Histidine competition in the gut microbiome links dietary glutamate to systemic imidazole propionate

The gut microbiome produces numerous metabolites that influence mammalian health. Microbiome composition and diet have been implicated in microbial metabolite production, yet how these factors mechanistically interact remains largely unknown. Here we characterize functionally distinct classes of peptide-consuming gut bacteria that differ in whether their proteolytic activity is subject to carbon catabolite repression, identifying Odoribacter and Butyricimonas as specialist consumers that constitutively catabolize peptides regardless of carbohydrate availability, in contrast to generalists such as Bacteroides thetaiotaomicron that suppress protein fermentation when preferred substrates are present. Building on this regulatory framework, we find that production of imidazole propionate (ImP), a microbially derived metabolite elevated in patients with cardiometabolic and neurodegenerative diseases, is determined by the balance of competing microbial metabolic pathways that convert histidine to either ImP or short-chain fatty acids (SCFA). Glutamate acts as a preferred substrate that selectively inhibits conversion of histidine to SCFAs, shifting the metabolic balance and increasing ImP production across microbial communities. In the context of dietary monosodium glutamate (MSG), modulation of histidine competition translates to elevated systemic ImP levels and impaired glucose tolerance in mice. These findings demonstrate that systemic ImP reflects predictable interactions between diet and competing microbial pathways and establish a mechanistic framework for understanding gut-derived metabolite production.