Silva, S.; Procopio, P.; Zinina, V.; Segura Munoz, R. R.; Segbefia, S.; Bae, S.; Lobel, L.; Nardella, L.; Sacchetti, A.; Joosten, R.; Verhagen, M. P.; Aktuna, F.; Pauck, K.; Sourjik, V.; Garn, H.; Blumberg, R. S.; Puschhof, J.; Garrett, W. S.; Fodde, R.; Schmitt, M.

Dietary patterns are major determinants of colorectal cancer risk, yet how nutritional cues are molecularly integrated to reprogram intestinal stem cell identity and fuel tumor initiation is not well understood. Here, we demonstrate that a Western-style diet (WSD) rapidly and reversibly reprograms intestinal stem cell identity. WSD suppresses canonical Lgr5 stem cells while enhancing epithelial proliferation and stemness through activation of alternative stem cell states in Paneth and deep crypt secretory (DCS) cells in the small and large intestine, respectively. These diet-reprogrammed cells exhibit inflammatory and genotoxic stress and yet remain proliferative, suggesting increased susceptibility to tumor-initiating mutations. Mechanistically, WSD-induced remodeling is mediated by the gut microbiota, specifically through the expansion of enterotoxigenic Bacteroides fragilis (ETBF). ETBF and its secreted toxin fragilysin suppress Lgr5 stem cells while directly promoting multipotency of c-Kit DCS cells via Wnt signaling. Collectively, our findings identify diet-driven gut microbial shifts as a key regulator of stem cell plasticity, linking environmental exposure to epithelial reprogramming and colorectal cancer risk.