Early-life colonization by enterotoxigenic Bacteroides fragilis remodels gut epithelial stem cell states to drive colorectal cancer susceptibility

Abstract

Early-life microbial exposures can shape lifelong disease risk, yet how developmental timing influences the host-microbe interaction remains unclear. During neonatal colonization by enterotoxigenic Bacteroides fragilis (ETBF), the metalloprotease toxin BFT enables lamina propria niche entry and remodeling of colonic epithelial cell states. Early-life ETBF exposure expands murine Lgr5+ stem cells, enhances Atoh1+ secretory differentiation, and induces distal colon-specific Wnt hyperactivation. These epithelial alterations coincide with increased formation of precancerous lesions in ApcMin/+ mice. ETBF preferentially forms intracellular bacterial aggregates within these lesions, establishing a persistent reservoir that reinforces epithelial remodeling. Colonization with non-toxigenic B. fragilis during this critical developmental window prevents lesion formation, revealing that developmental context dictates whether microbial colonization imprints protection or predisposition toward colorectal cancer.