intestinal infection; intestinal homeostasis; spore germination; gnotobiotic mouse; bile acids; commensal organisms; metagenome; Clostridium scindens; human gut; obesity; 7-dehydroxylation; bile acid receptors
Marion Solenne, Desharnais Lyne, Studer Nicolas, Dong Yuan, Notter Matheus D., Poudel Suresh, Menin Laure, Janowczyk Andrew, Hettich Robert L., Hapfelmeier Siegfried, Bernier-Latmani Rizlan (2020), Biogeography of microbial bile acid transformations along the murine gut, in Journal of Lipid Research
, 61(11), 1450-1463.
Perino Alessia, Demagny Hadrien, Velazquez-Villegas Laura Alejandra, Schoonjans Kristina (2020), Molecular Physiology of Bile Acid Signaling in Health, Disease and Aging, in Physiological Reviews
Ingle Patrick, Groothuis Daphne, Rowe Peter, Huang He, Cockayne Alan, Kuehne Sarah A., Jiang Weihong, Gu Yang, Humphreys Christopher M., Minton Nigel P. (2019), Generation of a fully erythromycin-sensitive strain of Clostridioides difficile using a novel CRISPR-Cas9 genome editing system, in Scientific Reports
, 9(1), 8123-8123.
Woods Craig, Humphreys Christopher M., Rodrigues Raquel Mesquita, Ingle Patrick, Rowe Peter, Henstra Anne M., Köpke Michael, Simpson Sean D., Winzer Klaus, Minton Nigel P. (2019), A novel conjugal donor strain for improved DNA transfer into Clostridium spp., in Anaerobe
, 59, 184-191.
Marion Solenne, Studer Nicolas, Desharnais Lyne, Menin Laure, Escrig Stéphane, Meibom Anders, Hapfelmeier Siegfried, Bernier-Latmani Rizlan (2019), In vitro and in vivo characterization of Clostridium scindens bile acid transformations, in Gut Microbes
, 10(4), 481-503.
It is becoming increasingly apparent that, in addition to their role in lipid digestion and removal of cholesterol, bile acids (BAs) play a crucial role as signaling molecules. They are transformed by the gut microbiota and, through enterohepatic recirculation and spill-over in the systemic circulation, reach target organs including the intestinal mucosa, the liver, brown and white fat depots, 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. A group of intestinal bacteria is of particular importance as it catalyzes the dehydroxylation of liver-derived (primary) BAs at the C7 position (i.e., 7-dehydroxylation, 7-DH-ion) and produces secondary BAs. Specific receptors for secondary BAs are associated with regulation of energy expenditure and glucose management, protection from liver steatosis and inflammation as well as improved glucose homeostasis after bariatric surgery. In addition, secondary BAs are also associated with protection from infection by specific intestinal pathogens (i.e., Clostridium difficile). Thus, through their action on primary BAs, 7-dehydroxylating (7-DH-ing) bacteria play an important role in health promotion and in the functioning of major physiological feedback loops in the body such as insulin response, satiety, and intestinal immunity. On the other hand, excessive abundance of secondary BAs, possibly linked to overabundance of 7-DH-ing bacteria correlates with an increased risk for colon cancer and cholesterol gallstone disease. Despite these potentially important roles in the mammalian host, the 7-DH-ing bacteria are poorly studied and much remains to be deciphered regarding their metabolism, diversity, abundance in the gut, and colonization dynamics in the host. We hypothesize that there is a direct link between the activity of these microorganisms and host health and set out to establish the existence of this connection. The major goal of the project is, therefore, to provide a thorough understanding of the microbiology of BA 7-DH-ing bacteria and their role in regulating host metabolism and controlling infection. Through the involvement of four applicants and one partner, this project takes an interdisciplinary approach to investigating the microbiology and genetics of 7-DH-ing bacteria, their abundance and diversity in the human and mouse gut, their colonization of the mouse gut, their role in regulating metabolism and immunity.The primary impact of this work is the refinement of the current understanding of the role of a highly relevant but still poorly characterized gut microbial group in host health. We expect to show that BA 7-DH-ing bacteria play a significant role in metabolic and immune function.