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bioRxiv · 10.64898/2026.09.28.755180

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.
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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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Russell, S. K., Valguarnera, E., Pak, J. J., Bubeck Wardenburg, J.. 2026-09-29. Early-life colonization by enterotoxigenic Bacteroides fragilis remodels gut epithelial stem cell states to drive colorectal cancer susceptibility. https://doi.org/10.64898/2026.09.28.755180

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