Evaluating the role of short-chain fatty acids receptor GPR43 in the regulation of central nervous system autoimunity by gut microbiota

Emerging evidence has shown that gut microbiota plays a key regulatory role of host physiology, affecting the metabolism, hormone production and immunity. Thereby, the alteration in the composition of gutmicrobiota (dysbiosis) has been involved in the physiopathology of metabolic, endocrine and autoimmune disorders as well as in cancer. It has been shown that regulation of host physiology by gut-microbiota might be mediated by structural components of bacteria as well as by bacterial-derived metabolites, such as neurotransmitters and short-chain fatty acids (SCFAs). Interestingly, SCFAs have been described to play a relevant role in the development of different inflammatory disorders. In this regard, three SCFAs receptors have been described in the host, GPR41, GPR43 and GPR109a. Among these receptors, GPR43 is the main SCFAs expressed in immune cells. Despite T-cells and B-cells play a fundamental role in the autoimmune response to central nervous system (CNS) involved in multiple sclerosis (MS), the role of GPR43-signaling in lymphocytes in the development CNS-autoimmunity has not been addressed before. Advanced work from this proposal shows that splenic T- and B-cells sorted from healthy mouse expressed GPR43 at mRNA level, and interestingly the expression of this receptor is reduced in EAE-induced animals. Moreover, treatment with broad spectrum antibiotics impairs disease development significantly in EAE-mice without changes in gpr43 expression. Together, these results suggests that GPR43 expression on lymphocytes has a relevant role suppressing EAE development and confirms that gut-microbiota is fundamental to disease induction in this model of autoimmunity.
The hypothesis of this project is that short chain fatty acids derived from intestinal microbiota attenuate the inflammatory response involved in experimental autoimmune encephalomyelitis directly through the stimulation of GPR43 expressed in cells of the adaptive immune system.