Molecular Mechanisms of Microbiota-Mediated Pathology in Irritable Bowel Syndrome
"> Figure 1
<p><b>Overview of pathogenesis related to IBS.</b> IBS is a multifactorial disorder affected by various genetic and environmental factors. Altered diet, aberrant usage of antibiotics, or exposure to severe enterocolitis induce gut dysbiosis, resulting in mucosal immune activation and low-grade inflammation, as well as gut barrier dysfunction through increased epithelial permeability. These pathways along with psychological factors influence the brain-gut-microbiome axis, which is mediated by aberrant neuroendocrine factors, transmitters, and metabolites, resulting in altered gut motility and visceral hypersensitivity. Chronic status of such gut dysfunctions shapes IBS symptoms including abnormal bowel movements and visceral pain. TLR, Toll-like receptor; CRH/HPA, corticotropin-releasing hormone/hypothalamic-pituitary-adrenal axis; ENS, enteric nervous system; CNS, central nervous system.</p> "> Figure 2
<p><b>Mechanisms of dysbiosis-mediated intestinal dysfunction in IBS.</b> In dysbiosis related to IBS, both the quality and quantity of microbial metabolites (BA, SCFAs, Vit D, B6, Trp-related), neurotransmitters (His, Glu, GABA, NA, DA, ACh), compounds (TLR ligands), neuroendocrine factors (GLP-1, PYY), and protases are significantly altered as compared with those in a healthy condition. In addition, activated 5-HT with weakened Ind and Kyn signaling can be observed in the Trp pathway. These alternations potentially increase mucosal permeability, while microbial products (TLR ligands, etc.) or antigens can easily penetrate into sub-mucosal areas and stimulate immune cells, thus inducing low-grade inflammation. Prolonged mucosal inflammation and some microbial products directly or indirectly influence ENS and CNS functions through CRH/HPA, GI motility alteration, and hypersensitivity as part of the pathogenesis of IBS. BA, bile acids; SCFA, short-chain fatty acids; Vit, vitamin; Trp, tryptophan; QS, quorum sensing; 5-HT, 5-hydroxytryptamine; Ind, indole; Kyn, kynurenine; His, histamine; Glu, glutamine; GABA, γ-aminobutyric acid; NA, noradrenaline; DA, dopamine; Ach, acetylcholine; GLP-1, glucagon-like peptide-1; PYY, Peptide YY; AhR, aryl hydrocarbon receptor; PARs, protease activated receptors; TJ, tight junction; TLRs, toll-like receptors; EC cells, enterochromaffin cells; CRH/HPA, corticotropin-releasing hormone/hypothalamic-pituitary-adrenal axis; ENS; enteric nervous system; CNS; central nervous system.</p> ">
Abstract
:1. Introduction
2. Role of Intestinal Resident Microbiota in IBS Pathology
3. Mechanisms of Action: Influence of Microorganisms on Intestinal Homeostasis and IBS
3.1. Microbial Neurotransmitters
3.1.1. Histamine
3.1.2. Serotonin
3.1.3. Glutamate
3.1.4. γ-Aminobutyric Acid (GABA)
3.1.5. Others
3.2. Microbial Compounds
3.2.1. Toll-Like Receptor Ligands
3.2.2. Cytokines
3.2.3. Other Microbial Products
3.3. Microbial Metabolites
3.3.1. Tryptophan
3.3.2. Short-Chain Fatty Acids
3.3.3. Bile Acids
3.3.4. Vitamins
3.4. Microbial Endocrine Factors
3.4.1. Glucagon-Like Peptide-1 (GLP-1)
3.4.2. Peptide YY (PYY)
3.5. Microbial Enzymes: Proteases
4. Conclusions
Author Contributions
Funding
Conflicts of Interest
References
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Microbial Products | Visceral Pain | GI Motility | Mucosal Permeability | Mucosal Inflammation | Influencing Dysbiosis | References |
---|---|---|---|---|---|---|
Neurotransmitters | ||||||
Histamine | ↑↑ | ↑ | ↑ | ↑ | [53,78,79,80,81,82,83,84] | |
Serotonin | ↑ | ↑ | ↑ | ↑ | ++ | [7,85,86,87,88] |
Glutamate | ↑↑ | ↓? | ↑ | + | [89,90,91,92,93,94,95,96,97,98,99] | |
γ-aminobutyric acid | ↓ | ↓ | ↓ | [92,100,101,102,103,104,105] | ||
Noradrenalin | ↑ | ↑ | ↑ | ↑↓ | [106,107,108,109,110,111] | |
Dopamine | ↓ | ↑↓ | ↑? | ↓? | + | [112,113,114,115,116,117,118] |
Acetylcholine | ↑ | ↓ | [111,112,119,120] | |||
Compounds | ||||||
Toll-like receptor ligands | ↑↓ | ↑↓ | ↑↓ | ↑↓ | [121,122,123] | |
Cytokines | ↑↓ | ↑↓ | ↑↓ | ↑↓ | [52,124,125,126,127,128,129,130] | |
Pore-forming toxins, N-formylated peptides | ↑ | ↑ | ↑ | [124,131,132,133] | ||
Metabolites | ||||||
Tryptophan (aryl hydrocarbon receptor, kynurenine pathways) | ↓↑ | ↓ | ↓ | + | [89,124,134,135,136,137,138,139,140,141] | |
Short-chain fatty acids | ↑↓ | ↑ | ↓ | ↓ | [70,142,143,144,145,146,147,148,149,150,151,152,153,154] | |
Bile acids | ↓ | ↑ | ↑ | + | [155,156,157,158,159,160] | |
Vitamin D and B6 | ↓ | ↓ | ↓ | + | [161,162,163,164,165,166,167,168,169,170] | |
Endocrine factors | ||||||
Glucagon-like peptide-1 | ↓ | ↓ | ↓ | [171,172,173,174,175] | ||
Peptide YY | ↓ | ↓ | [172,176,177,178] | |||
Enzymes | ||||||
Proteases | ↑ | ↑↓ | ↑↑↑ | ↑ | [124,179,180,181,182,183,184,185,186] |
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Mishima, Y.; Ishihara, S. Molecular Mechanisms of Microbiota-Mediated Pathology in Irritable Bowel Syndrome. Int. J. Mol. Sci. 2020, 21, 8664. https://doi.org/10.3390/ijms21228664
Mishima Y, Ishihara S. Molecular Mechanisms of Microbiota-Mediated Pathology in Irritable Bowel Syndrome. International Journal of Molecular Sciences. 2020; 21(22):8664. https://doi.org/10.3390/ijms21228664
Chicago/Turabian StyleMishima, Yoshiyuki, and Shunji Ishihara. 2020. "Molecular Mechanisms of Microbiota-Mediated Pathology in Irritable Bowel Syndrome" International Journal of Molecular Sciences 21, no. 22: 8664. https://doi.org/10.3390/ijms21228664