Investigating molecular mechanisms behind gut bacterial transamination and IBD.

Microbiota small molecules correlate with IBD pathogenesis, yet the molecular mechanisms behind remain elusive. We recently developed gene manipulation tools in multiple gut Clostridia commensals, and by mutating the responsible gene and mono-colonizing germ-free mice with the mutant, we can switch specific microbiota metabolites on/off in vivo and found that metabolites derived from Clostridia amino acid transamination, like branched short-chain fatty acids (BSCFAs) suppress intestine IgA plasma cells. Many microbiota-associated metabolites, including BSCFAs, are derived via microbial transamination of dietary amino acids and are highly abundant in the host. Multiple studies have shown that this group of microbial metabolites is significantly different between IBD patients and healthy humans. We hypothesize that microbiota metabolites from amino acid transamination mediate intestine immunity and inflammation. Herein we will apply Clostridium CRISPR-based toolsets to modulate these amino acid-derived metabolites in vitro and in vivo, investigate their effects on intestinal immunity and inflammation in germ-free and colitis mouse models, and look into clinical samples to determine if their levels are positively correlated with disease severity in IBD patients. Our findings will uncover previously unknown molecular mechanisms behind microbiome-IBD correlation and facilitate the identification of new therapeutic targets and new biomarkers for IBD prevention and treatment.