Early-life colonization with <i>Clostridioides difficile</i> remodels the developing gut.

Abstract

<i>Clostridioides difficile</i> causes severe disease in adults but commonly colonizes infants asymptomatically. The consequences of early-life colonization on host development remain unknown. In a neonatal mouse model, <i>C. difficile</i> colonization drove proinflammatory and tissue repair responses in the intestinal epithelium, enriching injury-associated intestinal stem cell populations and skewing differentiation toward secretory lineages. Despite transient colonization, exposure to <i>C. difficile</i> early in life led to persistent changes into adulthood. Epithelial responses were toxin dependent, as colonization with nontoxigenic strains or maternal vaccination with a <i>C. difficile</i>-targeted messenger RNA-lipid nanoparticle vaccine protected neonates. Human infant intestinal epithelial cells were sensitive to <i>C. difficile</i> toxins, and biopsies from colonized infants exhibited altered intestinal stem cell behavior. This study redefines <i>C. difficile</i> as an underappreciated early-life pathogen with lasting effects on host development.