The gut microbiota-adipose tissue axis in the pathogenesis of obesity and its related metabolic disorders: molecular mechanism and clinical implications – GAD

The prevalence of obesity and its related comorbidities, including diabetes and cardiovascular disease, has reached epidemic proportions worldwide.Recent advances from metagenomic studies have generated an entirely new prospective demonstrating that alterations of gut microbiota, a complex ecosystem that is composed of approximately 400-500 bacterial species with over 300 million genes, is a major contributor to the rapid rise in obesity and its related disorders. Both animal and clinical investigations provided compelling evidence that a complex interaction between microbiota, the gut and tissue immune systems is a prerequisite for the development of metabolic diseases, suggesting that modulation of gut microbiota and microbiota-host interaction may represent a promising therapeutic strategy to prevent the global epidemic of obesity and its medical complications. However, the pathological events that link alterations in gut microbial ecosystem and metabolic dysfunction still remain poorly understood.

Our recent studies demonstrated that obesity is associated with increased translocation of living bacteria and bacterial products (such as lipopolysaccharide, LPS) through intestine mucosa to the bloodstream, suggesting that both tissue bacteria and chronic endotoxinemia are involved in the onset and progression of obesity and diabetes. Furthermore, we found the presence of live commensal intestine bacteria in large numbers in adipose tissues of mice shortly after high fat diet. Therefore, we propose that adipose tissues are one of the major action sites for gut microbiota, where it modulates adipocyte size and function, triggers inflammation and alters adipokineproduction, thereby leading to systemic insulin resistance and metabolic dysregulation.

To test this hypothesis, we plan to synergize the strength of our French team in characterization and manipulation of gut microbiota, identification and profiling of tissue bacteria, bioinformatics and immunology, together with the expertise of the Hong Kong team on adipose biology, adipokine research and metabolic phenotyping, to (1) interrogate the dynamic relationship between gut microbiota, adipose tissue inflammation and adipokine secretion by conventionalization of germ-free mice; (2)comprehensively identify and compare bacterial species in the adipose tissues of lean and diet-induced obese mice with different degrees of glucose dysregulation; (3) to determine whether and how bacterial products exert direct effects on adipose tissue inflammation and adipokine secretion; and (4) to investigate whether genetic ablation of adipose tissue inflammation or pro-inflammatory adipokines blocks gut microbiota-mediated systemic insulin resistance and metabolic dysregulation in mice. Moreover, we will explore the clinical relevance of these animal studies by analyzing and correlating the composition of bacterial species, inflammation status, adipokine expression in adipose tissues of obese individuals with their metabolic profiles. The findings from this study will not only enrich our fundamental knowledge on how the gut microbiota-adipose tissue interaction influences our metabolism and health, but also help to develop new diagnostic tools and/or therapeutic strategies for prevention of obesity and its associated medical complications.