Microbial regulation of host immune responses via the synthesis of small molecule metabolites
Bile acids are cholesterol-derived, natural surfactants produced in the liver. They are critical to lipid digestion, antibacterial defense, and cholesterol synthesis, as well as other aspects of human biology. Importantly, bile acid dysregulation has been linked to intestinal bowel disease.
Intestinal inflammation is modulated through a fine balance between the intestinal microbiota and the mucosal immune system. Imbalance can activate immune signaling pathways, leading to uncontrolled, pathological immune responses. Gut-residing bacteria in both the small and large intestines are exposed to significant amounts of bile acids and are known to convert host-derived bile acids into more hydrophobic, and thus, more bioavailable derivatives.
We hypothesize that bacteria-produced secondary bile acids directly regulate the differentiation and/or function of key immune cells under inflammatory conditions, allowing commensal bacteria to communicate with the mucosal immune system. We propose 1) to dissect the mechanisms of bile acid-mediated immune modulation and identify bile acid immune cell targets, and 2) to identify bacteria-generated bile acid metaboltes that regulate gut inflammation in vivo, at physiological concentrations. Elucidation of these mechanisms will not only provide novel therapeutic options for inflammatory diseases, but will also open exciting avenues to study unique regulatory interactions between gut-residing microorganisms, small molecule metabolites and host immune cells.
Synthetic small molecule inhibitors
The nuclear hormone receptor RORgt was shown to play crucial roles in the pathogenesis of multiple diseases including inflammatory bowel disease (IBD). With the help of RORgt small molecule inhibitors that we and others have previously identified, we will explore therapeutic options for IBD treatment by chemically modulating RORgt function.