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

Russell, S. K.; Valguarnera, E.; Pak, J. J.; Bubeck Wardenburg, J.

2026-09-29 cancer biology
10.64898/2026.09.28.755180 bioRxiv
Show 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.

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