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Neurogastroenterology & Motility

Neurogastroenterol Motil (2012) 24, 305–311 doi: 10.1111/j.1365-2982.2012.01895.x


Obesity and its associated disease: a role for microbiota?


*Division of Digestive Diseases, Emory University, Atlanta, GA, USA

 Atlanta Veterans Affairs Medical Center, Decatur, GA, USA
àImmunity & Infection and Department of Biology, Center for Inflammation, Georgia State University, Atlanta, GA, USA

Abstract ture thus favoring energy storage. Factors that can

Background Gut microbiota have recently been promote this imbalance are widely appreciated to
implicated in the pathogenesis of the obesity and its include genetics, high-fat food, high-fructose diet, and
related metabolic diseases. A variety of factors physical inactivity.3,4 Less appreciated, and the focus of
including diet, genetic background, environment and this brief review, is the possibility that the gut microbi-
host innate and adaptive immune responses define an ota might play a role in the pathophysiology of obesity.5–7
individual’s gut microbiota. Purpose In this review we The human gastrointestinal (GI) tract harbors a large
outline potential mechanisms by which gut microbi- diverse community of bacteria collectively referred to
ota can contribute to the development of obesity as the gut microbiota, which is increasingly appreci-
focusing on specific processes such as microbial energy ated to play an intricate role in health and well-being,
extraction, microbiota induced-inflammation and particularly in terms of digestive health and immune
regulation of appetite. We review the current under- function.8 The study of the entire microbial commu-
standing of each of these processes on regulating nities using metagenomics approaches estimates that
metabolism and examine potential therapeutic strat- gastrointestinal tract in an adult human contains
egies for the treatment or prevention of the metabolic approximately 1012 micro-organisms per milliliter of
syndrome. We explore the hypothesis that alteration luminal content and harbors approximately 15 000
in gut microbiota may be an initial event leading to species of bacteria.9 Amongst these species, Bacterio-
altered feeding behavior and/or systemic inflamma- detes and Firmicutes, account for more than 90% of all
tion, ultimately leading to weight gain and the the phylotypes of colonic bacteria. Methanobrevibacter
metabolic syndrome. Smithi is a hydrogen consuming methanogen that
dominates the Archae domain of gut microbiota. The
Keywords gut, microbiota, obesity.
gut microbiome is established during the first year of
life and is influenced by multiple host and external
Obesity is a growing epidemic in many developed and
factors including diet and antibiotics. Recent studies
developing countries including the United States.1,2 The
show that obese and lean people are different in their
prevalence of obesity in adults has increased more than
gut microbiota composition, specifically in the propor-
75% since 1980 with currently more than half of the US
tion of Bacteriodetes and Firmicutes. In obese people
population is overweight.2 At its simplest level, obesity
the Firmicutes are dominant and when they lose
stems from an alteration in energy balance that can result
weight, the proportion of Firmicutes become more like
from increased energy intake and/or reduced expendi-
lean people.10 Some studies have demonstrated that
gut microbiota have a substantial correlation with
Address for Correspondence obesity through regulation of metabolism.5,7,10,11 This
Shanthi Srinivasan, Rm 201A, Whitehead Research Building, review explores the recent advances in understanding
615 Michael Street, Atlanta, GA 30322, USA. the role of gut microbiota in pathogenesis of obesity
Tel: 404 727 5298; fax: 404 727 5767;
and regulation of satiety. Specifically, we review some
Received: 21 October 2011 of the major processes by which gut microbiota
Accepted for publication: 20 January 2012 can influence weight gain, including modulation of

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A. Bonakdar Tehrani et al. Neurogastroenterology and Motility

the inflammatory response to microbiota, nutrient both harvest energy from the diet and store this energy
extraction of calories by microbiota and also microbial in adipocytes. Specifically, the microbiota promoted
influence of satiety through the brain-gut axis. absorption of monosacharrides from the gut through
activation of the signaling protein ChREBP. There was
also an increase in hepatic lipogenesis due to an
increase in the expression of LPL and SREBP-1, genes
influencing fatty acid synthesis. Microbiota from
Gut microbiota are involved in energy harvest through genetically obese leptin deficient mice, the ob/ob
breaking down complex dietary macromolecules, syn- mice, contained genes encoding enzymes that break
thesizing micronutrients, fermenting indigestible food down indigestible dietary polysaccharides. Transfer-
substances, assisting in absorption of electrolytes, and ring the bacteria from the ob/ob mice to germ free mice
growth and differentiation of the intestinal and colonic led to greater fat gain compared to mice receiving
epithelium through regulating the diverse aspects of microbiota from the lean mice.11
cellular differentiation and gene expression.8,12 Such Thus, by fermentation of indigestible dietary poly-
bioactivities result in the microbiota regulating nutri- saccharides, increased intestinal absorption of mono-
ent acquisition and energy extraction. The gut micro- saccharides and short chain fatty acids and increased
biota provides enzymes involved in the utilization of hepatic lipogenesis, microbiota can influence the
non-digestible carbohydrates, cholesterol reduction development of obesity. In a study examining energy
and biosynthesis of vitamins (K and B group), isopre- harvesting in lean and obese individuals fed varied
noids and amino acids (e.g., lysine and threonine).8,12 caloric diets, it was noted that an increase energy
In particular, the ability of the commensal microbiota harvest correlated with the predominance of a Firmi-
to utilize complex dietary polysaccharides which cutes and a reduction in Bacteriodetes, demonstrating
would otherwise be inaccessible to human subjects, the cross talk between the nutrients and flora ulti-
to generate short-chain fatty acids (SCFA) seems to mately modulating nutrient assimilation.16
contribute to the ability of the host to harvest energy Methanogenic Archaea can also contribute to
from the diet.5 In addition, the commensal microbiota increased energy extraction. In a study by Samuel and
and its metabolites regulate the expression of genes Gordon they found that colonization with Methano-
involved in the processing and absorption of dietary brevibacter Smithii increased the efficiency of energy
carbohydrates and complex lipids in the host adipose extraction from dietary polysaccharides and conse-
tissue, favoring fat storage. Gut microbiota can also quent adiposity.17 Thus M. Smithii could be a potential
modulate serum lipids by taking part in bile acid therapeutic target for reducing energy harvesting in
metabolism.5,13,14 obese humans.
Gut microbiota can facilitate extraction of calories
from ingested dietary substances that can then be
stored as adipose tissue or provide nutrients for micro-
bial growth. The greater the energy extraction effi-
ciency of the microbiota the more predisposition an
individual may have towards the development of A complex mucosal immune system defends the
obesity.15 Studies conducted in germ-free animals, intestine from potentially pathogenic bacteria that
indicate gut microbiota have a profound influence on can be members of the gut microbiota. Indeed, one of
the onset and progression of human disease such as the powerful triggers for inflammation is the presence
obesity and particularly, energy regulation and fat of microorganisms in sites where they do not belong.
storage.5 This is thought to be achieved by diverse Emerging evidence over the past decade has shown that
mechanisms including improvement of diet macronu- systemic, hepatic or adipose tissue inflammation can
trient utilization, generation of metabolites involved in be one of the crucial mechanisms in the development
energy balance and regulation of host gene expression. of obesity-associated insulin resistance, T2DM and
Backhed et al. demonstrated that conventionally related diseases.18 Diabetes, the metabolic syndrome,
reared mice have a 40% higher body fat content than and obesity are metabolic diseases which based on
germ-free mice even though they consume less food recent demonstration are associated and characterized
than their germ-free counterparts.5 Colonization of by low-grade systemic inflammation.19–22 By regulat-
germ-free mice with microbiota from normal mice ing gut microbiota innate immunity may influence
resulted in a 60 % increase in total body fat.5,6 The metabolism and the development of obesity. Recently
microbial colonization increased the host’s ability to we have shown a strong relationship between meta-

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Volume 24, Number 4, April 2012 Microbiota and obesity

Figure 1 Schematic diagram of proposed mechanism of gut microbiota regulation of obesity. A variety of factors shape the human gut
microbiota. The microbiota in turn can influence metabolic pathways by modulating energy extraction, inflammation and satiety, leading to the
development of obesity. ChREBP, carbohydrate response element binding protein; GLP-1, glucagon like peptide-1; LPS, lipopolysaccharide; NPY,
neuropeptide Y; PYY, peptide YY; SCFA, short chain fatty acids; SREBP-1, sterol regulatory element binding protein-1; TLR4, Toll-like receptor 4;
T5KO, TLR5 knock out.

bolic syndrome and Toll-like-receptor (TLR5). The resistance and resultant metabolic syndrome. This
TLR5 is a transmembrane protein that is highly phenotype was worsened when the T5KO mice were
expressed in intestinal mucosa and that recognizes fed a high fat diet. There were no differences in energy
bacterial flagellin. Loss of TLR5 (T5KO) resulted in an harvesting in these mice as assessed by bomb calorim-
alteration in the gut microbiota which is responsible etry and short chain fatty acids. Treatment of the
for low grade inflammatory signaling.7 These mice T5KO mice with antibiotics for three months reversed
were 20% greater in weight than their wild type (WT) the metabolic syndrome. Finally transferring of gut
counterparts and had all the features of insulin microbiota from T5KO to wild-type germ-free mice

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A. Bonakdar Tehrani et al. Neurogastroenterology and Motility

resulted in development of most features of metabolic remain undefined, such mechanisms are plausible
syndrome to the recipients.7 Comparison of the com- contributors to metabolic disease.
position of microbiota in WT and T5KO mice demon-
strated a significantly different species composition
between the two groups of mice. The conclusion from
this series of experiments was that loss of TLR5
resulted in low grade inflammation leading to insulin The hypothalamus and the brain stem are sites of
resistance and subsequent hyperphagia and the devel- central regulation of appetite. Satiety signals include
opment of the metabolic syndrome. Microbiota that various hormones, neuropeptides as well as the con-
initially colonizes the human gut may be one of the stant bidirectional communication between the gut
factors that determine the ultimate metabolic pheno- and the brain called the brain-gut axis. The brain-gut
type of an individual. axis is a multi-component conceptual model describing
Another study linking obesity and inflammation the communication pathways connecting the brain
relates to Toll like receptor 4 and its ligand Lipopoly- with gut, enteric nervous system and the immune
saccharide. Cani et al. demonstrated another mecha- system.33 The impact of gut microbiota on behavior
nism linking the gut microbiota to the development of and central nervous system (CNS) function is a new
obesity. They hypothesized that bacterial lipopolysac- research area,34 and the idea that microbiota may
charide (LPS) which is an important structural compo- signal beyond the gut to the brain is supported by some
nent of gram-negative bacteria cell walls, acts as a studies that showed the gut microbiota could activate
triggering factor linking systemic inflammation to vagal sensory neurons and regions of the brain associ-
high-fat diet-induced metabolic syndrome.23 They ated with central autonomic network.35–38 Gut micro-
found that mice injected with LPS showed increased biota, through developmental programming, a process
weight gain and insulin resistance without affecting whereby an environmental factor impact on structure
the energy intake.23 High plasma LPS levels could and function of an organ, could affect other organs
result from an increased production of endotoxin due functionality.8,39,40 Recently a study demonstrated
to in the gut microbiota.24 High-fat feeding signifi- modulation of brain development by gut microbiota.41
cantly changes gut microbiota composition,24–26 Thus, one can postulate that the host microbiota can
specifically resulting in a decreased number of bifido- influence the development of the central regulation of
bacteria, a group of bacteria which has been shown to appetite and satiety. The brain receives signals from
reduce intestinal LPS levels in mice and to improve the gastrointestinal tract through sensory nerves, a classi-
mucosal barrier function.25,27,28 In addition, it has been cal example being, gastric vagal simulation or balloon
shown that higher levels of serum free fatty acids distension induced satiety.42 The vagal afferent path-
(FFAs) play a role in intestinal inflammation and way is a major neural pathway conveying information
activate pro-inflammatory pathways.29,30 Further, from gastrointestinal luminal contents to the brain and
FFAs activate Toll-like receptor 4 (TLR4) signaling in thereby influencing gastrointestinal motility and feed-
adipocytes and macrophages, and can induce metabolic ing behavior. It has been shown that systemic endo-
inflammation.31 toxemia can lead to changes in neuronal function
In another study examining the effects of high fat including vagal afferent neurons.43–45 In a model of
diet, de al Serre et al., demonstrated that high-fat diets chronic infection with Helicobacter pylori, altered
induces changes in the gut microbiota, but it is the feeding behavior was noted two months after eradica-
development of inflammation that is associated with tion of infection, implying a role for gastric inflamma-
the appearance of hyperphagia and obesity phenotype. tion regulating feeding behavior.46 In addition to gut
The high-fat diet led to alteration in microbial flora and microbiota regulating feeding behavior, the brain can
resultant changes in intestinal alkaline phosphatase in turn influence the colonization of the gut. The
and TLR4 expression. In particular, the obesity prone hypothalamic-pituitary-adrenal (HPA) axis is the cen-
rats had increased expression of TLR4, increased ileal tral neuorendocrine pathway in man and activation of
inflammation, altered tight junctions, increased epi- this axis takes place in response to a variety of physical
thelial permeability and plasma LPS levels. It was and psychological stressors. Studies in germ free mice
postulated that increased serum LPS levels could then have demonstrated an exaggerated stress response that
influence insulin resistance leading to the metabolic can be reversed with fecal recolonization (Sudo et al.).
syndrome.32 Overall, although the relative role of these In animal models of stress differences in gut micro-
mechanisms in promoting gut inflammation, and biota have been noted.47 Studies on gut microbiota
consequently metabolic disease, in human disease regulation of satiety through the brain-gut axis are

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Volume 24, Number 4, April 2012 Microbiota and obesity

ongoing and more research is needed to understand the new strategies to transplant human gut microbiota to
exact mechanism of this pathway of microbiota regu- gnotobiotic mice.54Using these models, the effects of
lation of feeding behavior. diet, physical activity, stress, innate and adaptive
immunity on microbiota can be carefully assessed
and seem to play an interrelated role in regulating
weight gain. Ongoing studies involving transfer of
human microbiota from specific communities around
the world to identify metabolic phenotype patterns are
Alteration of gut microbiota through administration of being performed.55 These ‘humanized’ gnotobiotic
probiotics and prebiotics can modulate weight gain.48 animals can be important tools for understanding the
Cani et al. found that in the presence of prebiotic role of diet and genetics in regulating obesity. Lastly,
oligofructose, there was an increase in Bifiobacterium placebo-controlled trials have been initiated in humans
spp. Further there was a reduced impact of high fat diet to examine if microbiota transplants can improve
induced metabolic endotoxemia and inflammatory metabolic health.56
disorders. This was achieved by preventing increased
gut permeability through increased synthesis of
GLP2.49,50 The GLP2 is associated with intestinal
growth and adaptation. In another study administra- In summary with the rapidly spreading obesity epidemic
tion of prebiotics (inulin and oligofructose) resulted in new strategies for the prevention and treatment are
increase in the lactobaccilus species and bifidobacteri- critical. Fig. 1 summarizes the proposed mechanism of
um species numbers and in addition there was an gut microbiota regulation of obesity. Understanding the
increase in satiety hormones GLP-1 and peptide YY role of gut microbiota in regulating metabolism can
(PYY).51 Reduction in the load of microbiota with broad provide new targets for therapy. Microbiota can
spectrum antibiotics can prevent diet-induced obesity influence weight gain by enhancing energy extraction,
through reduction in adipose tissue inflammation, creating a smoldering inflammatory response and by
oxidative stress, and macrophage infiltration in high- enhancing food intake through stimulation of the brain
fat diet-fed mice. This supports the idea of modulation gut axis. Future studies to identify specific bacterial
of gut microbiota as a therapeutic strategy.25,52 species or populations associated with a lean or obese
phenotype can help in directing obesity therapy by
altering the human microbiome.
Further insights into the human microbial community
can help us understand the generation of varied
metabolic phenotypes. The human microbiota is This work was supported by the grants NIH-RO1 (AG) and NIH-
RO1 DK080684 and VA MERIT award (SS).
shaped by the diet that is consumed,53 the host innate
and adaptive immunity, host genetics and other factors
influencing its environment. Gnotobiotic mice can DISCLOSURE
help us understand the role of specific microbiota in
No competing interests declared.
influencing metabolic phenotypes. Kau et al. report

4 Raoult D. Obesity pandemics and the Natl Acad Sci U S A 2007; 104: 979–
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