Microbially-catalyzed conjugation of GABA and tyramine to bile acids

Bile acids (BAs) are cholesterol-derived molecules in the human gut that aid in digestion and nutrient absorption, regulate host metabolic processes, and influence gut microbiome composition. Both the host and its microbiome contribute to enzymatic modifications that shape the chemical diversity of BAs in the gut. Several bacterial species have been reported to conjugate standard amino acids to BAs, but it was not known if bacteria conjugate other classes of amines to BAs. We show that Bacteroides fragilis strain P207, isolated from a bacterial bloom in the J-pouch of a patient with ulcerative colitis (UC) pouchitis, conjugates standard amino acids and the neuroactive amines γ-aminobutyric acid (GABA) and tyramine to deoxycholic acid. We extended our analysis to other human gut isolates and identified bacterial species that conjugate GABA and tyramine to primary and secondary BAs, and further identified diverse BA-GABA and -tyramine amides in human stool. A time-series metabolomic analysis of UC J-pouch contents revealed a lack of secondary bile acids and a shifting BA conjugate profile before, during and after onset of pouchitis, including temporal changes in several BA-GABA amides. Treatment of pouchitis with ciprofloxacin was associated with a marked reduction of nearly all BA amides in the J-pouch. Our study expands the known repertoire of conjugated bile acids produced by bacteria to include BA conjugates to the neuroactive amines GABA and tyramine, and demonstrates that these molecules are present in the human gut.