Microbiome histidine competition mediates dietary control of systemic imidazole propionate

Abstract

The gut microbiome produces numerous metabolites that influence mammalian health. While microbiome composition and diet influence metabolite concentrations, how these factors interact remains incompletely defined. Here we find production of imidazole propionate (ImP), a microbial metabolite associated with cardiometabolic and neurodegenerative diseases, is determined by the balance of competing metabolic pathways that catabolize histidine to ImP or short-chain fatty acids (SCFAs). We show glutamate serves as a preferred substrate that selectively inhibits histidine conversion to SCFAs, redirecting flux to increased ImP production across mouse- and human-derived microbial communities. We find dietary monosodium glutamate (MSG) acting via this mechanism boosts ImP production in the mouse gut, transiently impairing glucose tolerance and increasing systemic ImP. These findings show that predictable interactions between dietary substrate and microbial competition control systemic ImP levels, providing a mechanistic framework for understanding microbiome metabolite production more broadly.