Western diet suppresses canonical intestinal stem cells and reprograms c-Kit+ reserve stem cells via proinflammatory dysbiosis

Abstract

While colorectal cancer (CRC) is thought to originate primarily from resident stem cells, diet heavily influences intestinal stem cell homeostasis and disease onset. In this study, we demonstrate that a Western-style diet (WSD) alters intestinal homeostasis by uncoupling canonical stemness from tumorigenesis. WSD exposure suppresses canonical Lgr5 stem cells while activating an alternative pool of facultative c-Kit secretory cells. Although these reprogrammed stem-like cells exhibit genotoxic stress, they remain proliferative under prolonged dietary exposure, suggesting increased susceptibility to tumor-initiating mutations. We identify diet-induced microbial shifts and the expansion of enterotoxigenic Bacteroides fragilis (ETBF) as the upstream driver. ETBF and its toxin fragilysin autonomously trigger multipotency in c-Kit+ cells through Wnt/{beta}-catenin and YAP signaling. Importantly, these alterations are fully reversible upon dietary intervention. Together, our results highlight a targetable dietary-microbial axis that shapes epithelial stemness and underscores the role of facultative stem cells in diet-induced CRC onset.