Glutathione is a host-derived cysteine source for Clostridioides difficile

ABSTRACT: Clostridioides difficile is the leading cause of nosocomial diarrhea, afflicting approximately half a million people each year in the USA, burdening both individuals’ quality of life and the healthcare system. In the gastrointestinal (GI) tract, C. difficile must acquire essential nutrients to colonize, establish infection, and persist in a polymicrobial environment. C. difficile is a cysteine auxotroph and the GI tract contains low levels of cysteine, highlighting gaps in our understanding of how C. difficile acquires this amino acid during infection. One possible source of cysteine for C. difficile during infection is glutathione (GSH), a tripeptide thiol found in mammalian cells. Our data indicate that C. difficile encodes two functionally redundant enzymes (UgaA and UgbB) that allow it to use GSH as a source of cysteine. Using murine models of C. difficile infection, we show that C. difficile uses its toxins to increase available GSH in the GI tract during infection. Finally, we show that the ability to utilize GSH gives wild-type C. difficile a fitness advantage over a GSH-deficient mutant in vivo. These findings establish GSH metabolism by C. difficile as a virulence-linked metabolic program and as a possibly impactful target for future therapeutic development.

INSTRUMENT(S): Liquid Chromatography MS - negative - reverse-phase

PROVIDER: MTBLS14740 | MetaboLights | 2026-06-10

REPOSITORIES: MetaboLights