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

Western-style diets, characterized by higher fat and protein, and low micronutrient levels, promote the development of colorectal cancer (CRC). Here, we investigate the role of a Western diet on microbiome composition, sulfide production, and intestinal epithelial damage in pre-CRC mice, and validate taxonomic changes in a meta-analysis of human CRC patients.

Methods

NWD1 is a purified Western-style diet that produces sporadic intestinal and colon tumors in wild-type C57BL/6 mice in the absence of genetic or carcinogen exposure. To determine how this diet influences cancer risk by shaping microbial composition and sulfide chemistry, mice were fed NWD1 or a purified control diet for 24 weeks. Microbiome composition, sulfide production, and intestinal stem cell mRNA expression were assessed. Observed microbiome changes were validated in a human CRC meta-analysis.

Results

Fecal sulfide levels were tripled in NWD1-fed mice ( P< 0.00001 ), concurrent with increased abundance of the sulfidogenic Erysipelotrichaceae family. NWD1-fed mice had increased expression of mitochondrial sulfide oxidation genes in Lgr5 ^hi intestinal stem cells, demonstrating an adaptive response to elevated sulfide. In a meta-analysis of human CRC studies, we observed that Erysipelotrichaceae were associated with CRC, validating both canonical CRC microbes such as Solobacterium moorei and highlighting the potential contribution of previously unrecognized, disease-associated microbes.

Conclusions

Our analyses connect the risk factors of Western diet, sulfide, and epithelial damage in a pre-cancer mouse model to microbiome changes observed in human CRC patients and suggest that microbial signatures of CRC and gut ecosystem alteration may manifest long before disease development.