The research shows that the gut bug Clostridioides difficile uses the amino acid glycine for energy, and a natural immune peptide called LL‑37 from the host can turn on this pathway, making the bacteria grow faster, produce more toxin, and form more spores, which worsens infection.

<i>Clostridioides difficile</i> is a leading cause of antibiotic-associated diarrheal disease. <i>C. difficile</i> colonization, growth, and toxin production in the intestine is strongly associated with its ability to use amino acids to generate energy, but little is known about the impact of specific amino acids on <i>C. difficile</i> pathogenesis. The amino acid glycine is enriched in the dysbiotic gut and is suspected to contribute to <i>C. difficile</i> infection. We hypothesized that the use of glycine as an energy source contributes to colonization of the intestine and pathogenesis of <i>C. difficile</i>. To test this hypothesis, we deleted the glycine reductase (GR) genes <i>grdAB</i>, rendering <i>C. difficile</i> unable to ferment glycine, and investigated the impact on growth and pathogenesis. Our data show that the <i>grd</i> pathway promotes growth, toxin production, and sporulation. Glycine fermentation also had a significant impact on toxin production and pathogenesis of <i>C. difficile</i> in the hamster model of disease. Furthermore, we determined that the <i>grd</i> 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.