Diet links gut chemistry with cancer risk in C57Bl/6 mice and human colorectal cancer patients

The gastrointestinal tract is a complex ecosystem in which host tissues, microbial communities, and dietary inputs interact to shape metabolic outputs and epithelial homeostasis. Western-style diets, characterized by high fat and protein and low micronutrient content, represent a sustained ecological perturbation linked to colorectal cancer (CRC), yet specific mechanisms that impact risk remain poorly defined. Here, using a purified Western-style diet (NWD1) that induces sporadic intestinal and colon tumors in wild-type C57BL/6 mice we demonstrate how chronic dietary disturbance restructures gut community composition and sulfur metabolism, and how these changes modulate intestinal stem cell responses. Mice fed NWD1 for 24 weeks exhibited consistent shifts in ecosystem function, including a threefold increase in fecal sulfide production (P < 0.00001) and expansion of Erysipelotrichaceae family taxa. This altered chemical landscape associates with increased expression of mitochondrial sulfide oxidation pathways in Lgr5hi intestinal stem cells. Meta-analysis of human CRC cohorts revealed concordant enrichment of Erysipelotrichaceae, alongside established CRC-associated taxa such as Solobacterium moorei, indicating conserved ecological signatures across systems. Together, these findings support a model in which the Western-style diet drives a persistent shift in gut ecosystem structure and function toward a sulfide producing state that challenges epithelial homeostasis, with conserved microbial and metabolic configurations emerging prior to overt disease in mouse models.