Early-life colonization with Clostridioides difficile remodels the developing gut.

Clostridioides difficile 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, C. difficile 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 C. difficile early in life led to persistent changes into adulthood. Epithelial responses were toxin dependent, as colonization with nontoxigenic strains or maternal vaccination with a C. difficile-targeted messenger RNA-lipid nanoparticle vaccine protected neonates. Human infant intestinal epithelial cells were sensitive to C. difficile toxins, and biopsies from colonized infants exhibited altered intestinal stem cell behavior. This study redefines C. difficile as an underappreciated early-life pathogen with lasting effects on host development.