Interactions between gut microbiota and intestinal epithelium functions in metabolic disorders associated with obesity

Everard, Amandine [UCL]

Obesity represents a major public health problem in the world and is nowadays recognized as an epidemic disease. Obesity and overweight are associated with a cluster of metabolic disorders such as type-2 diabetes and cardiovascular diseases thereby constituting a leading risk for global deaths. Identifying novel targets with therapeutic potential would bring hope to control obesity whereas actual drugs are particularly ineffective to treat or prevent this epidemic disease. Metabolic alterations related to obesity are associated with a low-grade inflammation that contributes to the onset of these disorders. The gut microbiota has been associated with several hallmarks of metabolic syndrome and growing evidence suggests that gut microbes contribute to the onset of the low-grade inflammation characterizing these metabolic disorders via mechanisms associated with gut barrier dysfunctions. Moreover, gut microbiota modulations using prebiotics such as in inulin-type fructans improve gut barrier functions, metabolic endotoxemia and inflammation in obesity and type-2 diabetes. This work was aimed to identify novel potential mechanisms involved in the cross-talk between gut microbiota and the host to control gut permeability, inflammation and metabolic disorders associated with obesity. We discovered that gut microbiota modulation using prebiotic treatment increases the number of enteroendocrine cells (i.e., L-cells) producing GLP-1 and GLP-2 in the jejunum and colon. These peptides are involved in the beneficial effects of prebiotics on glucose homeostasis and gut barrier functions respectively. Thus, these results suggest that targeting enteroendocrine L-cells could be a novel therapeutic approach to treat the disorders associated with obesity and type-2 diabetes. Moreover we have discovered that gut microbiota is also able to control leptin sensitivity in diet-induced obese and type-2 diabetic mice and this could participate to the beneficial effects of gut microbiota modulation in obesity. By profiling the gut microbiota after prebiotic treatment in obese mice we identified a catalog of putative bacterial targets that may affect host-metabolism in obesity and diabetes. Among these bacteria we concentrated in particular on Akkermansia muciniphila which is a mucin-degrading bacterium that resides in the mucus layer. We found that the abundance of Akkermansia muciniphila is decreased in obese and type-2 diabetic mice and we demonstrated that Akkermansia muciniphila treatment is able to reverse high-fat diet-induced metabolic disorders, including fat-mass gain, metabolic endotoxemia, adipose tissue inflammation, and insulin resistance. Importantly, these effects could be mediated by mechanisms depending on interactions between gut microbiota, enteroendocrine functions, endocannabinoid system and immune system since Akkermansia muciniphila administration increased the intestinal levels of endocannabinoids that control inflammation, the gut barrier, and gut peptide secretion and also abolished gut barrier dysfunction by restoring mucus layer thickness and stimulating the production of colon antimicrobial proteins (i.e., regenerating islet-derived 3-gamma, RegIIIγ) during obesity. The last part of the thesis was dedicated to studying the role of the innate immune system in the interaction between gut microbiota, intestinal immune functions and host metabolism. In conclusion, this work revealed novel mechanisms involved in interactions between gut microbiota and the host epithelium to control gut barrier functions and metabolic disorders associated with obesity. We have identified potential targets such as the modulation of host-gut microbiota interactions through the regulation of enteroendocrine functions, the intestine endocannabinoid and the intestine immune system. We propose that some of these targets could constitute interesting novel therapeutic approaches for the development of drugs to treat and, or prevent obesity and type-2 diabetes.