Bacteria-host interactions through bile acid 7-dehydroxylation
Bile acids (BAs) are small molecules synthesized by the host and chemically modified by the microorganisms inhabiting the intestinal tract. It is becoming increasingly apparent that, beyond their ancestral role in lipid digestion, bile acids play a crucial role as signaling molecules. They are metabolized by the gut microbiota and, through enterohepatic recirculation and spill-over into the systemic circulation, reach target metabolic organs, tissues and immune cells. The microbial transformation of BAs in the gut is critical to BA-mediated signaling as it modifies their amount and affinity for specific BA receptors. One of the major receptors for secondary BAs is the G protein-coupled BA receptor 1 (GPBAR1), also known as Takeda G-protein receptor 5 (TGR5), and it is associated with regulation of energy expenditure and glucose management, protection from liver steatosis and inflammation. Bile acid 7-dehydroxylating bacteria are intestinal commensals of particular importance as they catalyze the dehydroxylation of liver-derived (primary) bile acids at the C7 position (i.e., 7-dehydroxylation) and produce secondary bile acids. In addition, 7-dehydroxylated bile acids are also associated with protection from infection by specific intestinal pathogens (e.g., Clostridioides difficile). Thus, through their action on primary BAs, 7-dehydroxylating bacteria play an important role in health promotion and in the functioning of major physiological processes in the body such as insulin secretion, thermogenesis and immune responses. On the other hand, excessive abundance of secondary BAs, possibly linked to overabundance of 7-DH-ing bacteria correlates with an increased risk of intestinal cancer and cholesterol gallstone disease. Despite these potentially important roles in the mammalian host, bile acid 7- dehydroxylating bacteria are believed to have very low abundance in the gut; they are poorly studied and much remains to be deciphered regarding their metabolism, diversity, and colonization dynamics in the host.
The main goal of our research is to provide a better understanding of this key group of commensals. Greater insight into the biology of bile acid metabolism and the important 7-dehydroxylating bacterial community is the foundation for understanding the impact bile acids on host health and physiology.
This project is funded by a Sinergia grant from the Swiss National Science Foundation.