Pidgeon, R.; Mitchell, S.; Shamash, M.; Suleiman, L.; Dridi, L.; Maurice, C. F.; Castagner, B.

Urolithin A is a polyphenol derived from the multi-step metabolism of dietary ellagitannins by the human gut microbiota that can affect host health. Most, but not all, individuals harbor a microbiota capable of urolithin A production; however, the enzymes that dehydroxylate its dietary precursor (urolithin C) are unknown. Here, we use a combination of untargeted transcriptomics, proteomics, and comparative genomics to uncover an inducible urolithin C dehydroxylase (ucd) operon in Lachnospiraceae. Biochemical characterization and structural modeling of proteins encoded by ucd demonstrated that urolithin C dehydroxylation was NADH-dependent, required strict anaerobic conditions, and used urolithin C as an electron acceptor. By combining functional assays in complex fecal communities with publicly available metagenomic data, our study reveals that both urolithin C-metabolizing bacteria and ucd operon genes are widely distributed in gut metagenomes and likely comprise keystone species in the metabolism of urolithins by the human gut microbiota.