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

2025 · doi:10.1101/2025.01.27.635083
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The study examined how a purified Western-style diet (NWD1) influences gut microbiome composition, fecal sulfide production, and intestinal epithelial stem-cell gene expression in C57BL/6 mice developing sporadic pre-cancer and validated related microbial changes in a meta-analysis of human colorectal cancer studies. After 24 weeks on NWD1, fecal sulfide levels tripled and the sulfidogenic Erysipelotrichaceae family increased in abundance, while Lgr5hi intestinal stem cells showed higher expression of mitochondrial sulfide-oxidation genes as an apparent adaptive response; in human CRC meta-analysis, Erysipelotrichaceae were associated with CRC alongside canonical taxa like Solobacterium moorei. A limitation is that the mouse model used a diet-driven pre-CRC setting without genetic or carcinogen exposure and the human validation relied on associations from heterogeneous published studies. Relevance to endometriosis: the paper is not about endometriosis or adenomyosis, but it includes microbiome–metabolite (sulfide) and epithelial-damage mechanisms relevant to corpus keyword matching, despite not explicitly discussing endometriosis/adenomyosis.

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Abstract

ABSTRACT 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 Lgr5 hi 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.
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Abstract

Background & Aims 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 Lgr5hi 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. Competing Interest Statement The authors have declared no competing interest. Footnotes Author names in bold designate shared co-first authorship. Grant Support: ZC was supported by a National Institutes of Health (NIH) training grant 2T32GM007288-45 (Medical Scientist Training Program) at Albert Einstein College of Medicine. LA is supported in part by NCI R01CA229216, NIH R01CA214625, and USPHS P30CA013330. LK is supported in part by NIH R01HL069438. Abbreviations - AIN - AIN76A diet - CRC - colorectal cancer - Ethe1 - ethylmalonic encephalopathy 1 - H2S - hydrogen sulfide - IACUC - Institutional Animal Care and Use Committee - NWD1 - New Western Diet 1 - sqrdl - sulfide-quinone reductase-like protein - suox - sulfite oxidase - tst - thiosulfate transferase/rhodanese

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