a drug affecting bit iary composition and flow, a bile acids sequestrant, a dopamine antagonist, a proton pump inhibitor, an opioid, an opioid receptor antagonist, an analgesic, a sleep drug, a cardiac glycoside, a phosphodiesterase inhibitor, a thiazide, a diuretic, a potassium sparing diuretic, an aldosterone antagonist, an osmotic diuretic, a drug for arrhythmia, a beta adrenoreceptor blocking drug, a hypertension drug, a drug afftteting the renin-angiotensin system, a nitrate, a.
calcium blacker, an antianginal drug, a peripheral vasodilator, a sympathomimetic, an anticoagulant, a protamine, an antiplatelet drug, a fibrinolytic drug, an antifibrinolytic drug, a lipid regulating drug, an omega three fatty acid compound, a. CNS drug, an anti-infective, or another drug selected from the group consisting of Benztropine, procyelidine, biperiden, Amantadine, Bromocriptine,..Pergolide, Entacapone, Tolcapone, Selegeline, .Pramipexole, budesonide, formoterol, quetiapine fumarate, olanzapine, pioglitazone, montelukast,

- 7 -Zoledrotnic Acid, vaisartan, latanoprost, Irbesartan, Clopidogrel, Ato.moxetinc, Dexamfetamine, Methylphenidate, Modena BleOmycin, Dactinomycin, Datmorubicin, Idarubicin, Mitomycin, Mimantrone, Azacitidine, Capecitabine, Cladribine, Clofarabine, Cytarabine, Fludarabine, Flourouracil, Gemeitabine, mercaptopurine, methotrexate, Nelarabine, .Pemettexed, Rakitrexed, Thioguanine, Apomorphine, Betametha.sone, Cortisone, Deflancort, Dexamethosoneõ Hydrocortisone, Methylprednisolone, Prednisolone, Triameinolone, Cielosporine, Sirolimus, Taerolimus, Interferon Alpha, and Interferon Beta.
100261 in another aspect, the disclosure provides formulations comprising (a) a lysate composition comprising (I) a bacterial. lysate and/Or lysate fraction capable of activating at:
least one or more toll-like receptors (TIR) or Nod-like receptors (NUS);
(ii)..an optional promoter for enhancing absorption of the composition; and (iii) an optional carrier fbr increasing a volume of the composition; and (b) an isolated human anti-INFalpha antibody or antigen-binding fragment thereof or TN? inhibitor: in-seine embodiments, the human anti-TNFalpha antibody or antigen-binding fragment thereof is adalimtimab: In another aspect, the disclosure provides uses of such formulations in the manufacture of a medicament for the treatment of rheumatoid arthritis (RA), late-onset RA, or psoriatic arthritis in a subject. In another aspect, the disclosure provides methods for the treatment of rheumatoid arthritis (RA.), late-onset RA, or psoriatie arthritis in a subject, the method comprising administering to the subject a therapeutically effective amount of such formulations.
[0027i in some embodiments of any of the methods or compositions disclosed herein, the bacterium is a Gram-positive or Gram-negative bacterium, in -some embodiments of any of the methods or compositions disclosed herein, the Gram-positive bacterium is selected from the group consisting of a bacterium of Lactobacillaccae family, a bacterium of Streptoeoecace:ae family, a bacteritun'aBilidobaciVriaeeae Family, and a bacterium of Bacillace4e family. In some embodiments:, the Gram-positive bacterium is selected from the group consisting of Bacillus coagultins, Lactobacillus .sporogenes, Streptococcus therm ophilus, Bsiobacteratm aniutalis, Billtiobacterium. animalis, subspecies an/ma/is.
Btfidobacteriuoi Elands, .11ifidobacteriunz /ovum, Bffidobaeterium breve, Lactobacillus atidophilus, Lactobacillus plantarzon, LactobacilluS casei,Lactobacillus-delbnieckii, Lactobacillus delbriteckil subspecies bulgaricus, LactoeOceus locus, Lactococcus /oats subspecies lactic, Streptococcus lactis,Streptococcta thermophilits, Bifidobacterium locus, BOdobacterium breve, Pediococcus acidtlactici, and Lactobacillus belveticus.
100281 in some enibodiments of any.of the methods or compositions disclosed herein, the Gram-negative bacterium is selected from the group consisting of a bacterium of

- 8 -Pseudomona$ genus, Kieb.viella genus, Ximrhomonas genus, Shigelia emus, and Enterobacter genus. In some embodiments, the Gram-negative bacterium is selected from the group consisting of Klebsielia axylacia, Shigella jlerneK, Xanthomonas carnpestric, and Pseudomonas flourescens.
100291 in some embodiments of any of the methods or compositions disclosed herein, the TLR agonist, lysate, lysatcfraction, or cell wall fraction activates at least one or more of TLR 2, TLR 3, TLR 4, TLR 5, TLR 7, TLR 8, TLR 9, NODI , and NOM. In some embodiments, the TLR agonist, lysate, lysate fraction, or cell wall fraction activates two or more of TLR 2, TLR 3, TLR 4, TLR 5, TLR 7,TLR 8, TLR 9õ NODI., and NOD2. In some embodiments, the MR. agonist, lysate., lysate fraction, or cell wall fraction activates UR. 2 and TLR 4. In some embodiments, the TLR agonist lysate, lysate fraction, or cell wall fraction activates three or more of TLR 2,. TLR 3, TLR4, TLR 5, TLR. 7, TLR.
8, TLR 9, NOD I , and NOD2, 100301 In some embodiments of any of the methods or compositions disclosed herein, the promoter is selected from the group consisting of amino acids, amino sugars, and sugars.
In some embodiments, the carrier is selected from the group consisting of a binder, a gum base, and combinations thereof In some embodiments, the gum base comprises at least one hydrophobic polymer and at least one hydrophilic polymer. In some embodiments, the binder is selected from the group consisting of a sugar, a sugar alcohol, and combinations thereof. In some embodiments, the sugar alcohol is selected from the group consisting of mannitol,-sorbitol, .xylitol, and combinations thereof.
100311 In some embodiments, the compositions are manufactured as a dosage form selected from the group consisting of a lozenge, a chewing gum, a chewable tablet, a candy, anda dissolving tablet. in some embodiments, the dosage form delivers the TLR
ag.ohist to = an oral mucosa. In some embodiments, the oral mucosa is selected from the group consisting of the sublingual mucosa, buccal mucosa, and a combination thereof.
100321 in some embodiments of any of the methods and compositions disclosed herein, the compositions are formulated for oral mucosa' delivery; in some embodiments, the compositions are formulated for sublingual or buccal delivery. in some embodiments, the compositions are formulated to dissolve in not less than 1 minute after administration.
100331 These as well as other aspects, advantages, andalternatives, will become apparent to those of ordinary skill in the art by reading the following detailed description, with reference where appropriate to the accompanying drawings, and taken together with the accompanying claims.

- 9 -BRIEF DESCRIPTION OF THE DRAWINGS
[00341 Figure 1 shows a diagrammatic representation of a toll-like receptor (TLR) showing various response pathways.
[0035j Figure 2 shows the exemplary stimulatory effects of a composition of the present invention on select TLRINLR cell lines; the values in the graph correspond to an average of three screening experiments.
100361 .Figure 3 shows results of Tut. stimulation for a Pediococcus acidilactici lysate as compared to a Lactobacillus bulgaricus lysate.
[00371 :Figure 4 shows results of TLR stimulation for Bacillus coagulans lysates with differing times of harvest.
[0038j 'Figure 5 shows results of MR stimulation for Gram-positive bacterial lysates from Lactobacillus acidophilus, Lactobacillus helviticits, Lactobacillus plantarum, and Simptococcits therituiphilus.
100391 Figure 6 shows- results of TLR stimulation for Gram-negative bacterial lysates .from Escherichia coil, Kleb.siella oxytocia, Shigella fle.meri,Xanthornonas campestris, and .Pseudontonasj7ourescens.
100401 Figure 7 shows the results of TLR. stimulation for aXanthomonas campestrts lysate as compared to xanthan gum.
100411 Figure 8 shows a decrease in the levels of urinaty isoprostane in the urine of PTSD-diagnosed combat veterans following administration of a composition of the disclosure.
100421 Figure 9 shows .a decrease in sleep deficits of PTSD-diagnosed combat veterans following administration of a composition of the disclosure.
100431 Figure 10 shows a decrease in neuropathy symptoms in PTSD-diagnoscd combat veterans followina administration of a composition of the disclosure.
100441 Figure 11 shows an improvement-in the overall mood of PTSD-diagnosed combat veterans following administration of a composition of the disclosure.
100451 Figure 12 shows an increase in overall energy levels in PTSD-diagnosed combat veterans following. administration of a composition of the disclosure.
100461 Figure 1.3 shows an increase in overall satisfaction with the health of the joints of .PTSD-diagnosed combat veterans following administration of a composition. of the disclosure.

-10-100471 Figure 14 shows an increase in levels of satisfaction of the -digestive health Of VISD-diagnosed combat veterans following administration of a composition of the disclosure.
100481 Figure 1.5 shows a decrease in levels of irritability of PTSD-diagnosed combat veterans, following administration of a composition of the disclosure.
100491 Figure 16 shows an increase in overall kvels of self-reported satisfaction with sexual function of PTSD-diagnosed combat veterans following administration of a composition of the disclosure.
100501 Figure 17 shows a decrease in daytime sleepiness of PTSD-diagnosed combat veterans following administration of a composition of the disclosure.
100511 Figure 1.8 shows an increase in overall levels of self-reported satisfaction with the lives PTSD-diagnosed combat veterans following administration of a composition of the disclosure..
100521 Figure 19 shows a decrease in levels of depression in PTSD-diagnosed combat veterans following administration of a composition of the disclosure.
100531 Figure 20 shows a decrease in isoprostane levels in an individual With a history of concussion following administration of a lysate of the disclosure.
DETAILED DESCRIPTION
100541 All publications, patents and patent applications cited herein are hereby expressly incorporated by reference for all purposes.
100551 Cellular redox (oxidation-reduction) state varies widely. Oxidation and reduction reactions are key to cellular bioenergeticS. Normally when oxidation of food molecules results in electron transport and ultimate capture of energy as energy rich molecules such as NADP (nieotinamide adenine din ucleotide phosphate) and ATP (adenosine triphosphate), ILRs are activated in such a manner such that downstream oxidation/reduction reactions are balanced. As used herein., the term "balance" refers to a homeostatic balance;
that is, not necessarily a situation in which the amount of oxidation equals the amount of reduction in a given system, but rather where oxidation and reduction are in immunologic and thus metabolic homeostasis for the host However, there are a number of cellular situations where the redox state changes. Usually, the cell is armed with antioxidant molecules, but where such molecules become depleted, the redox status of the cell changes. One likely cause for this is the purposeful production of reactive oxygen species (ROS) such as Or (superoxide radical), OH (hydroxyl. radical) and H202 (hydrogen peroxide) for defensive or similar purposes.

-11 -When the redox balance is shifted, oxidative stress may ensue. Oxidative stress is a pathological condition triggered by the damaging action on the cells and tissues of the body¨of abnormally increased levels of ROS. Oxidative stress is the direct consequence of an increased, immunologically uncontrolled, generation of ROS and/or a reduced physiological activity of antioxidant defenses against excess ROS.
Inflammation (whether chronic or acute) as well as other stresses and infection can lead to the increased production and release of ROS from damaged and/or inflamed tissues thereby shifting the redox balance of the cell and as a result contribute to oxidative stress. At the same time, inflammation can result from oxidative stress as ROS durnage tissues. A wide range of diseases and disease states are associated with changes in redox state and oxidative stress brought on by chronic or acute inflammation or vice versa. Current therapies for treating chronic or acute inflammation do not come without harmful. side effects. Described herein are compositions and methods for altering redox levels in the-treatment of oxidative stress and related conditions.
1100561 Before describing the disclosed methods and compositions in detail, a number of temis will be defined. As used herein, the singular forms "a", "an" and "the"
include plural referents unless the context clearly dictates otherwise. For example, reference to "nucleic acid" means one or more nucleic acids.
100571 For the purposes of describing and defining this invention it is noted that the term "substantially" is utilized herein to represent the inherent degree of uncertainty that can be attributed teany quantitative comparison, value, measurement, or other representation. The term "substantially" is also utilized herein to represent the degree by which a quantitative representation can vary from a stated reference without resulting in a change in the basic function of the subject matter at issue.
100581 As described above, pathogen-associated-molecular patterns (PAMPs) can activate innate immune responses by stimulating nits, which generally are activated by conserved rionsself biochemical structures, thus protecting a host from infection. Bacterial lipopolysaccharide (LPS) is found on the bacterial cell membrane of some bacteria, and is considered to be the prototypical PAMP. LPS is specifically recognized by MR4, a recognition receptor of the innate immune system. Other PAMPs include bacterial flagellin (recognized by MR5), lipoteiehoic acid, peptidoglycan, and nucleic acid variants normally associated with Viruses, such as double-stranded RNA (cISRNA), recognized by MRS or unmethylated CpG motifs, recognized by MR9, 100591 In some eases, however, .PAMPs reduce inflammation. EPS (exo-polysaccharide), a material that typically stimulates an immune response, has been shown to stimulate

- 12-negative regulators of TL-Rs, thus leading to a reduced inflammatory response.
More specifically, :EPS has been shown to stimulate expression of immunoglobin IL-i related receptor, toll interacting protein, B-cell lymphoma 3-encoded protein, A20, mitogen-activated, protein kinase phosphate-I, and interleukin associate kinase M, and has been shown to lead to the negative regulation of TLRs and inflammation.
100601 Thew seemingly contradictory effects of PAMPs are at least partly explained by the innate immune system's interaction with the microbiome. The immune system does not exist in a vacuum. Even when an organism has no active inflammatory responses taking place, immune cells are responding to an onslaught of PAMPs from the environment¨
particularly from the micro.biOme. Given the various TLR receptors that are activated are producing a downstream redox state that is in immunologic and metabolic homeostasis, the system issues an "All Clear" signal to avoid inadvertent responses which might damage the essential mierobiorne consdtuetitt. Hence, presenting the-right combination of PA MPs to the cells of the innate immune system can control the entire redox system, down-regulating or up-regulating it to achieve, or in some cases restore, immunologic and metabolic homeostasis.
100611 Figure 1 shows a diagrammatic representation of a transmembrane a TLR.
Although the ligand accepting (stimuli) portion of the molecule is located on the surface of the plasma membrane, the transmembrane domain of the protein is able to conduct signal to the cytoplastnic surface of the membrane through conformational changes that occur when a ligand. is bound. At the cytoplasmic surface this signal (arrows) is coupled to a number of different signaling pathways Proliferation/differentiation and stress-response pathways are shown. Note that one TLR type does not simultaneously control both pathways at in this generalized diagram. Rather some TLIks control one pathway or set or pathways and other TIAs control a different pathway or set of pathways. In addition, it is likely-that one type of MR controls different pathways depending on which cell type it is located in;
thus, delivering the cotrect balance of TLR agonists is important for maintaining homeostasis.
100621 The downstream signaling mechanisms may be shared to a greater or lesser extent In Figure 1, the proliferation response largely uses the ERK. pathway whereas the stress response uses-the MEKK. and TAK pathways. In each pathway, signal molecules are phospholylated and there can be a phosphorylation cascade to amplify the siunal. Ultimately the phosphorylated protein enters the nucleus (through the nuclear pores).
where the phosphorylate intermediates alter both transcription and translation. In this way. TIAs are able to control entire suites of genes. In all, thousands of genes are activated by TLR

- 13-signaling, and collectively, the ILRs constitute one of the most *ion-epic yd tightly regulated gateways for gene modulation.
109631 One of the primary responses of ILR activation is to shift the downstream redox status of the cell when warranted. The initiation of a redox change and the resulting inflammatory response to pathogens is a critical component of the innate immune response designed to control infection. Inflammation (whether chronic or acute) results from and leads to the increased production and release of free radicals and other ROS from damaged and/or inflamed tissues and as a result contributes to or causes oxidative stress. At the same time, inflammation can result from oxidative stress when .ROS damage tissues. As such, inflammation and the various conditions associated with it can also be regarded as an "oxidative stress-related disease or condition."
100641 Oxidative stress, being a biochemical condition, generally does not exhibit any specific clinical symptoms or clinical signs apart from the specific pathdlogicilconditiont it induces; It may generally remain undiscovered, with 'concomitant damage to the patient, until a clinician suspects its existence and decides to assay for oxidative stress.
(00651 Various common diseases and/or conditions are frequently associated with oxidative stress. One example is Alzheimer's disease. Studies have shown that chronic oxidative stress increases the levels of tan phosphorylation, a known biomarker of Alzheimer's disease. Studies have also shown that oxidative stress results in tau-induced neurodegeneration in models of Alzheimer's disease.
(00661 Other known "oxidatiVe stress-related diseases or conditions"
include, but are not limited to: aceruloplasminemia, acute and chronic alcoholic liver diseases, acute autoimmune myocarditis, acute chest syndrome of sickle cell disease, acute pancreatitisõ
acute respiratory distress syndrome, alcoholic liver disease, Amyotrophic Lateral Sclerosis, arterial/systemic hypertension, asbestosis, asthma, ataxia telargiertasia, atherosclerosis, atopic dermatitis, brain ischemia, bronchopulmoriary dysplasia, bums, some cancers, cardiopulmonary bypass, cardiovascular diseases, cataract, cellulitis, chemotherapeutic side-effect, chronic fatigue syndrome, chronic Hepatitis C, chronic kidney disease, chronic obstructive pulmonary disease, chronic renal failure, cOlitis, coronary artery disease, Creutzfeldt--Jakoh disease, Crohn's disease, cutaneous leishmaniasis, cystic fibrosis, diabetes mellitus type I, diabetes mellitus type 2, dyslipidemia, Down's syndrome, eclampsiaõ end-stage renal disease, erectile dysfunction. Fricdreich ataxia, headache, heart failure, Helkobacier priori infection/inflammation, hemodialysis side effects, hepatie.eirrbosis, Human Immunodeficiency Virus infection, Huntington disease, byperbaric diseases,

- 14-hypercholesteroleinia, hyperhomocysteinetnia, hyperlipidemia idiopathic pulmonary fibrosis, interstitial lung disease, ischemiaiteperfusion injuryjuvenile chronic arthritis, kidney transplantation failure, leukemia, lung cancer, lung. injury, macular degeneration, male Meniere's syndrome, meningitis, mild cognitive impairment, Multiple Sclerosis, myelodisplastic syndromes, myocardial infarction, myocarditis, neonatal brortchopulmonary dysplasia, obesity, osteoarthritis, osteoporosis, pancreatitis. Parkinson's disease, periodontal disease, peritoneal dialysis side effects, photoaseing, post-traumatic stress disorder, pre-eclampsia, primary biliary cirrhosis, broncopulmonary diseases, progeria, psoriasis, psoriatic arthritis, pulmonary hypertension, radio-therapy side effects, reactive arthritis, renal cell carcinoma, respiratory distress syndrome, retinopathy of prematurity, retrolenticolar fibroplasy, rheumatic disease, rheumatoid arthritis, SaretlitIOSiS, sepsis, sickle cell disease, sleep apnea, spherocytosis, spinal cord injury, stroke, synucleinopathies, systemic atnyloidosis, systemic lupus erythematesus,.systemie sclerosis (seleroderma),.throinbophily, tatiopathies, traumatic stress tubercolosis, unstable angina, uremia, venous insufficiency, Werner syndrome,- and Zellweger syndrome.
00671 Oxidative stress mediates the pathological symptoms of a great many disorders and control of redox levels, and control of redox levels, and hence oxidative stress, will prevent much tissue damage thereby allowing more ready control of the-underlying disease where reducing oxidative stress is not sufficient to achieve control Of the disease. For example, myocardial ithrction is death or damage to heart muscle caused by a vascular blockage. Leaving aside the possible role for oxidative stress in causing vascular blockages, once a blockage has occurred, the affected muscles cells become anoxic and ultimately die.
However, if the blockage is rapidly reversed (e.g., by "clot busting" drugs), circulation is restored and, in -theory, the affected muscle cells: will be saved. However, brinany cases, the initial injury provokes an inflammatory- response resulting in oxidative stress and muscles cell damage in, spite of the prompt restoration of circulation. Controlling this oxidative stress can virtually eliminate damage to the heart muscle cells: In all of these diseases and disorders, regulation of oxidative stress might alleviate or treat the Symptoms and/or causes of the disease or disorder.
100681 Changes in redox status can resultin oxidation of sulfhychyl groups on key proteins, but these proteins, themselves, are often difficult to measure.
However, increased oxidative stress or redox change, either chronic or acute, can and will alter a number of other cellular constituents either by the previously mentioned oxidation of sulfhyd.tyl-groups or by

- 15-other chemical oxidative mechanisms, such as peroxidation, that result in the transfer of electrons.
100691 Isoprostanes are prostaglandin-like compounds formed in vivo from the free radical-catalyzed peroxidation of essential fatty acids (primarily arachidonic acid) without the direct action of cyclooxygena.se (COX) enzymes, which are the normal mechanism of prostaglandin formation, These compounds possess potent biological activity as inflammatory mediators that augment the perception of pain. These molecules are controlled by at least two different pathways. One pathway is mediated by COX enzymes that transform lipids into isoprostanes in response to gene activation and signal molecules.
In the alternate pathway, lipids are directly oxidized into isoprostanes in response to a high oxidative. redox status. Because isoprostanes are mediators of inflammation they form part of the positive feedback. loop that can maintain damaging oxidative redox status.
100701 isoprostanes, such as F2-isoprostanes, are thus accurate markers of oxidative redox status in both animal and human models of oxidative stress, and measuromentof isoprostanes has emerged as one of the most reliable approaches to assess oxidative stress in trivo due to their inherit stability and their ease of measurement in bodily fluids such as urine and blood. This ease and stability has made measurement of isoprostanes an important and reliable tool to explore the role of oxidative stress in the pathogenesis of human disease.
Lsoprostane levels are directly correlated with oxidative redox status and resulting oxidative stress. Even if the site of oxidative rain status is limited in extent, isoprostanes generated there can he measured in *bodily fluids, e.g,, urine, remote from the site of oxidative stress. and resultant inflammation, 100711 Other biological compounds that could be oxidized include, but are not limited to, proteins,Jnetalloproteins, enzymes, lipids, fatty acids, carbohydrates, neurotransmitters, DNA,. vitamins, polyphenols, antioxidants, and coenzymes. Thus, constituents such as, but not limited to, superoxide dis.mutase(SOD), peroxidases,glutathione, as well oxidized forms of cellular constituents due to exposure to reactive species such as, but not limited to, advanced oxidized proteins, malondiadehyde, 8-hydroxydeoyattanosine, are other potential biomarkers for oxidative stress.
100721 Given the importance of inflammation in the immune response and the hannfid consequences it can cause via oxidative stress, oxidative stress-related diseases or conditions and/or other processes, it is important that an organism maintain close control of redox status.
Also, given the intertwined relationship between oxidative stress and inflammation, biomarkers that measure inflammation have been proposed as indirect biontarkers of oxidative stress. These

- 16-biomarkers, such as but not limited to C-reactive protein, serum amyloid A.
and cytokines, are limited in their ability to pick up low grade changes in inflammation and consequently limited in their ability to pick up low grade redox changes. An alternative is to focus on biomarkers, such as isoprostanes, to measure redox status, and mechanisms to alter redox status.
100731 Redox can be changed either by increasing reducing species (antioxidants) or by decreasing oxidants. There has been little success in controlling hartrifid redox levels through added. antioxidants or antioxidant therapy (sear Ho eta!, Biological markers of oxidative stress:
Applications to cardiovascular research and practice. 2013 Redox Biology).
Them is evidence for the long term. use of dietary antioxidants¨perhaps as preventative agents.
However, when the immune system is not able to achieve or maintain homeostatic redox levels, added antioxidants are generally ineffective at correcting the balance.
100741 An alternative route to affixting redox status is to aim at downstream targets; such strategies include the use of aspirin and glucocorticoids to bled NF-KB
activation and the targeting of specific inflammatory mediators such as INF-a. Given their role in mediating the innate immune response and inflammation, TI,Rs present another target for contr011ing the innate and inflammatoly responses.
100751 As discussed above, TI,Rs help mediate the innate immune response by inducing or suppressing genes that orchestrate the inflammatory reaction. IlAs recognize and respond to a variety of signals. These signals bind to specific ItRs to promote or block signal pathways that can induce or suppress genes mediating inflammation. By tweeting specific Thits with specific agents, immune responses and inflammatory possesses can be mediated.
100761 Inhibition of multiple TI.Rdependent responses or activation of specific ones by targeting a common signaling component, may prove to be an effective approach to controlling an inflammatory response. Accordingly, compositions disclosed herein may be used to treat an. oxidative stress disorder associated, with aTLR-signaling pathway (e.g.,õ
ILR-induced inflammation), the method comprising the administration of therapeutically effective amount of a composition as described herein, wherein the MR affected is one or more of MR2, MR4, MRSõ .171.127 andILR9.
100771 As used herein, the term "therapeutically effective amount" refers to an amount administered to a subject that is sufficient to cause a desired effect in the subject.
100781 As used herein, the terms '`phannaceutical formulation" and "pharmaceutical composition" refer to a preparation which is in such form as to permit a.
biological activity of an active ingredient to be effective; and which contains no additional components which are unacceptably tokic to a subject to which the formulation would be administered. The terms

- 17-"the product," -"the supplement," and "the composition" are used herein interchangeably in reference to pharmaceutical compositions comprising bacterial lysates, lysate fractions, and/or cell wall fractions of the disclosure.
100791 Compositions described herein can be modified to target individual TLRs or groups of TLRs. By targeting individual TLRs or groups of TLRs, compositions described herein can be used to mediate instances of acute or Chronic inflammation. In addition, compositions described herein can be used to curb instances ofaberrant inflammation and restore healthy levels of inflammation.
(00801 Thus, described herein are compositions and methods for regulatintoxidative stress. The compositions are able to activate various TLRs as assessed by measuring NF-ic:B
expression in a variety of cell lines. The compositions described herein can also reduce or downregulate the activity of TLRs thus leading to reduced or regulated levels of inflammation. When the proper balance of TLR activation is.:achieved., cellular redox status is optimized and oxidative stress is reduced. This can be achieved by providing compositions containing PAMPs that simultaneously bind to two or more different types of TLRs.
10081] In some cases a lysate of a single type of microorganism can act as an ationist to two or more TLRs. As disclosed herein, the precise manner of processing a microorganism lysate can affect which TLRs are stimulated. by the lysate. In some embodiments, activation of a panel of TLRs may be accomplished by combining different lysates or fractions from a single type of microorganism or lysates or fractions from more than type of microorganism.
100821 There are many different but similar PAMPs that bind to a given TLR
typeõ albeit with different affinities. There are also PAMP molecules that stimulate an entirely different TLR type.. How the lysate or fraction is processed can affect the PAMP
assemblage present in the final product. Thus, different types of microorganisms present ctifferent palettes of PAMPs with which to work. As is disclosed haein, providing a composition that simultaneously Stimulates (acts as an agonist for). particular TLR types results in dramatic downregulation of oxidative stress.
[0083j Unexpectedly, stimulating MRS does not necessarily lead to an increase in oxidative stress. Rather, constant stimulation of TLRs by the microbiome is the normal situation and does not result in improper redox status and oxidative stress.
Part of the explanation may be related to the location of a given TLR receptor as well as the type of the TLR receptor. Activation of MR receptors located, on mucosa. gives a different result than activation of the same typesof TLR receptors located in interior tissues of the body. Without being bound to a particular explanation or mechanism, the disclosure provides methods of

- 18-applying or augmenting the normal microbiome signal, which reasserts homeostasis and "resets" the overall system by interrupting the positive feedback loop that powers abnormal redox status and oxidative stress.
100841 'The therapeutically active compositions of the present disclosure include a non-synthetic biologically active agent, preferably meor more cell wall fractions of one or more microorganisms including Gram-positive bacteria, Pram-negative bacteria, or combinations thereof; such as in the form of a lysate, along with a promoter, and optionally, one or more other additives, including control-release ingredients, so as to allow the composition to be absorbed into, or interact with, a mucosa wall of 'a subject_ in need of therapy.
100851 As used herein, the terms "dose" and "dosage" shall encompass bolus or loading dose, and also encompass chronic or maintenance dosingõAccording to the present invention, the active therapeutic agent is alysate, lysate fraction, or cell wall fraction of a bacterium, such as a Grain-positive bacterium or a Gram-negative bacterium in an amount ranging from about 0,01 mg -therapeutic agent per kilogram of body weight to about 1.00 ma per kilogram body weight, as required to act as waists for two of more TIRs depending upon the specific therapeutic application. In some embodiments, the active therapeutic agents of the disclosure are administered in a dosage of from about 0.01 mg therapeutic agent per kg body weight -to about .10 am therapeutic anent per ke body weight. In some embodiments, the active therapeutic agents of the disclosure are administered in a dosage of from about 0.01 mg therapeutic agent per kg body weight to about I gm therapeutic agent per kg body weight. In some embodiments, the active therapeutic-agents of the disclosure are administered in a dosage of from about 0.01 mg therapeutic agent per kg body weight to about 50 mg therapeutic agent per kg body weight. In some embodiments, the active therapeutic agents of the disclosure are administered in a dosage of from about 0.05 mg therapeutic agent per kg body weight to about 30 mg therapeutic agent per kg body weight_ in some embodiments, the active therapeutic agents of the disclosure are administered in a dosage of from about 0.05 tug therapeutic agent per kg body weight to about 5 mg therapeutic agent per kg body weight.
In some embodiments, the active therapeutic agents disclosed herein are administered in a dosage of about 0.1 mg therapeutic agent per kg body weight, or of about 0.2 tug therapeutic agent per kg body weight, or of about 0.3 mg therapeutic agent per kg body weight, or of about 0,4 mg therapeutic agent. per kg body weight, or of about 0,5 mg therapeutic agent per kg body weight, or of about 0,6 mg therapeutic agent per kg body weight, or of about 0,7 mg therapeutic agent per kg body weight, or of about 0.8 mg therapeutic agent per .kg body weight, or of about 0.9 mg therapeutic agent per kg body weight, or of about I
tug therapeutic

- 19-agent per kg body weight, or of about 2 mg therapeutic agent: per kg by weight, or of about 3 mg therapeutic agent per kg body weight, or of about 4 mg therapeutic agent per kg body weight, or of about 5 mg therapeutic agent per kg body weight, or of about 6 mg therapeutic agent per kg body weight, or of about 7 mg therapeutic agent per kg body weight, or of about 8 mg therapeutic agent per kg body weight, or of about 9 mg therapeutic agent per kg body weight, or of about 10 mg therapeutic agent per kg body weight. In sonic embodiments, the above dosages describe the total amount of active ingredient administered per day to a subject, wherein the total amount may be divided among two or more administrations per day, or may be the amount administered in a single daily dosage.
100861 As used herein, the terms "therapeutic agent" and "active ingredient" refer to a lysate, lysate fraction, andlor cell wall fraction of the disclosure, or a combination thereof, as opposed to the non-active ingredients in in a composition or formulation.
10087) In some embodiments, the pharmaceutical compositions disclosed herein are administered in formulations, such as in oral formulations, including tablet formulations, comprising from about 0.01 mg to about 10 gm active ingredient per dose, or of from about 0.5 mg to about 50 mg active ingredient per dose, or of from about 3 ma to about 30 mg active ingredient per dose, or of from about 10 to about. 30 mg active ingredient per dose. in some embodiments, the pharmaceutical formulations are formulated. and/or administered with about 0.5 ma, or about I mg, or about 5 mg, or about 10 mg, or about 15 ma, or about 20 mg, or about 25 in or about 30 mg active ingredient per dose. In some embodiments, the pharmaceutical compositions of the disclosure are formulated as tablets, with each tablet comprising about 0.5 mg to about 30 mg active ingredient: per tablet. In sonic embodiments, the tablets each comprise about 0.5 mg active ingredient. In some embodiments, the tablets each comprise about I mg active ingredient. In some embodiments, the tablets each comprise about 5 mg active ingredient. In some embodiments, the tablets each comprise about. fl) mg active ingredient. In some embodiments, the tablets each comprise about 15 mg active ingredient. In some embodiments, the tablets each comprise, about 25 mg active ingredient. In some embodiments, the tablets each comprise about 40 twg active ingredient. hi some embodiments, the tablet; each comprise about 50 mg active ingredient in some embodiments, the tablets each comprise about I gm active ingredient. In some embodiments the tablets each comprise about 10 am active ingredient, 100881 Tn sonic embodiments the pharmaceutical formulations of the disclosure are administered from one time per day to three times per day. In some enibodiments, the pharmaceutical formulations of the disclosure are administered once per day.
In some embodiments, the pharmaceutical formulations of the disclosure are administered two times per

- 20-day. In sonic embodiments, the pharmaceutical formulations of the disclosure are adininistered three times per day.
100891 In some embodiments, the pharmaceutical formulations are administered at a dosage level and frequency such that the subject receives a total of from about 0.01 mg to about 10 gm of active therapeutic agent per day, or a total of from about 1 mg to about 1 gm of active therapeutic agent per day, or a total of from about 5 ma to about 1 gm of active therapeutic agent per day, or a total of from about 5 mg to about 500 mg active therapeutic per day, or a total of from about .12 to about 375 mg per day. In some embodiments, the pharmaceutical formulations of the disclosure are administered at a dosage level and frequency such that the subject receives a total of about I tug, or about 2 mg, or about 3 mg, or about 4 tug, or about 5 ma, or about 6 mg, or about 7 mg, or about $
mg, or about 9 mg, or about 10 mg, or about 1.1 mg, or about 12 mg, or about 13 mg, or about 14 mg, or about 15 mg active ingredient (i.e., lysate, lysate fraction, and/or cell wall fraction, or combination thereof) per day, or more as needed. In some embodiments, the pharmaceutical formulations of the disclosure are administered at a dosage level and frequency such that the subject receives a total of about 12 mg, or about 24 mg, or about 36 mg, or about 48 mg, or about 60 mg, or about 72 mg, or about 84 mg, or about 96 mg, or about 108 tug, or about 120 mg, or about 132 nv, or about 144 mg, or about 156 mg, or about 168 m& or about 180 mg active ingredient (i.e, lysate, lysate fraction, and/or cell wall fraction, or combination thereof) per day, or more as needed. In some embodiments, the pharmaceutical formulations of the disclosure are administered at a dosage level and frequency such that the subject receives a total of about 15 tiv, or about 30 mg, or about:
45 mg, or about 60 tug, or about 75 mg, or about 90 mg, or about 105 mg, or about 12.0 rug, or about 135 mg, or about 150 tug, or about 165 mg, or about 180 mg, or about 195 mg, or about 210 mg, or about 225 tug active ingredient lysate, lysate fraction, and/or cell wall fraction, or combination thereof) per day, or more as needed. In some embodiments, the pharmaceutical formulations of the disclosure are administered at a dosage level and frequency such that the subject receives a total of about 25 mg, or about 50 mg, or about 75 mg, or about. 100 mg, or about 125 mg, or about 150 ma, or about 175 ma, or about 200 ini4 or about 225 ma, or about.
250 mg, or about 275 mg, or about 300 mg, or about 325 tug, or about 350 mg, or about 375 mg, or about 4(X) rug active ingredient lysate, lysate fraction, and/or cell wall fraction, or combination thereof) per day or more as needed.
100901 Any and all of the above dosage amounts and administration amounts are applicable to both monotherapeutic administration of active ingredients of the disclosure, as well as to embodiments in which active ingredients of the disclosure are administered in combination with one or more other therapeutic or pharmaceutical agents.

- 21 -Active ingredients 100911 Active ingredients to be used in the cOmpositions and methods of the disclosure comprise a bacterial lysate, lysate fraction, or cell wall fraction. Active ingredients may be manufactured, produced, or derived from any Gram-positive or Gram-negative bacterial organism.
100921 The term "lysate" as used herein refers to a composition prepared from a. lysed cell, such as a bacterial cell. .A lysate contains the entire cellular contents as well as, in some oribodiments, associated surface components such as exo-polysacc:haride, depending on the precise process conditions used to produce the lysate.
100931 A non-limiting example process for producing an active ingredient according to the disclosure is set forth in Example .1, and in general involves the steps of (I) fermenting a bacterium in growth media: (2) centrifuging the bacterial suspension to harvest the bacteria therefrom; (3) washing and pasteurizing the harvested bacteria; (4) disrupting the cell walls of the bacteria to lyse the bacteria; and (4) lyophilizing the resulting mixture to obtain an active ingredient, such as a bacterial lysate, lysate fraction, or cell wall fraction.
100941 The structures present in lysates, lysate fractions, and/or cell wall fractions of the disclosure that are responsible for TM activation and oxidative stress reduction are structures common to and conserved among all bacterial microorganisms. Thus, in principle, any bacterial organism can be used to produce an active ingredient of the disclosure(L, lysate, lysate fraction, and/or cell wall fraction).
100951 'in some embodiments, the bacterial organism used to produce active ingredients of the disclosure is a Gram-positive bacterium. In some embodiments, the Gram-positive bacterium is selected from: Ladolxicillus ocidophilus, Lactobacillus buchneri.
1,actobeicillus case!, LactobaCillustotenajining lactobacillus cellobiOsus, Lactobadllus dispaing Ladobacillus curvonis, Lactobacillus delbrucckil. Lactobacillus delbrueckitsubsp..bulgerricus, Lactobacillus delbrueckii subsp: Lactis, Lactobacillus hdvdicus. Lactobacillus jensenii.
Lactobacillus leichrnannii, 1,actobacillus mim,lu .Lactobacillus ixtracasel. Lactobacillus plantetrum.
Lactobacillus rhainnoste, Lactobacillus rogosete, Lactobacillus saliwritis, Lactobacillus .sporogenes (also known as Bacillus coagulansA Lactobacillus bmvisõ
Lactobacillus gasser", Lactobacillus fermentum, .Bffidobacterium adolescentis.-Bilidobacterium an/ma/is (especially B.
minions, subspecies animaliv), Bifidobacterium angulatum, Bifidobacteriwn byldum., Bifidobacterium breve, Widobacterium cadmic:awn, Biticlobacterium denims Bifidobacterhan erIksonü. Bylelobacterium WOW*, Bifidobacterium lades Milieloboderium animal's subsp. lactkv). Bilidobacterium lonpm, Ilijiclob cterlump/aniarwn.
Bijklobacternon

-22-pseudo-eau:inflation, lqidobacterium pseudo-longuni, LeptococcuS facto, StriVococcus (also referred to as Lactococcus loafs stibsp. lactis)õS'ireptococcus reinolactis, Addaminococcits Jenne:14 0,tophaga frrmentans, Rhodoferax jermentans, Cellulomonas .fertnentans, Zymomonas mobilis, l'ediococcus acidilactici, or Streptococcus thermophilits, as well as functionally equivalent variants thereof 100961 In some embodiments, the bacterial organism used to produce active ingredients of the disclosure is a Gram-negative bacterium. In some embodiments, the Gram-negative bacterium is selected from: Acinetobacrer baurnanniiõ4ctinabaciillia,Acetobacter liacteroicles thetalotaottiicron, Bacteroidesfrogaliv,:lionletella pernissis, Brucelki abOrtus, campylobacterjOtini, Citobackifremiclit,.Entepobactor clOacae,lititerobactqrsakasakii, = Oxinobacteria,.Erwinia amylovom, Esthetic/Ito colt, Thinciscella Warmish, Helicobacter pykirt, Haemophilia influenza, Lexionella ptimanophila,MOrayellit catarrhalis,.Areisseria gonorrhoeire, Privet's mirabiiis, Pseudomonas aeruginosa,Pkntilomonas fienirascensõalmonella enteritidis.
Salmonella iyphi,Serratia mareescens, Shigeo .ficenert, Yibrio cholera, Ralstorna solanacecienon, klj:robacterium tubettuloskt, Wobackiriuni /amass', .Klebsiella -ovocia, and Kle:bsiella pneumonia, and Xanthomonds aunpesiris.hi some embodiments, the Gram-negative bacterium is selected from: the genera of Pseudornonas, Klebsiella, Xanthomonasõ Shigella and. Entero.bacter. In some embodiments,. the Gram-negative bacterium is one or more of Eseherieitia co/i. Klebsiella oxyfocia, Shigella flerneri, Psesulomonas flourescaa, and Xanth.omonas campestrls, as well as functionally equivalent variants thereof 100971 All of the bacteria described above are believed to produce immune-stimulating cell components, such as but not limited to, EPS (exo-polysaccharide), which is distinct from the EPS (lipopolysacchatide) found in many bacteria. Other species of bacteria can also be used. in the compositions and methods of the disclosure, for example, those disclosed in the state of the art ari4 generally available in culture collections, such as the ECACC(European Collection of Cell Cultures), ASTM (American Society for Testing and Materials). ATCC
(American Type Culture (.:olleetion), and DSIvil (German Collection of Microorganisms and Cell Cultures).
100981 With regard to the fermentation step for producing lysates, lysate fractions, or cell wail fractions according to the disclosure, acceptable growth media to be used. for fermentation will depend on the particular bacterium being grown. Typical growth media include those which comprise:. a nitrogen source (I- 4%), which may include one or more of the following yeast extract, milk protein and casein hydrolyzates, soy and soy hydrolyzates,

- 23 -meat extracts, peptones or ammonia salts; a-simple sugar or ingredient that contains simple sugars or hydrolyzed carbohydrates that will yield simple sugars, such as but not limited to glucose or lactose (0.5-3%); and minerals (0,05- 0.3%), which may include salts of sodium, manganese, magnesium, calcium and potassium. Surfactant; eysteine HCL, and ribonucleotides (0.001-0.75%) maybe added to support cell growth. Growth media are adjusted to a pH between 6 and 8. In some embodiments, depending on the particular bacterium being grown, the pH of the growth media ranges from about 6.0 to 6.5. In some embodiments, the pH of the growth media ranges from about 6.5 to 7:0. In some embodiments, the pH of the growth media ranges from about 7.0 to 7.5.
100991 In some embodiments, inoculated media is incubated during fermentation at between 30-50 "C. In some embodiments, inoculated media is incubated during fermentation at between. 30740 T. In some embodiments, inoculated media is incubated at around 30 T, or around 31 T, or around 32 T, or around. 33 "C, or around. 34"C, or around 35 T, or around 36 T., or around 37 C, or around 38 T, or-around 39 C, or around 40 T,or around 45 C. In some embodiments, inoculated media is incubated at around 30 C. In some embodiments, inoculated media is incubated at around 33 "C. In sOme embodiments, inoculated media is incubated at mound 35 T. In some embodiments, inoculated media is incubated at around 37 T. In some embodiments, inoculated media is incubated at around 40 T. In some embodiments, inoculated media is incubated at around 45 C.
[01001 In some embodiments, fermentation is continued from about 6bours to about 120 hours prior to harvesting the bacteria. In some embodiments, fermentation is continued 'from about 12 hours to about 48 hours prior to harvesting the bacteria. In some embodiments, fermentation is continued from about 12 hours to about 24 hours prior to harvesting the bacteria. In some embodiments, fermentation is continued for about 14 hours, or about 15 hours, or about 16 hours, or about 17 hours, or about 18 hours, or about 19 hours, or about 20 hours, or about 22 hours, or about 24 hours, or about 48 hours. In some embodiments, fermentation is continued until bacterial growth reaches the mid-logarithmic phase, the late-logarithmic phase, the early stationary phase, the mid-stationary phase, or the late stationary phase. In some embodiments, fermentation is continued until the bacteria mach the stationary growth phase. In some embodiments, the fermentation may be held prior to downstream processing using techniques known to those skilled in the art, such as but not limited to, chilling and pH control, for up to 14 days or longer as warranted, 10104 After fermentation, the broth is typically chilled and the bacteria harvested by centrifugation. In some embodiments, the broth is chilled post-fermentation to from about

- 24 -to about 25 C. In some embodiments, the broth is chilled to about I 8C, or to about 2 'V, or to about 3 "C., or to about 4 'V, or to about 5 C. or to about 6 C, or to about 7 C. or to about 8 or to 'about 10 C. in some embodiments, the 'broth is chilled from to about 4 "C to about 7 C.
101021 After chilling, centrifugation is performed to separate the cells from the surrounding growth media. Cells are then washed in fresh media, deionized water, water, or other solution via repeated centrifutiations and resuspensions, and then re-suspended in fresh media or other solution in preparation for the pasteurization step.
101.031 In some embodiments, the washed bacteria are pasteurized. In some embodiments, the bacteria are pasteurized at from about 75 "C to. about $5 'C for 30 minutes to 60 minutes.
In some embodiments, the harvested bacteria are pasteurized at about 80 "C. In some embodiments, pasteurization proceeds for about 30minutes, or about 45 minutes, or about 60 minutes.
101041 Following pasteurization, the cell concentrate is mated to disrupt cell walls and thereby expose TLR agonists. Disruption of the cell walls may be accomplished by using chelating agents, detergents, surfactants, and hydrolytic enzymes. Examples of hydrolytic enzymes that may be used include, but are not limited to, lysozyme, such as chicken (hen) egg white lysozytne (for example,. INOVKIR41), LYSOLACC, DELVOZYME)õ
LYSOVINV, or LYSOBACO), lysins., endolysins, and hydrolases. In some embodiments, lysozyme is added to the pasteurized bacterial cell suspension to a final concentration of 0.01-4% by volume. In some embodiments, lysozyme is added to the pasteurized bacterial cell suspension to a final concentration of about 0.5%, or about 1%, or about 2%, or about 3%, or about 4% by volume. In some embodiments, treatment of the pasteurized bacterial suspension with lysine enzymes continues from about 1 to about 10 hours, or from about 6 to about 8 'hours, or for about 5 hours, or for about 6 hours, or for about 7 hours, or for about 8 hours, or for about 9 hours, or for about .10 hours. In some embodiments, treatment of the pasteurized bacterial suspension with lysine enzymes is performed at a temperature of from about 25 to about 50 C, or from about' 30 'C to about 45 C, or at about 35 "C, or at about .37 "C, or at about 40 "C, or at about 42 'V, or at about 4.5*C. After lysis, the lysate is typically frozen and lyophilized.
101051 In some embodiments, and as is described in more detail below, the lyophilized.
material is then blended with a promoter, such as N-acetyl D alucosamine HO
(NAG).
Optionally, other formulation excipients may be added to generate a solid form pill or powder, as appropriate.

-25-101061 In some embodiments, the particular TLR or TLRs that are activated or stimulated by a particular lysate can be altered by changing raw materials, process materials, or process conditions. As used herein. the term 'TLR specificity" refers to the particular TLR or TLRs that are activated by a given composition of the disclosure comprising a bacterial lysate, lysate fraction, and/or cell wall fraction. In some embodiments, TLR
specificity is altered depending on the density to which bacterial cells are grown during-fermentation In some embodiments, the particular bacterial species or subspecies from which the active ingredient is produced also results indifferences in MR specificity. In some embodiments, the-particular enzyme used to lyse the bacterial cells following -pasteurization results in differences in TM. specificity.
101071 As used herein, the terms "activation," "Stimulation," "targeting,"
and "agonism,"
when used in relation to a receptor or other biomolecular target, are interchangeable and refer to the binding to and activation of a receptor; Stich-as-a toll-like receptor, such that the signaling cascade downstream of the receptor is altered, modulated, or otherwise affected.
101081 it will be understood that the cells can be fractionated prior to lysis or that the lysate as produced above can be fractionated by well-known biochemical procedures, including, for example, differential centrifugation or column chromatography, such as eel-permeation ehromatography ion exchange chromatography, chromatography over hydrophobic media, or precipitation, and the like. in some embodiments, lysate fractionation produces fractions with differing TLR specificities; for example, fractions may be produced that are targeted to a smaller number of TLRs than a complete lysate.
101091 In sonic embodiments, ingredients comprising exo-polysaccharides may be combined with the lysatcs, lysate fractions, and/or cell. wall fractions of the disclosure. Exo- -.polysaccharides are able to activate Mts. Thus, for example, .xanthan gum, which is derived from Xantkomoit.as coopofris, may be used in combination with the lysates, lysate fractions, and/or cell wall fractions of the disclosure to increase TLR activation andfor alter the TLR.
specificity of a composition. In some embodiments, xanthan gum is itself a lysate fraction, for example, in embodiments where xanthart gum is derived from a lysate produced from fermentation. of Xamhomonas campestris, such as by fractionation of a Xanihomonas campestris lysate.
Other ingredients and delivery forms 101:101 The therapeutic compositions of the present disclosure may further and optionally comprise one or more promoters, to assist in the therapeutic delivery of the active agent across a biological membrane. The promoter useful in accordance with the present disclosure

- 26 -can be amino. acid, N-alkylated peptide, sugar, amino sugar or amino sugar chelate. An amino sugar chelate comprising one or more amino sugar bonds, one or more saturated hydroxylated carboxylic acid litands, and a nutritionally acceptable metal, wherein at least one of the one or more amino sugar ligands is glucosamine, and wherein thernetal is selected from the group consisting of manganese, magnesium, sodium, potassium, and zinc, and wherein the one or more saturated hydroxylated carboxylic acid ligands is gluppnic acid, and wherein the glucosamine ligand to nutritionally acceptable metal ratio is 2:1, wherein the nutritionally metal is nonferrous.
101111 In accordance with one aspect of present diSclosure,-the therapeutic formulations may include one-or more. acetyl:00;d or deacetylated amino sugars selected from the group consisting of NAG, galactosamine, N-acetylgalactosarnine,.mannosamine, and N-acetylmannosamine in the-form of monomers, oligomers, andlor polymers thereof including chitin, and human glueosaminoglycans, as well as-derivatives. thereof. The term "derivatives thereof" used herein with reference to amino sugars means derivatives of the amino sugars having the same or essentially the same ability to form cytotoxic degradation products during sterilization. In accordance with select further aspects of the present disclosure, the promoter is a mother selected from the group consisting of glucosamine, poly-L
arginine, galactosanctine, N-acetylmannosamine (NAM; ..ISI-Ac-Man),.N-15 acetyighicosamine (NAG; N- Ac-G1c),N,N'-diacetylglucosamine (NAG-NAG; N,Nt-diacetYlehitobiose), N,N", N", N'"- tetraacetylglucosamine (NAG-NAG-NAG-NAG; N,KN",-N'"-tetraacetylehitotetraose), and mixtures thereof.
101121 Optionally, and equally acceptable, the promoter may be an acylanal glycosyloxy sugar or an optionally acylated oligoglycosyloxy sugar moiety of 2 to 12, a-I, 2 and/hr a-I , 6 linked sugars, wherein the sugar(s) are selected from the group consisting of D-matmose, 0-galactose, 1)-glucose, D-glucosamine, N-acetylglucosamine, and 6-deoxy-L-mannose, wherein an oligoglycosyloxy sugar moiety may comprise the same or different sugars.
E01131 in another embodiment, the compositions of the present invention are in a dosage form selected from the group consisting of a lozenge, a chewing gum, a chewable tablet, and a dissolving tablet such as a slow-dissolving tablet, a quick-dissolving tablet, or a controlled-release tablet or other suitable controlled-release formulation.
101141 In an embodiment, the active agent of the present. disclosure is delivered across an oral mucosa of a subject, the oral mucosa being selected from the group consisting of the sublingual mucosa, the buccal mucosa, and a combination thereof. The composition can be

-27 -administered sublingually so that the activeingredient is delivered across the sublingual mucosa.
fO l 151 In another embodiment, the carrier is typically a solid, semi-solid, or liquid such as a binder, a gum base, or combinations thereof. Suitable. binders for use in the compositions of the present invention include, without limitation, sugar alcohols such as mannitol, sorbitol, and xylitol; sugars such as lactose, dextrose, sucrose; glucose, and powdered sugar; other substances such as inositol, molasses, maltodextrin, starch, cellulose, microcrystalline cellulose, polyvinylpyrrolidone, acacia gum, guar gum, tragacanth gum, alginate, extract of Irish moss, panwar pm,.ghatti gum, mucilage of isabgol (psyllium) husks, VEEGUMV,-larch arabogalactan, gelatin, nethylcellulose, ethyleellulose, carboxymethyltellulose, hydroxypropylmethyleellulose, polyaerylic acid (e.g., Carbopol), calcium silicate, calcium phosphate, diealcium phosphate, calcium sulfate, kaolin, sodium chloride, polyethylene glycetand combinations thereof. Suitable. gum bases for use in the compositions of the present invention include, for example, materials selected from among the many water-insoluble and saliva insoluble gum base materials known in the art, In certain instances, the gum base comprises at least one hydrophobic polymer and at least one hydrophilic polymer.
examples of suitable hydrophobic and hydrophilic polymers for gum bases include both natural and synthetic polymers such as elastomers, rubbers, and combinations thereof Examples of suitable natural polymers include, without limitation, substances of plant origin such as chicle, jelutong, gutta percha, crown gum, and combinations thereof Examples of suitable synthetic polymers include elastomers such as butadiene-styrene copolymers, isobutylene and isoprene copolymers (e.g., "butyl rubber"), polyethylene, polyisobutylene, polyvinylester (e.g., polyvinyl acetate and polyvinyl acetate phthalate), and combinations thereof. in other instances, the gum base comprises a mixture of butyl rubber (i.e., isobutylene and isoprene copolymer), polyisobutylene, and optionally, polyvinylacetate (e.g., having a Molecular weight of approximately 12,000).
E01161 in yet another embodiment, the compositions of the present invention can further comprise a sweetening agent, a flavoring agent, a protecting agent, a plasticizer, a wax, an elasto.meric solvent, a filler material, a preservative, or combinations thereof. In still yet another embodiment, the compositions of the present invention can further comprise a lubricating agent, a wetting agent, an emulsifying agent, a solubilizing agent, a suspending agent, a coloring agent, a disintegrating agent, or combinations thereof. in an embodiment, the average particle size of the drug in the compositions described herein is about 20 micrometers, as compared tO a typical average drug particle size of from about 75 to about

- 28-100 micrometers. In another embodiment, the average particle site of the drug in the compositions described herein is less than or equal to the average particle size of the carrier ingredients (e.g., gum base, binders, etc.).
101171 In one aspect of the present disclosure, the therapeutic composition may optionally include a buffer system to raise the pH of saliva to a pH of from about 8.0 to about 11, irrespective of the starting pH of saliva in the oral cavity of the subject to be treated.
Suitable therapeutic agents for use in the present invention are described above. Suitable carbonate salts and bicarbonate salts for use in the buffer systems of the present invention arc also described above. In certain instances, composition further comprises a non-biologic therapeutic agent, such as an NSAID.
101181 Suitable citrate, phosphate, and borate salts include, without limitation, any salt of citric acid, phosphoric acid, or boric acid known in the art. For example, in some embodiments, the citrate salt is selected from the group consisting of sodium citrate, potassium citrate, calcium citrate, magnesium citrate, and ammonium citrate.
[01191 In other embodiments, the phosphate salt is selected from the group consisting of monobasic sodium phosphate, dibasic sodium phosphate, monobasic potassium phosphate, dibasic potassium phosphate, monobasic calcium phosphate, dibasic calcium phosphate, monobasic magnesium phosphate, diba.sie magnesium phosphate, monobasic ammonium phosphate, and dibasic ammonium phosphate. In yet other embodiments, the borate salt is selected from the group consisting of sodium borate, potassium borate, calcium borate, magnesium borate, and ammonium borate. In certain instances, the buffer system comprises a carbonate salt, a bicarbonate salt, and/or a citrate salt. In certain other instances, the buffer system comprises a carbonate salt, a bicarbonate salt, and/or a phosphate salt. In further instances, the buffer system comprises a carbonate salt, a bicarbonate salt, and/or a borate salt, 101201 In addition to a buffer system comprising a carbonate salt, a bicarbonate salt, and/or a metal oxide, other buffer systems are suitable for use in the compositions of the present invention. For example, in an alternative embodiment, the ternary buffer system comprises a carbonate salt, a bicarbonate salt, and a citrate, phosphate, or borate salt. In another alternative embodiment, the buffer system comprises a carbonate salt or a bicarbonate salt and. two or more buffering agents selected from the group consisting-of a metal oxide, a citrate salt, a. phosphate salt, and a. borate salt. in yet another alternative embodiment, the buffer system is a binary buffer system comprising a carbonate salt or a bicarbonate salt and a metal oxide. In still yet another alternative embodiment, the buffer

- 29 -system is a binary buffer system comprising, a carbonate salt or a bicarberiate salt and a citrate, phosphate, or borate salt. In a further alternative embodiment, the buffer system is a binary buffer system comprising a metal oxide and a citrate, phosphate, or borate salt. in still yet another alternative embodiment, the buffer system is a binary buffer system comprising a carbonate salt and a bicarbonate salt.
Delivery forms 101211 The therapeutic compositions of the present invention may take the form of solid, semi- solid, lyophilized powder, or liquid dosage forms, such as, for example, tablets (e.g., chewable, slow-dissolving,quick-dissolving), pills, capsules, lozenges, candies, gums, powders, solutions, suspensions, emulsions, aerosols, or the like. The dosage form can. be a chewing gum, quick- dissolving tablet, candy, or lozenge.
101221 As used herein, the term "dosage form" refers to physically discrete units suitable at unitary dosages for human subjects, mammals, and other non-mammalian animals, each unit containing a predetermined quantity of therapeutic agent calculated to produce the desired onset, tolerability, and therapeutic effects, in association with one or more suitable pharmaceutical eacipients such as carriers. Methods for preparing such dosage forms are known or will be apparent to those skilled in the art. For example, in some embodiments, a chewing gum dosage form of the present invention can. be prepared according to procedures standard in the industry. In other embodiments, a tablet, lozenge, or candy dosage form (e.n,, a sucker or lollipop) of the present invention can be prepared according to the procedures set forth in, for example, Remington's 'The Science and Practice of Pharmacy, 20th Ed.,"
[Lippincott, Williams & Wilkins (2003); and, "Pharmaceutical Dosage Forms, Volume 1:
Tablets," 2nd Ed., Marcel Dekker, Inc., New York, N.Y. (1989)1 The dosage form to be administered will, in any event, contain a quantity of the -activetherapeutic agent in a therapeutically effective amount for relief of the condition being treated when administered in accordance with the teachings of this invention.
101231 As used herein, the term "carrier" refers to a typically inert substance used as a diluent or vehicle for a drug such as a therapeutic agent. The term also encompasses a typically inert substance that imparts cohesive qualities to the composition.
Suitable carriers for use in the compositions of the present invention include, without limitation, a solid, semi-solid, or liquid such as a. binder or a gum base. Examples of binders are known by one of ordinary skill in the art. Binders can be pre-processed to improve their flowability and taste by methods known in the art such as freeze drying Iseeõc.gõ "Fundamentals of Freeze-Drying," Pbarm. Biotechnol., Vol. 14, pp. 281-360(2002): "Lyophilization of Unit Dose

- 30 -Pharmaceutical Dosage Forms," Drug. Dev. md. Pharin., Vol. 29, pp. -595-602 (2003)1; solid-solution preparation; and lubricant dusting and wet-granulation preparation with a suitable Inbricating agent (see, e.g., Remington: The Science and Practice of Pharmacy, supra). When a binder is included in the formulation, the compositions of the present invention can comprise from about .15% to about 90% by weight of the binder, and from about 35% to about 80%. However,.oneskilled in the art will appreciate that the compositions of the present invention can be made without any binders, e.g., to produce a highly friable dosage form.
Tablets 101241 When the. dosage form is a tablet such as a dissolving tablet.
(i.e., disintegrating tablet) or chewable tablet, the compositions of the present invention comprise a therapeutic agent as described herein derived from one or more bacteria, or a pharmaceutically acceptable salt thereof, a promoter, a carrier such as a binder, and a buffer system, including binary or ternary buffer systems. The tablet composition may further comprise lubricating agents, wetting agents, emulsifying agents, suspending agents, preserving agents, sweetening agents, flavoring agents, coloring agents, and disintegrating agents.
Typically, the tablet compositions of the present invention comprise from about 0.001% to about 10.0% by weight of the active therapeutic agent (in whatever chosen forrn, measured as per its free base form), and more typically from about 1.0% to about 5.0%. One skilled in the art understands that the foregoing percentages will vary depending upon the particular source of active therapeutic agent utilized, the amount of theactive therapeutic anent desired in the final formulation, as well as on the particular release rate of the active therapeutic agent desired. The buffer system of the tablet composition provides for a final salivary pH in excess of at least about 8.0, at least about. 9.5, and/or in the range of from about pH 9.9 to about pH 11.
101251 In certain embodiments, the tablet is a dissolving tablet such as a slow-dissolving or quick-dissolving tablet that is dissolved by a subject's saliva, without the need for chewing. For example, a dissolving tablet placed on the subject's tongue can be used for buccal delivery of the therapeutic agent. Alternatively, a dissolving tablet placed underneath the subject's tongue can be used for sublingual delivery of the therapeutic agent. This type of dosage form may be particularly desirable for pediatric and geriatric patients, since small children and aged individuals often have difficulty chewing certain items.
Typically, the dissolving tablet. is formulated to dissolve within about 1 to about 15 minutes, within about 2 to about 1.0 minutes, e.g., within about 2,, 3,4, 3, 6,..7, .8,9, or 10 minutes, following administration. One skilled in the art will understand that quick-dissolving tablets dissolve

- 31 -faster than slow-dissolving tablets, Which are typically dissolved gradually rather than rapidly by a subject's saliva. In an embodiment4he slow-dissolving or quick-dissolving tablet delivers the therapeutic agent across the sublingual mucosa over a period of time greater than about 1 minute.
101261 In certain other embodiments, the tablet is a chewable tablet that is chewed by a subject and formulated to-dissolve either rapidly or gradually. For example, a chewable tablet placed on the subject's tongue can be used for buccal delivery of the therapeutic agent.
During chewing, the chewable tablet can be moved around within the mouth and can sometimes be parked between the gums and the cheeks or Underneath the tongue.
As a result, at least a portion of the therapeutie.ageocontained within a chewable tablet may also be.
delivered sublingually (i.e., across the sublingual mucosa). Typically, the chewable tablet is formulated to dissolve within about I to about 15 minutes, within about 2 to about 10 minutes and. not less than I minute, ó.g.. within about 2, 3,4, 5, 6,7, 8, 9, or 10 minutes, following administration, 101271 As described above, the dissolving and chewable tablets of the present invention are typically formulated to dissolve within about I to 15 minutes following administration, and not less than about 1 minute after administration. HOWCVef, while these time frames are amenable to maximum exposure of the therapeutic agent to the oral mucosa (e.g,õ to the sublingual and/or buccal mucosa), they are not always amenable to user compliance (e.g., users may swallow too frequently and, therefore, hinder maximal transmucosal absorption).
Consequently, in certain instances,, it may be desirable to strike a balance between patient compliance and maximum exposure time of the therapeutic agent to the oral mucosa. This can be accomplished, for example, by reducing the tablet size (e.g., from about 700-800 mg to about. 200-300 mg) Without reducing the concentration or amount per unit dose of the buffer system or the. therapeutic agent. In addition, subtle changes to the tablet formulation such as, for example, replacing one flavoring agent for another (e.g., chocolate for spearmint) or replacing one binder or sweetening agent for another (e.g., lactose for mannitol or sorbitol) may be used to reduce salivation.
Combinations with other pharmaceutical agents 101281 Many pharmaceutically active agents generate detrimental side effects, which are driven by ROS that are produced as the active agent proceeds through biochemical and other metabolic reactions. 'Thus, the compositions described herein are attractive candidates for the treatment of oxidative stress and oxidative stress-related diseases and conditions and can be combined with one or more pharmaceutical agents known in the aitõ such as any

- 32-pharmaceutical agent listed in the Physician's Desk Reference (available at-http:liwww.pdr.net).
101291 In some embodiments, the active ingredients of the disclosure. are combined with known pharmaceutical agents that target oxidative stress, inflammation, the immune response and/or oxidative. stress-related diseases or conditions, or they can be combined with pharmaceutical agents that produce oxidative stress as a side effect. Where the pharmaceutical agent targets some other disease state but produces oxidative stress as a side effect, combination with the inventive compositions reduces damage caused by oxidative stress and also enhances the effectiveness of the pharmaceutical agent by allowing higher doses without prohibitive damage caused by oxidative West. It will be appreciated that optimum results with a particular combination may require adjustment of the lysates to optimally target the correct TLRs in the presence of the added pharmaceutical agent.
[0130) Thus, in one aspect, the disclosure provides methods for reducing or alleviating one or more oxidative stress-related side effects associated with administration of a phaimacentia agent, the methods comprising administering a lysate, lysate fraction, and/or cell wall fraction of the disclosure in combination with the pharmaceutical agent. In some embodiments, the pharmaceutical agent and lysate composition are administered simultaneously or in any order, and through the same or different routes of administration. In some embodiments, the pharmaceutical agent is any pharmaceutical agent with one or more oxidative stress-related side effects, such as any pharmaceutical agent listed in the Physician's Desk Reference (available at flitp://wµ,m4Vir.nell with one or more oxidative stress-related side effects. In some embodiments, the pharmaceutical agent is selected from the group consisting of anti-rheumatic drugs, anti-inflammatory agents, chemotherapeutic agents, radiotherapeutics, immunosuppressive agent, interferons, interferon-based chemotherapeutics, and eytotoxic drugs. In some embodiments, the oxidative stress-related side effects are selected from aceruloplasminemia, arterial/systemic hypertension, arthritis, asthma, atherosclerosis, atopic dermatitis, cancer, bladder cancer, leukemia, uterine cancer, cervical cancer, dizziness, nausea, vomiting, constipation, diarrhea, insomnia, drowsiness, lightheadedness, reduced libido, blackouts, shakes, jaundice, arrhythmia, increased heart rate, decreased heart rate, hives, depression, clinical depression, brain ischemia, bronehoptilmonary dysplasia, cardiovascular diseases, cataract, cellulitis, chemotherapeutic side-effect, chronic fatigue syndrome, colitis, coronary artery disease, dyslipidemia, eclampsia, erectile dysfunction, ataxia, headache, heart failure, hemodialysis side effects, hepatic cirrhosis, hypercholesterolemia, hyperhomocysteinemia, hyperlipidemia, interstitial

- 33-lung disease, lung injury, macular deireneration, male infertility, mild cognitive iinpairnient, myocardial infarction, myocarditis, myopathy, neuropathy, obesity, osteoarthrifis, osteoporosis, .pancreatitis, periodontal disease, peritoneal dialysis side effects, post-traumatic stress disorder, preeclarnpsia, psoriasis, psoriatic arthritis, pulmonary hypertension, radio-therapy side effects, reactive arthritis, respiratory distress syndrome, rhabdomyolysis, rheumatic disease, sepsis, sleep apnea, stroke, suicidal thoughts, amyloidosis, thrombophily, tauopathies, unstable angina, uremia, or venous insufficiency.
01311 in some embodiments, the pharmaceutical agent having one or more oxidative stress-related side effects is selected from the group consisting of Antispasmodics selected from the group consisting of atropine sulphate, dicycloverine hydrochloride, hyoscine butylbromine, proparithcline bromide, alverine citrate, and mebeverine hydrochloride;
Motility stimulants selected from the group consisting of inctoclorpramide and domperidone;
H2-Receptor antagonists selected from the groupconsisting of Cimetidine, famotidinenizatidine, and ranitidine; Antimuscarinics; Chelates-selected from the group consisting of Tripotassium dicitratbismuthate and sucralfate; Prostaglandin analogues;
Aminosalicylates selected from the group consisting of balsazide sodium, mesalazine, olsalazine, and sulphasalazine; Corticosteroids selected from the group consisting of beclometasone dipropionate, budenoside, hydrocortisone, and prednisolone;
Affecting immune response selected from the group consisting of ciclosporin, mereaptopurine, methotrexate, adalimumab, and infliximab; Stimulant Laxatives selected from the group consisting of bisacodyl, dantron, docusate, and sodium picosulfate; Drugs affecting ',flinty composition and flow; Bile acids sequestrants selected from the group consisting of colestyramine, Oxyphencyclimine, Carnyloftri, Mebeverinc, Trimebutine, Roeiverinc, Dicycloverine, Dihexyverine,.Difemerine, Piperidolate, Benzilone, Mepenzolate, Pipenzolate, Olycopyrronium, Oxyphcnonium, Penthienate, Methantheline, Propanthelinc, Ofiloniurn bromide, Tridihexethyl, Isopropamide, Hexocyclium, Poldine, Bevonium, Diphernanil, Tiemotiium iodide, Minium bromide, Timepidium bromide, fenpiverinium, Papaverinc, Drotaverine, Moxaverine, -5-HT3.antagonists, 5-HT4 agonists, Feripipranc, Diisopromine, Chlorbenzoxamine, Pinaveriurn, Fenoverine, Idanpramine, .Proxazole, .Alverine, Trepibutone, isometheptenc, Caroverine, Pbloroglucinol, Silicones, Trimethyldiphenylpropylamine, Atropine, Hyoscyamine, Scopolamine, Butylscopolamine, Methylscopolatnine, Methylatropine, Fentonium, Cimetropium bromide, and primarily dopamine antagonists .; Proton pump inhibitors selected from the group consisting of.
Omeprazole, lansoprazole, pantoprazole, esomeprazole, and rabeprazole sodium;
Opioids and

- 34 -opioid receptor antagonists; Atialgesica selected from the group- consisting of Aectarninaphen, Dielofenae, Difltmisal, Etodolac, Fenoproft; Flurbiprofen, Ibuprofen, lndomethacin, Ketoprofen, Ketorolac, Mcclofenamate., Mefenamic Acid, 'Metoxicant, Nabutnetone, .Naproxen, Oxaprozin, Phenylburazone, Piroxicam, Sulindac, Tolmetin, Celeeoxib, .Buprenorphine, Butorphanol, Codeine, Hydrocodone, Hydromotphone, .Levorphanol, Meperidine, Methadone, Morphine, Nalbuphine, Oxycodone, Oxymorphone, Pentazoeine, Propoxyphene, and Tramadol; Sleep drugs selected from the group consisting of Nitrazeparn, Flurazepain, Loprazolam, Lormetazeparn, Temazepam, Zalepton, Zolpidem, Zopiclone, Chloral Hydrate, Melo-ids, Clomethiazole, Quazepam, triazolam, Estazolatn, Clonazepam, Alprazolam, Eszopielone, Rozerem, Trazodone, .Amitriptyline, Doxepin, Benzodiazepinc drugs, mclatonin, diphenhydramine, and herbal remedies; Cardiac glycosides selected from the group consisting of Digoxin and digitoxin; Phosphodiesterase inhibitors selected from the troup consisting of enoximonc and milrinone; Thiazidcs and related diuretics selected from the group consisting fbendroflumethiazide, chlortalidone, eyclopenthiazide, inapamide, metolazone, and xipamide; Diuretics selected from the group consisting of .furosemide, butnetanide, and torasemide; Potassium sparing diuretics and aldosterone antagonists selected from the group consisting of amiloridc hydrochloride, triamterene, weplerenone, and spironolactont; Osmotic. diuretics; Drugs for arrhythmias selected from the group consisting of adenosine, amioclarone hydrochloride, disopyramide, flecainide acetate, propafenone hydrochloride, and lidocaine hydrochloride;
Beta admnoreceptor blocking drugs selected from the group consisting of propanalol, atenolol, acebutolol, bisprolol fumarate, carvedilol, celiprolol, esmolol, lebatolol, metoprolol tartrate, nadoloi, nebivolol, oxprenolol., pindolol, solatol, and timolol; Hypertension, drugs selected from the group consisting of anibritentart, bosentan, diazoxide, hydralazine, iloprost, sildenatil, sitaxentan, sodium nitroprusside, clonidine, methyldopa, moxonidine, guanethidine monosulphate, doxazosin, indoramin, prazosin, terazosin, phenoxybenzaminc, and phentolatnine mesilate; Drugs affecting the renin-ant,ziotensM system selected from the group consisting of Ca:ptroprilõ Cilazapril, .Enalapril Maleate, Fosinopril, Moexipril, Perindopril Erbumine, Quinapril, Ramipril, Trandolapril, Candesartan Cilexetil, Eprosartan, lrbesartan, Losartan, Ohnesartan Medoxomil, Telmisartan, Valsartan, and Aliskiren; Nitrates, calcium channel Blockets, and antianginal drugs selected from the group consisting of Glyeeryl trinitrate, Isosorbide Dinitrate, lsosorbide Mononitrate, Amlodipine, Diltiazem, Felodipine, .Isradipine, Lacidipine, Lercanidipine, Nicardipine, Nifedipine, Nimodipine, Verapamil, Ivahradine, Nicorandil, and Ranolazine;
Peripheral

- 35-Vasodilators and related drugs selected from the group consisting of Cilostatol, inositol Nicotinate, Moxisylyte, Naftidrofitryl Oxalate, and Pentoxifylline;
Sympathomimetics selected from the group consisting of Dopamine, Dopexamine, Ephedrine, Mctaraminol, Noradrenaline Acid Tartrate, Norephidrine Bitartrate, and Phenylephidrine;
Anticoagulants and Protarnirie selected from the group consisting of Heparin, Bemiparin, Dalteparin, Enoxaparin, Tinza.parin, Danaparoid, Bivalirudin. Lepirudin, Epoprostenolõ.Fondaprinitx, Warfarin, Acenocoumarol, Phenindione, Dabigatran Etexilate, Rivaroxahan, and Protamine Sulphate; Antiplatelet Drugs selected from the group consisting of Ahciximab, .Asphin, Clopidogrel, Dippidaniole, Eptifibatide, Pra.stigrel, and Tinafiban;
Fibrinolytic and atitifibrinolytic drugs selected from the group consisting of Alteplase, Reteplase, Streptokinase, Teneeteplase, Llrokinase, Etamsylate, and Tranexamic Acid;
Lipid Regulating Drugs selected from the group consisting of Atorvastatin, Fluvastatin, Pravastatin, Rosuvastatin, Sitnvastatin, Colesevam, Colestyramine,:Colestipcil, Ezetitnibe, Ben fibrate, Ciprofibrate,..Fenofibrate, Gemfibrozyi, Aciptnox, NictOtinic Acid, Omega three fatty acid compounds, Ethanolamine Oleate, and Sodium Tetradecyl Suphate; CNS Drugs selected from the group consisting of Benperidol, Chlorpromazine, Flupentixol, Haloperidol, Levomepromazine, Pericyazine, Perphenazine, Pimozide, Proehlorperazine, Promazine, Sulpiride, Trifluoperazineõ Znelopenthixol, Arnisulpride, Aripiprazolc, Clozapine, Olanzapine, Paliperidonc, Quetiapine, Riperidone, Sertindole, Zotepine, Flupentixol, Fluphenazine, Olanzapine Embonate, Pipotiazine Paimitate, Risperidoneõ
Zuclopenthixol Dccanoate, Carhamazxpinc, Valproate, Valproic acid, lithium Carbonate, Lithium Citrate.
Amitriptyline, Clo.mipramine, Dostilepin, Imipramine, Lofepramine, Nortriptyline, Trimipramine, mianserin, Trazodone, Phenelzine, Isocarboxazid, Tranylcypromine, Moclobemide, Citalopram,:Escitalopram, Fluoxetine, Fluvoxamine, Paroxetine, Sertraline, Agomelatine, Duloxetine,.Flupentixol, Mirtazapine, Reboxetine, Trytophan, Venflaxine, Atornaxetine, Dexametamine, Methylpheriidate, Modafirtil, Esticarbazepine, Ocarbazepene, Ethosuximidc, Gahapentin, Pregabalin, Lacosatnide, Latnotrigine, Levetiracetain, Phenobarbital, Primidone, Phenytoin, Rufinamide, Tiaga.bine, Topiratnate, Vigabatrin, Zonisamide, ropirtirole, Rotigotine, Co-Beneldopa, Levodopa, Co-Careldopa, Rasattiline, Selegilinc, Emacapone, Tolcapone, Amaritidine, Orphenadrine, .Procyclidine, Trihexyphenidyl, Haloperidol, Piracetam, Rihizoic, Tetrabenaiine, Aeamprosate, Disulfiram, Bupropion, Varenieiline, Buprenorphine, Lofexidine, Donepezil, Galantamine, Memantinc, and Rivastigimine; Anti-Infectives selected from. the group consisting of Benzylpenicillin, Phenoxymethylpenicillin, Flucloxacillin, Ternocillin, Amoxicillin, Ampicillin, Co-

- 36 -Ainoxichtv, Ticarcillin, Pivmecillinam, Cephalosporins, Cefaelor, Cefadroxit, Cefalexin, Cefixime, Cefotaxime, Cefradite, Cetlazidime, Cc:fat-mime, Ertapenern, Imipenem, Meropencm, Aztreonam, Tetracycline, Demeclocycline, Doxoeyeline, Lymecycline, Minocycline, Oxytetracycline, Tigecycline, Gentamicin, Amikaciri, Neomycin, Tobramyein, Erythromycin, Azithro.mycin, Clarithromycin, Telithromycin, Clindamycin, Chloramphenieol, Fusidie Acid, Vancomyein, Teicoplanin, Driptotnyein, Linezolid, Quinupristin, COlistin, Co-Trimoxazole, Sulpadiazine, Trimethoprim, Caprcomyein, Cycloserine, Ethambutol, Isoniazid, Pyrazinamide, .Rifabutin, Rifampicin, Streptomycin, Dapsdneõ.Clofliziinine, Metronidazole, Tinidazolc, Ciprinflaxaein, Levoflaxacin, kloxifloxacit, Nàlidixic Aeid,.Norflaxine, Orflaxatin,'Nintfurantoiri, Methertamine flippurate., Amphotericin, Ariidulafungin, Caspofiniginõ Fluconazole, Flucytosirie, Cnisedfluvin, Itraconzole, Ketoconazole, Micafungin, .Nystatin, Posaconazolc, Terbiriafine, .Voriconazole, Abaeavir, Didanosine, Emtricitabine, Lantivudine, Stavudinc, Tenofovir Disoproxil, Zidovudine, Atazanavir, Darunavir, Fosamprenavir, Indinavir, Lopinair, Nelfinavir, Ritonavir, Saquinavir, Tipranavir, .Efavirenz, Etravirinc, Nevarapinc, .EttfirVirtide, Maraviroc, Raltegravir, Aticlovir, Fameiclovir, Inosine Pranobex;
Valaciclovir; Cidofovir, Gangciclovir, Foscarnet, Valgangoiclovir, Adefovir Dipivoxil, Entecavir;
Telbivudine, Amantadinc, Oseltamivir, Zanamivir, Palivizuinab, Ribavirin, Arternether,.Chloroquine, Mefloquine, Primaquine, Proguanil, Pyrimethamine, Quinine, Doxycyclin, Diloxanide Furoate, Metronidaziole, Tinidazole, Mepacrine, Sodium Stiboglaconate, Atovaquone, Pentamidine lsetionate, Mebendazole, and Piperazine; Other drugs selected from the group consisting of Benztropine, procyclidine, biperiden, Amantadine, Bromocriptine, Pergolide, Entacapone, Tolcapone, Selegeline, Pramipexole, budesonide, fort/Iowa quetiapine fumarate, olanzapine, pioglitazonconontelukast, Zoledromic Acid, valsartart, latartoprost, Irbesartanõ Clopidogrel, Atomoxetine, Dexamfetamine, Methylphenidate, Modafinil, Bleomycin, Dactinomycin, Daunombicin, Idarubicin, Mitomycin, Mitoxantrone, Azacitidine.õ
Capecitabine, Cladribine, Clofarabine, Cytarabine, Fludarabine, Flourouracil, Gemcitabine, rnercaptopurine, methotrexate, Nelarabinc, Pemetrexed, Raltitresed, 'Thioguaninc, Apomorphine, Betatnethasone, Cortisone, Deflazacort, Dexamethosone, Hydrocortisone, Methylprednisolone, Prednisolone, Triamcinolone, Ciclosporine, Sirolimus, Tacrolimus, Interferon Alpha, and Interferon Beta, 01321 Thus, the therapeutic formulations of the disclosure may further comprise one or more additional therapeutic agents, such as any of the therapeutic agents described below. In some embodiments, the compositions are supplied as part of a sterile, pharmaceutical

- 37-composition that includes a pharmaceutically acceptable carrier. Such compositions comprising additional therapeutic agents can be in any suitable form (depending upon the desired method of administering it to a patient). In some embodiments, the active ingredients of the disclosure, are co-administered with one or more additional therapeutic agents, though are not necessarily combined into a single formulation with the one or more additional therapeutic agents. In some embodiments, the active ingredient(s) of the disclosure are administered via one route of administration, whereas the co-administered additional therapeutic agent(s) are administered via a second route of administration.
For example, the active ingredients of the disclosure might be administered orally, mucosally, sublingually.
Weedily, etc., whereas the to-administered one or more additional. therapeutic agents are administered parenterally, intravenously, etc.
101331 Examples of compounds that can be combined with the inventive compositions include anti-rheumatic drugs, anti-inflammatory agents, chemotherapeutic agents, radiotherapeutics, immunosuppressive agent, intcrferons, interferon-based chernotherapeuties, or cytotoxic drugs.
PIA Anti-rheumatic drugs include, but are not limited to, auranofin, azathioprine, chtoroquine, D-penicillamine, gold sodium thiomalate hydroxychloroquine, MyocrisM and sulfasalazine methotrexatc.
[0135j Anti-inflammatory agents include, but are not limited to, dexamethasone, pentasa, mesalazine, asacol, codeine phosphate, benorylate, tenbufen, naprosyn, diclofenac, etodolac and indomethacin, aspirin and ibuprofen, .as well as other non-steroidal and anti-inflammatory agents (NSAIDS).
101361 Chemotherapeutic agents include, but are not limited to, radioactive molecules, toxins, also referred to as cytotoxins or cytotoxie agents, which includes any agent that it detrimental tothe viability of cells, agents, and liposomes or other vesicles containing cheinotherapeutic compounds. Examples of suitable chemotherapeutic agents include but are not limited to I -dehydrotestosterone, 5-fluorouracil deearbazine, 6-mercaptopurine, 6-thionuanine, actinornyein 13, adriarnycin, aldcsletikin, aikylating agents, allopurinol sodium, altretamine, amiftastine,anastrozole, anthramycin (AMC)), anti-mitotic agents, cis-dichlorodiamine platinum (II) (DDP) cisplatin), diamino dichloro platinum, arithracyclines, antibiotics, antimentbolites, asparaginase, BCG live (intravesical), betamethasone sodium phosphate and betamethasone acetate, bicalutamidc, blcomycin sulfate, busulfan, calcium leucovprin, calicheamicin, capeeitabine, earboplatin, lounittine(CCNU), carmustine (BSNU), Chlorambucil, Cisplatin, Cladribine, Colchicin, conjugated estrogens,

-38-Cyclophosphamidc, Cyclothosphamicle, Cytarabine, Cytatabineõ cytochalasin B, Cytoxan, Dacarbazine, .Dactinornycin, dactinomycin (formerly actinomycin), datmirubicin HCL, daunorucbicin citrate, denileukirt dittitox, Dexrazoxane. Dibromomannitol, dihydroxy anthracin dione, Docetaxel, dolasetron mesylate, doxorubicin HCL, dronabinol., E. coli L-asparaginase, emetine, epoetin-alpha.õ .Etwinia L-asparaginase,esterified estrogens, cstradiol, estramustine phosphate sodium, ethidium bromide, ethinyl estradiol, etidronate, ctoposide citrovorum factor, etoposide phosphate, filgrastim, floxuridine, fluconaz.ole, fludarabine phosphate, fluorouraeil, flutamide, .folinic acid, Remeitabine HCL, glucocorticoids, goserelin acetate, gramicidin D,g;ratiisetron 11CLõhydroxyurea, idaruhicin HCL, ifosfamide, interferon alpha.-2b, irinoteean HCLõ ictrozole, leucovorin calcium, leuprolide acetate, levamisole HCL, lidocaine, loinustine, maytansinoidonechlorethamine HCL, nedroxyprogesterone acetate, megestrolacetate, .melphalan HCL, mercaptopurine, mesna, methotrexate, methyltestosterone, mithramycinonitornyein-C, mitotarte, mitoxantrorte, nilutamide, octreotide acetate, ondansetron HCL, paclitaxel, pamidronate disodiurn, pentostatin, pilocarpine HCL, phinyein, polifeprosan with camatstine implant, porfnner sodium, procaine, procarbazine HCL,propranoloi, rituxirnab, sarammostim, streptozotocin, tamoxifen, taxa teniposide, tenoposide, testolactone, tetracaine, thioepa, chlorambucil, thioguanine, thiotepa, topotecan HCL,.torcmifene citrate, trastuzumab, tretinoin, valrubicin, vinblastine sulfate, vincristine sulfate, and vinorelbine tartrate.
101371 In yet other aspects of the disclosure, active ingredients of the disclosure are administered in combination with a TN17-rt antagonist man anti-INF- nantibody.
Examples of such TNF- a antagonists include, but are not limited to, soluble TNF- a receptors;
etanercept (ENB.REIA; Immunex) or a fragment, derivative or analog thereof infliximab (REM1CADE*; CentacOr) or a derivative, analog or antigen- binding fragment theredt.
Adalimumab-(Hurnira and Exemptia), IL-10, which is known to block TNF-a production Wei interferon-y-activated macrophages, TINIFR-IgG; the murine product TBP-1; the vaccine CytoTAb (Protherics); antisense molecule 104838 (ISIS); the peptide RDP-58 (SangStat);
thalidomide (C:elgene); CDC-801 (Celgenc); DPC-333 (Dupont); VX-745 (Vertex);
AGM-4207 (AtheroGenics); ITF-2357 (Italfarmaco); NP1-13021-31 (Nereus); SC10-469 (Seios);
TAC.E ander (Immunix/AHP); CLX-120500 (Calyx); Thiazolopyrim (Dynavax);
attranofin (Ridattra) (SmithKline Beecham Pharmaceuticals); quinacrine (mepactine dichlorohydrate);
tcnidap (Enabiex); Melanin (Large Scale Biological); and anti-p38 MAPK agents by thiach.
101381 In further aspects of the present disclosure, active ingredients of the disclosure are administered in combination with rapamycin, or similar macrocyclic antibiotics. As used

- 39 -herein, rapamycin includes rapamycin and all analogs, derivatives and congeners thereof, and other immunophilins that possesses the same pharmacologic properties as rapamycin is including inhibition of TOR or in-l'OR (mammalian target of rapamycin) (e.gõ
acting as a TOR kinase inhibitor). Other immunosuppressives that can be used as the one or more pharmaceutical or therapeutic agents include, but are not limited to, cyclosporine, tacrolimus (PK-506), azathloprine, and mycophenolam mofetil, 101391 Further therapeutic agents that may. be combined with the active ingredients of the disclosure include angiogenic agents such as vascular endothelial growth factor (VEGF) and fibroblast growth factor (FGF); angiotensin receptor blockers; nitric oxide donors; andsense oligotatcleotides.and combinations thereof; celleyele inhibitorsonTOR
inhibitors, and.
growth factor receptor signal transduction kiriase inhibitors; retinoids;
cyclinICDK
inhibitors; HMG co-enzyme reductase inhibitors (e.g., statins); and protease inhibitors.
TNF Inhibitors 101401 A tumor necrosis factor (TNF) inhibitor, specifically a TNFa inhibitor which is used in the methods andcompositions of the invention includes any agent which interferes with INfo activity, In a preferred embodiment, the TNFa inhibitor can :neutralize TNFri activity, particularly detrimental TNFa activity which is associated with oxidative stress diseases and disorders, such as [see definition], and. related complications and symptoms.
101411 The term "human TNFa" (abbreviated herein as hINFet, or simply hTNF), as used herein, is intended to -refer to a human cytokine that exists as a 1 7 kD
secreted form and a 26 kD membrane associated form, the biologically active form of which :it -compOsed of a trimer of noncovalently bound 17 kD niolecules. 'The structure of WINFo is described further in, for exam*, Pennica, D., etal. (1984) Mrture 312:724-729; Davis, 3, M., et al.
(1987) Bioehettrisiry 26;13224326;-and Jones, E. V., etal. (1989) Nature 338:225-a28, The term human TNFti. is intended to include recombinant human INFa (rliTNFei), which can be prepared by standard recombinant expression methods or purchased commercially (for example, from R. & D Systems, Minneapolis, Mimi.), INFa is also referred to herein equivalently as TNF.
101421 The term "TNFa inhibitor" refers to anagent which interferes with TNFit activity.
The term also includes each of the anti-TNFa human antibodies and antibody portions described herein as well as those described MUS, Patent Nos. 6,090,382;
6,258õ5(2;
6,509,015, and in U.S. Patent No, 7,223,394). In one embodiment, the TNFtt inhibitor used in the invention is an anti-TNFa antibody, or a fragment thereof, including infliximab.
(Remicade, Johnson and Johnson; described in U.S. "Pat. No. 5,656;272, incorporated by

-40-refivence herein), CDP571 (a humanized monoclonal anti-INF-alphalgG4 antibody), CDP
.870 (a humanized monoclonal anti-TNF-alpha antibody fragment), an anti-TNF
dAb (Pepteeh). CNTO 148 (golinamiab; Medarex and Centocor, see WO 02/12502), and adalimumab (Hurnire Abbott Laboratories, a human anti-TNF mAb, described in U.S.
Patent No.-6,090,382 as "D2E7"). Additional TNF antibodies which can be used in the invention are described in U.S. Patent Nos: 6,593,458; 0,498,237; 6,451,983;
and 6,448,380, each of which is incorporated by reference herein. In another embodiment, the INFa inhibitor is a INF fusion protein, e.g., etanercept (Enbree. Amgen; described in WO.
.91/03553. and WO 09/406.476, incorporated by reference herein). In =Other embodiment, the TNFa inhibitor is a recombinant INF binding protein (r-THP4) (Serono).
101431 The term "antibody", as used herein, is intended to refer to immunoglobulin.
molecules comprised of four polypeptide chains, two heavy (H) chains and two light (L) chains inter-connected by disulfide bonds. Each heavy chain is comprised of a heavy chain variable region (abbreviated herein as .HCVR or VH) and. a heavy chain Constant region. The heavy chain constant region is comprised of three domains, CHI, Clf2 and CH3.
Each light chain Is comprised of a light chain variable region (abbreviated herein as LCVR or VL) and a light chain constant region. The light chain constant region is comprised of one domain, CL.
The VII and VL regions can be further subdivided into regions of bypervariability, termed complementarily determining regions (CDR), interspersed with regions that are more conserved, termed framework regions (FR). Each VII and VL is composed of three CDRs and four FRs,.ananged from amino-termittus to earboxy-terminus in the following order FR FR2, CDR2, .FR3, CDR3, FR4. The antibodies of the invention are described in further detail in U.S. Patent NM. 6,090,382; 6,258,562; and 6,509,015, each of Which is incorporated herein by reference in its entirely.
101441 The term "human antibody", as used herein, is intended to include antibodies having variable and constant regions derived from human germline immurtoglobulin sequences. The human antibodies of the invention may include amino acid residues not encoded by human gentility irtimunoglobulin sequences (e.g., mutations introduced by random or site-specific mutagenesis in vitro or by somatic mutation in vivo), for example in the CDRs and in particular CDR3. However, the term "human antibody", as used herein, is not intended to include antibodies in which CDR sequences derived from the gemiline of another mammalian species, such as a mouse, have been grafted onto human framework sequences.

- 41 -101451 The term "recombinant human antibody", as used herein, is intended to include all human antibodies that are prepared, expressed, created or isolated by recombinant means, such as antibodies expressed using a recombinant expression vector transfected into a host cell (described further beloW), antibodies isolated from a recombinant, combinatorial human antibody library (described further below), antibodies isolated from an animal (e.g., a mouse) that is transgenie for human immunoglobulin genes (see e.g., Taylor et al.
(1992) Hue!. Act*
Res. 20:6287) or antibodies prepared, expressed, created or isolated by. any other means that involves splicing of human immunoglohulin gene sequences to other DNA
sequences. Such recombinant human antibodies have variable and constant regions derived from human germline inununoglobulin sequences. In certain embodiments, however, such recombinant human antibodies are subjected m in vitro mutagenesis (or, when an animal transgenic for human Ig sequences is used, in vivo somatic mutagenesis) and thus the amino acid sequences of the VH and VL regions of the recombinant antibodies are sequences that, while derived from and related to human itermline VH and VL sequences, may not naturally exist within the human antibody gennline repertoire in vivo.
101461 In one embodiment, the term "TNFa inhibitor excludes infliximab, In one embodiment, the term "Thina inhibitor" excludes adalimumab. In another embodiment, the term "TNFa inhibitor" excludes adalimumab aadinfliximab.
(01471 In one embodiment, the term "TNFot inhibitor" excludes etanercept, and, optionally, adalimumab, infliximab, and adalimumab and infliximab.
101481 in oneenibodiment, the term "TNFo antibody" excludes infliximab. In one embodiment, the term "TNFa antibody" excludes adalimumab. In another embodiment, the term "TNFa antibody" excludes adalimumab and infliximab.
101491 In one embodiment. the invention features -uses and composition for treating or determining the efficacy of a INFa inhibitor for the treatment of Crohn's disease, wherein the TNFa antibody is an isolated human antibody, or antigen-binding portion thereof, that binds to human *Mina with high affinity and a low off rate, and also has a high neutralizing capacity. Preferably, the human antibodies used in the invention are recombinant, neutralizing human anti-hTNFa antibodies. The most preferred recombinant, neutralizing antibody of the invention is referred to herein as D2E7, also referred to as ITUM1RA! or adalimumab (the amino acid sequence of the D2E7 VL region is shown in SEQ11) NO: 1; the amino acid sequence of the D2E7 VH region is shown in SEQ ID NO: 2). The properties of D2E7 (adalimumab/ HUMIRA4) have been described in, and, which are each incorporated by reference herein. The methods of the invention may also be performed using chitrteric and

- 42 -humanized murine anti-hINFa antibodies Which have undergone Clinical testing for treatment of rheumatoid arthritis (see e.g., Elliott, MI, etal. (1994) Lancet 344:1125-1127; Elliot, MI, et al. (1994) Lancet 344:1105-11M Rankin, E.C.,-etal. (1995) Br. J.
Rheumatol.
34:334-342).
101501 Thus, in one aspect, the disclosure provides toll-like receptor (TLR) agonist compositions for regulating redox status in a subject, the compositions comprising: (a) a TLR agonist comprising at least one or more lysate and/or lysate fraction of a bacterium, wherein the TLR agonist activates at least one or more TLRs or NLRs; (b) an optional promoter for enhancing absorption of the composition; and (c) an optional.
carrier for increasing a volume of the composition; wherein administration of an effective amount of the composition. to the subject measurably reduces oxidative stress levels in the subject. In some embodiments, the agonist activates at. least two different TLRs and/or NLRs. In some embodiments, the bacterium is a Gram-positive bactetitun or a Gram-negative bacterium.
101511 In some embodiments, the compositions are administered in combination with a pharmaceutical agent so as to enhance activity Of the pharmaceutical agent. In some embodiments, the compositions are administered in combination with a pharmaceutical agent so as to reduce a side effect of the pharmaceutical agent. lu some embodiments, the side effect of the pharmaceutical agent is oxidative stress.
[0152i In another aspect, the disclosure provides methods of regulating redox status in a subject, the methods comprisingadministering a therapeutically effective amount of any of the lysate or lysate fraction compositions disclosed herein to a subject in need thereof. In some embodiments, redox status regulation is assessed ideally by measuring changes in isoprostane concentration or by other methods including but not limited to gene expression in the subject. In some embodiments, the subject is a mammal. In some embodiments, the mammal is a human. In some embotlimous, the subject is an animal which is not a mammal, such as, but not limited to, fish, fowl, crustaceans, and insects, such as Drosophila. In some embodiments, the redox status is oxidative and. results in oxidative stress.
In some embodiments, the oxidative stress in the human is related to post-traumatic stress disorder.
101.531 In another aspect, the disclosure provides methods of regulating redox status in a subject, the method comprising the steps of (a) repeatedly administering to a subject in need thereof doses spaced apart in time and consisting of a composition comprising:
(i)a toll-like receptor (TLR) agonist comprising at least one lysate and/or lysate fraction, wherein the agonist activates at least one or more different TLRs; (ii) an optional promoter for enhancing

- 43 -absorption of the composition; and (iii) an optional -eanier for increasing a volume of the composition; and (b) making measurements of a bodily fluid oldie subject to detect changes in oxidative stress-levels. In some embodiments, the TLR agonist activates at least three different ILRs. In some embodiments, the TLR. agonist comprises lysate(s) and/or lysate fraction(s) and/or cell wall fraction(s) from a single species of bacteria. In some embodiments, the TLR agonist comprises lysate(s) and/or lysate fraction(s) from at least two species or strains of bacteria.
01541 In some embodiments, making measurements of a bodily fluid assesses changes in isoprostane concentration in the subject. In some enibodinierris, changes in isoprostane concentration are measured indirectly by methods including .but not limited to gene expression in the subject. In some embodiments, the sub.ject is a mammal. In some embodiments, the mammal is a human. In some embodiments, the subject is an animal other than a mammal, such as, but not limited to, fish, fowk.crustacearis, and insects, such as Drosophila; In some embodiments, the oxidative stress in the human is relatedto post-traumatic stress disorder.
101551 In another aspect, the disclosure provides methods of decreasing the amount of isoprostane in the urine or blood of a subject, the method comprising the steps of: (a) determining the level of isoprostane in the urine or blood of the subject; (b) administering to the subject an effective amount of a composition comprising: (i) a toll-like receptor (TLR) agonist comprising at least one bacterial lysate and/or lysate fraction from a bacterium, wherein the TLR agonist activates at least one or more TLRs or NI:Rs; and (ii) an optional.
promoter for enhancing absorption of the composition; and (c) continuing administration of -the composition until the level of isoprostane in the urine or blood of the subject is decreased.
101561 In. another-aspect, the disclosure provides compositions comprising:
(a) a bacterial lysate and/or lysate fraction capable of activating at least one or more toll-like receptors (ThRs) or Nod-like receptor (NLR); (b) an. optional promoter for enhancing absorption of the composition: and (c). an optional carrier for increasing a volume of the composition.
101.571 In another aspect, the disclosure provides pharmaceutical formulations comprising any of the compositions disclosed herein. In some embodiments, the pharmaceutical formulations are formulated for buccal or sublingual administration. In some embodiments, the pharmaceutical formulations are formulated to dissolve in not less than I
minute after administration.

-44-(0158.1 In another aspect, the disclosure provides mettiodS of producing a bacterial lysate, the method comprising the steps of (a) fermenting a Gram-positive or Gram-negative bacterium in a. growth medium to the stationaty growth phase to produce a fermentation broth; (b) harvesting bacteria from the fermentation broth; (c) pasteurizing the harvested bacteria; and (d) lysing the pasteurized bacteria with a lysozyme to produce a bacterial lysate. In some embodiments, the lysate is harvested at different times of the growth cycle after beginning any particular fermentation. In some embodiments, the bacteria are fermented. in a characteristically defined media.
(01591 In another aspect, the disclosure provides bacterial lysates produced aceordingto a process, the process comprising the steps of (a) fermenting a Grant-positive or ciratn-negative bacterium in a growth medium to the stationary growth phase to produce a fermentation broth; (b) harvesting bacteria from the fermentation broth; (c) pasteurizing the harvested bacteria; and (d) lysing the pasteurized bacteria with a lysozymeto prOduce a bacterial lysate. In some embodiments, the lysate is harvested at different times of the growth. cycle after beginning any particular fermentation. In some embodiments, the bacteria are fermented in a characteristically defined media.
KIM In another aspect, the disclosure provides methods for alleviating one or more oxidative stress-related side effects associated with administration of a pharmaceutical agent, the method comprising administering in combination with the pharmaceutical agent a therapeutically effective amount of a composition comprising: (a) a lysate and/or lysate fraction fa bacterium;. (b) an optional promoter for enhancing absorption of the composition; and (c) an optional. carrier for increasing a volume of the composition; wherein the pharmaceutical agent and lysate composition are administered simultaneously or in any order, and through the sameordifferent routes of administration, in some embodiments, the lysate and/or lysate fraction activates at least one or moreThRs orNIRs. In some embodiments, the lysate and/or lysate fraction activates at least two TLIZs and/or NIAs. In some embodiments, the lysate and/or lysate fraction activates at least three TLRs and/or NIRs.
101611 In some embodiments, the one or more oxidative stress-related side effects are selected from the group consisting of: aceruloplasminemia, arterial/systemic hypertension, arthritis, asthma, atherosclerosis, atopic dermatitis, cancer, bladder cancer, leukemia, uterine cancer, cervical cancer, dizziness, nausea, vomiting, constipation, diarrhea, insomnia, drowsiness, liahtheadedness, reduced libido, blackouts, shakes, jaundice, arrhythmia, increased heart rate, decreased heart rate, hives, depression, clinical depression, brain

- 45 -ischemia, bronchopulmonaty dysplasia, cardiovascular diseases, cataract, cellttlitis, chemotherapeutic side-effect, chronic fatigue syndrome, colitis, coronary artery disease, dyslipidemia, eclampsia, erectile. dysftmetion, ataxia, headache, heart failure, hemodialysis side effects, hepatic cirrhosis, hypercholesterolemia, hyperhoinocysteinemia, hyperlipidemia, interstitial lung disease, lung injury, macular degeneration, male infertility, mild cognitive impairment, myocardial infarction,. myocardifis, myopathy, nettropathyõ
obesity,-osteoarthritis, osteoporosis, paricivatitis, periodontal disease, peritoneal dialysis side effects, post-traumatic stress disorder, preeelampsia, psoriasis, psoriatic arthritis, pulmonary hypertension, radio-therapy side effects, reactive arthritis, respiratory distress syndrome, rhabdomyolysis, rheumatic disease, sepsis, sleep apnea, stroke, suicidal thoughts, atnyloidosis, thrombophily, tauopathies, unstable angina, uremia, and venous insufficiency.
161621 In another aspect, the disclosure provides methods for treating oxidative stress-related diseases.or conditions in a subjeet,The methods comprising administering to the subject a therapeutically effective amount of a composition comprising: (a) a bacterial lysate and/or lysate fraction capable of activating at least one or more toll-like receptors (TI.,14) or Nod-like receptors (INILRs); (b) an optional promoter for enhancing absorption of the composition; and (e) an optional carrier for increasing a volume of the composition.
101631 In some embodiments, the oxidative stress-related condition is aceruloplasminernia, acute and chronic alcoholic liver diseases, acute auto immune myocarditis, acute chest. syndrome of sickle cell disease, acute pancreatitis, acute respiratory distress syndrome, alcoholic liver disease, Amyotrophie Lateral Sclerosis, arterial/systemic hypertension, asbestosis, asthma, ataxia telangiectasia, atherosclerosis, atopic dermatitis, brain ischemia, bronehopulmonaty dysplasia, bums, some cancers, cardiopulmonary bypass, cardiovascular diseases, cataract, cellulitis, chemotherapeutic side-effect, chronic fatigue syndrome, chronic Hepatitis C, chronic.kidney disease, chronic obstructive pulmonary disease, chronic renal failure, colitis, coronary artery disease, Creutzfeldt-Jakob disease, Crolm's disease, cutaneous leishmaniasis, cystic fibrosis, diabetes mellitus type I, diabetes mellitus type 2,.dyslipidemia, Down's syndrome, eelampsia, end-stage renal disease, erectile dysfunction, Friedreich ataxia, headache, heart failure, Helicobacter pylon infection/inflammation, hemodialysis side effects, hepatic cirrhosis, Human linnumodeficiency Virus infection, Huntington disease, hyperbarie diseases, hypercholesterolemia, hyperhomocysteinemia, hyperlipidernia, idiopathic pulmonary fibrosis, interstitial lung disease, isehemialreperfusion injury, juvenile chronic arthritis, kidney transplantation failure, leukemia, lung cancer, lung injury, macular degeneration,

- 46 -male infertility, Moni&et-syndrome, meningitis, mild cognitive impairment, Multiple Sclerosis, myelodisplastic syndromes, myocardial infarction, myocardifis, neonatal bronchopulmonary dysplasia, obesity, osteoarthritis, osteoporosis, pancreatitis, Parkinson's disease, periodontal disease, peritoneal dialysis side effects, pliotoageing, post-traumatic stress disorder, preeclampsia, primary biliary cirrhosis, broneopulmonary diseases, progeria, psoriasis, psoriatic arthritis, pulmonary hypertension, radio-therapy side effects, reactive.
arthritis, renal -cell carcinoma, respiratory distress syndrome, retinopathy of prematurity, retrelenticolar fibroplasy, rheumatic disease, rheumatoid arthritis, sarcoidosis, sepsis, sickle cell disease, sleep apnea, spherocytosis, spinal cord injury, stroke, synucleinopathies, systemic amyloidosis, systemic lupus erythematosus, systemic sclerosis (scleroderma), thrombophily, tauopathies, traumatic stress tubercolosis, unstable angina, uremia, venous insufficiency. Werner syndrome, or Zellweger syndrome.
101641 in another aspect; the disclosure provides Methods for reducing oxidative stress in a subject, the methods comprising: (a) determining the level of oxidative stress in the subject by measuring the amount of isoprostane in the urine or blood of the subject; (0) administering to the subject an effective amount of a composition comprising: -(i) a toll-like receptor (TLR) agonist comprising at least one lysate and/or lysate fraction from a Gram, negative or Gram-positivebacteriu.m,.wherein the TLR.agonist activates at least one or more different TLRs orNLRs; and (ii) an optional promoter for enhancing absorption of the composition; and (c) continuing administration of the composition until the level of oxidative stress is reduced, as determined by a. decreased amount of isoprostarie in the urine of the subject.
101651 In some embodiments, of any of the above aspects, administration of the bacterial lysate is continued until the amount -oliSoprostane in the urine of the subject is less than about 3 ng per mg creatinine, less than about 2 ng per mg creatinine, less than about I ng per rog creatinine, or less than about 0.5 ng per mg of creatinine.
101661 In another aspect, the disclosure provides pharmaceutical formulations comprising the combination of: (a) a lysate composition comprising (i) a bacterial lysate and/or lysate fraction capable of activating at least one or more toll-like receptors (TLR) or Nod-like receptors (NLR); (ii) an optional promoter for enhancing absorption of the composition;.and (iii) an optional carrier for increasing a volume of the composition;- and (b) one or more pharmaceutical agents. in some embodiments, the one or more pharmaceutical agents are selected, from the group consisting of: an antispasmodic, a motility stimulant, an H2-Receptor antagonist, antimuscarinic; a dictate, a prostaglandin analog, an

- 47 -aminosalicylate, a corticosteroid, an drug affecting immune response, a stimulant laxative, a drug affecting biliary composition and flow, a bile acids sequestrant, a dopamine antagonist, a proton pump inhibitor, an opioidõ an opioid receptor antagonist, an analgesic, a sleep drug, a cardiac glycoside, a phosphodiesterase inhibitor, a thiazide, a diuretic, a potassium sparing diuretic, an aldosterone antagonist, an osmotic diuretic, a drug for arrhythmia, a bbeta adrenoreeeptor blocking drug, a hypertension drug, a drug affecting the renin-angiotensin system, a nitrate, a calcium blocker, an antianginal drug, a peripheral vasodilator, a sympathomimetic, an anticoagulant, a protamine, an antiplatelet drug, a fibrinolytic drug, an antifibrinolytic drug, a lipid regulating drug, an omega three fatty acid compound, a CNS
drug, an. anti-infective, or another drug selected from the group consisting of Benztropine, procyclidine, biperiden, Amantadine, Bromocriptine, Pcrgolide, Entacapone, Tolcapone, Sclegeline, Pramipcxole, budesonide, formoterol, quetiapine fumarate, olarrzapine, pioglitazone, montelukast, Zoledromie Acid, valsartan, latanoprost, Irbesartan, Clopidogrel, Atomoxctine, .Dexamfetamine, Methylphertidate, Modafinil, Bleomycin, Dactinomyein, Daunorubicin, Idarubicin, Mitomycin, MitexantroneõAzacitidine, Capcvitabinc, Cladribine, Clofarabine, Cytarabine, Fludarabine, Flourouracil, Gemeitabine, mercaptopurine, methotrexate, Nelarabine, Pemetrexed, Raltinexed, Thioguanine, Apomorphine, Betamethasone, Cortisone, Deflazacort, Dex.amethosone, Hydrocortisone, Methylprednisolone, Prednisolone, Triaincinolone, Cielosporine, Sirolimn;
'Nerolimas, Interferon Alpha, and 'Interferon Beta, 10l 671 in another aspect, the disclosure provides formulations, such as pharmaceutical formulations, comprising: (a) a lysate composition comprising (i) a bacterial lysate and/or lysate fraction capable of activating at least one or more toll-like receptors (711,Rs) or Nod-like receptors (NLIts); (ii) an optional promoter for enhancing absorption of the composition; and (iii) an optional carrier for increasing a volume of the composition; and (b) an isolated human anti-TNFalpha antibody or antigen-binding fragment thereof or TNF
inhibitor. In some embodiments, the human and-INFalpha antibody or antigen-binding fragment thereof is adalinunnab. In some embodiments, the disclosure provides uses of the combination formulations of this aspect in the manufacture of a medicament .for the treatment of rheumatoid arthritis (RA) or late-onset RA in a subject. In some embodiments, the disclosure provides methods for the treatment of rheumatoid arthritis (RA) or late-onset RA in a subject, the method comprising administering to the subject a therapeutically effective amount of the combination formulation of this aspect, and as disclosed herein. In some embodiments, the subject is over SO years old. In some embodiments, the human anti-

- 48 --TNFalpha antibody or antigen-binding fragment thereof is administered to the subject in a biweekly dosing regimen. In some embodiments, the human anti-TNFalpha antibody or antigen-binding fragment thereof is administered to the subject in a dose of 30 mg or greater.
In some embodiments, the TNFalpha inhibitor a TNFalpha fusion protein. In some embodiments, the INFalpha fusion protein is etanercept. In some embodiments, the anti-INFalpha antibody or antigen-binding fragment thereof is infliximab or golimumab. In some embodiments, the anti-TNFalpha antibody or antigen-binding fragment thereof is adalimumab.
101681 In another aspect, the disclosure provides methods for inhibiting oxidative stress-related disease or disorder progression in a human subject having an oxidative stress-related disease or disorder associated with a disorder in which TNFa activity is detrimental, the method comprising: administering to the subject having an oxidative disease or disorder a lysate, lysate fraction, and/or cell wall frattion of the diselosure,and. an isolated human anti-TNFoi antibody, or antigen-binding portion thereof, such that oxidative stress disease progression is inhibited in the subject, wherein the human anti-TNEV antibody, or an antigen-binding portion thereof, neutralizes human TNFa cytotoxicity in a standard in vitro L929 assay with an ICso of lx10-1M or less. In some embodiments, the lysate of the disclosure and the human anti-INFa, or antigen-binding portion thereof, are administered at different times under different. dosing regimens. In some embodiments, the human anti-TNFct antibody is eolimumab, or an antigen-binding portion thereof In some embodiments, the human .anti-TNFa antibody is adaliniumak or an antigen-binding portion thereof In some embodiments, the human anti-TNEV antibody, or antigen-binding portion thereof; is administered to the subject on a biweekly dosing regimen. In some embodiments, the methods further comprise administering an additional therapeutic agent to the subject. in some embodiments, the lysate of the disclosure is administered for a period of at least 24 weeks. in some embodiments, the anti-INFo antibody, or antigen-binding portion thereof, is administered for a period of at least 24 weeks. In some embodiments, the lysate of the disclosure, the anti-TNFa antibody, or antigen-binding portion thereof, or both, repairs or prevents oxidative damage to the subject by a combination of one or more different mechanisms.
101691 In some embodiments of any of the methods or compositions disclosed herein, the bacterium is a Gram-positive or Gram-negative bacterium. In some embodiments of any of the methods or compositions disclosed herein, the Gram-positive bacterium is selected from the group consisting of a bacterium of Lacto.baeilloceae family, a bacterium of

-49-Streputcoccaccoe family, a bacterium cfpidobaeteriacear family, and a bacterium of Bac)!!acme family, ht some embodiments,-the Gram-positive bacterium is selected from the group consisting of Bacillus coagulans, Lactobacillus sporogetws, Streptococcus thermophilus, Bifidobacterium animalis,.8ifidobacterium, animaliv, subspecies animalis, .Bilidobacterium infantis, Bitidobacterium .longum,.8ifidobacterium breve, Lactobacillus acidophilus, Lactobacillus..plania.rum, Lactobacillus easel, Lactobacillus tlelbrueckii, Lactobacillus delbnteckii subspecies bulgaricus, Lactococcus Jacils, Lactococcus lactis subspecies lactic, Streptococcus tact's, Streptococcus therntophilus, Byldobacterium ilifidobtieteritim breve, Pediacoccus aeidiladici, and LaCtobacillui helvetiMis.
101701 In some embodiments-of any ofthe methods or compositions (including formulations) disclosed herein, the Gram-negative bacterium is selected from the group consisting of a bacterium of Pseptiomonas genus, Klebsiella genus, Xanthomonas genus, Shigelk genus, and Enterobacter genus, In some embodiments, the Gram-negative battetiwn is selected from the group consisting of Klebsiefla oxyrocia, Shigellaflexneri, Xanthomonas campestris, and Pseudomonas sflourcscens.
101711 In some embodiments of any of the methods or compositions (including formulations) disclosed herein, the TLR agonist,- lysate, lysate fraction, or cell wall fraction activates atleast one or more of Tut 2, MR 3, TLR 4, TLR 5, TLR 7, TLR 8, TLR
9, NOD I, and-NOD2. In some embodiments, the TLR agonist, lysate, lysate fraction, or cell wall fraction activates two or more of TLR 2, TLR 3, TLR 4, TLR 5, TLR 7, TLR
8, TLR 9, "NOD I. and NOD2. -In some embodiments, the TLR. agonist, lysate, lysate fraction, or cell wall fraction activates TLR 2 and TLR 4. In some embodiments, the TLR agonist, lysate, lysate fraction, or cell wall fraction activates -three or More of TLR 2, TLR
3, TLR 4, TLR S.
TLR 7, TLR $, TLR 9, NODIõ and NOD2, 101721 In some embodirneMsof any of the methods or compositions (including formulations) disclosed herein, the promowr is selected from the group consisting of amino acids, amino sugars, and sugars. In some embodiments, the carrier is selected from the group consisting of a binder, a gum bast, and combinations thereof In some embodiments, the gum base comprises at least one hydrophobic polymer and at least one hydrophilic polymer.
In some embodiments, the binder is selected from the group consisting of a sugar, a sugar alcohol, and combinations thereof. In some embodiments, the sugar alcohol is selected from the group consisting of mannitol, sorbitol, xylitol, and combinations thereof 101731 In some ethbodiments, the compositions are manufactured as a dosage form selected from the group consisting of a lozenge, a chewing gum, a chewable tablet, a candy,

- 50 -and a dissolving tablet. in some embodiments, the dosage form delivers the-TLR
agonist to an oral mucosa. In some embodiments, the oral mucosa is selected from the group consisting of the sublingual mucosa, buccal mucosa, and a combination thereof.
101741 In some embodiments of any of the methods or compositions (including formulations) disclosed herein, the compositions are formulated for oral mucosal delivery; in some embodiments, the compositions are formulated for sublingual or buccal delivery. In some embodiments, the compositions are formulated to dissolve in not less than 1 minute after administration.
EXAMPLES
101751 The Examples that follow are illustrative of specific embodiments of the invention, and various uses thereof They are set forth for explanatory purposes only, and arc not to be taken as limiting the invention.
Example 1: Preparation of active ingredient for TLR agonist compositions 101761 An example of how to formulate the composition includes the following process.
101771 Active Ingredient. The active ingredient was derived from a bacterial fermentation and cell isolation process as described below. Lactobacillus delbrtieckii;
ssp, blligurieus (referred to herein as L. bulgaricus) was the organism used in this example, but the bacterial organism may be any Gram-positive or Gram-negative bacterium, or both.
10178.1 Lactobacillus delbrueckii asp buigaricus was fermented in growth media comprising 1.5% casein hydrolysate. I% yeast extract, 3% lactose, 0.2% sodium acetate, 0,02% sodium formate,-0Øl% disodiuM 5-inosinate,Ø01%-mangonese sulfate, 0:05%
magnesium sulfate, and 0.05% polysorbate 80, pH 6.4. Inoculated media was incubated at 37 0C. until the fermentation reached stationary growth, as determined by cessation of metabolism. Fermentation broth was chilled. to 4 "C and. harvested by eentrillination at about 4000-4500 x g.
101791 The concentrated cells were washed two sequential times using chilled water and by. running the cells through the centrifuge again. Washed cell concentrate was pasteurized at 800C for 45 minutes.
101801 Following .pasteurization,-the cell concentrate was treated to disrupt cell walls and thereby lyse the bacteria and expose TLR agonists. Disruption of bacterial cell walls was

- 51 -:ketiritpliAM tiattg thi&ett edg white: 1.y,o ,me.attreoncentrafionof 3%
b:j.;,. Wt. fot:77 &Aura at 40 "C. The regniting lysate was frOteti: and IvophiliML:
101811 The lyophilized material wasblended with a prom:Met:0th as Is,I.,atety D
,glueosarnine:HCI (NAG), to form a mixture of lysed.Lactobooifirm delbeveckii subsit .aidgarkio arid NAG. Optionally, other thrmulation exeipient to generate a solid form pill or powder were added, as appropriate. This product was then used in the following screening tests.
Examplel::TLR screening assay j0I8721 reeeptorfTLRYstiinulati00 was tested by assessing NF-KB
activation in HEK293 eel4e;gpreping a given TLR or Nod-like receptor (NIS). The activities of the sa.mple4 were tested on gyen:different human TL Rs: TLR2, 34& 7, 8 and 9 (Invi \town, Stn Diego, CA), and on two different human NLRs. nueleotide,binding oligoinctization domain-containing proteins I and 2 (NOD] and NOD2) Each hand was tested at a final concentration of):i 00 of the stock solution on theLR. or NLR cells, and compared to control ligands, as described below. This step wa.sperformed in triplicate.
(0183j The cOntrol ligands,tontrol cell lines, andgittnple productusedifthe examples Were :$ 410% in Table 1:: (.'outrnliligands and,contRil cell line infolmation used in ligand screening tests.
ILR2: HKLM (heat-killed Lineria monocylog6les.) at 109 ce) Poly(1:C) at 1 pg/mL
TI.:R4: E. (:vii KI2 LPS at 100 nglinL
'MR5. S. t,ppithaurittrn flagellin at 100 nglinl Control Ligands CL097 at , TLR8: C1075 at I
TLR9: CpG ODN 2006 at 100 /vita NOD) = CT2iED AP at 1.0 w,IniT, NoD2: L18-M DP at 100 ngiinL
HEK293:Null INF-alpha at (control for htire MR 2, 3, 5, 8, 9 and NOD 1) IlEk293/Nuil -k: TNF-alpha at 1 ugiml.:
Control Cell Lines (control for human ILR7) FIEK293;1\hill21 TNF-alpha at I walmr, (control for human TUN and NOD2) Lysate ofL oclobactliffs subsp. bifigariens Sample (I;10 dilution prepared in stet de, endotoxin-free water)

- 52 -101841 General Procedure. TER stimulation in the screening is tested by assessing NF-KB activation in the HEK293 cells expressing a. given TLR. The secreted alkaline phosphatase reporter is under the control of a promoter inducible by the transcription factor NF-KB. MR stimulation in the screening was tested by assessing NP-KB
activation in the HEK293 cells expressing a given TLR or NLR. This reporter gene allows the monitoring of signaling through the TLR/NLR, based on the activation of NF-KB. In a 96-well plate (200 iL total volume) containing the appropriate cells (50,000-75,000 cells/wel1),204-of the Sample (lysate product) or the positive control ligands-to the wells. The media added to the wells is designed for the detection of NFKB induced SEAP (secreted. alkaline phosphatase) expression. After a 16-20 hr incubation, the OD (optical density) at 650 nm was read on a Molecular Devices Spectra Max 340PC absorbance detector and recorded.
10189 The screening results of these experiments are shown graphically in Figure 2.
These results show that a typical lysate produced as described above is a strong agonist for at least TL11.2 (and TLR4 to a lesser extent) and NOD2.
Example 3: Effects of changes in process variables on TLR signaling 101861 Through observations of the effects of certain process changes on TLR signaling, it wasnoted that MR signal pattern could be altered:
1;01811 Figure 3 shows the difference of the cell morphology has on the TLR
signal for a Grain-positive organism. Lysate from Pediwocairs.acidflactifeii-a cocci ornanism, produced higher 11-114- and lowerNOD2 signals compared to L. hulgifrictis,A rod organism; while the TLR 2 signal produced by P. acidliactki was only slightly higher than that produced by L
buktarieuv. NOD2 activation was significantly lower in P. addifactici which is reflective of the lower muramylpeptides found in cocci.
1.01$81 UR signal patterns were also impacted by the time of culture harvest for a Bacillus coagulans lysate, as depicted in Figure 4. Bacillus coaguians was grown using a standard yeast extract /glucose media with a pH of 6.5 in shake flasks incubated at 451.", and 250 rpm. Harvest of the cultures followed the lysate production process of Example 1 but by varying the time of harvest of bacteria after fermentation according to growth phase: mid-logarithmic phase, late-logarithmic phase, early stationary phase, mid-stationary phase, and late stationary phase as determined by OD, substrate depletion, metabolite production and EPS. In general, these data demonstrate that ILK activation specificity can be altered by changing the time of bacterial harvest after fermentation. For example, lysate produced from cultures harvested at the mid-log phase activated all targets tested except for TLR 4 and had

- 53-the highest -signal-for TLIks 2,-3, 5, 8, 9 and NODI. TLR signal strength decreased as the culture left log phase and went into stationary phase, with a complete cessation of 'MR signal during late stationary. Cell culture was plated at all stages of harvest and cell count was noted to be greater than 5x108 Mimi at all time points. No endospores were noted upon visual inspection of the culture. The TLR effects noted from the lysates were from vegetative cells.
A large amount of EPS was noted on the sidcwalls of the late stationary culture.
[01891 Figure 5 shows TLR signal patterns obtained from lysates of selected Gram-positive organisms. Streptococcus thennaphilus, Lactobacillus helveticus, Lactobacillus acidophilus, LaotabatilluS plantakum, Bilidobadetitan animal& subsp /dais, and Bacillus subalis were grown nna standard yeast extract/lactose/casein hydrolyzate Media at pH 5.5 in.
shake flasks incubated at 37 't and 110 rpm. Lactobacillus plowman, Bifidobacterium animalis subsp. lactis (B.lactis), and Bacillus subtilis were grown on yeast extract media/glucose media at pH 6.5 in shake flasks incubated at 37 'Cand.11-0 tpm, whereas.B.
stabilliv was incubated at 37 C and 250 rpm. B. !veils also had 0.05% cysteine HCL added-to the media. Harvest of the-cultures followed the lysate production process of Example I. S
theemOphilits, a cocci organism, gave a TLR signal pattern (high TLR 2 and TLR
4, and low NOD2) that was similar to the other cocci -culture P. acidilactici, as noted in Example 4.
However, B. Meth,. although a different morphology than L. bulgaricus gave a similar TLR
pattern. Them was little similarity in the TLR pattern across the Gram-positive rod cultures of L. helviticus, L. acidophilus. L .plantarum, and B. subtilis. beliviticus produced a TLR
pattern similar to the TLR pattern of L bulgarieas. 1.. aotclophilus, although lower in signal strength, produced results similar to the patterns produced by the cocci. L
addophilus did not produce any noticeable EPS when the culture was harvested and concentrated, whereas L.
helviticas, and B. lactis all produced noticeable EPS, and all produced similar ..11:R. signal patterns. L piantartop lysate had. a very different TLR signal pattern than the other Grain-positive organisms, in whiCh all TLR signals were muted. This muting of the signal. pattern was not obvious from the characteristics of the fennentation, but L plantarum is known to produce numerous metabolites that may account for the reduction in TLR
signals. B. subtilis had a similar TLR pattern to the log-phase-harvested culture of B.
coagndans, except it produced higher TLR 4 activation. ()Vera, TLR signal patterns across Gram-positive organisms varied according to the morphology, EPS production, and metabolites of the organisms.
101901 Figure 6 shows TLR signal patterns obtained from lysates of selected Gram-negative organisms. Escherichia colt, Klebsiella arytocia, Shigellajlexneri, Pseudomonas

-54-,fietoeseen.s, and Xtinihonfolias- campestri* were grown using Try, ptic Soy Broth in shake flasks. K. oxylocia, E. coif, and S.fierneri were incubated at 37 C and250 rpm while P.
liourescens andXanthomonas campestris were incubated at 30 "C and 250 rpm.
Xanthomonas compestris was grown using a yeast extract /glucose media supplemented. with calcium carbonate at 1%. Prior to harvesting, the CaCO3 was removed by centrifugation at .500.x gfor 3 minutes, Harvest of the cultures from the fermentation broth followed the 1y-sate production process of Example I. Surprisingly and unexpectedly, the TLR signal pattern of the lysate from Gram-negative organisms, including K coil, when tested at similar concentration* were much lower in signal strength than the lySates of Gram-positive organisms, wept for TLR. 5 And 9..In general, the Gram-negative bacteria membrane/cell wall is easier to break than that of Gram-positive bacteria, which may explain the higher TLR
9 signal. K argocia and X campestris was observed to produce EPS during fermentation and. also produced relatively high activation of TLR 3, 4 and 9. K idytocia produced the highest TLR2 and NOM activation of the strains tested. EPS appears to alter the TLR signal pattern as compared to non-EPS producing strains (S.flexneri). Interestingly, all Gram-negative bacteria had significant activation of the NF-kappaB of the Null cells in the TLR
assay. This NE--kappaB activity was subtracted from the TLR signal and explains the slightly negative activities for TLR 7 and NOD2 for P. flouraceos..
[01911 Lastly, Figure 7 shows TLR signaling for a lysate composition comprising xanthan gum. These data demonstrate that the lysate produced from the strain Ximihomonas compoiei..c,.ai well as .xanthan gum itselt.the EPS produced by the strain .Xanthotrtemas campestris, both produce TLR activation. There is strong stimulation by both the strain and the EPS xanthan gum at TLR5 and moderate activity at ThRs 4 and 9. These data.
suggest that. the lysate fromagiVen bacterial strain, as well as the corresponding EPS
from that strain (e.g., xanthan gum in this example) can both be used in or blended into a formulation for a targeted TLR. activity.
101921 Surprisingly and unexpectedly, these data demonstrate that the TLR
signal pattern resulting-I/Om a given lysate, as well as the strength of the TLR signal, is dependent On the manufacturing process as well as choice of raw materials, including, but not limited to, media and microorganisms. These data demonstrate that TLR activation specificity can be altered and tailored by changing process, bacterial organism, raw material, and-reagent parameters.
Example 4: Oxidative stress, cognitive and quality of life indicators in post-traumatic stress disorder (PTSD)-diagnosed combat veterans

- 55 -101931 PTSD is an oxidative stress-related disease or condition. The purposes of the study were four-tiald: (I) to evaluate the effectiveness of the inventive composition in .quantitatively reducing levels of the oxidative stress marker isoprostanc in PTSD-diagnosed combat veterans; (2) to evaluate the effectiveness of the inventive.
composition in qualitatively mincing levels of nitric oxide in PISD-diagnosed combat veterans; (3) to evaluate the effectiveness of the inventive composition in improving word finding and word recall in PTSD-diagnosed combat veterans; and (4) to evaluate the effectiveness of the inventive composition in improving quality of life parameters in PTSD-diagnosed combat veterans.
101941 Emerging evidence-based literature supports the link between oxidative stress and post-traumatic stress disorder (PTSD). Oxidative stress occurs in the body and on the cellular level as a result of an imbalance between circulating oxidants and anti-oxidants. Many studies have shown that this cellular oxidative Stress results from the effect of free radicals on the body's neurophysiology. Nitric oxide has been implicated as playing an important role in protecting against oxidative stress.
101951 Word-finding is often affected in individuals who suffer from Traumatic Brain Injury as well as in combat veterans. Closed Head Injury/Traumatic Brain Injury (CHI/TBI) and p.m) are frequently co-morbid conditions.
101961 Criteria for stitycei selection.
10197) The anticipated number of participants in the study was a minimum of 10 and maximum of 15.
101981 The anticipated gender distribution was as dote to 50% male and 50%
female as possible. Due to the larger numbers of male veterans diagnosed with PTSD, it was possible that there could be a slightly larger male percentage in the participant pool.
10199) Pregnant women were not allowed to participate in the study.
102001 The only age restriction was due to the military recruitment minimum age, 18 years old, so the anticipated agerange for the study was from 18 to approximately 80, with the upper limit -dictated by level of health.
102011 There were no racial or ethnic origin restrictions. The intended percentages based on race mirrored those of the greater Houston area, from Which the participants were recruited. These percentages are roughly: 44% Hispanic, 26% white, 23% African America, 6% Asian. I% other.
102021 Inclusion and Exclusion criteria are outlined in Table 2 below.

- 56 -Table 2. Inclusion and exclusion criteria for Example 3.
Inclusion Criteria Exclusion Criteria combat or military veteran pregnant females any psychiatric hospitalization within the resides in the greater Houston area past 10 months HST.) diagnosis from the Veteran Health Administration of the U.S. Department of current probiotic use Veterims Affairs He-threatening medical condition unstable Physical health children or participants under the age of 18 classification as "other traditionally defined vulnerable subjects such as prisoners"
lack of adequate capacity to render informed.
consent.
10203! Methods end procedures [02041 tinder informed consent, participants were evaluated to assess levels of cellul0.
.:b.xidative stress, nitric oxide levels, languaaetword-finding ability, le=d S of aux i'ety and:
depression. And etliTCW.:(P alay of life oaratneters:
[02051 Participants were provided Willi 15 days of the composition,, :$:vhich nypothesizedto.roduce oxidative stress, as indicatedspecificall:,' by a reductiortimtritto Isoprostanelevels"Two (2) 12-mg product tablets:woreitalten.sublingually two (2) times:per day, for a total of 48..mgduily...
102001 To Oilinti4emeasuretnent fluctuation no placebos wereuse0, and will&
is.served as their. own theasUtemein coritxo1sAU subjeCtSwcre asSigncd.to the same study group and received, the same procedure.
102071 04idatt,..,e stress.Vameasured victurinalys is of isoprostane usinga eomincroially.
.availableessay (Oxford Biomedical Roswell), Samples collected were normalized ereatine USina a creatinine assay kit (Oxford Biomedical Research) to control for differences in the jcvel of concentration. of the urine..
102081 Each participant had hi/her urineteSted.for isoprostane levelS, at a minimum. on day.- I .and I. A Consistent subset Ofindividuals wet ea.sked to samit. urine samples taeh.of the 15 dot..of tht.Study.tatatAbliAdata pointgas.:ameauS.:01=thining possible .isoprOStane

- 57 -changes over time. A third patty (naive to the study goals) was retained to conduct the isoprostane assays.
102091 All participants had three (3) language tests administered in private rooms on days 1 and 15..The language tests used were the Receptive One-Word Picture Vocabulary Test, 4th edition (ROWPVT-4), the Expressive One-Word.Picture Vocabulary Test, 4th edition (EOWPVT-4), and the Test of Non-Verbal Intelligence, 4th edition (TONl4).
102101 Additionally each participant-was asked-to-complete-a Zung Self-Rating Scale for Anxiety and Depression, a Satisfaction with Life Scale (SWLS), and the Eppworth Sleepiness Scale on days I and IS. These forms were filled our in private rooms and were coded using standard methods to mask identifying information of participants.
102111 Each participant filled out a daily Quality of Life (Q0L).Survey which was entailed to him/her every morning at 4:00 am. In order to familiarize each participant with the QM -Survey format and to establish a stronger baseline of data, each individual began recording his/her scores on the QOL Survey a minimum of four (4) days prior to beginning his/her use of product.
10214 Data anatysts and data Monitoring.
102131 After the aforementioned parameters were gathered over 15 days, the study data were analyzed for trends in identifying oxidative stress and nitric, oxideleyels,-word-find ability, the presence of anxiety/depression, and overall quality of life ratings. The statistical analysis methods used were straightforward as only one quantitative parameter, isoprostane, was assessed. Appropriate innitivariate statistical tests were used to analyze the data.
[02141 Risktenefit assessment.
[02151 Risk category: The risk category for this trial was "Minimal." As such, consent for injury language in the consent form was not necessary, and a clinical trial agreement (CIA) was therefore not necessary. The minimal risk category was due to the fact that the product being tested is recognized as a food-grade GRAS compound found in yogurt Furthermore, there were no invasive procedures being performed as urine and saliva were the only body fluids being collected, [02161 At the time of data collection, there were approximately 35 individuals taking -the product, both male and female. At the time of the study, the longest using individual started the product 17 months prior and reported no negative side effects from use of the product. Of approximately 35 total individuals who were administered the product, no negative side effects were reported.
[02171 Method ql Subject Identification and .Recruitment

-58-102181 The study used a convenience sample, the method of 'recruiting participants being based largely on personal and professional contacts of the investigators.
102191 &Oleo' capacity 102201 If the individual was deemed to lack adequate capacity to consent, they were not allowed to participate in the study. There were no minors involved in this study, and no one who required an assent form or legal representative present.
[02211 Suiyect comprehension 102221 To assess that adequate comprehension has taken place, the participant was required to explain the study back to the individual doing the consent process before they were allowed to enroll in the study. The subject confirmed that all their questions were answered adequately.
302231 Results (0224) In the study, effects of the supplement were assessed by meastuing/
analyzing: 1) isoprostane levels; 2) quality of life survey Maths; 3) Zungl psychological survey results; and 4) speech language results.
(0225) As shown in Figure 8, treatment with the supplement caused a decrease in the levels of .urinary isoprostane, 1soprostanes are prostaglandin-like compounds formed in vim from the free radical-catalyzed peroxidation of essential fatty acids (primarily arachidonic acid) without the direct action of cyclooxygenase (('OX) enzymes usually involved in prostaglandin production. These compounds are accurate markers of lipid peroxidation in both animal and human models of oxidative stress. At day 15õ most subjects displayed decreased isoprostane levels. By day 70, all subjects displayed isoprostane levels lower than at day 1.
(02261 As seen in Table 3A and Table 313, treatment with the composition resulted in maiked decreases in the amount of isoprostane after just 15 days of treatment.
Table 2A
displays the raw data from the study, While table 38 displays the results following calculation of percentage reduction and percentage improvement of oxidative stress marker.
In Tables 3A
and 3B, "PTSDf" is a participant who was diagnosed with PTSD. "PTSD --" is a participant not diagnosed with pTsD. ¨rxi-" is a participant who used the composition prior to the study.
is participant who was naive to thecomixisition.
[02271 As seen in Table 38, subjects displayed over a 60% reduction. in isoprostane levels after 15 days of treatment followed by an additional 3,18% of reduction in isoprostane levels after 70 days of treatment. In addition, subjects displayed over a 469%
improvement in levels of oxidative stress biomarker after 15 days of treatment followed by an additional

- 59-5119% iniprovetteitt in levels of oxidatik stri':tibtnatker (iSoOtuatatie).
aftdr. 70::days=:(if treatment Table 3A: PTSD Oxidative Stress Study Raw Data Day 1 Day 15 Day 70 ioprostane Isoprostane (nem lsbprostanc (ng/ing (naling creatinine) creatinine) creatinine) , PTSD-i-iTX- P001 a ft 897 0.320 0.564 PTSD-P-; i X- P002a .1.736 0.956 0.4294 PTSD ITX- P004a 1.667 0.470 0.4068 PTSD /TX- P005a 1.365 1.456 0.3997 PTSD+/TX- P006a 3.2154 0.759 0.3514 PTSD+/TX- P007a 3.923 0.177 0.2156 PTSD /TX- P008a 0.851 0.195 0.3407 PTSD+ITX P009a 0.566 0.834 0.483 PTSD-/TX+ P010a 1.471 0.401 0.499 PTSD-/TX- P011a 7.542 0.507 0.441 PTSD-/TX- P012a 1.002 1.348 0.360 Table 3B: PTSD Oxidative Stress Study Data Day 1 to Day 15 Day 15 to 70 Different: c,'DIZeductio '...arnproventen Dificren E.: ..'Iteductio "/-11:nprovenien e n t e n t PTSD+1 TX- -0.577 -64.30 -1180.12 0.243 75.96 43.17 P001 a PTSD+1 TX- -0713 44,94 48162 -0.53 -55.07 -122.57 P002a PTSD /
TX- -1.198 -71.85 -255.20 -0.06 -13.33 -15.38 P004a TX- (0902 0.,.06 614 -1.06 -72.55 -264.24 Ptioa PTSDfl TX- -2455 =-4639 =a2155 -0.41 -53.69 -115.95 P006a

- 60 -PTSD /
TX- -3.746 -95.49 -2116.18 0.039 21.81 17.30 P007a PTSD /
TX- ;-0.656 7770 0.146 74.63 4513:
11µ..K.)8 Emgggggg Enggg gmg gmgggggggmEmggggggggggggggggggEgggggggggg 041gtvijm mN604itom Em4t#51Egnma23mmax,:itvgmgmnis9A, )mgm 1.)TSD+1 TX+ 0.269 47:47 32:19:: ,035: -4106 -7160 P009a PTSD-.4.07 ,26670 0.097 24.48 1954.
PO I Oa PISD-.1TX- -2,035 = -40:1.50 -0.07 -13.06 -15.02 POlia PTSD-3434. 25.67 -0.99 -73.31 -274.66 PO I 2. a .
Reduetkm Oxidative Stress Biolila.rker 60.48% 3.18%
-- (PTsry,./Tx-) s improverneof Strit.'sg 409.52N.. 59.19(Y0 Bioniarker [02281. :Siibjetts:.-0::A kedio.: elfagsest. raid *Eitel Ifieir'SletTi.
eintit.gcale!.ofl -10, whtre,til value.cif 1 etrion clod t6,11.dtfic.iitn sleep:11nd Tvailittilf 10 cOrreSpOndoil.:tcitio deficit in slecp.,..,As tech by day 70 all sobjects.:showed.:deereattdefieitg:irt..Itep...as.
c.otrillare4.:twsc1f7.04sgswd T.tality ofslccp:ratings at day 1.
f0229i .S-il:),jott. ..tvete..i.lsked:td..klf,.ASsis:arid rate theit:ndiut patti,V ',Ornptobehydett:ki.
.seale of 1-10., .:tvlicte.::gi valw..bf 1.:0jrkspondedlo great discOthfottand p1717ottilleuropattly..=
:symptoms and a value .0i I 0.corresponded to inininiA di.-..::,comfort..tind.
pain from seuropatily :rnptoms: AS seen in Fre 10,...at day 15 AT:subjects buttW.O.:(P03 and PO4) showed.
'minimal discomfort and pain from rieurc.)pathy vniptoms as compared to day 1, At day 70, all patienti.except for WIC i.P0.3) showed either minimal.diSpOnitbd. 41'14 pain frontnettrop4-tby ..symptoms the case of P01 no difference in discomfort (note that PO4 indicate4.
ininnr.ial discomfort and pain from neuropathy symptoms at the onset of the.
study.).a,s:
compared to day 1.

- 61 -102301 Subjects were asked to self-assess and rate their overall mood on a scale of 1-10, where a value of I corresponded to a generally unhappy or uneasy mood and a value of 10 corresponded to a general happy or relaxed mood. As seen in Figure 11, at day 15 all subjects but two showed an improvement in overall mood. At day 70, all patients except for one (PO4) showed an improvement in overall mood as compared to day 1.
102311 Subjects were- asked to self-assess and. rate their overall levels of energy on a scale of 1-10, where a value of 1 corresponded to a low level of energy and a value of 10 corresponded to a high level of energy. As seen in Figure 12, at days 15 and 70 all subjects (except P03) displayed an increase in energy levels as compared to day L
102321 Subjects were asked to self-assess and rate their overall satisfaction with the health of their joints (as determined by evaluating several factors including flexibility, stiffness and pain) on a scale of 1-10, where a value of .1 corresponded to a low level, of satisfaction and a value of 10 corresponded to a high level of satisfactionõ
As teen in Figure 13, at day 15 all subjects (except for P03 and PO4) displayed improved levels of satisfaction with. their joints as compared today 1. This trend Continued at day 70.
102331 Subjects were asked to self-assess and rate their overall satisfaction with their digestive health on a scale of 1-10, where a value of I corresponded to a low level of satisfaction and a value of 10 corresponded to a high level of satisfaction_ As KO in Figure 14, at day 15 all subjects (except for P01 and PO4) displayed improved levels of satisfaction with their digestive health as compared to day 1. This trend continued at day 70.
102341 Subjects were asked to self-assess and rate their overall level of irritability 0:11.a scale of 1-10, where a value of I corresponded to a high level of irritability and a value of 10 corresponded to the lowest level of irritability. As seen in Figure 15, at day 70 all subjects displayed decreased levels of irritability as compared to day 1.
102351 Subjects were asked to self-assess and rate their overall level of satisfaction with their sexual function on a scale of 1.-10, where a value of 1 corresponded to a low level, of satisfaction and a value of 10 corresponded to a high level of satisfaction.
As seen in Figure 16, at day 70 all subjects (except PO4 and P05) displayed increased levels of satisfaction with their sexual performance as compared to day 1.
102361 Subjects were asked to self-assess and rate their overall level of daytime sleepiness in accordance with the guidelines of the Epworth Sleepiness Scale (ESS). The ESS' is a self-administered questionnaire with 8 questions. It provides a measure of a person's general level of daytime sleepiness, or their average sleep propensity in daily life. It has become the world standard method for making this assessment. The ESS asks people to rate, on a4-point scale (0 3), their usual chances of dozing off orfalling asleep in 8 different situations or activities that most people engage in as part of their daily lives, although not necessarily every day. It does not ask people how often they doze off in each situation. That would depend very much on how often. they happened to be in those situations.
Rather it asks what the chances are that they would doze off wheneverthey were in each situation. This requires a mental judgment which, it seems, most people are able to make in a meaningful way. The total .ESS score is the sum of 8 item-scores and can range between 0 and 24. The higher the score, the higher the person's level of daytime sleepiness. The total ESS score provides an estiniate of a general characteristic of each person¨their average level of sleepiness in daily life.
102371 As seen in Figure 17, all subjects displayed decreased daytime sleepiness by day 15. At day 70, all subjects completing the study (except P03) displayed decreased day-time sleepiness as comparedto day 1.
102381 Subjects were asked to self-assess and rate their overall level of satisfaction with their life on a Seale of 1-40, where a value of I corresponded to a low level of satisfaction and a value of 40 corresponded to a high level of satisfaction. As seen in Figure 18, at day 15 all subjects displayed increased levels of satisfaction With -their lives as compared to day 1. This trend continued to day 70, 102391 Subjects were asked to self-assess and rate their overall level of anxiety in accordance with the guidelines ate Zung Self-Rating depression scale. The Zung Self-Rating Depression Scale was designed by Duke University psychiatrist William-W.K. Zang MD (1929-1992) to assess the level of depression for patients diagnosed with depressive disorder.
102401 The Zung Self-Rating 'Depression Scale is a short self-administered survey to quantify the depressed status of a patient. There are 20 items on the scale that rate affective, psychological, and somatic symptoms associated with depression. There are ten positively worded and ten negatively worded questions. Each question is scored on a scale oft through 4 (based on these replies: "a little of the time", "some of the time", "good part of the tune", "most of the time"). Scores on the test range from 20 through 80. The scores fall into four ranges, where: 20-44 correlates to a normal range, 45-59 correlates to a state of mild depression, 60-69 correlates to the state of moderate depression, and 70+
correlates to a state of severe depression. As seen in Figure 19, at day 15 all subjects except for POI and P05 displayed decreased levels of depression. as compared to day 1. At day 70, subjects P02, P03, PO4, P06 and P07 all displayed decreased levels of anxiety as compared to day I.

Example 5: Reduction of oxidative stress-related side effects 102411 Reduction of headache. A 17-year-old male that experienced three concussions in the 1.5 years prior to treatment was administered a lysate of the disclosure at a time of 45 .mg twice daily. At day 14 of treatment, the dosage was increased to 75 mg active ingredient twice daily. Prior to treatment, the patient reported frequent headaches. Pre-treatment F2-isoprostane (F2IsoP) was measured in urine at. 2.4 ng per mg creatinine. Rpm.
20 shows a decrease over 85 days in isoprostane as measured in the patient's urine, with an average of 0..82 ng isoprostanoi tug creatinine from days 72 - 85. Letters A-H in Figure 20 denote the following events: (A) Days 1 to 3, baseline F2IsoP leve1s;-(13) Day 3, severe headache. at the.
9.99 nginig F2IsoP peak; (C) Days I to .13, using 45 mg bid. lysate, with daily headaches;
(D) Day 13, patient begins using 75 mg bid. lysate to address headaches; (E) Days 18 to 89, headaches now resolved and continue to be resolved; (F.) Day .30, new impact event playing football, headache for 18 hours with visual and neurological disturbances;
(Cl) Day 81, situational stress event, showing elevated F2IsoP levels, but did not result in headache; (H) Days 1 to 89, trend line of isoprostane showing 98% reduction over 89 days.
Overall, these data suggest a concomitant decrease in oxidative stress in response to lysate administration.
Additionally, the subject reported a marked deereas.ein headaches following.lysate administration.
[0242i Reduction of other oxidative stress-related side effects. A patient, experiencing one or more side effects associated with administration of a pharmaceutical agent is co-administered a bacterial lysate of the disclosure at a dose of 45400 mg b.
i.d. Prior to beginning co-administration of lysate, F2-isoprostane levels are measured in blood or urine.
Co-administration of lysate produces a continual decrease in F21soP levels:
over time, with approximately 50% overall reduction in F2IsoF levels over about 45 days, and approximately 95% reduction in F.21soP levels over about. 90 days, with concomitant reduction in drug-related oxidative stress-associated side effects.
Example 6: .Lysateladalimumab combination is effective for treatment of skin disease in psoriatic arthritis 102431 A study is performed to evaluate the efficacy of a therapeutic composition comprising adalimumab in combination with a bacterial lysate composition of the disclosure, administered in conjunction or separately, -for -cutaneous disease in patients with psoriatic arthritis (PsA), an oxidative stress disorder.

10201 A randomized Phase 111 study of adahmumab is studied in patients with active PsA (?.3 swollen and ?.3 tender joints) who had failed NSA1D therapy.
Randomization is centrally stratified. by methotrexate (MIX) use and extent of psoriasis (<3%
or >3 % body surface area psAD at baseline. Patients completing Week 24 will be eligible to continue in an open-label extension study.
02451 Patients are included if they have a history of psoriasis; are-over 18 years; ?..3 swollen and i-13 tender joints; and inadequate response to NSAID therapy.
Exclusion criteria includes prior anti-TNF therapy; alefaeept .within 12 weeks. prior to study entry; other biologics within 6 weeks prior to study entry; DMARDs (except MIX)within 4 weeks prior to study entry; systemic therapies for psoriasis within 4 weeks prior to study entry; and phototherapy and topicals within 2 weeks prior to study entry.
02461 Patients are stratified by methotrexate use (yes/no) and degree of psoriasis (<: 3%
and ?3% BSA involvement) and receive lysate.20-60 mg orally on a daily basis, in combination with adalimumab, 40 mg every other week or placebo for 24 weeks.
102471 Efficacy measures to be used include: ACR response criteria (co-primary endpoint: ACR20 response at Week 12); Psoriasis Area and Severity Index (PASI) in patients with significant psoriasis at study entry (.?_3% BSA); and Physicianis Global Assessment (PGA)of psoriasis.. The study examines patients according to the severity of psoriasis at baseline: PASI<I0 vs. PASI?.10 [02481 Thus, efficacy measures in patients with psoriasis-affecting .?.3%
BSA at baseline include PAS1, PGA of psoriasis,.and DLQI. ACR. response -criteria are also used as an efficacy measurement A post-hoc analysis is conducted for patients with baseline PASI<Itl vs. those with PASI.?..10. PASI analyses are by NRI, and PGA and DLQI scores are calculated as LOCF.
102491 The treatment group receiving co-administered lysate experiences amelioration of injection site reactions (such as pain, redness, or irritation) and less overall oxidative stress-related side effects, which will allow for increased adherence and compliance with treatment, -Which in turn allows a water opportunity for ameliorating the primary:disease.
Example 7: Lysateistatin/ACE inhibitor combinations are effective for treatment of hypertension 102501 A human subject being treated. for hypertension and receiving a combination of 20 mg QD pravasta tin and 20 mg QD lisonopril was experiencing oxidative stress-related side effects of skin rash and insomnia.

10251j When the patient was additionally administered 4Z Mg bid of a lysate encompassed by the disclosure herein, the skin rash and insomnia side effects resolved within 60 days.
'Example 8: Lysate/SSRI combination is effective for treatment of clinical depression [052j A human subject being treated for depression and receiving 60 mg QD
duloxetine (CYMBALTA*) was experiencing oxidative stress-related side effects of anoraasmia, dizziness, numbness, and irritability.
102531 When the patient was additionally administered 45 mg bid of a lysate encompassed by the. disclosure herein, anoraasmia resolved within 10 days, dizziness resolved within 7 days, numbness resolved within 10 days, and irritability resolved within 5 days.
Example 9: 14We/hormone combination is effective for treatment of hypothyroidism 02541 A human subject being treated for hypothyroidism and receiving 150 mcg Qaof levothyroxine -(SYNTHROIDGI)) was experiencing oxidative stress-related side effect of hair loss.
102551 When the patient was additionally administered 75 mg bid of a lysate encompassed by the disclosure herein, the hair loss side effect resolved within 180 days.
Example 10: 14We/reverse transcriptase inhibitor combination is effective for treatment of HIV infection 102561 A human subject being treated for HIV (non-AIDS) and receiving one tablet QD
of efavirenzietraricitabineitenofeivirdisoproxil futnarate (ATRIPLAO) was experiencing oxidative stress-related side effects of erectile dysfunction, neuropathy, insomnia, and brain fog.
E02571 When the patient was additionally administered 45 mg bid of a lysate encompassed by the disclosure herein, erectile dysfunction resolved within 10 days, neuropathy resolved within 10 days, insomnia resolved within 3 days, and brain kit resolved within 3 days.
Example 11: Lysate/direct-acting antiviral drug combination is effective for treatment of hepatitis C

102581 A human subject being treated for Hepatitis C and receiving one tablet QE) of ledipasvirisofosbuvir (FIARVONII) was experiencing oxidative stress-related side effects of brain fog. headaehe, and.arthritis.
102591 When the patient was additionally administered 75 mg hid of a lysate encompassed by the disclosure herein, brain fog resolved within 3 days, headache resolved within 10 days, and arthritis resolved within. 14 days.
Example 12: Lysatetanti-cancer drug combination is effective for treatment of cancer (02601 A human subject being treated for cancer and receiving a biweekly dose of topnisoinerase I inhibitotivinca .alkaloids/alkylating antineoplastie (1RINOTECANO, .VINCRI$TIN00, TEMODARg) was experiencing oxidative stress-related side effects of braining, malaise, insomnia, and rash.
111261) When the patient was additionally administered 75 me bid of a lysate encompassed by the disclosure herein, brain fog resolved within 3 days:, malaise resolved within 5 days, insomnia resolved within 5 days, and rash resolved within 1.4 days.
Example 13: Lysaterinsulin analog combination is effective for treatment of type 2 diabetes [02621 A human subject being treated for type 2 diabetes and receiving a daily dose of the insulin analog insulin glarethe (LANTUSC) was experiencing oxidative stress-related side effects of rash (injection site), irritability, and headache.
[02631 When the patient was additionally administered 45 mg bid of a lysate encompassed by the disclosure herein, irritability resolved within 5 days, headache resolved within 7 days, andraSh (injection site) resolved within 10 days.
Example 14: Lysate/antibiotic combination is effective for treatment of rheumatoid arthritis [02641 A human subject diagnosed with rheumatoid arthritis and being treated with an 'INF inhibitor was also being treated with antibiotics that caused Grade 3 diarrhea as determined by National Cancer Institute (NCI) standards for the prior ten months.
Concurrently the subject was receiving additional antibiotics in order to combat a Clostridium difficile infection due to the severe diarrhea. Without changing current phaimacologic therapies, the subject was additionally administered 45 mg lysate twice a day.
Diarrhea began to resolve within 2 weeks and improved to an NCI Grade 2 standard in one month.

Example 15: Lysateiradiation combination is effective for treatment of cancer 102651 A human subject was being treated for prostate cancer and received radiation treatments increasing in intensity and/or duration over the course of 40 days of prescribed therapy as Mows:- 8 sessions at 180 eGy (IcGy = 1 rad) during week day on nine points in two bursts one at 8 seconds one at 5 seconds; .8 sessions at 180 eGy with bursts of 12 and 9 seconds; 9 sessions at 180 cGy with bursts of 1.4 and 10 seconds on the right 2 quadrants and then 12 and 9 seconds on the left; and 16 sessions at 200 cGy two continuous full circtunference passes for 80:Seconds:-and every-Other session being two complete continuous, full circumference passes in opposite directions. The radiation dose change was always on a Monday and the patient was seen by a physician each subsequent Tuesday to assess side effects. Each increase resulted in 3 hrs. of nausea, occurring approximately 2 hrs.. post treatment and resolved completely in no more. than 6 hrsatter-any treatment session. In combination with the radiation treatment the-patient was administereda lysate of the disclosure at a dose of 73 mg, three times a day. The patient was not administered any other treatment for nausea, vomiting or bleeding. On a Quality a Life scale of I to 10 ("1" being the worst, "10" the best) the patient reported an 8 through commencement of the final escalation of exposure.. The patientreparted nausea to be no worse than. a 7 at the greatest_ exposure and continued to function daily in his work duties throughout treatment.
102661 -Given the Variety of Mechanising- Of action of the above drugs with which the lysate compositions of the disclosure -are co-administered, and given the mechanism of action of the lysate itself, the lysate compositions disclosed herein can be reasonably extrapolated to provide beneficial adverse-effect-reducing results With -most any drug: For example, with FIUM1RAO, an injectable a-TWeci-administintion- with lysate produces amelioration of injection site irritations. Per package insert this druginidentifind as causing arthritis as is seen in the Direct Acting Antiviral, HARVONIls. When a patient_ uses a lysate of the disclosure in conjunction with a prescribed-HCV medication such as .HARVONIO, side effects are diminished during treatment and do not persist post treatment.
102671 It should be understood the arrangements and ftmctions described herein are presented for purposes of example only, and that numerous variations arc possible. For instance, elements can be added, omitted, combined, distributed, reordered, or otherwise modified. The following claims are thus to be understood to include what is specifically illustrated and described above, what is conceptually equivalent, what can be obviously substituted and also what essentially incorporates the essential idea of the invention. Those skilled in the art will appreciate that various adaptations and modifications of the just-described embodiments can be configured without: departing from the scope of the invention.
The exemplified embodiments have been set forth only for the purposes of example and that should not be taken as limiting the invention. Therefore, it is to be understood that, within the scope of the appended claims, the invention may he practiced other than as specifically described .hercin.

Claims

WHAT IS CLAIMED IS:

1. A toll-like receptor (TLR) agonist composition for regulating redox status in a subject, the composition comprising:
(a) a TLR agonist comprising at least one lysate and/or lysate fraction of a bacterium, wherein the TLR agonist activates at least one or more TLRs or NLRs;
(b) an optional promoter for enhancing absorption of the composition; and (c) an optional carrier for increasing a volume of the composition, wherein administration of an effective amount of the composition to the subject measurably reduces oxidative stress levels in the subject.
2. The composition according to claim 1, wherein the agonist activates at least two different TLRs and/or NLRs.
3. The composition according to claim 1, wherein the agonist activates at least three different TLRs and/or NLRs.
4. The composition according to claim 1, wherein the bacterium is a Gram-positive bacterium or a Gram-negative bacterium.
5. The composition according to claim 4, wherein the at least one Gram-positive bacterium is selected from the group consisting of a bacterium of Lactobacillaceae family, a bacterium of Streptococcaceae family, a bacterium of Bifidobacteriaceae family, and a bacterium of Bacillaceae family; and wherein the at least one Gram-negative bacterium is selected from the group consisting of a bacterium of Pseudomonas genus, Klebsiella genus, Xanthomonas genus, Shigella genus, and Enterobacter genus.
6. The composition according to claim 4, wherein the at least one Gram-positive bacterium is selected from the group consisting of Bacillus coagulans, Lactobacillus sporogenes, Streptococcus thermophilus, Bifidobacterium animalis, Bifidobacterium, animalis, subspecies Widobacterium infinity, Bifidobacierium kingwfl, Eifidobacteriion breve, Lact()bacillus acidophilus, Lactobacillus plamarum, Lactobacillus easel, Lactobacillus delbrueckii, Lactobaefflus delbrueckii subspecies bulgaricus, Lactococcus Laciococcus locus subspecies .lercas, Streptococcus lactis, Streptococcus thennwhihisõ Bifidobacterium Iacas, Bifidobacterium breve.
Pecliococcus acidilactict, and Lactobacillus heiveficus; and wherein the at least one Gram-negative bacterium is selected from tbe group consisting of Klebsicila oxytocia, Singela flexneri, Xamhomonas myosins, and Pseudomorias flouracens, 7. The composition according to claim I ,. wherein the TLR agonist activates at least one or more of UR 2, TLR 3, TLR 4, TLR 5, TLR 7, TLR 8, TLR 9, NOD1, and NOM.
8. The composition according to claim 2, wherein the TLR agonist activates TLR 2 and TLR 4.
9. The composition according to claim 1, wherein the TLR agonist acfivates two or more of TLR 2, TLR 3, TLR 4, TLR 5, TLR 7õ TLR 8, TLR 9, NOD1, and NOD2.
10. The composition according to claim 1, wherin the TLR agonist activates three or More of TLR. 2, TLR 3, TLR 4, TLR 5, TLR 7, TLR TLR 9, NOD1, and NOD2, 11. The composition according to claim 1, wherein the promoter is selected from the group consisting of amino acids, amino sugars, and sugars.
12. The composition according to claim 1, wherein the carrier is selected from the group consisting of a binder, a gum base, and combinations thereof 1.3 The composition according claim 12, wherein the gum base comprises at least one hydrophobic polymer and at least one hydrophilic polymer.
14. The composition according to claim 12, wherein the binder is selected from the group consisting of a sugar, a sugar alcohol, and combinations thereof 15. The composition according to claim 14, wherein the sugar alcohol is selected from the group consisting of mannitol, sorbitol, xylitol, and combinations thereof.
16. The composition according to claim 1, wherein the composition is manufactured as a dosage form. selected from the group consisting of a lozenge, a chewing gum, a chewable tablet, a candy, and a dissolving tablet, 17 The composition according to claim 16, wherein the dosage form delivers the agonist to an oral mucosa.
18 The composition.according to claim 17, wherein the oral mucosa is selected from the group consisting of the sublingual mucosa, buccal mucosa, and a combination thereof 19 The composition according to claim 1 wherein the composition administered in.
combination with a pharmaceutical agent so as to enhance activity of the pharmaceutical agent.
20. The composition according to claim 1, wherein the composition administered in combination with a pharmaceutical agent so as to reduce a Side effect of the pharmaceutical agent.
21. The composition according to &fin 20, Wherein the side effect of the pharmaceutical agent is oxidative stress.
22. A method of regulating redox status in a subject, the method comprising administering a therapeutically effective amount of the composition according to claim 1 to a subject in need thereof.
23. The method according to claim 22, wherein redox status regulation is assessed by measuring changes in isoprostane concentration in the subject.
24. The method according to claim 23, wherein the subject is a mammal.

25. The method according to claim 24, wherein the mammal is a human.
26. The method of claim 23, wherein the subject is a non-mammal.
27. The method of claim 26, wherein the subject is a fish, fowl, crustacean, or insect.
28 The method of Claim 27, wherein the insect is Drosophila.
29. The method according to claim 25, wherein the redox status is oxidative and results in oxidative stress.
30. The method according to claim 29, wherein the oxidative stress in the human is related to post-traumatic stress disorder.
31. A method of regulating redox status in a subject, the method comprising the steps of:
(a) repeatedly administering to a subject in need thereof doses spaced apart in time and consisting of a composition comprising:
(i) a toll-like receptor (TLR) agonist comprising at least one lysate and/or lysate fraction of a bacterium, wherein the agonist activates at least one or more different TLRs or NLRs;
(ii) an optional promoter for enhancing absorption of the composition;
and (iii) an optional carrier for increasing a volume of the composition; and (b) making measurements of a bodily fluid of the subject to detect changes in oxidative stress levels.
32. The method of regulating redox status in a subject according to claim 31, wherein the agonist activates at least two different TLRs and/or NLRs.
33. The method of regulating redox status in a subject according to claim 32, wherein the agonist activates at least three different TLRs and/or NLRs.
34. The method of regulating redox status in a subject according to claim 31, wherein the bacterium is a Gram-positive or Gram-negative bacterium.

35. The method of regulating redox status in a subject according to claim 34, wherein the at least one Gram-positive bacterium is selected from the group consisting of a bacterium of Lactobacillaceae family, a bacterium of Streptococcaceae family, a bacterium of Bifidobacteriaceae family, and a bacterium of Bacillaceae family; and wherein the at least one Gram-negative bacterium is selected from the group consisting of a bacterium of Pseudomonas genus, Klebsiella genus, Xanthomonas genus, Shigella genus, and Enterobacter genus.
36. The method of regulating redox status in a subject according to claim 34, wherein, the at least one Gram-positive bacterium is selected from the group consisting of Bacillus coagulans, Lactobacillus sporogenes, Streptococcus thermophilus, Bifidobacterium animalis, Bifidobacterium animalis, subspecies animalis, Bifidobacterium infantis, Bifidobacterium longum, Bifidobacterium breve, Lactobacillus acidophilus, Lactobacillus plantarum, Lactobacillus casei, Lactobacillus delbrueckii, Lactobacillus delbrueckii subspecies bulgaricus, Lactococcus lactis, Lactococcus lactis subspecies lactis, Streptococcus lactis, Streptococcus thermophilus, Bifidobacterium lactis, Bifidobacterium breve, Pediococcus acidilactici, and Lactobacillus helveticus; and wherein the at least one Gram-negative bacterium is selected from the group consisting of Klebsiella oxytocia, Shigella flexneri, Xanthomonas campestris, and Pseudomonas flourescens.
37. The method of regulating redox status in a subject according to claim 31, wherein the TLR agonist activates at least one or more of TLR 2, TLR 3, TLR 4, TLR 5, TLR
7, TLR 8, TLR 9, NOD1, or NOD2.
38. The method of regulating redox status in a subject according to claim 31, wherein the TLR agonist activates two or more of TLR 2, TLR 3, TLR 4, TLR 5, TLR 7, TLR 8, TLR 9, NOD1, or NOD2.

39. The method of regulating redox status in a subject according to claim 31, wherein the TLR agonist activates three of more a TLR 2, TLR 3, TLR 4, TLR 5, TLR 7, TLR
TLR 9, NOD1, or NOD2.
40. The method of regulating redox status in a subject according to claim 38, wherein the TLR agonist activates TLR 2 and TLR 4.
41. The method of regulating redox status in a subject according to claim 31, wherein the promoter is selected from the group consisting of amino acids, amino sugars, and sugars.
42. The method of regulating redox status in a subject according to claim 31, wherein the carrier is selected from the group consisting of a binder, a gum base, and combinations thereof.
43. The method of regulating redox status in a subject according to claim 42, wherein the gum base comprises at least one hydrophobic polymer and at least one hydrophilic polymer.
44. The method of regulating redox status in a subject according to claim 42, wherein the binder is selected from the group consisting of a sugar, a sugar alcohol, and combinations thereof.
45. The method of regulating redox status in a subject according to claim 44, wherein the sugar alcohol, is selected from the group consisting of mannitol, sorbitol, xylitol, and combinations thereof.
46. The method of regulating redox status in a subject according to claim 31, wherein the composition is manufactured as a dosage form selected from the group consisting of a lozenge, a chewing gum, a chewable tablet, a candy, and a dissolving tablet.
47. The method of regulating redox status in a subject according to claim 46, wherein the dosage form delivers the agonist to an oral mucosa.

48. The method of regulating redox status in a subject according to chum 31, wherein the oral mucosa is selected from the group consisting of the sublingual mucosa, buccal mucosa, and a combination thereof.
49. The method of regulating redox status in a subject according to claim 31, wherein making measurements of a bodily fluid assesses changes in isoprostane concentration in the subject.
50. The method of regulating redox status in a subject according to claim 31, wherein the subject is a mammal.
51. The method of regulating redox status in a subject according to claim 50, wherein the mammal is a human.
52. The method of claim 31, wherein the subject is a non-mammal.
53. The method of claim 52, wherein the subject is a fish, fowl, crustacean, or insect.
54. The method of claim 53, wherein the insect is Drosophila.
55. The method of regulating redox status in a subject according to claim 54, wherein the oxidative stress in the human is related to post-traumatic stress disorder.
56. A method of decreasing the amount of isoprostane in the urine or blood of a subject, the method comprising the steps of:
(a) determining the level of isoprostane in the urine or blood of the subject;
(b) administering to the subject an effective amount of a composition comprising:
(i) a toll-like receptor (TLR) agonist comprising at least one bacterial lysate and/or lysate fraction from a bacterium, wherein the TLR
agonist activates at least one or more different TLRs or NLRs; and (ii) an optional promoter for enhancing absorption of the composition;
and (c) continuing administration of the composition until the level of isoprostane in the urine or blood of the subject is decreased.
57. The method of claim 56, wherein the bacterium is a Gram-positive or Gram-negative bacterium.
58. The method of claim 57, wherein the bacterium is (a) a Gram-positive bacterium selected from the group consisting of Bacillus coagulans Lactobacillus sporogenes, Streptococcus thermophilus, Bifidobacterium animalis, Bifidobaderiam. animalis, subspecies animalis..
Bifidobacterium infantis, Bilidobacterium longum, Bifidobactertum breve, Lactobacillus acidophilus, Lactobacillus plantarum, Lactobacillus casei, Lactobacillus delbrueckii, Lactobacillus delbrueckii subspecies bulgaricus.
Laclococcus loctis, Loctococcus lactis subspecies lactis, Streptococcus lactis Streptococcus thermophilus, Bifidobaciertum lactis, Bifidobacterium breve, Pediomoccus acidilactia, and Lactobacillus helveticus; or (b) a Gram-negative bacterium selected from the group consisting of.
Kiebsielia oxylocia, SIsigella flexneri, Xanthomonas campestris, and Pseudomonas flourescens.
59 A composition comprising:
(a) a bacterial lysate and/or lysate fraction capable of activating at least one or more toll-like receptors (TLRs) or Nod-like receptors (NLRs);
(b) an optional promoter for enhancing absorption of the composition, and (c) an optional carrier for increasing a volume of the composition 60 A pharmaceutical formulation comprising the composition of claim 59, wherein the pharmaceutical formulation is formulated for buccal or sublingual administration 61, The pharmaceutical formulation of claim 60, wherein the pharmaceutical formulation is thrmulated to dissolve in not less than 1 minute after administration.

62. The composition of claim 59, wherein the bacterial lysate and/or lysate fraction is a Gram-negative Or Gram-positive bacterial lysate and/or lysate fraction.
63. The composition of claim 62, wherein the bacterial lysate and/or lysate fraction is:
a Gram-positive bacterial lysate and/or lysate fraction selected from the group consisting of a Laciobacillaceae bacterial lysate and/or lysate fraction, a Streptococcaceae bacterial lysate and/or lysate fraction, a Bifidobacteriaceae bacterial lysate and/or lysate fraction, or a Bacillaceae bacterial lysate and/or lysate fraction; or a Gram-negative bacterial lysate and/or lysate fraction selected from the group consisting of: a Pseudomonas bacterial lysate and/or lysate fraction, a Klebsiella bacterial lysate and/or lysate fraction, a Xanthomonas bacterial lysate and/or lysate fraction, a Shigella bacterial lysate and/or lysate fraction, or a Enterobacter bacterial lysate and/or lysate fraction.
64. The composition of claim 62, wherein the bacterial lysate and/or lysate fraction is:
(a) a Gram-positive bacterial lysate and/or lysate fraction selected from the group consisting of: a Bacillus coagulans, Lactobacillus sporogenes, Streptococcus thermophiles, Bifidobacterium animalis, Bifidobacterium, animalis, subspecies animalis, Bifidobacterium infantis, Bifidobacterium longum, Bifidobacterium breve, Lactobacillus acidophilus, Lactobacillus plantarum, Lactobacillus casei, Lactobacillus delbrueckii, Lactobacillus delbrueckii subspecies bulgaricus, Lactococcus lactis, Lactococcus lactis subspecies lactis, Streptococcus latus, Streptococcus thermophilus, Bifidobacterum lactis, Bifidobacterium breve, Pedipcoaus acidilactiei, or Lactobacillus helveticus lysate and/or lysate fraction; or (b) a Gram-negative bacterial lysate and/or lysate fraction selected from the group consisting of a Klebsiella oxytocia, Shigella flexneri, Xanthomonas campestris, or Pseudomonas flourescens lysate and/or lysate fraction.
65. A method of producing a bacterial lysate comprising the steps of:
(a) fermenting a bacterium in a growth medium to the stationary growth phase to produce a fermentation broth;
(b) harvesting bacteria from the fermentation broth;

(c) pasteurizing the harvested bacteria; and (d) lysing the pasteurized bacteria with a lysozyme to produce a bacterial lysate.
66. The method of claim 65, wherein the bacteria are harvested in the mid-logarithmic phase, the late-logarithmic phase, the early stationary phase, the mid-stationary phase, or the law stationary phase.
67. The method of claim 65, wherein-the bacterium is a Gram-positive bacterium or a Gram-negative bacterium.
68. The method of claim 67, wherein the Gram-positive bacterium is selected from the group consisting of a bacterium of Lactobacillaceae family, a bacterium of Streprococeaceae family, a bacterium of Bifidobacteriaceae family, and a bacterium of Bacillaceae family;
and wherein the Gram-negative bacterium is selected from the group consisting of a bacterium of Pseudomonas genus, Klebsiella genus, Xanthomonas genus, Shigella genus, and Enterobacter genus.
69. The method of claim 67, wherein the Gram-positive bacterium is selected from the group consisting of Bacillus coagulans, Lactobacillus sporogenes, Streptococcus thermophilus, Bifidobacterium animalis, Bifidobacterium. animalis, subspecies animalis, Bifidobacterium infantis, Bifidobacterium longum,Bifidobacterium breve, Lactobacillus acidophilus, Lactobacillus plantarum, Lactobacillus casei, Lactobacillus delbrueckii, Lactobacillus delbrueckii subspecies bulgaricus, Lactococcus lactis, Lactococcus lactis subspecies lactis, Streptococcus lactis, Streptococcus thermophilus, Bifidobacterium lactis, Bifidobacterium breve, Pediococcus acidilactici, and Lactobacillus helveticus: and wherein the Gram-negative bacterium is selected from the group consisting of Klebsiella oxytocia. Shigella flexneri, Xanthomonas campestris, and Pseudomonas flourescens.
70. A bacterial lysate produced according to the method of any one of claims 65-69.

71. A method for alleviating one or more oxidative stress-related side effects associated with administration of a pharmaceutical agent, the method comprising administering in combination, with the pharmaceutical agent a therapeutically effective amount of a lysate composition comprising:
(a) a lysate and/or lysate fraction of a bacterium;
(b) an optional promoter for enhancing absorption of the composition; and (c) an optional carrier for increasing a volume of the composition;
wherein the pharmaceutical agent and lysate composition are administered simultaneously or in any order, and through the same or different routes of administration.
72. The method of claim 71, wherein the lysate and/or lysate fraction activates at least one or more TLRs or NLRS.
73. The method of claim 71, wherein the lysate and/or lysate fraction activates at least two TLRs and/or NLRs.
74. The method of claim 71, wherein the lysate and/or lysate fraction activates at least three TLRs and/or NLRs.
75. The method of claim 71, wherein the lysate and/or lysate fraction activates at least one or more of TLR 2, TLR 3, TLR 4, TLR 5, TLR 7, TLR 8, TLR 9, NOD1, and NOD2.
76. The method of claim 71, wherein the lysate and/or lysate fraction activates TLR 2 and TLR 4.
77. The method of claim 71, wherein the lysate and/or lysate fraction activates two or more of TLR 2, TLR 3, TLR 4, TLR 5, TLR 7, TLR 8, TLR 9, NOD1, and NOD2.
78. The method of claim 71, wherein the lysate and/or lysate fraction activates three or more of TLR 2, TLR 3, TLR 4, TLR 5, TLR 7, TLR 8, TLR 9, NOD1, and NOD2.

79. The method of claim 71, wherein the bacterium is a Gram-positive bacterium or a Gram-negative bacterium.
80. The method of claim 79, wherein the Gram-positive bacterium is selected from the group consisting of bacterium of Lactobacillaceae family, .a bacterium of Streprocoecaceae family, a bacterium-of Bifidobacteriaceae family, and a bacterium of Bacillaceae family;
and wherein the Gram-negative bacterium is selected from the group consisting of bacterium of Pseudomonas genus. Klebsiella genus, Xanthomonas genus, Shigella genus, and Ergerobacter genus.
81. The method of claim 79, wherein the Gram-positive -bacterium is selected from the group consisting of Bacillus coagulans, Lactobacillus sporogenes, Streptococcus thermophilus, Bifidobacterium animalisõ Bifidobacterium. animalis, subspecies animalisõ
Bifidobacterium infantis, Bifidobacterium longum, Bifidobacterium breve, Lactobacillus acidophilus, Lactobacillus plantarum, Lactobacillus casei, Lactobacillus delbrueckii, Lactobacillus delbrueckii subspecies bulgaricus, Lactococcus lactis, Lactococcus lactis subspecies lactis, Streptococcus lactis, Streptococcus thermophilus, Bifidobacterium lactic, Bifidobacterium breve, Pediococcus acidilactici, and Lactobacillus helveticus and wherein the Gram-negative bacterium is selected from the group consisting of Klebsiella oxytocia, Shigella flexneri, Xanthomonas campestris, and Pseudomonas flourescens 82. The method of claim 72, wherein the one or more oxidative stress-related side effects are selected from the group consisting of. aceruloplasminemia, arterial/systemic hypertension, arthritis, asthma, atherosclerosis, atopic dermatitis, cancer, bladder cancer, leukemia, uterine cancer, cervical cancer, dizziness, nausea, vomiting, constipation, diarrhea, insomnia, drowsiness, lightheadedness, reduced libido, blackouts, shakes, jaundice, arrhythmia, increased. heart rate, decreased heart rate, hives, depression, clinical depression, brain ischemia, bronchopulmonary dysplasia, cardiovascular diseases, cataract, cellulitis, chemotherapeutic side-effect, chronic fatigue syndrome, colitis, coronary artery disease, dyslipidemia, eclampsia, erectile dysfunction, ataxia, headache, heart failure, hemodialysis side effects, hepatic cirrhosis, hypercholesterolemia, hyperhomocystememia, hyperlipidemia, interstitial lung disease, lung injury, macular degeneration, male infertility, mild cognitive impairment myocardial infarction, myocarditis, myopathy, neuropathy, obesity, osteoarthritis, osteoporosis, pancreatitis, periodontal disease, peritoneal dialysis side effects, post-traumatic stress disorder, preeelampsia, psoriasis, psoriatic arthritis, pulmonary hypertension, radio-therapy side effects, reactive arthritis, respiratory distress syndrome, rhabdomyolysis, rheumatic disease, sepsis, sleep apnea, stroke, suicidal thoughts, amyloidosis, thrombophily, tauopathies, unstable angina, uremia, and venous insufficiency 83. A method for treating an oxidative stress-related disease or condition m a subject, the method. comprising administering to the subject a therapeutically effective.amount of a composition comprising-(a) a bacterial lysate and/or lysate fraction capable of activating at least one or more toll-like receptors (TLRs) or Nod-like receptors (NLRs);
(b) an optional promoter for enhancing absorption of the composition;
and (c) an optional carrier for increasing a volume of the composition 84. The method of claim 83, wherein the oxidative stress-related condition is aceruloplasminemia, acute and chronic alcoholic liver diseases, acute autoimmune myocarditis, acute chest syndrome of sickle cell disease, acute pancreatitis, acute respiratory distress syndrome, alcoholic liver disease, Amyotrophic Lateral Sclerosis, arterial/systemic hypertension, asbestosis, asthma, ataxia telangiectasia, atherosclerosis, atopic dermatitis, brain ischemia, bronchopulmonary dysplasia, burns, some cancers, cardiopulmonary bypass, cardiovascular diseases, cataract, cellulitis, chemotherapeutic side-effect, chronic fatigue syndrome, chronic Hepatitis C, chronic kidney disease, chronic obstructive pulmonary disease, chronic renal failure, colitis, coronary artery disease, Creutzfeldt--Jakob disease, Crohn's disease, cutaneous leishmaniasis, cystic fibrosis, diabetes mellitus type 1, diabetes mellitus type 2, dyslipidemia, Down's syndrome, eclampsia, end-stage renal disease, erectile dysfunction, Friedretch ataxia, headache, heart failure, Helicobacter pylori infection/inflammation, hemodialysis side effects, hepatic cirrhosis, Human lmmunodeficiency Virus infection, Huntington disease, hyperbaric diseases, hypercholestemlemia, hypexhomocysteinemia, hyperlipidemia, idiopathic pulmonary fibrosis, interstitial lung disease, ischemia/reperfusion injury, juvenile chronic arthritis, kidney transplantation failure, leukemia, lung cancer, lung injury, macular degeneration, male infertility, Méniére's syndrome, meningitis, mild cognitive impairment, Multiple Sclerosis, myelodisplastic syndromes, myocardial infarction, myocarditis, neonatal bronchopulmonary dysplasia, obesity, osteoarthritis, osteoporosis, pancreatitis, Parkinson's disease, periodontal disease, peritoneal dialysis side effects, photoageing, post-traumatic stress disorder, preeelampsia, primary biliary cirrhosis, broncopulmonary diseases, progeria, psoriasis, psoriatic arthritis, pulmonary hypertension, radio-therapy side effects, reactive arthritis, renal cell carcinoma, respiratory distress syndrome, retinopathy of prematurity, retrolenticolar fibroplasy, rheumatic disease, rheumatoid arthritis, sarcoidosis, sepsis, sickle cell disease, sleep apnea, spherocytosis, spinal cord injury, stroke, synucleinopathiesõ systemic amyloidosis, systemic lupus erythematosus, systemic sclerosis (seleroderma), thrombophily, tauopathies, traumatic stress tubercolosis, unstable angina, uremia, venous insufficiency, Werner syndrome, or Zellweger syndrome.
85. The method of clam 83, wherein the bacterium is:
(a) a Gram-positive bacterium selected from the group consisting of:
Bacillus coagulans, Lactilbacillus sporogenes. Streptococcus thermophilus, Bifidobacterium animalis, Bilidobacterium animalis, subspecies animalis, Bifidobacterium infantis, Bifidobacterium longum,Bifidobacterium breve, Lactobacillus acidophilus, Lactobacillus plantarum, Lactobacillus casei, Lactobacillus delbrueckii, Lactobacillus delbrueckii subspecies bulgaricus, Lactococcus Iactis, Lactococcus lactis subspecies lactis, Streptococcus lactis, Streptococcus thermophilus, Bifidobacterium lactis, Bifiobacterium breve, Pediococcus acidilactici, and Lactobacillus helveticus; or (b) a Gram-negative bacterium selected from the group consisting of Klebsiella arytocia, Shigella flexneri, Xamhomonas campestris, and Pseudomonas flourescens 86. A method for reducing oxidative stress in a subject, the method comprising:

(a) determining the level of oxidative stress in the subject by measurin the amount of isoprostane in the urine or blood of the subject;
(b) administering to the subject an effective amount of a composition comprising:
(i) a toll-like remptor 0111) agonist comprising at least one lysate and/or lysate fraction from 4 bacterium, wherein the TLR agonist activates at least one or more TLRs or NIRs; and (ii) an optional promoter far enhancing.absorption of the composition;
and (c) continuing administration of the composition until the level of oxidative stress is reduced, as determined by a decreased amount of isoprostane in. the urine of the subject.
87. The method of elaim 86, wherein administration of the baeterial lysate is continued until the amount of isoprostane in the urine of the subject is less than about 3 ng per mg creatinine, less than about 2 us per mg creatimne, less than about I rig per mg creatinine, or less than about 0.5 ng per mg of creatinine.
88. The method of Claim 86, wherein the bacterium is a Gram-nen:an ve bacterium or a Gram-positive bacterium.
89 The method of claim 86, wherein the bacterium is:
(a) a Gram-positive bacterium selected from the group consisting of:
Bacillus coagulans, Lactobacillus spomenes,Streptococcus thermophilus, Bifidobacterium animalls, Bifidobactertum. animalis, subspecies anima/is, Byidobacterium Wands, Btfidatiacterium /ovum, Biftdobactertum breve, Lactobacillus acidoplulus, Lactobacillus plantarum, Lactobacillus easel, Lactobacillus delbrueckil, Lactobacillus delbrueckii subspecies bulgaricus, Laciococcus lactis,Lactococcus loafs subspecies hulls, Streptococcus lactic, Streptococcus thermophilus, BOidobacterium locus, Midobacterium breve!, Pediococcus aciddactia and Lactobacillus helveticus; or (b) a Gram-negative bacterium selected, from the group consisting of Klebsiella oviocia, Shigella flexneri,Xanthomonas campestris, and Pseudomonas flourescens, 90. The method of claim 86, wherein the lysate and/or lysate fraction activates at least one or more TLRs or NLRs.
91. The method of claim 86, wherein the lysate and/or lysate fraction activates at least two TLRs and/or NLRs.
92 The method of claim 86, wherein the lysate and/or lysate fraction activates at least three TLRs and/or NLRs 93. The method of claim 86, wherein the lysate and/or lysate .fraction activates at least one or more of TLR2, TLR 3, TLR 4, TLR 5, TLR 7, TLR 8, TLR 9, NOD1, and NOD2.
94. The method of claim 86, wherein the lysate and/or lysate fraction activates TLR 2 and TLR 4, 95. The method of claim .8,6, wherein the lysate and/or lysate fraction activates two or more of TLR 2, TLR 3, TLR 4, TLR 5, UR 7, MR 8, TLR 9, NOD1 , and NOD2.
96. The method of clami 86, Wherein the lysate andfor lysate fraction activates three.or more of TLR 2, TLR 3, MR 4, TLR 5, TLR 7, TLR 8, TLR 9, NOD1 , and NOD2.
97. A therapeutic coltibination. compris.ing:
(a) a lysate composnion comprising (i) a bacterial lysaw and/or lysatc fraction capable of activating at kast one or more toll-like receptors (TLRs) or Nod-like receptors (NLRs);
(n) an optional promoter for enhancing absorption arise composmon;
and (m) an optional carrier for increasing a volume of the compositirm; and (b) one or more pharmaceutical nents;
wherein the lysate composition and the one or more pharmaceutical agents are administered simultaneously or in any ordsr, and wherein the lysats composition and the one or more pharmaceutical agents are administered via the same or different routes of administration.
98. The therapeutic combination of claim 97, wherein the lysate composition is administered sublingually or buecally, 99 A pharmaceutical formulation comprising the combination of (a) a lysate composition comprising (i) a bacterial lysate and/or lysate fiactitin capable of activating at least one or more toll-like receptors (TLRs) or Nod-like receptors (NLRs);
(ii) an optional promoter for enhancing absorption of the composition;
and (iii) an optional carrier for increasing a volume of the composition; and (b) one or more pharmaceutical agent, 100. The therapeutic combination of claim 97 or the pharmaceutical formulation of claim 99, wherein the one or more pharmaceutical agents are selected from the group consisting of:
an antispasmodic, a motility stimulant, an H2-Receptor antagonist, antimusearinic; a chelate, a prostaglandin analog, an aminosahcylate, a corticosteroid, an drug affecting immune response, a stimulant laxative, a drug affecting, biliary composition and flow, a bile acids sequestrant, a dopamine antagonist, a proton pump inhibitor, an opioid, an opioid receptor antagonist, an analgesic, asleep drug, a cardiac glycoside, a phosphodiesterase inhibitor, a thiazide, a diuretic, a potassium sparing diuretic, an aldostorone antagonist, an osmotic diuretic, a drug for arrhythmia, a bbeta adrenoreceptor blocking drug, a hypertension drug, a drug affecting the renin-angiotensin system, a nitrate, a calcium blocker, an antanginal drug, a peripheral vasodilatot a sympathomimetic, an anticoagulant, a protamine, an antiplatelet drug, a fibrinelytic drug, an antifibrinolytic drug, a lipid regulating drug, an omega three fatty acid compound, a CNS drug, an anti-infective, or another drug selected from the group consisting of Benztropinc, procyclidine, biperiden, Amantadme, Brornoetiptine, Pergolide, Entacapone, Tolcapone, Selogeline, Pramipexole, budesomde, formoterol, quetiapine fumarate, olanzapine, pioglitazomi, montelukast, Zoledromic Acid, valsartan, latanoprost, Irbesartan, Clopklogrel, Atomoxetinc, Dexamfetamine, Methylphenidate, Modafinil, Bleomycin, Dactinomyeiti, Daunorubicin, Idarublem, Mitomycnl, Mitoxantrone, Azacitidme, Capeotabine, Cladribine, Clofarabine, Cytarabine, Fludarabinc, Flourouracil, Gemcitabine, mercaptopurine, methotrexate, Nelarabine, Pemetrexed, RaIntrexed, Thioguanine, Apomorphine, Betamethasone, Cortisone, Deflazacort, Dexamethosone, Hydrocortisone, Methylprednisolone, PmdMsolone, Triamcinolone, Ciclosporine, Sirolimus, Tacrolimus, Interferon Alpha, and Interferon Beti 101 The therapeutic combination of claim 97 or the pharmaceutical formulation of claim 99., wherein the one or more pharmaceutical agents are selected from the group consisting of:
Antispasmodics selected from the group consisting of atropine sulphate, dicycloverthe hydrochloride, hyoscine butylbromme, propantheline bromide, verine citrate, and mebeverine hydrochloride;
Motihty stimulants selected from the group consisting of metoclorpramide and domperidone;
H2-Receptor antagonists seleeted from the group consistine of Cimetidine, famotidinenizatidme, and ranitidine;
Antimusearmics, Chelates selected from the group consisting of Tnpotassium dicitrathismuthate and sueralfate;
Prostaglandin analogues;
Aminosalicylates selected from the group consisting of halsazide sodium, mesalazine, olsalazine, and sulphasalazme, Corticosteroids selected from the group consisting of beclometasonc dipropionate, budenoside, hydrocortisone, and prediusolone; Drugs affecting immune response selected from the group consisting of ciclosporin, mercaptopurine, methotrexate, adalimurnab, and infliximab, Stimulant Laxatives selected from the group consisting of hisacodyl, dantron, docusate, and sodium picosulfate, Drugs affecting bihary composition and flow;
Bile acids sequestrants selected from the group consisting of colestyramine, Oxyphencyclimmeõ Camylofm, .Mebeverine, Trimebutineõ Rociverine, Dicycloverine, Dihexyverine, Difemerine, Piperidolate, Benzilone, Mepenzolate, Pipenzolate, Glycopymonium, Oxyphenonium, Penthienate, Methanthchne, Propantheline, Ottlomum bromide, Thdthexothyl, Isopropamide, Hexocyclium, Poldme, Bevoniturt, Diphemanil, Timonium ochde, Prifinium bromide, Timepidium bromide, Fenpiverinium, Papaverme, Drotaverine, Moxaverine, 54113 antagonists, 5-HT4 agonists, Fenpiprane, Disopromine, Chlorhenzoxamine, Nnaveriumõ Fenoverine, Idanpramine, Proxazolc, Alverine, Trepibutone, isometheptene, Caroverinc, Phloroglucinol, Silicones, TrimethyldiphenylpropylamineõAtropme, Hyoscyamine, Scopolamme, Butylscopolamine, Methylscopolamine,Methylatropine, Fentouium, Cimetropium bromide, and primarily dopamine antagonists;
Proton pump inhibitors selected from the group consisting of Omeprazole, lansoprazole, pantoprazole, esomeprazole, and rabeprazole sodium;
Optcnds and optoid receptor antagonists, Analgesics selected from the group consisting of Acetaminophen, Dielofenac, Etodolac, Fenoprofen, Flurbiprofen, Ibuprofen, Indomethacm, Ketoprofen, Ketorolac, Meclofenamate, Mefenamic Acid, Meloxicam, Nabumetone, Naproxen, Oxaprozin, Phenylbutazone, Piroxicam, Sulindac, Tolmetm, Celecoxib, Buprenorphine, Butorphanol, Codeine, Hydrocodone, Hydromorphone, Levorphanol, Meperidine, Methadone, Morphine, Nalbuphine, Oxycodone, Oxymorphone, Pentazocine, Propoxyphene, and Tramadol;
Sleep drugs selected from the group consisting of Nitrampam, Flurazepam, Loprazolam, Lormetazepam, Temazepam, Zaleplon, Zolpidem, Zopiclone, Chloral Hydrate, Triclofos, Clomethiazole, Quazepam, triazolam, Estazolam, Clonazepam, Alprazolam, Eszopiclone, Rozerem, Trazodone, Amitriptyline, Doxepin, Benzodiazepme drugs, melatonin, diphenhydramme, and herbal remedies;
Cardiac glycosides selected from the group consisting olDigoxinand digitoxin.
Phosphodiesterase inhibitors selected from the group consisting of enoximone and milrinone;
Thiazides and related diuretics selected from the group consisting of bendroflumethiazide, chlortalidone, cyclopenthiande, mapamide, metolazone, and xipatmde;
Diuretics selected from the aroup consisting of furosenude, bumetanide, and torasemide;

Potassium sparing diuretics and aldosterane antagonists selected from the group consisting of amiloride hydrochloride, triamterene, weplerenone, and spironolactone;
Osmotic diuretics;
Drugs for arrhythmias selected from the group consisting of adenosine, amiodarone hydrochloride, disopyramide, flecainide acetate, propafenone hydrochloride, and lidocaine hydrochloride;
Beta adrenoreceptor blocking drugs selected from the group consisting of propanalol, atenolol, acebutolol, bisprolol furmarate, carvedilol, celiprolol, esmolol, lebatolol, metoprolol tartrate, nadolol, nebivolol, oxprenolol, pindolol, solatol, and timolol;
Hypertension drugs selected from the group consisting of ambrisentan, bosentan, diazoxide, hydralazine, iloprost, minoxidil, sildenatil, sitaxentan, sodium.
nitroprusside, clonidine, methyldopa, moxonidine, guanethidine monosulphate, doxazosin, indoraman, prazosin, tetazosin, phenoxybenzamine, and phentolamine mesilate;
Drugs affecting the renin-angiotensin system selected from the group consisting of Captropril, Cilazapril Enalapril Maleate, Fosinopril, Imidapril, Lisinopril, Moexipril, Perindopril Erbumine, Quinapril, Ramipril, Trandolapril.
Candesartan Cilexetil, Eprosartan, Irbesartan, Losartan, Olmesartan Medoxomil, Telmisartan, Valsartan, and Aliskiren;
Nitrates, calcium channel Blockers, and antianginal drugs selected from the group consisting of Glyceryl trinitrate, Isosorbide Dinitrate, Isosorbide Mononitrate, Amlodipine, Diltiazem, Felodipine, Isradipine, Lacidipine, Lercanidipine, Nicardipine, Nifedipme, Nimodiprne, Verapamil, Ivabradine, Nicorandil, and Ranolazine;
Peripheral Vasodilators and related drugs selected from the group consisting of Cilostazol, Inositol Nicotinate, Moxisylyte, Naftidrofuryl Oxalate, and Pentoxifylline;
Sympathomimetics selected from the group consisting of Dopamine, Dopexamine, Ephedrine, Metaraminol, Noradrenaline Acid Tartrate, Norephrdrine Bitartrate, and Phenylephidrine;
Anticoagulants and. Protamine selected from the group consisting of Heparin, Bemiparin, Dalteparin, Enoxaparin, Tinzaparin, Danaparoid, Bivalirudin, Lepirudin, Epoprostenol, Fondaprinux, Warfarin, Acenocoumarol, Phenindione, Dabigatran Etexilate, Rivaroxaban, and Protamine Sulphate;
Antiplatelet Drugs selected from the group consisting of Abeiximab, Aspirin, Clopidogrel, Dipyridamole, Eptifibatide, Prasugrel, and.Tirofiban;
Fibrinolytic and antifibrinolytic drugs selected from the group consisting of Alteplase, Reteplase, Streptokinase, Tenceteplase, Urokinase, Etamsylate, and Tranexamic Acid;
Lipid Regulating Drugs selected from the group consisting of Atorvastatin, Fluvastatin, Pravastatin, Rosuvatatin, Simvastatin, Colesevam, Colestyramine, Colestipol, Ezetimibe, Bezafibrate, Ciprofibrate, Fenofibrate, Gemfibrozyl, Acipmox, Nictotinic Acid, Omega three fatty acid compounds, Ethanolamine Oleate, and Sodium Tetradecyl Suphate;
CNS Drugs Selected from the group consisting of Benperidol, Chlorpromazine, Flupentixol, Haloperidol, Levomepromazine, Pericyazine, Perphenazine, Pimozide, Prochlorperazine, Promazine, Sulpiride, Trifluoperazine, Zuclopenthixol, Amisulpride, Aripiprazole, Clozapine, Olanzapme, Paliperidone, Quetiapine, Riperidone, Sertindole, Zotepine, Flupentixol, Fluphenazine, Olanzapine Embonate, Pipotiazine Palmitate, Risperidone, Zuclopenthixol Decanoate, Carbamazepine, Valproate, Valproic acid, Lithium Carbonate, Lithium Citrate, Amitriptyline, Clomipramine, Dosulepin, Imipramine, Lofepramine, Nortriptyline, Trimipramine, mianserin, Trazodone, Phenelzine, Isocarboxazid, Tranylcypromine, Moclobemide, Citalopram, Escitalopram, Fluoxetine, Fluvoxamine, Paroxetine, Sertraline, Agomelatine, Duloxetine, Flupentixol, Mirtazapine, Reboxetine, Trytophan, Venflaxine, Atomoxetine, Dexametamine, Methylphenidate, Modatinil, Eshcarbazepine, Ocarbazepene, Ethosuximide, Gabapentin, Pregabalm, Lacosamide, Lamotrigine, Levetiracetam, Phenobarbital, Primidone, Phenytoin, Rufinamide, Tiagabine, Topiramate, Vigabatrin, Zonisamide, ropinirole, Rotigotine, Co-Beneldopa, Levodopa, Co-Careldopa, Rasagiline, Selegiline, Entacapone, Tolcapone, Amantidine, Orphenadrine, Procyclidine, Trihexyphenidyl, Haloperidolõ
Piracetam, Riluzole, Tetrabenazine, Acamprosate, Disulfiram, Bupropion, Vareniciline, Buprenorphine, Lofexidine, Donepezil, Galantamine, Memantine, and Rivastigimine;
Anti-Infectives selected, from the group consisting of Benzylpenicillin, Phenoxymethylpenicillin, Flucloxacillin, Temocillin, Amoxicillin, Ampicillin.
Co-Amoxiclav, Co-Fluampicil, Piperacillin, Ticarcillin, Pivmecillinam, Cephalosporins, Cefaclor, Cefadroxil, Cefalexin, Cefixime, Cefotaxime Cafradine, Ceftazidine, Cefuroxime, Ertapenem, Imipenem, Meropenem, Aztreonam, Tetracycline, Demeclocycline, Doxocycline, Lymecycline, Minocycline, Oxytetracycline, Tigecycline, Gentamicin, Amikacin, Neomycin, Tobramycin, Erythromycin, Azithromycin, Clarithromycin, Telithromycin, Clindamycin, Chloramphenicol, Fusidic Acid, Vancomycin, Teicoplanin, Daptomycin, Linezolid, Quinupristin, Colistin, Co-Trimoxazole, Sulpadiazine, Trimethoprim, Capreomycin, Cycloserine, Ethambutol, lsoniazid, Pyrazinamide, Rifabutin, Rifampicin, Streptomycin, Dapsone, Clofazimine, Metronidazole, Tinidazole, Ciproflaxacin, Levoflaxacin, Moxifloxacin, Nalidixic Acid, Norflaxine, Orflaxacin, Nitrofurantoin, Methenamine Hippurate, Amphotericin, Anidulafungin, Caspofungin, Fluconazole, Flucytosine, Griseofluvin, Itraconzole, Ketoconazole, Micafungin, Nystatin, Posaconazole, Terbinafine, Voriconazole, Abacavir, Didanosine, Eintricitabine, Lamivudine, Stavudine, Tenofovir Disoproxil, Zidovudine, Atazanavir, Darunavir, Fosamprenavir, Indinavir, Lopinair, Nelfinavir, Ritonavir, Saquinavir, Tipranavir, Efavirenz, Etravirine, Nevarapine, Enfuvirtide, Maraviroc, Raltegravir, Aciclovir, Famciclovir, Inosine Pranobex, Valaciclovir, Cidofovir, Gangoclovir, Foscarnet, Valgangciclovir, Adefovir Dipivoxii, Entecavir, Telbivudine, Amantadine, Oseltamivir, Zanamivir, Palivizumab, Ribavirin, Artemether, Chloroquine, Mefloquine, Primaquine, Proguanil, Pyrimethamine, Qumine, Doxycyclin, Diloxanide Furoate, Metronidaziole, Tinidazole, Mepacrine, Sodium Stibogluconate, Atovaquone, Pentamidine Isetionate, Mebendazole, and Piperazine; and Other drugs selected from the group consisting of Benztropine, procyclidine, biperiden, Amantadine, Bromomptine, Peraolide, Entacapone, Tolcapone, Selegeline, Pramipexole, budesonide, formoterol, quetiapine fumarate, olanzapine, pioghtazone, montelukast, Zoledromic Acid, valsartan, latanoprost, Irbesartan, Clopidogrel, Atomoxetine, Dexamfetarnine, Methylphenidate, Modafinil, Bleomycin, Dactinamycin, Daunorubicin, ldarubicin, Mitomycin, Mitoxantrone, Azacitidine, Capecitabine, Cladribine, Clofarabine, Cytarabine, Fludarabine, Flourouracil, Gemcitabine, mercaptopurine, methotrexate, Nelarabine, Pemetrexed, Raltitrexed, Thioguanime, Apomorphine, Betamethasone, Cortisone, Deflazacort, Dexamethosone, Hydrocortisone, Methylprednisolone, Prednisolone, Triamcinolone, Culosporine, Sirolimus, Tacrolimus, Interferon Alpha, and interferon Beta.

102. A formulation comprising (a) a ly sate composition comprising (i) a bacterial lysate and/or lysate fraction capable of activating at least one or more toll-like receptors (TLRs) or Nod-like receptors (NLRs);
(ii) an optional promoter for enhancing absorption of the composition;
and (iii) an optional carrier for increasing a volume of the composition; and (b) an isolated human anti-TNFalpha antibody or antigen-binding fragment thereof or TNF inhibitor 103 The formulation of claim 102, wherein the human anti-TNFalpha antibody or antigen-binding fragment thereof is adahmumab 104. The use of the formulation of claim 103 in the manufacture of a medicament for the treatment of rheumatoid arthritis: (RA.), late-onset RA, or psoriatic arthritis in a subject.
105 A method for the treatment of rheumatoid arthritis (RA), late-onset RA, or psoriatic arthritis in a subject, the method comprising administering to the subject a therapeutically effective amount of the formulation of clam 102.
106. The method of claim 105, wherein the human anti-TNFalpha antibody or antigen-binding fragment thereof is administered to the subject in a biweekly dosing regimen.
107. The method of claim 105, wherein the human anti-TNFalpha antibody or antigen-binding fragment thereof is administered to the subject in a dose of 30 mg or greater.
108. The method of claim 105, wherein the TNFalpha inhibitor a TNFalpha fusion protein.

109. The method of claim 108, wherein the TNFalpha fusion protein is etanereept 110, The method of claim 105., wherein the anti-TNFalpha antibody or antigen-binding fragment thereof is infliximab or golimumab 111. The method of claim 105, wherein the anti-TNFalpha antibody a antigen-binding fragment thereof is adalimumab.
112. The method of claim 105, wherein the anti-TNFalpha antibody or antigen-binding fragment thereof is adalimumab.