pH regulates gut bacterial tryptophan metabolism

Abstract Intestinal pH influences microbiota composition and activity, yet its impact on microbial metabolite production remains elusive. Gut bacterial tryptophan catabolism yields metabolites with opposing health effects. Indole, a precursor of indoxyl sulfate (IS), is linked to chronic kidney disease (CKD), while indolelactic acid (ILA) and indolepropionic acid (IPA) have positive health effects. Analysis of fecal pH and tryptophan metabolites in two human cohorts revealed positive correlations between fecal pH, indole, and urinary IS, and negative correlations with ILA and IPA. Fecal indole and pH showed no correlation with fecal tryptophanase (tnaA) gene abundance. In vitro fermentations showed that low pH (5.5) inhibited indole production by E. coli, enhancing tryptophan availability for C. sporogenes to produce beneficial metabolites. Human fecal cultures confirmed pH-dependent tnaA gene repression and indole suppression. These findings highlight the role of pH as a key regulator of gut bacterial tryptophan metabolism with therapeutic relevance for CKD.