Western diet suppresses canonical intestinal stem cells and reprograms c-Kit-pos reserve stem cells via proinflammatory dysbiosis
Western-style diet (WSD) is a major risk factor for colorectal cancer, yet its effects on intestinal stem cell identity remain unclear. We show that WSD suppresses canonical Lgr5-pos intestinal stem cells (ISCs) while reprogramming c-Kit-pos secretory cells into multipotent stem-like cells that sustain epithelial renewal despite inflammatory and genotoxic stress and reduced DNA repair capacity. These cells persistently replace canonical ISCs during prolonged western dietary exposure, a phenotype reversible upon dietary normalization. WSD induces microbiota dysbiosis and expansion of enterotoxigenic Bacteroides fragilis, which suppresses Lgr5-pos ISCs and confers stemness to secretory cells, whereas antibiotics restore ISC function. These findings reveal diet-microbiota interactions as central regulators of intestinal stem cell plasticity and drivers of tumor-initiating potential.