adult infectious diseases notes
a microbiological explanation for the obesity pandemic?
Louis Valiquette MD MSC FRCPC1, Stéphanie Sirard MSc1, Kevin Laupland MD MSC FRCPC2,3
T
he prevalence of obesity is increasing worldwide. According to the
Canadian Health Measures Survey, in 2011, one in four Canadians
was obese (25% of women; 27% of men) (1). In addition to the imbalance between energy intake and expenditure, sedentary lifestyle, a diet
high in saturated fats and sugars, and genetic predisposition, many
other factors may be involved in obesity. The presence of either symbiotic or pathogenic microorganisms may contribute to the development of obesity. With the progress of metagenomics and molecular
techniques in recent years was born an interest in the microorganisms
living on and inside us (2). More than 1014 microorganisms, which
represent up to 1150 different species and a total genome comprising
150-fold more genes than the human genome, live in our gastrointestinal tracts (3). The gut microbiota is known to play a role in protection against pathogenic bacteria, immune function and digestion by
degrading nondigestible carbohydrates such as cellulose, pectin and
starch (4,5). Over the past decade, several prominent publications
have led to an intriguing hypothesis that links differences in gut
microbial ecology to energy homeostasis. In simpler words, some individuals harbouring a microbiota more efficient at extracting energy
from the diet (eg, through the ability to degrade indigestible components) may be at higher risk for obesity. This hypothesis is interesting
but controversial, and raises several questions.
The bacterial phyla Firmicutes (which include genera Clostridium,
Ruminococcus and Lactobacillus) and Bacteroidetes (including genera
Prevotella and Bacteroides) account for 90% of the gut microbiota (6).
The balance of these populations is essential for the maintenance of a
healthy microbiota. The microbiota of genetically obese mice was
associated with a 50% reduction in Bacteroidetes and a proportional
increase in Firmicutes compared with lean animals (7). An interesting
observation was made when colonizing germ-free mice with the gut
microbiota of normal mice. This transplantation led to a 60% increase
in body fat and insulin resistance within two weeks, in spite of reduced
food consumption (8).
Findings about the implication of the proportion of Firmicutes and
Bacteroidetes in human obesity are contradictory because some studies
have found no difference in the Firmicutes and Bacteroidetes ratio
(9,10), while others have (11). A diet-induced weight loss in obese
individuals was associated with a reduction in the Firmicutes:
Bacteroidetes ratio, which was similar to the lean controls (11).
Recently, a decrease in specific species (Bifidobacterium animalis and
Methanobrevibacter smithii) and an increase in others, such as
Staphylococcus aureus, Escherichia coli and Lactobacillus reuteri, have
been associated with obesity (12). Normal-weight children had greater
bifidobacteria counts and fewer fecal numbers of S aureus compared
with overweight/obese children (13). These findings propose that gut
microbiota in infancy may predict obesity, reinforcing the importance
of prevention. Conflicting findings provide evidence of variability
among individuals and in one individual over time. Some changes in
gut microbiota may influence individuals to a different extent, and
more studies involving large obese populations are required to draw
more precise conclusions.
Although their exact contribution remains unclear, microorganisms
in the gut are believed to be involved in the development of obesity by
two different and complementary mechanisms. They can extract
energy from nondigestible polysaccharides and produce low-grade
inflammation (14). Because many Firmicutes are major butyrate producers, an abundance of bacteria from this phylum could be associated
with an increase in genes encoding enzymes that enable the degradation of complex polysaccharides and, in turn, increase the production
of monosaccharides and short-chain fatty acids (SCFAs) (15). Up to
10% of the total energy extracted from food corresponds to SCFA
production (10). In a mouse model, the obese microbiome was found
to be richer in enzymes involved in the digestion of complex polysaccharides. Consequently, higher concentrations of butyrate and acetate
were found in these mice cecum (16). This increased capacity for
extracting energy was also transferred to germ-free mice when they
were colonized with an obese microbiota (16). In a cross-sectional
study, overweight and obese individuals also exhibited higher fecal
levels of end products of colonic fermentation (butyrate, acetate and
SCFAs) than normal-weight individuals, thus suggesting a more efficient energy extraction process (10).
Obesity has been associated with chronic low-grade inflammation;
however, how they are linked remains unclear (17). The potential
implication of bacterial lipopolysaccharide (LPS) in obesity was highlighted in a mouse model. Interestingly, food was found to modulate
plasma LPS levels (endotoxemia) and these levels were related to fat
content. In addition, these concentrations were sufficient to induce
the development of metabolic disorders (essentially, diabetes and obesity) (18). Later, an association was reported between endotoxemia and
energy intake in humans, but not between LPS and weight or body
mass index (19). More studies are needed to elucidate the role of endotoxemia in human obesity. Over the past several years, studies investigating gut microbiota and obesity have accumulated. Even in the
absence of consensus, researchers agree that there is undoubtedly a
link between gut microbiota and metabolic diseases such as obesity.
In addition to the interaction between microbiota and obesity, some
studies have also attempted to show a direct relationship with some
pathogenic microorganisms. The concept of ‘infectobesity’ (obesity of
infectious origin) has recently become more popular. Nevertheless, over
the past 30 years, approximately 10 microorganisms (including canine
distemper virus, avian adenovirus [SMAM-1] and human adenoviruses)
have been linked with obesity in either humans or animals (20).
Currently, studies are focusing on adenoviruses, especially adenovirus 36 (Ad36), which is associated with adiposity and inflammation.
Although Ad36 has been reported to induce obesity in animal models
(21,22), results have been contradictory in humans. A greater prevalence of neutralizing antibodies was observed in obese individuals compared with nonobese individuals in both adults (23-25) and children
(26-29). However, some studies did not achieve the same results in
adults (30-32) or children (33). In a meta-analysis of 10 studies (34),
Ad36 infection was associated with an increased risk for obesity
(OR 1.9 [95% CI 1.01 to 3.56]; P=0.047) and weight gain (increase in
body mass index of 3.19 kg/m2). These variable results are questionable
because positive associations were essentially reported by a limited group
of authors from similar institutions and because Ad36 was identified
using serology in these studies. Discrepancies in detection and specificity
1Department
of Microbiology-Infectious Diseases, Université de Sherbrooke, Sherbrooke, Quebec; 2Department of Medicine, Royal Inland
Hospital, Kamloops, British Columbia; 3Departments of Medicine, Critical Care Medicine, Pathology and Laboratory Medicine, and
Community Health Sciences, University of Calgary, Calgary, Alberta
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Can J Infect Dis Med Microbiol Vol 25 No 6 November/December 2014
Adult Infectious Diseases Notes
may exist between studies using serology and those using viral culture or
polymerase chain reaction detection (35). Moreover, conclusions originate from observational studies; thus, a causal relation between Ad36
infection and obesity cannot be proven. In addition, studies appear to be
more consistent in children than in adults, likely indicating differences
in the time the infection occurred or in viral load. Ad36 antibodies were
also detected in nonobese individuals, reinforcing the contribution of
other factors to the development of obesity and calling into question the
implication of this particular adenovirus in obesity.
A potential vaccine for prophylactic treatment of Ad36-induced
obesity was evaluated in a mouse model (36). A greater body weight in
the control group and decreased levels of proinflammatory cytokines
in the vaccinated mice were observed. These results are promising,
although more studies targeting other adenoviruses are needed because
the relevance and applicability in humans is unknown.
Interindividual variation in microorganisms makes drawing conclusions more complex, but gut microbiota deserves more attention as
a potential target in prevention or control of obesity. Personalized
therapy based on the microbiome may be the key to overcome this
variation. Modulating gut microbiota by the consumption of beneficial
bacteria or the use of prebiotics or drugs targeting specific bacterial
populations could be an interesting avenue in the treatment of obesity.
Fecal microbiota transplantation (FMT) could also represent a potential therapy against obesity and metabolic diseases; however, given all
of the hurdles that are met by physicians willing to proceed with FMT
for recurrent C difficile infection, even while supported by strong evidence, we are still far from using FMT to treat other conditions. At the
time the present article was written, no clinical trial was registered on
www.clinicaltrials.gov on the effect of FMT on obesity. The hypothesis
of a single agent as a cause or a potentiator of obesity is less robust for
several reasons: the evidence is clearly not as strong as for the microbiota hypothesis; it comes mainly from the same research team; and
accepting this hypothesis would mean that obesity is transmissible,
which makes little sense in our opinion.
Although the primary cause of obesity will always be a misbalance
between energy intake and expenditure, its association with microbiology is only a small demonstration of how complex this multifactorial condition is. Nevertheless, beneficial as well as pathogenic
microorganisms deserve more attention as evidence of their contribution to metabolic disorders continues to accumulate.
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