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Abstract and Figures

The gut microbiome consists of trillions of bacteria which play an important role in human metabolism. Animal and human studies have implicated distortion of the normal microbial balance in obesity and metabolic syndrome. Bacteria causing weight gain are thought to induce the expression of genes related to lipid and carbohydrate metabolism thereby leading to greater energy harvest from the diet. There is a large body of evidence demonstrating that alteration in the proportion of Bacteroidetes and Firmicutes leads to the development of obesity, but this has been recently challenged. It is likely that the influence of gut microbiome on obesity is much more complex than simply an imbalance in the proportion of these phyla of bacteria. Modulation of the gut microbiome through diet, pre- and probiotics, antibiotics, surgery, and fecal transplantation has the potential to majorly impact the obesity epidemic.
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The Gut Microbiome and Obesity
George Kunnackal John
&Gerard E. Mullin
Published online: 2 June 2016
#Springer Science+Business Media New York 2016
Abstract The gut microbiome consists of trillions of bacteria
which play an important role in human metabolism. Animal
and human studies have implicated distortion of the normal
microbial balance in obesity and metabolic syndrome.
Bacteria causing weight gain are thought to induce the expres-
sion of genes related to lipid and carbohydrate metabolism
thereby leading to greater energy harvest from the diet.
There is a large body of evidence demonstrating that alteration
in the proportion of Bacteroidetes and Firmicutes leads to the
development of obesity, but this has been recently challenged.
It is likely that the influence of gut microbiome on obesity is
much more complex than simply an imbalance in the propor-
tion of these phyla of bacteria. Modulation of the gut
microbiome through diet, pre- and probiotics, antibiotics, sur-
gery, and fecal transplantation has the potential to majorly
impact the obesity epidemic.
Keywords Microbiome .Obesity .Microbiota .Diet .
Prebiotic .Probiotic .Microbial balance .Bacteroidetes .
The human microbiome encompasses several trillion mi-
crobes residing in the gut and the genes that are encoded by
them [1,2]. The majority of these microbes reside in the colon,
where they are present in a concentration of 10
mL [3]. There is clear evidence from animal and human stud-
ies that the gut microbiome plays a crucial role in the func-
tioning of the digestive tract and in harvesting energy from the
diet [4,5].
The microbiome maintains the integrity of the intestinal
epithelial barrier thereby offering protection from pathogenic
bacterial colonization [6,7]. In addition, the microbiome is
essential for metabolizing indigestible polysaccharides and
in the absorption of short-chain fatty acids produced by bac-
terial fermentation [8]. It also plays a key role in the regulation
of intestinal transit, thereby affecting the amount of energy
absorbed from the diet [9]. These and other key functions
elucidate the crucial role of the microbiome in weight gain
and metabolism and are reviewed in more detail [10,11].
Current data estimates that approximately 600 million peo-
ple around the world are obese, with an additional 1.9 billion
people being overweight [12]. One of the most cited
microbiome related factors differentiating obese and healthy
individuals has been the shift in the proportion of bacterial
flora belonging to the Firmicutes and Bacteroidetes phyla
which together comprise about 90 % of the microbiota of
the adult gut [13]. The Firmicutes phylum comprises gram
positive organisms from greater than 200 different genera in-
cluding Catenibacterium,Clostridium,Eubacterium,Dorea,
and Veillonella while the Bacteroidetes phylum consists of
gram negative bacteria from approximately 20 genera includ-
ing Bacteroides,Odoribacter,Prevotella,andTannerella [14].
Studies using 16S rRNA gene sequencing of the distal gut
microbiota of ob/ob mice show that there is significant reduc-
tion in the abundance of Bacteroidetes and a similar increase
in the Firmicutes phyla in obese mice [8]. However, subse-
quent studies have shown discrepancies in the proportion of
Bacteroidetes/Firmicutes and its relation to obesity and it is
This article is part of the Topical Collection on Integrative Care
*Gerard E. Mullin
Division of Gastroenterology and Hepatology, Johns Hopkins
Hospital, 600 N. Wolfe Street, Baltimore, MD 21287, USA
Curr Oncol Rep (2016) 18: 45
DOI 10.1007/s11912-016-0528-7
Content courtesy of Springer Nature, terms of use apply. Rights reserved.
... Individuals are born with a "unique network of microbiota that is determined by their DNA" [54]. Most of the human microbiota, primarily bacteria are found in the gut, and evidence suggests that the human gut microbiota has a "significant impact on maintaining immune and metabolic homeostasis and protecting against pathogens" [55]. Studying the microbiomics status of the gut allows determination of the microbial diversity and how they change over time. ...
... Several data show that there is a significantly reduced level in the abundance of Bacteroidetes and an increased level in the Firmicutes phyla in obese subjects [60][61][62]. The Bacteroidetes and Firmicutes are the two largest beneficial bacteria found in the human gut, which "together comprise 90% of the microbiota of the adult gut" and they play an important role in human metabolism and energy homeostasis [55]; however, other subsequent studies found no difference between obese and lean groups in the proportion of Bacteroidetes/Firmicutes and its relation to obesity development [63][64][65]. The discrepancy in the data illustrates that the influence of the gut microbiome on obesity is complex and multifactorial. ...
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Introduction Obesity is a multifactorial chronic disease that cannot be addressed by simply promoting better diets and more physical activity. To date, not a single country has successfully been able to curb the accumulating burden of obesity. One explanation for the lack of progress is that lifestyle intervention programs are traditionally implemented without a comprehensive evaluation of an individual’s diagnostic biomarkers. Evidence from genome-wide association studies highlight the importance of genetic and epigenetic factors in the development of obesity and how they in turn affect the transcriptome, metabolites, microbiomes, and proteomes. Objective The purpose of this review is to provide an overview of the different types of omics data: genomics, epigenomics, transcriptomics, proteomics, metabolomics and illustrate how a multi-omics approach can be fundamental for the implementation of precision obesity management. Results The different types of omics designs are grouped into two categories, the genotype approach and the phenotype approach. When applied to obesity prevention and management, each omics type could potentially help to detect specific biomarkers in people with risk profiles and guide healthcare professionals and decision makers in developing individualized treatment plans according to the needs of the individual before the onset of obesity. Conclusion Integrating multi-omics approaches will enable a paradigm shift from the one size fits all approach towards precision obesity management, i.e. (1) precision prevention of the onset of obesity, (2) precision medicine and tailored treatment of obesity, and (3) precision risk reduction and prevention of secondary diseases related to obesity.
... The intestinal flora contains 1000 to 1500 species of bacteria, which outnumber the body's cells by more than 10 times (Kim and Jazwinski, 2018) and have more than 100 times the total number of genes as humans (Cox et al., 2019). These bacteria play important roles in host metabolism, digestion, the immune system, and the central nervous system (John and Mullin, 2016;Rogers et al., 2016;Dinan and Cryan, 2017;Ipci et al., 2017;Kanji et al., 2018). The theory that the gut microbiota affects lipid metabolism has been extensively studied in mice. ...
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Second-generation antipsychotics (SGAs) are the mainstay of treatment for schizophrenia and other neuropsychiatric diseases but cause a high risk of disruption to lipid metabolism, which is an intractable therapeutic challenge worldwide. Although the exact mechanisms underlying this lipid disturbance are complex, an increasing body of evidence has suggested the involvement of the gut microbiota in SGA-induced lipid dysregulation since SGA treatment may alter the abundance and composition of the intestinal microflora. The subsequent effects involve the generation of different categories of signaling molecules by gut microbes such as endogenous cannabinoids, cholesterol, short-chain fatty acids (SCFAs), bile acids (BAs), and gut hormones that regulate lipid metabolism. On the one hand, these signaling molecules can directly activate the vagus nerve or be transported into the brain to influence appetite via the gut–brain axis. On the other hand, these molecules can also regulate related lipid metabolism via peripheral signaling pathways. Interestingly, therapeutic strategies directly targeting the gut microbiota and related metabolites seem to have promising efficacy in the treatment of SGA-induced lipid disturbances. Thus, this review provides a comprehensive understanding of how SGAs can induce disturbances in lipid metabolism by altering the gut microbiota.
... Microbial communities have been revealed to be closely related to many conditions, such as obesity [1][2][3], diabetes [4][5][6], and HIV [7][8][9]. With the development of highthroughput sequencing technologies enabling large-scale microbiome studies, human microbiome profiling studies for health conditions and diseases are gaining more attention. ...
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Background Microbial communities are known to be closely related to many diseases, such as obesity and HIV, and it is of interest to identify differentially abundant microbial species between two or more environments. Since the abundances or counts of microbial species usually have different scales and suffer from zero-inflation or over-dispersion, normalization is a critical step before conducting differential abundance analysis. Several normalization approaches have been proposed, but it is difficult to optimize the characterization of the true relationship between taxa and interesting outcomes. Results To avoid the challenge of picking an optimal normalization and accommodate the advantages of several normalization strategies, we propose an omnibus approach. Our approach is based on a Cauchy combination test, which is flexible and powerful by aggregating individual p values. We also consider a truncated test statistic to prevent substantial power loss. We experiment with a basic linear regression model as well as recently proposed powerful association tests for microbiome data and compare the performance of the omnibus approach with individual normalization approaches. Experimental results show that, regardless of simulation settings, the new approach exhibits power that is close to the best normalization strategy, while controling the type I error well. Conclusions The proposed omnibus test releases researchers from choosing among various normalization methods and it is an aggregated method that provides the powerful result to the underlying optimal normalization, which requires tedious trial and error. While the power may not exceed the best normalization, it is always much better than using a poor choice of normalization.
... Imbalance of the gut microbiome, caused by dietary or environmental changes, promote overgrowth of pathogenic organisms that may play an important role in the pathology of obesity [8]. In contrast, a healthy balance of gut microbiota may play a role in alleviating or preventing obesity [9,10]. ...
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Probiotics exert anti-obesity effects in high-fat diet (HFD) obese mice, but there are few studies on anti-obesity using heat-killed probiotics. Here, we investigated the effect of heat-killed Lactiplantibacillus plantarum K8 (K8HK) on the anti-differentiation of 3T3-L1 preadipocytes and on anti-obesity in HFD mice. K8HK decreased triglyceride (TG) accumulation in 3T3-L1 cells. Specifically, 1 × 10⁹ CFU/mL K8HK showed the greatest anti-obesity effect, while the same concentration of live L. plantarum K8 (K8 Live) showed cytotoxicity. K8HK increased suppressor of cytokine signaling (SOCS)-1, which might affect the JAK2-STAT3 signaling pathway activated during differentiation. As a result, the levels of transcription factors of adipogenesis such as Peroxisome proliferator-activated receptor γ (PPARγ) and CCAAT/enhancer binding protein α (C/EBPα) decreased in K8HK-treated cells. We also observed a decrease in the lipogenic enzymes and fatty acid binding protein 4 (FABP4). In the mouse study, oral ingestion of K8 Live and K8HK showed weight reduction and decrease in blood TG content at 12 weeks of feeding. In addition, TG synthesis was suppressed in liver and adipose tissues, and genes related to fat metabolism were suppressed. This study suggests that K8HK could be a good material to prevent obesity by inhibiting adipogenesis genes related to fat metabolism.
... Interestingly the two studies experimenting with high-fat diets found opposing results, with Ribeiro et al. [57] stating a decrease of Bacteroidetes phylum to be favorable for neurogenesis, whilst Ma et al. [38] found a decrease at the phylum level to reduce cell proliferation. Bacteroidetes are known to be reduced in obese mice and have been associated with weight loss in humans [103]. In a previous study, obesity led to impaired neurogenesis because of the accumulation of senescent cells in the subventricular zone [64]; how a whole phylum associates with these findings remains unclear. ...
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Growing evidence suggests a possible involvement of the intestinal microbiota in generating new neurons, but a detailed breakdown of the microbiota composition is lacking. In this report, we systematically reviewed preclinical rodent reports addressing the connection between the composition of the intestinal microbiota and neurogenesis and neurogenesis-affecting neurotrophins in the hippocampus. Various changes in bacterial composition from low taxonomic resolution at the phylum level to high taxonomic resolution at the species level were identified. As for neurogenesis, studies predominantly used doublecortin (DCX) as a marker of newly formed neurons or bromodeoxyuridine (BrdU) as a marker of proliferation. Brain-derived neurotrophic factor (BDNF) was the only neurotrophin found researched in relation to the intestinal microbiota. Phylum Actinobacteria, genus Bifidobacterium and genus Lactobacillus found the strongest positive. In contrast, phylum Firmicutes, phylum Bacteroidetes, and family Enterobacteriaceae, as well as germ-free status, showed the strongest negative correlation towards neurogenesis or BDNF mRNA expression. Age, short-chain fatty acids (SCFA), obesity, and chronic stress were recurring topics in all studies identified. Overall, these findings add to the existing evidence of a connection between microbiota and processes in the brain. To better understand this interaction, further investigation based on analyses of higher taxonomic resolution and clinical studies would be a gain to the matter.
... The gut microbiota is another factor significantly related to obesity. 12 Animal studies suggest that gut bacteria can influence the expression of genes related to lipid and carbohydrate metabolism and affect energy harvest from the diet. 13,14 Although likely oversimplified, many studies have reported that a shift in the proportion of phyla composition, such as the Bacteroidetes-to-Firmicutes ratio, is correlated with weight change. ...
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To understand what determines the success of short- and long-term weight loss, we conduct a secondary analysis of dietary, metabolic, and molecular data collected from 609 participants before, during, and after a 1-year weight-loss intervention with either a healthy low-carbohydrate (HLC) or a healthy low-fat (HLF) diet. Through systematic analysis of multidomain datasets, we find that dietary adherence and diet quality, not just caloric restriction, are important for short-term weight loss in both diets. Interestingly, we observe minimal dietary differences between those who succeeded in long-term weight loss and those who did not. Instead, proteomic and gut microbiota signatures significantly differ between these two groups at baseline. Moreover, the baseline respiratory quotient may suggest a specific diet for better weight-loss outcomes. Overall, the identification of these dietary, molecular, and metabolic factors, common or unique to the HLC and HLF diets, provides a roadmap for developing individualized weight-loss strategies.
Childhood acute lymphoblastic leukemia (ALL) is the most common childhood cancer with survival exceeding 90% for standard-risk groups. A debilitating side-effect of treatment is the development of overweight/obesity (OW/OB), which develops in approximately 40% of children by the end of treatment. The microbiome has been associated with the development of OW/OB. We examined fluctuations in the microbiome with the development of OW/OB during the first six months of treatment at diagnosis, and two subsequent timepoints (N = 62). Shotgun metagenomic sequencing was performed on Illumina Nextseq system, and taxa and functional pathways were extracted from sequences using kraken2 and humann2, respectively. An association of increased presence of several species (e.g., Klebsiella pneumoniae, Escherichia coli) was observed in children with OW/OB, while lean-promoting species (Veillonella, Haemophilus, and Akkermansia) were increased in children who maintained a normal weight. Pathway analysis revealed purine nucleotide biosynthesis, sugar nucleotide biosynthesis, and enzyme cofactor biosynthesis were positively correlated with Bacteroides spp. among children with OW/OB. We identified several taxa and functional pathways that may confer increased risk for the development of OW/OB. The associations observed in this pilot are preliminary and warrant further research in the microbiome and the development of OW/OB in childhood ALL.
Objective: To assess the effects of omega-3 (n3) supplementation on intestinal microbiota, fatty acids profile, neuroinflammation, and social memory of cafeteria diet (CAF)-fed rats. Methods: Male Wistar rats were fed with CAF for 20 weeks. Omega-3 (500 mg/kg/day) was supplemented between the 16th and 20th week. Colon morphology, intestinal microbiota composition, short-chain fatty acids (SCFA) and lipopolysaccharide (LPS) in the plasma, fatty acids profile, TLR-4 and claudin-5 expressions in the brain, and social memory were investigated. Results: CAF reduced colon length, crypts' depth, and microbiota diversity, while n3 increased the Firmicutes/Bacteroidetes ratio. CAF increased SCFA plasma levels, but n3 reduced butyrate and isobutyrate in obese rats. LPS was increased in CAF-fed rats, and n3 decreased its levels. In the cerebral cortex, n3 increased caprylic, palmitic, stearic, tricosanoic, lignoceric, myristoleic, and linoleic acids. CAF increased palmitic acid and TLR-4 expression in the cerebral cortex while decreasing claudin-5 in the hippocampus. In the social memory test, CAF-fed animals showed greater social interaction with no effect of n3. Conclusions: The lack of n3 effect in some of the evaluated parameters may be due to the severity of the obesity caused by CAF. However, n3 reduced LPS levels, suggesting its ability to reverse endotoxemia.
Carotenoids have been associated with a number of health benefits. Their dietary intake and circulating levels have been associated with a reduced incidence of obesity, diabetes, certain types of cancer, and even lower total mortality. Their potential interaction with the gut microbiota has been generally overlooked but may be of relevance, as carotenoids largely bypass absorption in the small intestine and are passed on to the colon, where they appear to be in part degraded into unknown metabolites. These may include apo-carotenoids that may have biological effects due to higher aqueous solubility and higher electrophilicity that could better target transcription factors, i.e., NF-κB, PPARγ, RAR/RXRs. If absorbed in the colon, they could have both local and systemic effects. Certain microbes that may be supplemented were also reported to produce carotenoids in the colon. While some bactericidal aspects of carotenoids have been shown in vitro, a few studies have also demonstrated a prebiotic-like effect, resulting in bacterial shifts with health-associated properties. Also, stimulation of IgA could play a role in this respect. Carotenoids may further contribute to mucosal and gut barrier health, such as stabilizing tight junctions. This review highlights potential gut-related health beneficial effects of carotenoids and emphasizes the current research gap regarding carotenoid – gut microbiota interactions.
Conference Paper
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The bacteria colonizing the human intestinal tract exhibit a high phylogenetic diversity that reflects their immense metabolic potential. By virtue of their catalytic activity, the human gut micro-organisms have an impact on gastrointestinal function and host health. All dietary components that escape digestion in the small intestine are potential substrates of the bacteria in the colon. The bacterial conversion of carbohydrates, proteins and nonnutritive compounds such as h,polyphenolic substances leads to the formation of a large number of compounds that may have beneficial or adverse effects on human health.
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The number of prokaryotes and the total amount of their cellular carbon on earth are estimated to be 4–6 × 1030 cells and 350–550 Pg of C (1 Pg = 1015 g), respectively. Thus, the total amount of prokaryotic carbon is 60–100% of the estimated total carbon in plants, and inclusion of prokaryotic carbon in global models will almost double estimates of the amount of carbon stored in living organisms. In addition, the earth’s prokaryotes contain 85–130 Pg of N and 9–14 Pg of P, or about 10-fold more of these nutrients than do plants, and represent the largest pool of these nutrients in living organisms. Most of the earth’s prokaryotes occur in the open ocean, in soil, and in oceanic and terrestrial subsurfaces, where the numbers of cells are 1.2 × 1029, 2.6 × 1029, 3.5 × 1030, and 0.25–2.5 × 1030, respectively. The numbers of heterotrophic prokaryotes in the upper 200 m of the open ocean, the ocean below 200 m, and soil are consistent with average turnover times of 6–25 days, 0.8 yr, and 2.5 yr, respectively. Although subject to a great deal of uncertainty, the estimate for the average turnover time of prokaryotes in the subsurface is on the order of 1–2 × 103 yr. The cellular production rate for all prokaryotes on earth is estimated at 1.7 × 1030 cells/yr and is highest in the open ocean. The large population size and rapid growth of prokaryotes provides an enormous capacity for genetic diversity.
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The rise in the occurrence of obesity to epidemic proportions has made it a global concern. Great difficulty has been experienced in efforts to control this growing problem with lifestyle interventions. Thus, attention has been directed to understanding the events of one of the most critical periods of development, perinatal life. Early life adversity driven by maternal obesity has been associated with an increased risk of metabolic disease and obesity in the offspring later in life. Although a mechanistic link explaining the relationship between maternal and offspring obesity is still under investigation, the gut microbiota has come forth as a new factor that may play a role modulating metabolic function of both the mother and the offspring. Emerging evidence suggests that the gut microbiota plays a much larger role in mediating the risk of developing non-communicable disease, including obesity and metabolic dysfunction in adulthood. With the observation that the early life colonization of the neonatal and postnatal gut is mediated by the perinatal environment, the number of studies investigating early life gut microbial establishment continues to grow. This paper will review early life gut colonization in experimental animal models, concentrating on the role of the early life environment in offspring gut colonization and the ability of the gut microbiota to dictate risk of disease later in life.
Obesity increases the risk of type 2 diabetes, cardiovascular diseases, and certain cancers, which are among the leading causes of death worldwide. Obesity and obesity-related metabolic diseases are characterized by specific alterations in the human gut microbiota. Experimental studies with gut microbiota transplantations in mice and in humans indicate that a specific gut microbiota composition can be the cause and not just the consequence of the obese state and metabolic disease, which suggests a potential for gut microbiota modulation in prevention and treatment of obesity-related metabolic diseases. In addition, dietary intervention studies have suggested that modulation of the gut microbiota can improve metabolic risk markers in humans, but a causal role of the gut microbiota in such studies has not yet been established. Here, we review and discuss the role of the gut microbiota in obesity-related metabolic diseases and the potential of dietary modulation of the gut microbiota in metabolic disease prevention and treatment.
Introduction: Recent studies found that Helicobacter pylori (H. pylori) infection plays a role in cardiometabolic disorders. The objective of this study was to assess the association between H. pylori infection and overweight or obesity in a Chinese population. Methodology: A cross-sectional analysis using data from the subjects who underwent a health examination between January 2010 and June 2012 in the department of comprehensive medicine was performed. Diagnosis of H. pylori infection was achieved using the carbon urea breath test (14C-UBT). The participants were divided into H. pylori infection-positive group and H. pylori infection-negative group by 14C-UBT. Results: A total of 2,050 subjects were enrolled in the study. The H. pylori infection-positive group had significantly higher body mass index (BMI) levels than did the H. pylori infection-negative group (25.32 vs 24.95, p = 0.008). There was a positive association between H. pylori infection and BMI levels (β = 0.30 ± 0.12, p = 0.015). After additional adjustment for white blood cell count (WBCC), the statistical significance disappeared (β = 0.24 ± 0.12, p = 0.053). Furthermore, a positive association between H. pylori infection and overweight/obesity according to different BMI criteria (BMI ≤ 24, BMI ≤ 23) was found. However, the association between H. pylori infection and obesity was consistently significant only based on the Asian criteria (BMI ≤ 27.5), but not significant based on the Chinese criteria (BMI ≤ 28). Conclusion: H. pylori infection was significantly and positively associated with overweight/obesity in a Chinese population.
Studies of the human microbiome have revealed that even healthy individuals differ remarkably in the microbes that occupy habitats such as the gut, skin and vagina. Much of this diversity remains unexplained, although diet, environment, host genetics and early microbial exposure have all been implicated. Accordingly, to characterize the ecology of human-associated microbial communities, the Human Microbiome Project has analysed the largest cohort and set of distinct, clinically relevant body habitats so far. We found the diversity and abundance of each habitat’s signature microbes to vary widely even among healthy subjects, with strong niche specialization both within and among individuals. The project encountered an estimated 81–99% of the genera, enzyme families and community configurations occupied by the healthy Western microbiome. Metagenomic carriage of metabolic pathways was stable among individuals despite variation in community structure, and ethnic/racial background proved to be one of the strongest associations of both pathways and microbes with clinical metadata. These results thus delineate the range of structural and functional configurations normal in the microbial communities of a healthy population, enabling future characterization of the epidemiology, ecology and translational applications of the human microbiome.
The gut microbiota helps balance key vital functions for the host, including immunity and nutritional status. Studies have also linked the microbiome to human mood and behavior, as well as many gut disorders, eczema, and a number of systemic disorders (Azad et al., CMAJ 185:385–394, 2013). Changes in the gut microbiota composition and/or activity may be implicated in the control of inflammation, fat storage, and altered glucose response in obese patients. Dietary short-chain fatty acids appear to be “indirect nutrients” produced by the gut microbiota that can modulate adiposity and immunity as well as send signals to the gut to produce hormones that regulate appetite, permeability, and inflammation. Numerous data have been published regarding differences in the composition of the gut microbiota in obesity. Taken together, the data currently published suggest that specific changes in the gut microbiota occur in overweight or obese patients and are either positively or negatively linked with adiposity, inflammation, and glucose or lipid homeostasis. Manipulation of the microbiota though diet can promote healthy weight loss by altering gut function and metabolism. Probiotics and prebiotics are interesting research tools to assess the relevance of specific bacteria in obesity. Prebiotics may lessen obesity and related metabolic stress by modulating gut peptides involved in the control of appetite and gut barrier function.