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

Abstract

SUMMARYThe amino acid glycine is enriched in the dysbiotic gut and is suspected to contribute toClostridioides difficileinfection. We hypothesized that the use of glycine as an energy source contributes to colonization of the intestine and pathogenesis ofC. difficile. To test this hypothesis, we deleted the glycine reductase genesgrdAB, renderingC. difficileunable to ferment glycine, and investigated the impact on growth and pathogenesis. We found that thegrdpathway promoted growth, toxin production, sporulation, and pathogenesis ofC. difficilein the hamster model of disease. Further, we determined that thegrdlocus 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.