The Role of the Gut Microbiome in the Pathogenesis and Treatment of Obesity

Francis Okeke, MD, Bani Chander Roland, MD, and Gerard E. Mullin, MD

Francis Okeke, Division of Gastroenterology and Hepatology, Johns Hopkins University School of Medicine, Baltimore, Maryland, United States.

Contributor Information.

Corresponding author.

Correspondence Gerard E. Mullin MD [email protected]

INTRODUCTION: OBESITY AND THE MICROBIOTA

The human body is colonized by microorganisms that number in the hundreds of trillions (10¹⁴), essentially outnumbering the total number of eukaryotic cells (60 trillion) that make up a human.¹ These organisms can be found all over the body and throughout the gastrointestinal (GI) system from the mouth to the rectum, with the highest concentration of organisms localized to the colon (10¹¹-10¹²). Over time, humans and these microorganisms have found a method to live in symbiosis—in essence helping one another survive. This community of microorganisms forms an ecosystem that exists in and on every human is broadly termed the microbiome. There exists a skin microbiome, urogenital microbiome, and a gastrointestinal microbiome (composed of bacteria, archaea, microeukaryotes, fungi, and viruses). This review will focus primarily on the gut microbiome and its relationship to obesity.

CLASSIFICATION

The gut microbiome has been classified into close to 1000 different species.¹ To date, only about 29 to 52 bacterial phyla have been identified. Of these, 10 have been identified to colonize the colon, with 2 phyla predominating (>90%)²—the Bacteroidetes (eg, genera Bacteroides and Prevotella) and Firmicutes (eg, genera Clostridium, Ruminococcus, Enterococcus, and Lactobacillus). Other phyla that have been identified include Actinobacteria (eg, genus Bifidobacterium, a strict anaerobic bacteria has been implicated in early colonization of newborn babies as early as day 3 and has been thought to play a key role in stabilizing the microbiome during the weaning phase of life³); Proteobacteria (eg, genus Helicobacter and Escherichia); Fusobacteria; Spirochaetae; and Verrucomicrobia.²

The number of organisms that constitute the human microbiome outnumber the host’s eukaryotic cells by a factor of 10.⁴ Additionally, the genome of the microbiome is thought to contain close to 150 times the number of genes in humans.¹ This gives the gut microbiome the symbolic status of an organ consisting of prokaryotic cells working in conjunction with its human host’s eukaryotic cells to maintain good health.⁵

FUNCTIONS OF THE GUT MICROBIOME

The microbiome presumably carries out specific functions unable to be performed by the host. In this issue of Global Advances in Health and Medicine, Dr Gregory Plotnikoff discusses in detail the various functions of the gut microbiome. Some relevant functions that are pertinent to our discussion of its impact upon the development of obesity include:

1. Synthesis of vitamins and cofactors⁶

2. Digestion and breakdown of complex polysaccharides to short-chain fatty acids (SCFA; eg, propionate, butyrate, acetate, the main nutritional substrate for colonic epithelial cells)^7,8

3. Regulation of gastrointestinal motility and vascularization of the GI tract.^9–12

4. Influence fatty acid composition of the retina and lens of the eye¹²

5. Affect bone density¹²

6. Development of adaptive immunity.¹³

EUBIOSIS: THE GUT MICROBIOME IN HEALTH

This issue of Global Advances in Health and Medicine is dedicated to the microbiome and its impact upon health and disease. It has been said that “a healthy microbiota is defined by high diversity and an ability to resist change under physiological stress. In contrast, microbiota associated with disease (ie, dysbiosis) is defined by lower species diversity, fewer beneficial microbes, and/or the presence of pathobionts.”²

The intrauterine environment was previously hypothesized to be sterile; however, recent evidence suggests that this is not the case. Traces of microorganisms, including DNA and cell structures from intestinal bacteria, have been detected in the placenta, amniotic fluid, and fetal membranes.^14–16 It has also been proposed that the colonization of the gut appears to develop according to a prescheduled plan already in place once we are born. Additionally, it is presumably affected by a variety of extrinsic factors such as mode of delivery of the baby, exposure to antimicrobials, and type of nutrition (breast milk, cow milk, formula, and/ or other dietary exposures), environment, host genetics, maternal diet, and other extrinsic factors.²

Despite the above factors that influence the overall microbiota, further studies with metagenomics suggest that the overall human gut microbiome is predominantly made up of three clusters/subtypes which have been dubbed “enterotypes” and include Bacteroides (enterotype 1), Prevotella (enterotype 2) and Ruminococcus (enterotype 3).¹⁷ These enterotypes were shown to be independent of gender, ethnicity, age, weight, or body mass index (BMI) but do appear to be strongly associated with long-term dietary habits, especially high protein, red meat, and animal fat, which affects enterotype 1-Bacteroides, while consumption of a high-carbohydrate diet or vegetarian diet affects enterotype 2-Prevotella,^2,5,18 and consumption of a diet high in resistant starch has been identified as affecting enterotype 3-Ruminococcus.^19,20

DYSBIOSIS: THE GUT MICROBIOME IN DYSFUNCTION

Perturbations to the intestinal ecosystem typically occur on a nearly daily basis given that this is the main portal for a large percentage of the daily intake into our bodies. These perturbations can come about in a variety of ways including nutrition/diet, antibiotics, and exposure to environmental factors, including pathogens and chemicals. It has been hypothesized that shortterm insults to the microbiome do not usually result in long lasting effects, as the microbiome has been described as plastic and thus able to adapt to short-term perturbations. On the other hand, prolonged exposure to these insults appear to induce changes in the microbiota, which result in a variety of effects on the host, some deleterious and others not yet understood.

Studies have hypothesized that a dysbiotic (as opposed to a eubiotic) microbiome predisposes the host to a variety of gastrointestinal disorders (Table 1). Imbalances in the gut microbiome have been described for a number of disorders such as irritable bowel syndrome (IBS), functional bowel disorders (FBD),^21,22 inflammatory bowel disease (IBD, eg, ulcerative colitis and Crohn’s disease,^23,24 and colorectal cancer,^25,26 as well as global/systemic illnesses such as allergic diseases,²⁷ non-alcoholic steatohepatitis (NASH),^28,29 arteriosclerotic diseases,^30,31 and metabolic syndromes, most notably obesity,^32–34 and diabetes,^35,36 which are the subject of this review.

DIET AND THE MICROBIOME

The effect of different diets on the gut microbiome has been studied extensively in mouse models. Fewer studies have been done in humans to evaluate the effects of various dietary components on the gut microbiome. The findings in animal and human studies are summarized in Table 2, adapted from Chan et al.²

The above studies lend credence to the fact that dietary habits have an immediate and lasting effect on the microbiome, and further studies are required to address what these effects are long term and how we can intervene to lead to better health outcomes.

OBESITY

Several changes have been reported in regards to the microbiome in overweight and obese individuals. These changes have been noted not only in the composition, but also in the diversity of species and metabolic functions of the microbiome.⁵³ Composition changes previously reported include increase in Firmicutes; decrease in Bacteroidetes, Bacteroides, Bifidobacterium, and Akkermansia muciniphila; and increase/decrease in Desulfovibrionaceae, Ruminococcaceae, and Rikenellaceae, while changes in function include an increase in production of enzymes involved in membrane transport and processing of complex polysaccharides, downregulation of genes involved in transcription processes, synthesis of cofactors, vitamins, and metabolism of nucleotides. These changes have yet to be causally linked in humans. The majority of human studies done have reported some change in the microbiome of subjects with obesity as compared to lean subjects. Select studies are summarized in Table 3⁵⁴ and demonstrates the results of a few studies that have evaluated the intestinal microbiome in obese subjects.

RELATIONSHIP OF OBESITY AND THE MICROBIOME

Ley et al were the first to provide a strong link between obesity and the gut microbiome. Their group carried out the study in leptin-deficient mice (homozygous for an aberrant leptin gene ob/ob, which caused weight gain).⁶⁵ Using 16S ribosomal RNA (rRNA) gene sequencing, they found that the bacterial components of the ceca of the ob/ob mice were different from lean wild type mice (+/+), or heterozygous (ob/+) mice. They also reported a higher representation of the Firmicutes and fewer Bacteroidetes.

Metagenomic analysis of the same microbial communities revealed an upregulation in genes involved in energy extraction from food in the ob/ob population when compared to their lean counterparts. Turnbaugh PJ et al were able to demonstrate that transplantation of the cecal contents of ob/ob vs ob/+ vs +/+ into germ-free mice (GFM) led to more weight gain in the GFM receiving the obese mice microbiota than recipients of the lean mice microbiota over a 2-week period, despite having equivalent food intake.³²

Additional studies have been done looking at the microbiome in obese humans; however, the results have been somewhat difficult to translate into clinical practice. Most of the recent studies used varying methods to detect the microbiome in question, and this may in turn account for why the majority of studies are somewhat discordant in their findings.

Depending on the outcome in question, qualitative vs quantitative outcome, this usually drives the diagnostic tool applied such as culture based methods; fluorescence in situ hybridization (FISH); quantitative polymerase chain reaction (qPCR); DNA fingerprinting techniques, such as temperature gradient gel electrophoresis TGGE and denaturing gradient gel electrophoresis DGGE; DNA phylogenetic microarrays, such as MITChip, HITChip; next generation sequencing methods and Shotgun Sanger Sequencing method (shotgun, 454 pyrosequencing, Illumina, and SOLiD).⁵³ Most studies looking at the same outcomes were performed using different detection techniques, and this may account for their discordant findings. Angelakis et al performed a meta-analysis of the studies of the gut microbiome in obesity with respect to the 2 predominant phyla—Bacteroidetes and Firmicutes—as well as the preponderance of key bacteria including Bifidobacterium and lactobacillus (Figures 1–3).^{33,37,56,57,59–62,64–71,72}

Open in a separate window

Figure 1

Meta-analysis of the obesity-associated gut microbiota alterations at the phylum level.

Meta-analysis was performed with the comprehensive meta-analysis software version 2 (Biostat, Englewood, New Jersey). Each line represents a comparison between an obese group (right) and a control group (left). The first reported alteration⁶⁵ was a decrease in the relative proportion of Bacteroidetes (percentage decrease) represented by a deviation of the square (standardized difference in the means) to the left. The size of the square represents the relative weight of each comparison (random model). The length of the horizontal line represents the 95% CI and the diamond represents the summarized effect. The presence of a square to the right and left of the midline means studies with conflicting results corresponding to a substantial heterogeneity (12 >50%). Here, the only reproducible and significant alteration at the phylum level is the decrease in the absolute number of sequences of Firmicutes in obese subjects. Relative count of Bacteroidetes (n=4; SDM=−0.51; 95% CI=-1.7-0.67; P=.40 [I²=81%]); absolute count of Bacteroidetes (n=4; SDM=-0.07; 95% CI=-0.78-0.65; P=.86 [I²=85]); relative count of Firmicutes (n=3; SDM=0.88; 95% CI=-0.21-1.97; P=.11 [I²=79%]); absolute count of Firmicutes (n=3; SDM=-0.43; 95% CI=-0.72 to -0.15; P=.003 [I²=0%]).

Abbreviations: FCM, Flow cytometry; Ow, Overweight; qPCR, Quantitative PCR; SDM, standardized difference in the means.

Reproduced with permission from Angelakis E, Armougom F, Million M, et al. The relationship between gut microbiota and weight gain in humans. Future Microbiol. 2012;7(1):91-109.66

Open in a separate window

Figure 3

Meta-analysis of the obesity-associated gut microbiota alterations at the genus level for Bifidobacteria and Lactobacilli comparing the absolute number of sequences generated by genus-specific quantitative PCR.

For Bifidobacteria, a consistent difference was found by our meta-analysis between 159 obese subjects and 189 controls from six published studies showing that the digestive microbiota of the obese group was significantly depleted in Bifidobacteria. Low heterogeneity (I²=17%) shows that this result is very robust. Additional tests have shown that there was no small studies bias (Egger’s regression intercept test, P=.92; no change after Duval and Tweedie’s trim and fill). For Lactobacilli, no consistent and significant summary effect was found comparing 127 obese subjects and 110 controls from three studies. Bifidobacterium spp (n=6; SDM=-0.45; 95% CI=-0.69 to -0.20; P<.001 [I²=17%]); Lactobacillus spp (n=3; SDM=0.29; 95% CI=-0.31-0.90; P=.34 [I²=80%]).

Abbreviations: Ow: overweight; SDM, atandardized difference in the means.

Reproduced with permission from Angelakis E, Armougom F, Million M, et al. The relationship between gut microbiota and weight gain in humans. Future Microbiol. 2012 Jan;7(1):91-109.⁶⁶

Open in a separate window

Figure 2

Population of bacteria found to increase in obese and lean individuals.

Summary of evidence for consistent changes in the gut microbiome of obese human subjects versus lean individuals.

Reproduced with permission from Angelakis E, Armougom F, Million M, et al. The relationship between gut microbiota and weight gain in humans. Future Microbiol. 2012 Jan;7(1):91-109.⁶⁶

PATHOPHYSIOLOGIC MECHANISMS OF THE MICROBIOME AND OBESITY DEVELOPMENT

Data collected from a variety of mice models indicate that an altered microbiome can be found in a variety of metabolic diseases. Additionally, the disordered microbiome does not appear to be only a consequence of this disorder, but plays a key role in driving these metabolic disorders through the following potential mechanisms (Figure 4)^5,54,73–75:

Open in a separate window

Figure 4

The gut microbiome has a regulatory function on host energy metabolism.

By breaking down nondigestible polysaccharides, gut microorganisms produce monosaccharides and short-chain fatty acids (SCFAs). SCFAs bind to GPR 41/43 receptors and stimulate peptide YY (PYY) production, which inhibits gut motility and allows gut microbes to digest more polysaccharides. Gut microbes also regulate energy metabolism by reducing the expression of fasting-induced adipocyte factor (Fiaf) from gut epithelial cells. Suppressed Fiaf release results in the degradation of lipoproteins and deposition of free fatty acids in adipose tissues. The adiposity in liver and skeletal muscles is also regulated by microorganisms through the changes of phosphorylated adenosine monophosphate-activated protein kinase (AMPK) levels.

Abbreviations: LPL, lipoprotein lipase; VLDL, very low density lipoprotein.

Reproduced with permission from Brown RK, Zehra-Esra I, Dae-Wook K, DiBaise JK. The Effects of gut microbes on nutrient absorption and energy regulation. Nutr Clin Pract. 2012;27:201-214.⁷²

3. Microbiome and Inflammation

The gut microbiota has been implicated in inducing low-grade chronic inflammation in the gut directly or increasing systemic loads of microbial ligands, this effect has been most notable in subjects that consume a high-fat diet.^93,94

A high-fat diet has been shown to increase the serum levels of lipopolysaccharide (LPS).⁹⁵ LPS is a component of the cell wall of gram-negative bacteria (eg, Bacteroidetes), which leads to the production of pro-inflammatory cytokines in different tissues of the body. Another study demonstrated that microbiome changes associated with obesity led to increased metabolic endotoxemia, inflammation, and other associated disorders through a GLP-2 mediated gut permeability mechanism.⁸⁷ Cani et al found that subcutaneous infusion of LPS can lead to weight gain and insulin resistance in mice without changes in dietary intake.

• High Voltage Detox Reviews
• Does Aspirin Work to Pass a Drug Test

86

Other investigators reported that mice who were deficient in the toll-like receptor (TLR) 5 (a transmembrane protein expressed in the intestinal mucosa, which functions to recognize bacterial flagellin, and is also involved in the innate immune system that helps defend against infection), had subsequent development of similar features of metabolic syndrome including hyperphagia, obesity, insulin resistance, and hepatic disease. TLR5 deficiency was also noted to affect the microbiome and transfer of the microbiome of the TLR5 deficient mice to healthy mice resulted in development of similar features of metabolic syndrome.⁹⁶

Another mouse model demonstrated that a high fat diet induced obesity also led to changes in the microbiome and activation of TLR4 (acts by recognition of LPS) leading to subsequent gastrointestinal inflammation associated with the obese phenotype.⁹⁴ One murine study showed that mice lacking this TLR4 were as resistant to diet induced obesity and insulin resistance as germ free mice are.⁹⁷ Another study found that mice transplanted with an endotoxin-producing Enterobacter cloacae B29 strain that was isolated from an obese human led to development of obesity and disorders of glucose metabolism if the germ free mice were fed with a high fat diet, but not a normal diet.⁹⁸

Other investigators described a link of low-grade inflammation due to endotoxemia to obesity through the gut microbiome via upregulation of the endocannabinoid (eCB) system tone.⁹⁹ Indeed, the eCB system appears to control gut permeability and adipose tissue physiology through an LPS-eCB system regulated cycle, and also plays a part in obesity and adiposity (Figure 5).¹⁰⁰

Open in a separate window

Figure 5

Gut microbiota dysbiosis and the role of inflammation in the metabolic impairments of obesity.

The origin of metabolic diseases is multifactorial but the impact of deleterious feeding habits is certainly the major factor responsible. This directly modifies intestinal ecology and we first showed that upon an increased intestinal permeability it led to an increased circulating concentration of LPS from Gram-negative bacteria of intestinal origin86,101 called metabolic endotoxemia. The inflammatory factors LPS and other bacterial fragments can translocate toward target tissues such as the blood, the liver, and the adipose depots or the arterial wall to interfere with cells from the immune system to generate the chronic low-grade inflammation required for the development of metabolic and cardiovascular diseases.

Reproduced with permission from Burcelin R, Sermino M, Chabo C, et al. Acta Diabetol. 2011;48(4): 257-273.100

THERAPEUTIC TARGETS

The question that begs to be answered is whether the intestinal microbiota is a plausible target for obesity treatment. The authors believe that the microbiome offers a logical approach that may be targeted to potentially ameliorate a variety of metabolic and gastrointestinal diseases.

In that regard, certain obligatory steps will be necessary to target the microbiota prior to resulting in reasonable, long-term results; these steps include

1. standardization of detection techniques for most microbiome studies;

2. better collaboration among researchers who are studying the microbiome;

3. larger, prospective studies on humans evaluating the effects of a variety of diets on the microbiota using similar detection techniques; and

4. identifying specific species within the microbiome that can be easily targeted and manipulated without resulting in harmful effects to the host.

Therapies directed at the microbiome in an attempt to correct some of the underlying problems associated with obesity, including metabolic syndrome (hyperphagia, insulin resistance, liver disease, chronic low grade inflammation), may likely be beneficial in the long run to reduce the burden of obesity on the healthcare system. Obesity and its sequelae were estimated to cost the healthcare sector $147 billion in 2008. Additionally, it was also estimated to cost an obese person $1429 per year more as compared to a normal weight individual for medical treatment.¹⁰²

Some plausible targets for future therapies could look at manipulation of the pathways that have been associated with the microbiome and development of possible obesity and metabolic syndrome, including

1. Angptl4 pathway,

2. TLR4 and LPS pathway,

3. TLR5 and Bacterial flagellin pathway,

4. GPR41/Gpr43 and SCFAs pathways,

5. AMPK and oxidation of fatty acids, and

6. eCB and LPS pathway.

PREBIOTICS

Prebiotics are usually comprised of “nondigestible” elements that can serve as fuel for the microbiome and usually consist of oligosaccharides: fructooligosaccharides (FOS) and galactooligosaccharides (GOS). Some studies have shown that they can have beneficial health effects on the host by leading to changes in both activity and function of beneficial organisms in the microbiome,¹⁰³ and also by reducing adiposity.¹⁰⁴

Inulin is a naturally derived prebiotic (from plants, and FOS compounds) and is one of the most studied prebiotics, it has been shown to specifically stimulate the growth of Bifidobacteria, decrease weight gain, improvement in glucose metabolism,^98–100 and also reduction of metabolic endotoxemia.^87,108 It has been found to increase A muciniphila, shown to negatively correlate with body weight,⁸⁹ and it also has an influence on production of gut hormones like glucagon like peptide-1 (GLP-1), peptide yy (PYY), and ghrelin, both in mice^108–111 and humans.^112–114

A summary of a few prebiotic studies done in both mouse and humans are summarized here:

1. Prebiotic fiber supplemented in obese mice showed a reduction in the ratio of Firmicutes to Bacteroidetes in the microbiome and also reduction in hepatic de novo lipogenesis and a such help ameliorate the effects of nonalcoholic fatty liver disease (NAFLD).¹⁰⁹

2. Supplementation with fungal chitin glucan and noted that there was a significant increase in bacteria related to Clostridium cluster XIVa, including Roseburia spp, accompanied by a decrease in fat production and weight gain.¹¹⁵

3. Supplementation with galactooligosaccharides (GOS) in healthy subjects for 12 weeks led to an increase in the Bifidobacterium spp and a decrease in Bacteroides.¹¹⁶

4. Ninety-seven adolescents were supplemented with a prebiotic, and noted that subjects that received the prebiotic for 1 year had a smaller increase in their body mass index and fat mass index when compared to controls.¹¹⁷

5. Mice fed a high-fat diet and arabinoxylans derived from wheat were found to selectively restore the Bacteroides/Prevotella spp, Roseburia spp, and increase the number of Bifidobacterium spp, especially Bifidobacterium animalis lactis.¹¹⁸

6. Seven patients with NASH were given FOS vs placebo for 8 weeks and the prebiotic subjects were found to have reductions in LFTs and insulin levels that were significant.¹¹⁹

7. Inulin supplementation in diet of obese women was shown to increase Bifidobacterium spp and F praunsnitzii and decrease Bacteroides intestinalis, B vulgates, and Propionibacterium; there was only a aslight non-significant decrease in fat mass associated with these changes in the microbiome.¹²⁰

PROBIOTICS

Probiotics are living, commensal microbes that have a purported beneficial effect on the host. They are essentially thought to act by modulating the gut microbiome equilibrium, preventing translocation of bacteria, epithelial invasion, inhibiting adherence to mucosal surfaces of harmful bacteria, and stimulate the immunity of the host. The efficacy of probiotics remain highly debatable and studies to date have had varied results especially with regards to anti-obesity effects. A Cochrane review on use of probiotics in NAFLD, suggested the need for more large scale randomized controlled trials in NAFLD patients, but noted that some of the randomized trials did find it useful in this patient population.¹²¹

Some applications of probiotics with good evidence include prevention of antibiotic associated diarrhea,¹²² treatment of necrotizing enterocolitis in premature infants,¹²³ enhancing urogenital health in females,¹²⁴ and preventing infection and allergies as related to pulmonary function.^125,126

Delzenne et al reviewed the effects of prebiotics and probiotics on obesity and diabetes and is summarized in Table 4.¹²⁸

SYMBIOTICS

Symbiotics are a combination of prebiotics and probiotics, based on the hypothesis that this will be a synergistic relationship and possibly lead to better outcomes when either is administered alone. In the table from Chan et al, mentioned previously in the probiotic section, there were a total of three studies looking at symbiotics, which all had favorable outcomes.² One other study looking at symbiotics in a pediatric population¹³⁷ did report a significant increase in microbial counts when compared to participants that were given a placebo, although this was not compared to just a probiotic alone.

To date, there has not been any significant benefit reported over administering only probiotics or prebiotics as compared to symbiotics. This area merits further investigation.

ANTIBIOTICS

Antibiotics have been used for a variety of applications since they were first discovered to cure bacterial illnesses. One use of antibiotics has been to help livestock gain weight. Cho and colleagues demonstrated and the level of antibiotics present in meat and poultry is sufficient to cause weight gain in animal models of diet-induced obesity. It has been hypothesized that antibiotic use early in life may lead to disruptions in the microbiome, perhaps predisposing the host to the development of obesity.¹³⁸ Antibiotic use has also been implicated in the pathophysiological development of IBS^139,140 and Crohn’s disease. It has further been reported that antibiotic use during episodes of acute bacterial gastroenteritis may lead to long-term gastrointestinal sequelae¹⁴¹

It has also been hypothesized that eradication of H pylori in the industrialized nations might have some relationship to the obesity epidemic, through alterations in the serum/gastric ghrelin and gastric leptin levels.¹⁴² Francois et al demonstrated that eradication of H pylori led to significant increases in circulating meal-associated leptin and ghrelin levels and BMI, providing some direct evidence that colonization with H pylori does in fact play a role in regulation of these gut hormones with consequent effects on the morphology of the body.¹⁴³ Large population-based dataset analyses; however, have not shown any association between H pylori and obesity to date. Thus, further prospective studies are required.

Despite this, there may be a role for the shortterm use of intraluminal/poorly absorbed antibiotics or antimicrobial herbals in the management of obesity on the horizon.

SUMMARY AND CONCLUSIONS

In summary, the intestinal microbiota contributes to key vital functions for the host, including immunity and nutritional status. Prior studies have linked an altered microbiota to a number of metabolic, gastrointestinal, and systemic illnesses. In obesity, changes in the intestinal microbiota composition and function have also clearly been implicated in the control of inflammation, fat storage, and abnormal glucose response. Byproducts of the gut microbiota, such as short-chain fatty acids, also appear to modulate adiposity by producing hormones that regulate appetite, intestinal permeability and inflammation.

Prior studies have reported varying data regarding alterations in the composition of the gut microbiota in obesity. It is clear from the current literature; however, that specific changes in the microbiota composition do occur in overweight or obese individuals presumably leading to inflammation, and altered glucose and lipid homeostasis, thus predisposing to adiposity. Manipulation of the microbiota through diet and/or antibiotics may therefore promote weight loss by altering intestinal function and metabolism. Probiotics and prebiotics may also be of relevance of specific bacteria in obesity. Prebiotics have additionally been postulated to improve weight loss in obese subjects by modulation of gut peptides involved in the control of appetite and intestinal barrier function. There is a tremendous scope of research ongoing in this field, with exciting discoveries being made as new deep sequencing techniques emerge. We are hopeful that this research will subsequently translate into clinical practice for the treatment not only of obesity, but for a variety of metabolic disorders. This will likely only be achieved with increased collaboration among researchers and institutions, standardization of detection techniques, and large-scale, prospective trials.

Notes

Disclosures The authors completed the ICMJE Form for Disclosure of Potential Conflicts of Interest. Drs Okeke and Roland had no conflicts to disclose; Dr Mullin disclosed that he is a consultant for Abbott Laboratories, Chicago, Illinois.

Contributor Information

Francis Okeke, Division of Gastroenterology and Hepatology, Johns Hopkins University School of Medicine, Baltimore, Maryland, United States.

Bani Chander Roland, Division of Gastroenterology and Hepatology, Johns Hopkins University School of Medicine, Baltimore, Maryland, United States.

Gerard E. Mullin, Division of Gastroenterology and Hepatology, Johns Hopkins University School of Medicine, Baltimore, Maryland, United States.

REFERENCES