Glycine fermentation byC. difficilepromotes virulence, spore formation, and is induced by host cathelicidin

SUMMARY The amino acid glycine is enriched in the dysbiotic gut and is suspected to contribute to Clostridioides difficile infection. We hypothesized that the use of glycine as an energy source contributes to colonization of the intestine and pathogenesis of C. difficile . To test this hypothesis, we deleted the glycine reductase genes grdAB , rendering C. difficile unable to ferment glycine, and investigated the impact on growth and pathogenesis. We found that the grd pathway promoted growth, toxin production, sporulation, and pathogenesis of C. difficile in the hamster model of disease. Further, we determined that the grd locus is regulated by host cathelicidin (LL-37) and the cathelicidin-responsive regulator, ClnR, indicating that the host peptide signals to control glycine catabolism. The induction of glycine fermentation by LL-37 demonstrates a direct link between the host immune response and the bacterial reactions of toxin production and spore formation.