Diabetes, obesity and gut microbiota Everard, Amandine, M.Sc., Pharm; Cani, Patrice D., PhD
Baillière's best practice & research. Clinical gastroenterology,
02/2013, Letnik:
27, Številka:
1
Journal Article
Recenzirano
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Abstract The gut microbiota composition has been associated with several hallmarks of metabolic syndrome (e.g., obesity, type 2 diabetes, cardiovascular diseases, and non-alcoholic steatohepatitis). ...Growing evidence suggests that gut microbes contribute to the onset of the low-grade inflammation characterising these metabolic disorders via mechanisms associated with gut barrier dysfunctions. Recently, enteroendocrine cells and the endocannabinoid system have been shown to control gut permeability and metabolic endotoxaemia. Moreover, targeted nutritional interventions using non-digestible carbohydrates with prebiotic properties have shown promising results in pre-clinical studies in this context, although human intervention studies warrant further investigations. Thus, in this review, we discuss putative mechanisms linking gut microbiota and type 2 diabetes. These data underline the advantage of investigating and changing the gut microbiota as a therapeutic target in the context of obesity and type 2 diabetes.
Variations in N-acylethanolamines (NAE) levels are associated with obesity and metabolic comorbidities. Their role in the gut remains unclear. Therefore, we generated a mouse model of inducible ...intestinal epithelial cell (IEC)-specific deletion of N-acylphosphatidylethanolamine phospholipase D (NAPE-PLD), a key enzyme involved in NAE biosynthesis (Napepld
). We discovered that Napepld
mice are hyperphagic upon first high-fat diet (HFD) exposure, and develop exacerbated obesity and steatosis. These mice display hypothalamic Pomc neurons dysfunctions and alterations in intestinal and plasma NAE and 2-acylglycerols. After long-term HFD, Napepld
mice present reduced energy expenditure. The increased steatosis is associated with higher gut and liver lipid absorption. Napepld
mice display altered gut microbiota. Akkermansia muciniphila administration partly counteracts the IEC NAPE-PLD deletion effects. In conclusion, intestinal NAPE-PLD is a key sensor in nutritional adaptation to fat intake, gut-to-brain axis and energy homeostasis and thereby constitutes a novel target to tackle obesity and related disorders.
Obesity and type 2 diabetes are characterized by altered gut microbiota, inflammation, and gut barrier disruption. Microbial composition and the mechanisms of interaction with the host that affect ...gut barrier function during obesity and type 2 diabetes have not been elucidated. We recently isolated Akkermansia muciniphila , which is a mucin-degrading bacterium that resides in the mucus layer. The presence of this bacterium inversely correlates with body weight in rodents and humans. However, the precise physiological roles played by this bacterium during obesity and metabolic disorders are unknown. This study demonstrated that the abundance of A. muciniphila decreased in obese and type 2 diabetic mice. We also observed that prebiotic feeding normalized A. muciniphila abundance, which correlated with an improved metabolic profile. In addition, we demonstrated that A. muciniphila treatment reversed high-fat diet-induced metabolic disorders, including fat-mass gain, metabolic endotoxemia, adipose tissue inflammation, and insulin resistance. A. muciniphila administration increased the intestinal levels of endocannabinoids that control inflammation, the gut barrier, and gut peptide secretion. Finally, we demonstrated that all these effects required viable A. muciniphila because treatment with heat-killed cells did not improve the metabolic profile or the mucus layer thickness. In summary, this study provides substantial insight into the intricate mechanisms of bacterial (i.e., A. muciniphila) regulation of the cross-talk between the host and gut microbiota. These results also provide a rationale for the development of a treatment that uses this human mucus colonizer for the prevention or treatment of obesity and its associated metabolic disorders.
Each human intestine harbours not only hundreds of trillions of bacteria but also bacteriophage particles, viruses, fungi and archaea, which constitute a complex and dynamic ecosystem referred to as ...the gut microbiota. An increasing number of data obtained during the last 10 years have indicated changes in gut bacterial composition or function in type 2 diabetic patients. Analysis of this ‘dysbiosis’ enables the detection of alterations in specific bacteria, clusters of bacteria or bacterial functions associated with the occurrence or evolution of type 2 diabetes; these bacteria are predominantly involved in the control of inflammation and energy homeostasis. Our review focuses on two key questions: does gut dysbiosis truly play a role in the occurrence of type 2 diabetes, and will recent discoveries linking the gut microbiota to host health be helpful for the development of novel therapeutic approaches for type 2 diabetes? Here we review how pharmacological, surgical and nutritional interventions for type 2 diabetic patients may impact the gut microbiota. Experimental studies in animals are identifying which bacterial metabolites and components act on host immune homeostasis and glucose metabolism, primarily by targeting intestinal cells involved in endocrine and gut barrier functions. We discuss novel approaches (e.g. probiotics, prebiotics and faecal transfer) and the need for research and adequate intervention studies to evaluate the feasibility and relevance of these new therapies for the management of type 2 diabetes.
Obesity and type 2 diabetes are associated with low-grade inflammation and specific changes in gut microbiota composition. We previously demonstrated that administration of Akkermansia muciniphila to ...mice prevents the development of obesity and associated complications. However, the underlying mechanisms of this protective effect remain unclear. Moreover, the sensitivity of A. muciniphila to oxygen and the presence of animal-derived compounds in its growth medium currently limit the development of translational approaches for human medicine. We have addressed these issues here by showing that A. muciniphila retains its efficacy when grown on a synthetic medium compatible with human administration. Unexpectedly, we discovered that pasteurization of A. muciniphila enhanced its capacity to reduce fat mass development, insulin resistance and dyslipidemia in mice. These improvements were notably associated with a modulation of the host urinary metabolomics profile and intestinal energy absorption. We demonstrated that Amuc_1100, a specific protein isolated from the outer membrane of A. muciniphila, interacts with Toll-like receptor 2, is stable at temperatures used for pasteurization, improves the gut barrier and partly recapitulates the beneficial effects of the bacterium. Finally, we showed that administration of live or pasteurized A. muciniphila grown on the synthetic medium is safe in humans. These findings provide support for the use of different preparations of A. muciniphila as therapeutic options to target human obesity and associated disorders.
The gut microbiome has emerged as a key regulator of host metabolism. Here we review the various mechanisms through which the gut microbiome influences the energy metabolism of its host, highlighting ...the complex interactions between gut microbes, their metabolites and host cells. Among the most important bacterial metabolites are short-chain fatty acids, which serve as a direct energy source for host cells, stimulate the production of gut hormones and act in the brain to regulate food intake. Other microbial metabolites affect systemic energy expenditure by influencing thermogenesis and adipose tissue browning. Both direct and indirect mechanisms of action are known for specific metabolites, such as bile acids, branched chain amino acids, indole propionic acid and endocannabinoids. We also discuss the roles of specific bacteria in the production of specific metabolites and explore how external factors, such as antibiotics and exercise, affect the microbiome and thereby energy homeostasis. Collectively, we present a large body of evidence supporting the concept that gut microbiota-based therapies can be used to modulate host metabolism, and we expect to see such approaches moving from bench to bedside in the near future.
Obesity is associated with metabolic alterations related to glucose homeostasis and cardiovascular risk factors. These metabolic alterations are associated with low-grade inflammation that ...contributes to the onset of these diseases. We and others have provided evidence that gut microbiota participates in whole-body metabolism by affecting energy balance, glucose metabolism, and low-grade inflammation associated with obesity and related metabolic disorders. Recently, we defined gut microbiota-derived lipopolysaccharide (LPS) (and metabolic endotoxemia) as a factor involved in the onset and progression of inflammation and metabolic diseases. In this review, we discuss mechanisms involved in the development of metabolic endotoxemia such as the gut permeability. We also discuss our latest discoveries demonstrating a link between the gut microbiota, endocannabinoid system tone, leptin resistance, gut peptides (glucagon-like peptide-1 and -2), and metabolic features. Finally, we will introduce the role of the gut microbiota in specific dietary treatments (prebiotics and probiotics) and surgical interventions (gastric bypass).
The gut microbiota is involved in metabolic and immune disorders associated with obesity and type 2 diabetes. We previously demonstrated that prebiotic treatment may significantly improve host health ...by modulating bacterial species related to the improvement of gut endocrine, barrier and immune functions. An analysis of the gut metagenome is needed to determine which bacterial functions and taxa are responsible for beneficial microbiota-host interactions upon nutritional intervention. We subjected mice to prebiotic (Pre) treatment under physiological (control diet: CT) and pathological conditions (high-fat diet: HFD) for 8 weeks and investigated the production of intestinal antimicrobial peptides and the gut microbiome. HFD feeding significantly decreased the expression of regenerating islet-derived 3-gamma (Reg3g) and phospholipase A2 group-II (PLA2g2) in the jejunum. Prebiotic treatment increased Reg3g expression (by ∼50-fold) and improved intestinal homeostasis as suggested by the increase in the expression of intectin, a key protein involved in intestinal epithelial cell turnover. Deep metagenomic sequencing analysis revealed that HFD and prebiotic treatment significantly affected the gut microbiome at different taxonomic levels. Functional analyses based on the occurrence of clusters of orthologous groups (COGs) of proteins also revealed distinct profiles for the HFD, Pre, HFD-Pre and CT groups. Finally, the gut microbiota modulations induced by prebiotics counteracted HFD-induced inflammation and related metabolic disorders. Thus, we identified novel putative taxa and metabolic functions that may contribute to the development of or protection against the metabolic alterations observed during HFD feeding and HFD-Pre feeding.
Various metabolic disorders are associated with changes in inflammatory tone. Among the latest advances in the metabolism field, the discovery that gut microorganisms have a major role in host ...metabolism has revealed the possibility of a plethora of associations between gut bacteria and numerous diseases. However, to date, few mechanisms have been clearly established. Accumulating evidence indicates that the endocannabinoid system and related bioactive lipids strongly contribute to several physiological processes and are a characteristic of obesity, type 2 diabetes mellitus and inflammation. In this Review, we briefly define the gut microbiota as well as the endocannabinoid system and associated bioactive lipids. We discuss existing literature regarding interactions between gut microorganisms and the endocannabinoid system, focusing specifically on the triad of adipose tissue, gut bacteria and the endocannabinoid system in the context of obesity and the development of fat mass. We highlight gut-barrier function by discussing the role of specific factors considered to be putative 'gate keepers' or 'gate openers', and their role in the gut microbiota-endocannabinoid system axis. Finally, we briefly discuss data related to the different pharmacological strategies currently used to target the endocannabinoid system, in the context of cardiometabolic disorders and intestinal inflammation.
To investigate deep and comprehensive analysis of gut microbial communities and biological parameters after prebiotic administration in obese and diabetic mice.
Genetic (ob/ob) or diet-induced obese ...and diabetic mice were chronically fed with prebiotic-enriched diet or with a control diet. Extensive gut microbiota analyses, including quantitative PCR, pyrosequencing of the 16S rRNA, and phylogenetic microarrays, were performed in ob/ob mice. The impact of gut microbiota modulation on leptin sensitivity was investigated in diet-induced leptin-resistant mice. Metabolic parameters, gene expression, glucose homeostasis, and enteroendocrine-related L-cell function were documented in both models.
In ob/ob mice, prebiotic feeding decreased Firmicutes and increased Bacteroidetes phyla, but also changed 102 distinct taxa, 16 of which displayed a >10-fold change in abundance. In addition, prebiotics improved glucose tolerance, increased L-cell number and associated parameters (intestinal proglucagon mRNA expression and plasma glucagon-like peptide-1 levels), and reduced fat-mass development, oxidative stress, and low-grade inflammation. In high fat-fed mice, prebiotic treatment improved leptin sensitivity as well as metabolic parameters.
We conclude that specific gut microbiota modulation improves glucose homeostasis, leptin sensitivity, and target enteroendocrine cell activity in obese and diabetic mice. By profiling the gut microbiota, we identified a catalog of putative bacterial targets that may affect host metabolism in obesity and diabetes.
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