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Effect of the Gut Microbiota on Obesity and Its Underlying Mechanisms: an Update
 

Research Highlight

Effect of the Gut Microbiota on Obesity and Its Underlying Mechanisms: an Update*

QIAN Ling Ling1,2,?, LI Hua Ting1,?, ZHANG Lei1,2, FANG Qi Chen1, and JIA Wei Ping1,2,#

doi: 10.3967/bes2015.117

*This work was supported by the National Natural Science Foundation major international (regional) joint research project (81220108006) to WJ; Young Scientists Fund of National Natural Science Foundation (81200292); ‘Chen Guang’ project supported by Shanghai Municipal Education Commission and Shanghai Education Development Foundation (13CG11); Shanghai Rising-Star Program (13QA1402900); Hong Kong Scholars Program (XJ2013035); and Doctoral Fund of Ministry of Education of China (137000) to HL.

1. Department of Endocrinology and Metabolism, Shanghai Jiao Tong University Affiliated Sixth People’s Hospital, Shanghai Clinical Center for Diabetes, Shanghai Diabetes Institute, Shanghai Key Laboratory of Diabetes Mellitus, Shanghai Key Clinical Center for Metabolic Disease, Shanghai 200025, China; 2. Department of Medicine, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China


Obesity has become one of the most prevalent health issues of our time. According to a 2012 WHO report, around 3.4 million adults die each year as a result of being overweight or obese[1]. Humans are in fact superorganisms composed of both human and microbial cells with 2 sets of genes, those encoded in our own genome and those encoded in our microbiota. All these cells and genes have the potential to influence our health[2-3].

In adults, the commensal microbial communities are relatively stable, but can undergo dynamic changes because of their interactions with diet, genotype/epigenetic composition, and immuno- metabolic function. Moreover, differences in the composition of the microbiota in the distal gastrointestinal tract appear to distinguish lean versus obese individuals, suggesting that intestinal dysbiosis contributes to the development of obesity and its consequences[4-5]. By focusing on gut microbes involved in the pathogenesis of obesity, this review summarizes recent advances in understanding regarding the underlying mechanisms, host-gut metabolic interactions, and intervention methods targeting the gut microbiota in basic and clinical research.

Gut Microbiota

The distal human intestine can be viewed as an anaerobic bioreactor containing trillions of bacteria and archaea that are programmed to perform metabolic functions that we have not needed to evolve on our own, including harvesting otherwise inaccessible nutrients from our diet[6]. The human gut is thought to hold approximately 1014 cells (mostly prokaryotic), a number some 10-fold greater than the number of cells constituting the rest of the human body combined[7]. Bacteria are classified from the phylum to species level and the two most abundant bacterial phyla in humans and mice are the Firmicutes (60%-80% of total bacteria) and the Bacteroidetes (20%-40% of total bacteria)[8-9]. The high diversity of organisms in the gut and the infeasibility of standard culture techniques in identifying those organisms historically have limited their study. Only within the past decade, with the advent of shotgun genomic sequencing and array-based microbial identification, the whole breadth of the organismal diversity in the gut has become apparent.

The Gut Microbiota may Have a Causative Role in the Onset and Progression of Obesity in Humans and Animals   Using volunteers who received their own fecal microbiota as controls, researchers showed that obese volunteers who received microbiota donations from lean donors showed significantly improved insulin sensitivity in the serum (although not in the liver) over a 6-week period. This is the first time that the gut microbiota has been shown to have a causative role in the development of insulin resistance in humans[10].

The modified Koch’s postulates could be used to identify the correlation between the gut microbiota and obesity and insulin resistance. Evans[11] proposed a modified version of Koch’s postulates as a unified concept for establishing causation of a putative cause in infectious or non-infectious diseases. According to this concept, three kinds of evidence are required to support causation: an association between the disease phenotypes and the presence of the cells or genetic material of the putative cause, cross-sectionally and/or longitudinally; the reproduction or reduction of the disease phenotypes by experimental addition or removal of the putative cause in humans or animals; and the occurrence of host molecular responses that mechanistically connect the presence of the putative cause to the occurrence of the disease, for the whole concept to make biological or epidemiological sense[12].

Alterations in the compositional patterns of the gut microbiota have been observed in obesity. Several investigations have found that the gut microbiotas of obese humans and obese (ob/ob) mice had a greater ratio of members of the phylum Firmicutes to members of the phylum Bacteroidetes (the F/B ratio) compared to their lean counterparts[13-16]. When obese people lost weight by consuming either a low-fat or low-carbohydrate, calorie-restricted diet, the F/B ratio decreased in association with the percentage reduction in body weight (not caloric intake)[17]. However, other studies in humans and rodents have reported no difference in the F/B ratio in obese versus lean individuals, no effect of weight loss on the F/B ratio, or even a reversed F/B ratio in obese individuals[18-19]. Studying the intestinal microbial compositions of well-phenotyped human subjects enrolled in relatively large metagenome-wide association studies (MGWAS) in both Chinese and European populations has further increased our understanding of the gut microbiota as a contributor to the development of obesity[20-22]. Recently, a study showed that the gut microbial composition differed between obese and non-obese subjects in Japan, suggesting that it was related to obesity[16].

The important question has now become whether we can identify specific members of the gut microbiota that are more relevant than others are to the causative role of the microbiota in human obesity. If so, these members of the gut microbiota might serve as new targets for the control of obesity[4,23].

Bacterial Translocation and Inflammation Reveal the Mechanisms and Roles of the Gut Microbiota in Obesity and Insulin Resistance

Increased Gut Permeability, Gastrointestinal Inflammation, and Immune Dysfunction Lead to Bacterial Translocation   The intestinal epithelial cells provide a barrier that prevents the passage of toxic and potential pro-inflammatory molecules into the sub-mucosa and the systemic circulation. The tight junctions between the mucosal epithelial cells constitute the primary physical intestinal barrier towards the lumen, and leakiness can be caused by changes in the distributions of tight junctionproteins due to signaling from inflammatory cytokines[24]. The concept of ‘bacterial translocation’ is proposed, providing a direct cellular link between the intestinal microbiota and the host, in which intestinal phagocytes such as dendritic cells and macrophages capture bacterial intestinal antigens and transfer them into lysosomes for degradation[25]. Intestinal immune responses, such as the production of IgA antibodies and antimicrobial peptides, influence and are influenced by the gastrointestinal microbiota. Under homeostatic conditions, the intestinal immune system helps to preserve systemic ignorance of intestinal bacteria and regulates its composition over time[26]. Gastrointestinal permeability caused by either intestinal inflammation or intestinal immune dysfunction results in the penetration of bacteria or bacterial products [e.g., lipopolysaccharides (LPS) and DNA] into surrounding tissues and the circulation,   which can drive systemic inflammation[26]. The inflammatory process is characterized by an increased production of cytokines and infiltration of macrophages[27]. During obesity, there is a substantial increase in hepatic macrophages[28]. It has also been shown that obesity is associated with hypothalamic inflammation and that the resulting local production of pro-inflammatory cytokines can cause central leptin resistance, a key feature of obesity[29].

The Gut Microbiota Induces Obesity and Insulin Resistance via Toll-like Receptors (TLR) and Nucleotide-binding Oligomerization Domain (NOD) Proteins    A fat-enriched diet induces a low-grade infection that targets mesenteric adipose tissue through bacterial translocation, which is mostly responsible for the low-grade inflammation contributing to obesity[30]. Metabolic endotoxemia is defined as a moderate increase in the circulating concentration of LPS derived from gram-negative bacteria and it develops owing to alterations in the composition of the gut microbiota and an increase in gut permeability[31].

Intraluminal microbial detection requires the recognition of pathogen associated molecular patterns by pattern recognition receptors that are distributed on the cell surface and within the cytosol of innate immune cells. The TLR and NOD-like receptor families function as extracellular and intracellular pattern recognition receptors, respectively, and trigger innate immune responses[32-33]. In the TLR family, TLR4 is activated by LPS derived from gram-negative bacteria. TLR2, which forms a receptor complex with TLR1 or TLR6, recognizes peptidoglycans and lipoproteins from gram-positive bacteria[34]. Mouse studies have shown that TLR1, TLR5, TLR8, TLR9, and TLR12 are overexpressed in the visceral adipose tissue of diet-induced obese and genetically ob ese ob/ob mice[35].

To date, the precise roles of TLR2 and TLR5 have not been fully elucidated. Animals lacking TLR2 show either higher or lower adiposity/insulin resistance depending on the experimental conditions and their microbiota composition[36-37]. As for TLR5, studies in mice suggest that it is a protective factor. Mice lacking TLR5 (T5KO) exhibit hyperphagia and develop hyperlipidemia, insulin resistance, and increased adiposity[38]. In contrast, in human studies, loss of human TLR5 function protects from weight gain, but analogously to the animal model, the nonsense allele predisposes its carriers to T2DM[39]. A recent human study suggested that bacterial flagellin activated TLR5 inflammatory pathways, decreased insulin signaling, and increased glycerol secretion with an increased abundance of flagellated Clostridium cluster XIV bacteria[40]. Further work is needed to clarify how the gut microbiome modulates TLR5 in animals and humans.

NOD1 and NOD2 are intracellular proteins that recognize cell wall peptidoglycan moieties from gram-negative and gram-positive bacteria, respectively[41]. Peptidoglycan-induced activation of NOD1 in adipocytes or hepatocytes[42-43] and NOD2 in muscle cells[44] triggers insulin resistance through the production of inflammatory mediators and the activation of mitogen activated protein kinases signaling, leading to the desensitization of insulin receptor substrate 1 function.

The Gut Microbiota Mediate Interactions between the Host Metabolism and the Pathogenesis of Obesity and Insulin Resistance

Short-Chain Fatty Acids (SCFAs) and the Gut Microbiota   Non-digestible carbohydrates including xylans, resistant starch, and inulin are fermented in the colon by microbiota into SCFAs, mainly acetate, propionate, and butyrate, to harvest energy for microbial growth. SCFAs are energy substrates for the colonic epithelium (butyrate) and peripheral tissues (acetate and propionate)[45]. Acetate and propionate are taken up by the liver and used as substrates for lipogenesis and gluconeogenesis. Butyrate has many beneficial effects such as combating inflammation, enhancing epithelial barrier function, and increasing insulin sensitivity[46-48].

The positive effect of butyrate on insulin sensitivity is mediated by stimulating the excretion of gastric inhibitory polypeptide and glucagon-like peptide 1 (GLP-1)[47]. In addition, SCFAs can regulate gene expression by binding to the G-protein-coupled receptors GPR41 (FFAR3) and GPR43 (FFAR2). SCFAs suppress inflammation through GPR43 signaling in immune cells, improve insulin secretion, have anti-diabetic effects, and modulate the secretion of the hormone GLP-1 by stimulating enteroendocrine L-cells. The gut microbiota induces peptide YY expression by L-cells through a GPR41-dependent mechanism[48].

Choline Metabolism and the Gut Microbiota Alterations in the composition of the gut microbiota that lead to changes in its metabolism of choline have been shown to be associated with obesity, metabolic syndrome, and diseases such as non-alcoholic fatty liver disease and cardiovascular diseases. Choline metabolism by the gut microbiota also plays an important role in the regulation of glucose homeostasis. Choline is an important component of cell membranes that can be obtained from foods such as red meat and eggs and can be synthesized by the host[49]. Microbial and host enzymatic activities interact in choline’s transformation into toxic methylamines, which can be further metabolized to trimethylamine-N-oxide in the liver[49]. Plasma levels of trimethylamine-N-oxide and its metabolites are correlated with cardiovascular disease[50].

Bile-Acid Metabolism and the Gut Microbiota Cholesterol is used in the human liver to synthesize the primary bile acids, cholic acid and chenodeoxycholic acid. Primary bile acids are conjugated to glycine in humans, and are taken up in the distal ileum for transport to the liver. However, these bile acids are deconjugated by bacteria in the ileum and metabolized by the gut microbiota into secondary bile acids. Bile acids also function as signaling molecules and bind to cellular receptors, such as the bile-acid-synthesis controlling nuclear receptor farnesoid X receptor (FXR) and the G-protein-coupled receptor TGR5[48]. FXR is activated by primary bile acids and impairs glucose metabolism[51], while TGR5 binds secondary bile acids and exerts a beneficial effect by improving liver and pancreatic function and enhancing glucose tolerance through inducing the secretion of GLP-1 by enteroendocrine L-cells[52-53]. Furthermore, TGR5 can increase energy expenditure in brown adipose tissue and can protect against diet-induced obesity[48].

Other Metabolic Processes and the Gut Microbiota Diet-microbial interactions may affect the metabolome and can affect the insulin sensitivity of the host. For instance, the metabolism of phenolic amino acids to p-cresyl sulfates was shown to promote chronic kidney disease-associated insulin resistance[54]. Bacteria belonging to some genera, such as Bacteroides spp., Clostridium spp., and Fusobacterium spp., can promote the biotransformation of phenolic compounds to p-cresylsulfate[55-56]. Kuhn et al. found that the gut microbiota metabolized tryptophan to indole-3-propionic acid, which improves insulin resistance[57]. Some vitamins that are essential to the host are derived from metabolites produced by the gut microbiota, such as folic acid and cobalamin. Metabolic syndrome patients treated with these vitamins achieved improvements in their symptoms

 

of insulin resistance and endothelial dysfunction[58].

Gut Microbes That may Influence Obesity and Insulin Resistance

Summarized from published papers, the phylum Proteobacteria and the species Faecalibacterium prausnitzii and Akkermansiamuciniphila may be beneficial for weight control and insulin sensitivity. Mice with obesity and insulin resistance induced by a high-fat diet had improved insulin sensitivity concomitant with a significant over representation of the phylum Proteobacteria when given the antibiotics ampicillin, neomycin, and metronidazole by mouth, showing that the abundance of the phylum Proteobacteria and insulin sensitivity may be linked[59]. Rats subjected to Roux-en-Y gastric bypass surgery showed a decreased F/B ratio and a striking 52-fold increase in the abundance of the phylum Proteobacteria[60-61], and Zhang et al. demonstrated similar results[16].

An inverse correlation was found between fecal F. prausnitziiand serum concentrations of the inflammatory markers high-sensitivity C-reactive protein, interleukin 6, and orosomucoid[53]. F. prausnitziiare thought to exert such anti-inflammat- ory effects by producing butyrate, and some secreted metabolites are able to block nuclear factor κB activation and interleukin 8 production[62].


 

 

Figure 1. Potential mechanisms linking gut microbiota, host metabolism and obesity and insulin resistance. The disorder of gut microbiota can cause gastrointestinal inflammation, immune dysfunction and an increasing gut permeability, leading to bacterial translocation and the components of bacteria can mediate the TLR and NOD receptors causing systemic inflammation. The gut microbiota can also interact with the host metabolism and influence the pathogenesis of obesity and insulin resistance.


 

The abundances of Clostridium cocleatum and the mucin-degrading bacterium A. muciniphila were demonstrated to increase significantly in mice after metformin treatment[63]. Metformin also significantly improved the glycemic profile of high fat diet fed mice and led toa significant increase in the number of mucin-producing goblet cells in the gut[64].

The beneficial effect of A. muciniphila was demonstrated by Everard et al. that probiotic treatment with A. muciniphila reversed high-fat diet-induced metabolic disorders, including fat-mass gain, metabolic endotoxemia, adipose tissue inflammation, and insulin resistance[65].

Members of the endotoxin-producing genus Enterobacter may causatively contribute to the development of obesity in humans. The strain E. cloacae was isolated from a morbidly obese human’s gut and transferred to germfree mice, in which it induced obesity and insulin resistance. The relative abundance of Enterobacter spp. among the gut microbiota decreased from 35% to an undetectable level after the volunteer lost 51.4 kg of their initial body weight of 174.8 kg. The volunteer also recovered from hyperglycemia and hypertension after 23 weeks of adhering to a dietary intervention[66].

Dietary Interventions, Probiotics, and Fecal Microbiota Transplantation may Treat Obesity and Insulin Resistance by Targeting the Gut Microbiota

Dietary Interventions    Oligofructose intervention was shown to increase the abundance of A.muciniphila in obese and type 2 diabetic mice and result in an improved metabolic profile[65]. Oligofructose can also lower plasma LPS and inflammatory cytokine concentrations, and decrease hepatic expression of markers of inflammation and oxidative stress[67]. Feeding a 4-week high-amylose starch diet to male obese Sprague Dawley? rats led to a lower glycemic response and higher insulin sensitivity compared to feeding them with a high-amylopectin starch diet[68]. Dietary supplementation with resistant starch increased the abundance of representatives of the Actinobacteria and Bacteroidetes phyla and decreased the abundance of those of the Firmicutes phylum in humans[69]. A cranberry extract treatment reduced high fat/high sucrose-induced weight gain and visceral obesity, decreased liver weight and triglyceride accumulation, improved insulin sensitivity, and increased the abundance of the mucin-degrading bacterium A. muciniphila in mice[70]. Fei and Zhao used a diet of whole grains, traditional Chinese medicinal foods, and prebiotics to achieve effective weight-loss and benign metabolic results in an obese volunteer[66].

Probiotics   The administration of Lactobacillus gasseri was shown to decrease fat mass (visceral and subcutaneous) and body mass index in obese and type 2 diabetic patients[71]. In a double blind randomized study, the administration of Lactobacillus spp. was shown to preserve insulin sensitivity as evaluated by euglycemichyperinsulinemic clamp, whereas it decreased in the placebo group[72]. Amar et al. conducted a 1-month probiotic treatment with Bifidobacterium animalis (strain B420), which resulted in decreased bacterial translocation and improved insulin sensitivity, suggesting that certain probiotic interventions can reverse the adverse metabolic phenotype induced by a high-fat diet[30].

Fecal Microbiota Transplantation    Fecal microbiota transplantation (FMT) has proven a highly effective and successful treatment for patients with several diseases[73]. In the study conducted by Vrieze et al., male insulin-resistant subjects with metabolic syndrome received solutions of stool samples from lean donors and showed a significant improvement in peripheral insulin resistance and an altered intestinal microbiota composition[74]. In another study, treatment of obese subjects with metabolic syndrome by using vancomycin resulted in impaired peripheral insulin sensitivity and a decreased diversity of the gut microbiota[75].

Human-to-human FMTs have received considerable attention. However, the USA Food and Drug Administration (FDA) recently ruled that FMT has not received approval for any clinical indications at this point[76]. To justify the standard use of FMT, further large controlled studies are needed to demonstrate the efficacy of FMT[77].

Tables 1 and 2 summarize methods that    have recently been tested for the treatment of obesity and insulin resistance in animal and human research that have targeted the gut microbiota (Tables 1 and 2).

Conclusion

It can be concluded that the microbial community in the gut is complex and that interplay exists among bacterial translocation, chronic inflammation, the immune system, host material metabolism, and the composition of the gut microbiota. Additionally, the gut microbiota is involved in the regulation of multiple host metabolic pathways and host-microbiota metabolic and signaling pathways. Modulation of the gut microbiota through dietary interventions, probiotics, and/or fecal microbiota transplantation represents a promising approach for the treatment of obesity and insulin resistance. The naturally existing human gut microbiota may contain beneficial and harmful species, but precisely how the composition of the gut microbiota relates to health has not yet been clearly illuminated.

Considering the close association of the gut microbiota with the pathogenesis of obesity and insulin resistance, its causal role in the development of these conditions needs to be established and clarified. Further well-designed and longitudinal studies focusing on species-level changes in the composition of the gut microbiota are necessary and should examine deeper taxon levels. Such research has the potential to ameliorate the startling contemporary epidemics of obesity and metabolic disease worldwide.


Table 1. Summary of Treatment Methods of Obesity and Insulin Resistance in Animals by Targeting Microbiota

Treatment Methods

Ref.

Study Subjects

Results

Diet intervention

(a prebiotic diet)

[67]

ob/ob mice

 

prebiotic-treated mice: plasma LPS↓, cytokines↓, hepatic expression of inflammatory and oxidative stressmarkers↓

Diet intervention

(prebiotic treatment)

[65]

C57BL/6J mice

 

prebiotic treatment increased Reg3g expression and improved intestinal homeostasis; Gut microbiome at different taxonomic levels were affected

Diet intervention

(a cranberry extract treatment)

[70]

C57Bl/6J male mice

 

weight gain and visceral obesity↓, insulin sensitivity↑, intestinal triglyceride content, inflammation and oxidative stress↓, Akkermansia↑

Diet intervention

(1% Concord grape polyphenols)

[78]

C57BL/6J mice

weight gain, adiposity, TNF-α, IL-6, LPS, glucose intolerance↓, intestinal gene expression of TNFα, IL-6 Glut2↓, barrier function gene(occludin) ↑, Akkermansiamuciniphila↑, Firmicutes/Bacteroidetes↑

Diet intervention

(fermented green tea extract)

[79]

mice

body weight gain, fat mass ↓, mRNA expression levels of lipogenic and inflammatory genes↓,

glucose intolerance and fatty liver symptoms↓, restored the changes in gut microbiota composition (e.g., the Firmicutes/Bacteroidetes and Bacteroides/Prevotella ratios

Probiotics (ifidobacteriumanimalis subsp. Lactis420 treatment)

[30]

mice

 

bacterial translocation↓, insulin sensitivity↑

Probiotics

(Bifidobacteriumpseudocatenulatum CECT 7765)

[80]

male wild-type

C57BL-6 mice

Firmicutes↓, LPS-producing Proteobacteria↓, TNF-α↓, IL-17A↓,

pro-inflammatory macrophages↓, body weight gain↓, serum cholesterol, triglyceride, glucose and insulin levels↓, oral glucose tolerance and insulin sensitivity

Antibiotics

(vancomycin and bacitracin)

[81]

diet-induced obesity (DIO)

C57BL/6J mice

systemic glucose intolerance, hyperinsulinemia, and insulin resistance in DIO were ameliorated,

metabolically beneficial metabolites derived from the gut↑, Firmicutes and Bacteroidetes depleted

Prebiotics

(water extract of

Ganodermalucidum)

[82]

high-fat diet mice

Firmicutes-to-Bacteroidetes ratios↓, endotoxin-bearing Proteobacteria levels↓, metabolic endotoxemia↓, maintains intestinal barrier integrity

Table 2. Summary of Treatment Methods of Obesity and Insulin Resistance in Humanby Targeting Microbiota

Treatment Methods

Ref.

Study Subjects

Results

Diet intervention

(a WTP diet)

[66]

Human (n=1)

 

amelioration of hyperinsulinemia, hyperglycemia and hypertension, Enterobacter reduced from 35% to 1.8%

Diet intervention

(flaxseed mucilage)

[83]

obese postmenopausal women

(n=58)

C-peptide, insulin release↓, insulin sensitivity↑, relative abundance of 8 Faecalibacterium species↓, alterations in abundance of 33 metagenomic species

Diet intervention

(weight stabilisation diet)

[84]

overweight and obese adults (n=49, including 41 women).

Individuals with higher baseline A. muciniphila displayed greater improvement in insulin sensitivity markers and other clinical parameters after diet intervention. These participants also experienced a reduction in A. muciniphila abundance, but it remained significantly higher than in individuals with lower baseline abundance.

Diet intervention

(L-glutamine)

[85]

overweight and obese adults

(n=33)

Firmicutes/Bacteroidetes decreased from 0.85 to 0.57, genus Dialister, Dorea, Pseudobutyrivibrio and Veillonella(belonging to the Firmicutes phylum)↓

Prebiotics

(Rehmannia glutinosa Libosch,

ShuDihuang)

[86]

female middle-aged subjects

(n=12)

waist↓, phylum Actinobacteria and genus Bifidobacterium↑, phylum Firmicutes and genus Blautia↓ in response to the herbal treatment. B

Probiotics

(Lactobacillus gasseri SBT2055)

[71]

human (n=87)

 

abdominal visceral and subcutaneous fat areas↓,

body weight, BMI, waist, hip↓

Fecal microbiota transplantation

[74]

human (n=18)

 

peripheral and hepatic insulin sensitivity↑, gut microbiota diversity↑, 16 bacterial groups including Roseburiaintestinalis↑

 

These authors equally contributed to this work and are co-first authors of this manuscript.

#Correspondence should be addressed to JIA Wei Ping, Professor, PhD, Tel: 86-21-64367289; Fax: 86-21-64368031; E-mail: wpjia@sjtu.edu.cn

Biographical note of the first author: QIAN Ling Ling, female, born in 1990, Bachelor’s degree, majoring in endocrinology and metabolism.

Received: August 23, 2015;

Accepted: October 27, 2015

References

1. WHO. Obesity and overweight. Fact sheet no. 311. WHO Media Centre. Available from http://www.who.int/mediacentre/ factsheets/ fs311/en/(2014).

2. Nicholson JK, Holmes E, Wilson ID. Gut microorganisms, mammalian metabolism and personalized health care. Nat Rev Microbiol, 2005; 3, 431-8.

3. Zilber-Rosenberg I, Rosenberg E. Role of microorganisms in the evolution of animals and plants: the hologenome theory of evolution. FEMS Microbiol Rev, 2008; 32, 723-5.

4. Duncan SH, Lobley GE, Holtrop G, et al. Human colonic microbiota associated with diet, obesity and weight loss. Int J Obes (Lond), 2008; 32, 1720-4.

5. DiBaise JK, Zhang H, Crowell MD, et al. Gut microbiota and its possible relationship with obesity. Mayo Clin Proc, 2008; 83, 460-9.

6. Backhed F, Ley RE, Sonnenburg JL, et al. Host-bacterial mutualism in the human intestine. Science, 2005; 307, 1915-20.

7. Luckey TD. Introduction to the ecology of the intestinal flora. Am J ClinNutr, 1970; 23, 1430-2.

8. Arumugam M, Raes J, Pelletier E, et al. Enterotypes of the human gut microbiome. Nature, 2011; 473, 174-80.

9. Ley RE, Peterson DA, Gordon JI. Ecological and evolutionary forces shaping microbial diversity in the human intestine. Cell, 2006; 124, 837-48.

10.Nicholson JK, Holmes E, Kinross J, et al. Host-gut microbiota metabolic interactions. Science, 2012; 336, 1262-7.

11.Evans AS. Causation and disease: the Henle-Koch postulates revisited. Yale J Biol Med, 1976; 49, 175-95.

12.Zhao L. The gut microbiota and obesity: from correlation to causality. Nat Rev Microbiol, 2013; 11, 639-47.

13.Turnbaugh PJ, Ley RE, Mahowald MA, et al. An obesity-associated gut microbiome with increased capacity for energy harvest. Nature, 2006; 444, 1027-31.

14.Ley RE, Backhed F, Turnbaugh P, et al. Obesity alters gut microbial ecology. Proc Natl AcadSci USA, 2005; 102, 11070-5.

15.Turnbaugh PJ, Hamady M, Yatsunenko T, et al. A core gut microbiome in obese and lean twins. Nature, 2009; 457, 480-4.

16.Kasai C, Sugimoto K, Moritani I, et al. Comparison of the gut microbiota composition between obese and non-obese individuals in a Japanese population, as analyzed by terminal restriction fragment length polymorphism and next-generation sequencing. BMC Gastroenterol, 2015; 15, 100.

17.Ley RE, Turnbaugh PJ, Klein S, et al. Human gut microbes associated with obesity. Nature, 2006; 444, 1022-3.

18.Zhang C, Zhang M, Wang S, et al. Interactions between gut microbiota, host genetics and diet relevant to development of metabolic syndromes in mice. Isme j, 2010; 4, 232-41.

19.Zhang C, Zhang M, Pang X, et al. Structural resilience of the gut microbiota in adult mice under high-fat dietary perturbations. Isme j, 2012; 6, 1848-57.

20.de Vos WM, Nieuwdorp M. Genomics: A gut prediction. Nature, 2013; 498, 48-9.

21.Karlsson FH, Tremaroli V, Nookaew I, et al. Gut metagenome in European women with normal, impaired and diabetic glucose control. Nature, 2013; 498, 99-103.

22.Qin J, Li Y, Cai Z, et al. A metagenome-wide association study of gut microbiota in type 2 diabetes. Nature, 2012; 490, 55-60.

23.Collado MC, Isolauri E, Laitinen K, et al. Distinct composition of gut microbiota during pregnancy in overweight and normal-weight women. Am J ClinNutr, 2008; 88, 894-9.

24.Brun P, Castagliuolo I, Di Leo V, et al. Increased intestinal permeability in obese mice: new evidence in the pathogenesis of nonalcoholic steatohepatitis. Am J PhysiolGastrointest Liver Physiol, 2007; 292, G518-25.

25.Sansonetti PJ, Di Santo JP. Debugging how bacteria manipulate the immune response. Immunity, 2007; 26, 149-61.

26.Johnson AM, Olefsky JM. The origins and drivers of insulin resistance.Cell, 2013; 152, 673-84.

27.Weisberg SP, Hunter D, Huber R, et al. CCR2 modulates inflammatory and metabolic effects of high-fat feeding. J Clin Invest, 2006; 116, 115-24.

28.Obstfeld AE, Sugaru E, Thearle M, et al. C-C chemokine receptor 2 (CCR2) regulates the hepatic recruitment of myeloid cells that promote obesity-induced hepatic steatosis. Diabetes, 2010; 59, 916-25.

29.Milanski M, Arruda AP, Coope A, et al. Inhibition of hypothalamic inflammation reverses diet-induced insulin resistance in the liver. Diabetes, 2012; 61, 1455-62.

30.Amar J, Chabo C, Waget A, et al. Intestinal mucosal adherence and translocation of commensal bacteria at the early onset of type 2 diabetes: molecular mechanisms and probiotic treatment. EMBO Mol Med, 2011; 3, 559-72.

31.Burcelin R, Garidou L, Pomie C. Immuno-microbiota cross and talk: the new paradigm of metabolic diseases. SeminImmunol, 2012; 24, 67-74.

32.Kufer TA, Sansonetti PJ. Sensing of bacteria: NOD a lonely job. Curr Opin Microbiol, 2007; 10, 62-9.

33.Lundin A, Bok CM, Aronsson L, et al. Gut flora, Toll-like receptors and nuclear receptors: a tripartite communication that tunes innate immunity in large intestine. Cell Microbiol, 2008; 10, 1093-103.

34.Cani PD, Osto M, Geurts L, et al. Involvement of gut microbiota in the development of low-grade inflammation and type 2 diabetes associated with obesity. Gut Microbes, 2012; 3, 279-88.

35.Kim SJ, Choi Y, Choi YH, et al. Obesity activates toll-like receptor-mediated proinflammatory signaling cascades in the adipose tissue of mice. J Nutr Biochem, 2012; 23, 113-22.

36.Ehses JA, Meier DT, Wueest S, et al. Toll-like receptor 2-deficient mice are protected from insulin resistance and beta cell dysfunction induced by a high-fat diet. Diabetologia, 2010; 53, 1795-806.

37.Caricilli AM, Picardi PK, de Abreu LL, et al. Gut microbiota is a key modulator of insulin resistance in TLR 2 knockout mice. PLoS Biol, 2011; 9, e1001212.

38.Vijay-Kumar M, Aitken JD, Carvalho FA, et al. Metabolic syndrome and altered gut microbiota in mice lacking Toll-like receptor 5. Science, 2010; 328, 228-31.

39.Al-Daghri NM, Clerici M, Al-Attas O, et al. A nonsense polymorphism (R392X) in TLR5 protects from obesity but predisposes to diabetes. J Immunol, 2013; 190, 3716-20.

40.Pekkala S, Munukka E, Kong L, et al. Toll-like receptor 5 in obesity: the role of gut microbiota and adipose tissue inflammation. Obesity (Silver Spring), 2015; 23, 581-90.

41.Mogensen TH. Pathogen recognition and inflammatory signaling in innate immune defenses. Clin Microbiol Rev, 2009; 22, 240-73.

42.Schertzer JD, Tamrakar AK, Magalhaes JG, et al. NOD1 activators link innate immunity to insulin resistance. Diabetes, 2011; 60, 2206-15.

43.Zhao L, Hu P, Zhou Y, et al. NOD1 activation induces proinflammatory gene expression and insulin resistance in 3T3-L1 adipocytes. Am J Physiol Endocrinol Metab, 2011; 301, E587-98.

44.Tamrakar AK, Schertzer JD, Chiu TT, et al. NOD2 activation induces muscle cell-autonomous innate immune responses and insulin resistance. Endocrinology, 2010; 151, 5624-37.

45.Bergman EN. Energy contributions of volatile fatty acids from the gastrointestinal tract in various species. Physiol Rev, 1990; 70, 567-90.

46.Brahe LK, Astrup A, Larsen LH. Is butyrate the link between diet, intestinal microbiota and obesity-related metabolic diseases? Obes Rev, 2013; 14, 950-9.

47.Lin HV, Frassetto A, Kowalik EJ, et al. Butyrate and propionate protect against diet-induced obesity and regulate gut hormones via free fatty acid receptor 3-independent mechanisms. PLoS One, 2012; 7, e35240.

48.Tremaroli V, Backhed F. Functional interactions between the gut microbiota and host metabolism. Nature, 2012; 489, 242-9.

49.Dumas ME, Barton RH, Toye A, et al. Metabolic profiling reveals a contribution of gut microbiota to fatty liver phenotype in insulin-resistant mice. Proc Natl AcadSci USA, 2006; 103, 12511-6.

50.Wang Z, Klipfell E, Bennett BJ, et al. Gut flora metabolism of phosphatidylcholine promotes cardiovascular disease. Nature, 2011; 472, 57-63.

51.Sinal CJ, Tohkin M, Miyata M, et al. Targeted disruption of the nuclear receptor FXR/BAR impairs bile acid and lipid homeostasis. Cell, 2000; 102, 731-44.

52.Thomas C, Gioiello A, Noriega L, et al. TGR5-mediated bile acid sensing controls glucose homeostasis. Cell Metab, 2009; 10, 167-77.

53.Furet JP, Kong LC, Tap J, et al. Differential adaptation of human gut microbiota to bariatric surgery-induced weight loss: links with metabolic and low-grade inflammation markers.Diabetes, 2010; 59, 3049-57.

54.Koppe L, Pillon NJ, Vella RE, et al. P-Cresyl sulfate promotes insulin resistance associated with CKD. J Am SocNephrol, 2013; 24, 88-99.

55.Bone E, Tamm A, Hill M. The production of urinary phenols by gut bacteria and their possible role in the causation of large bowel cancer.Am J ClinNutr, 1976; 29, 1448-54.

56.Hughes R, Magee EA, Bingham S. Protein degradation in the large intestine: relevance to colorectal cancer. Curr Issues Intest Microbiol, 2000; 1, 51-8.

57.Kuhn B, Hilpert H, Benz J, et al. Structure-based design of indole propionic acids as novel PPARalpha/gamma co-agonists. Bioorg Med Chem Lett, 2006; 16, 4016-20.

58.Setola E, Monti LD, Galluccio E, et al. Insulin resistance and endothelial function are improved after folate and vitamin B12 therapy in patients with metabolic syndrome: relationship between homocysteine levels and hyperinsulinemia. Eur J Endocrinol, 2004; 151, 483-9.

59.Carvalho BM, Guadagnini D, Tsukumo DM, et al. Modulation of gut microbiota by antibiotics improves insulin signalling in high-fat fed mice. Diabetologia, 2012; 55, 2823-34.

60.Li JV, Ashrafian H, Bueter M, et al. Metabolic surgery profoundly influences gut microbial-host metabolic cross-talk. Gut, 2011; 60, 1214-23.

61.Li JV, Reshat R, Wu Q, et al. Experimental bariatric surgery in rats generates a cytotoxic chemical environment in the gut contents. Front Microbiol, 2011; 2, 183.

62.Sokol H, Pigneur B, Watterlot L, et al. Faecalibacterium- prausnitzii is an anti-inflammatory commensal bacterium identified by gut microbiota analysis of Crohn disease patients. Proc Natl AcadSciUSA ,2008; 105, 16731-6.

63.Lee H, Ko G. Effect of Metformin on Metabolic Improvement and the Gut Microbiota. Appl Environ Microbiol, 2014.

64.Shin NR, Lee JC, Lee HY, et al. An increase in the Akkermansia spp. population induced by metformin treatment improves glucose homeostasis in diet-induced obese mice. Gut, 2014; 63, 727-35.

65.Everard A, Belzer C, Geurts L, et al. Cross-talk between Akkermansiamuciniphila and intestinal epithelium controls diet-induced obesity. Proc Natl AcadSci USA, 2013; 110, 9066-71.

66.Fei N, Zhao L. An opportunistic pathogen isolated from the gut of an obese human causes obesity in germfree mice. Isme J, 2013; 7,880-4.

67.Cani PD, Possemiers S, Van de Wiele T, et al. Changes in gut microbiota control inflammation in obese mice through a mechanism involving GLP-2-driven improvement of gut permeability. Gut, 2009; 58, 1091-103.

68.Aziz AA, Kenney LS, Goulet B, et al. Dietary starch type affects body weight and glycemic control in freely fed but not energy-restricted obese rats. J Nutr, 2009; 139, 1881-9.

69.Martinez I, Kim J, Duffy PR, et al. Resistant starches types 2 and 4 have differential effects on the composition of the fecal microbiota in human subjects. PLoS One, 2010; 5, e15046.

70.Anhe FF, Roy D, Pilon G, et al. A polyphenol-rich cranberry extract protects from diet-induced obesity, insulin resistance and intestinal inflammation in association with increased Akkermansia spp. population in the gut microbiota of mice. Gut, 2014.

71.Kadooka Y, Sato M, Imaizumi K, et al. Regulation of abdominal adiposity by probiotics (Lactobacillus gasseri SBT2055) in adults with obese tendencies in a randomized controlled trial. Eur J ClinNutr, 2010; 64, 636-43.

72.Andreasen AS, Larsen N, Pedersen-Skovsgaard T, et al. Effects of Lactobacillus acidophilus NCFM on insulin sensitivity and the systemic inflammatory response in human subjects. Br J Nutr, 2010; 104, 1831-8.

73.Smits LP, Bouter KE, de Vos WM, et al. Therapeutic potential of fecal microbiota transplantation.Gastroenterology, 2013; 145, 946-53.

74.Vrieze A, Van Nood E, Holleman F, et al. Transfer of intestinal microbiota from lean donors increases insulin sensitivity in individuals with metabolic syndrome. Gastroenterology, 2012; 143, 913-7.

75.Vrieze A, Out C, Fuentes S, et al. Impact of oral vancomycin on gut microbiota, bile acid metabolism, and insulin sensitivity. J Hepatol, 2014; 60, 824-31.

76.Hecht GA, Blaser MJ, Gordon J, et al. What is the value of a food and drug administration investigational new drug application for fecal microbiota transplantation to treat Clostridium difficile Infection? Clin Gastroenterol Hepatol, 2014; 12, 289-91.

77.Singh R, Nieuwdorp M, Ten Berge IJ, et al.The potential beneficial role of faecal microbiota transplantation in diseases other than Clostridium difficile infection. ClinMicrobiol Infect, 2014.

78.Roopchand DE, Carmody RN, Kuhn P, et al. Dietary Polyphenols Promote Growth of the Gut Bacterium Akkermansia muciniphila and Attenuate High-Fat Diet-Induced Metabolic Syndrome. Diabetes, 2015; 64, 2847-58.

79.Seo DB, Jeong HW, Cho D, et al. Fermented green tea extract alleviates obesity and related complications and altersgut microbiota composition in diet-induced obese mice. J Med Food, 2015; 18, 549-56.

80.Moya-Pérez A, Neef A, Sanz Y. Bifidobacterium pseudocatenulatum CECT 7765 Reduces Obesity-Associated Inflammation by Restoring the Lymphocyte-Macrophage Balance and GutMicrobiota Structure in High-Fat Diet-Fed Mice. PLoS One, 2015; 10, e0126976.

81.Hwang I, Park YJ, Kim YR, et al. Alteration of gut microbiota by vancomycin and bacitracin improves insulin resistance via glucagon-like peptide 1 in diet-induced obesity. FASEB J, 2015; 29, 2397-411.

82.Chang CJ, Lin CS, Lu CC, et al. Ganoderma lucidum reduces obesity in mice by modulating the composition of thegut microbiota. Nat Commun, 2015; 23, 489.

83.Brahe LK, Le Chatelier E, Prifti E, et al. Dietary modulation of the gut microbiota - a randomised controlled trial in obese postmenopausal women. Br J Nutr, 2015; 2, 1-12.

84.Dao MC, Everard A, Aron-Wisnewsky J, et al. Akkermansia muciniphila and improved metabolic health during a dietary intervention in obesity: relationship with gut microbiome richness and ecology. Gut, 2015; pii: gutjnl-2014-308778.

85.de Souza AZ, Zambom AZ, Abboud KY, et al. Oral supplementation with L-glutamine alters gut microbiota of obese and overweight adults: A pilot study. Nutrition, 2015;31, 884-9.

86.Han K, Bose S, Kim YM, et al. Rehmannia glutinosa reduced waist circumferences of Korean obese women possibly through modulation of gut microbiota. Food Funct, 2015; 6, 2684-92.


 

 
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