Endocrine Abstracts

Communication between microbiota and the host is critical to sustaining the vital functions of the healthy host, and disruptions of this homeostatic coexistence are associated with a range of diseases including obesity and T2D. Microbiota-derived metabolites act both as nutrients and as messenger molecules to shape host pathophysiology. Succinate, which has the distinction of being produced by both the host and microbiota, is quickly becoming a poster child for these metabolites. Succinate is a by-product of some bacteria and a primary cross-feeding metabolite essential for the maintenance of a healthy resident gut microbiota. In this sense, the increase in succinate in some pathological conditions would be reflective of dysbiosis. For many years succinate has been considered as a danger signal via its intracellular and extracellular signaling properties. Nonetheless, unexpected pleiotropic functions, such as a positive regulator of intestinal gluconeogenesis and thermogenesis, have been ascribed to this metabolite. In this context, we have demonstrated that succinate via its cognate receptor SUCNR1 is a key mediator of the resolution of inflammation– a physiological mechanism that is not working properly in obesity. Thus, similar to what happens with other hormones as insulin and leptin, obesity and T2D is associated with higher circulating levels of succinate but impaired SUCNR1 signaling, which we have termed a succinate-resistant state. We have also proposed circulating succinate as a surrogate marker of metabolic control and an excellent predictive biomarker for diabetes remission after bariatric surgery. An important unanswered question concerns the source of circulating succinate. Along this line, we recently provided the first demonstration of a close relationship between circulating succinate and gut microbiota signature. To establish the contribution of gut microbiota to circulating levels of succinate as well as the use of probiotic interventions directed to decrease the higher circulating succinate and thus recover the physiological functions of succinate are our current research focus.