A high-fat diet alters the composition of the gut microbiome to promote intestinal tumorigenesis.

  • Major finding: A high-fat diet alters the composition of the gut microbiome to promote intestinal tumorigenesis.

  • Concept: Oncogenic Kras and diet-induced changes in gut microbiota impair immune-mediated antitumor function.

  • Impact: Modulation of dietary-induced dysbiosis may reduce the risk of intestinal cancer in patients.

Multiple studies have linked a high-fat diet (HFD) and changes in the gut microbiome composition independently with increased risk for intestinal cancer. However, although an HFD has been shown to induce alterations in the intestinal microbiota, the mechanisms by which HFD-induced dysbiosis promotes tumorigenesis are poorly understood. To study the molecular effects of HFD on tumorigenesis, Schulz, Atay, Heringer, and colleagues utilized a genetically susceptible mouse model of serrated hyperplasia driven by oncogenic Kras and exposed these mice to an HFD regimen. Compared with control mice, HFD-fed mice displayed a higher percentage of low-grade and high-grade dysplasia and invasive carcinoma in the small intestine, and an HFD accelerated tumor progression independent of obesity. HFD-fed mice exhibited an altered gut microbiota composition relative to mice fed a normal diet, supporting the importance of microbial dysbiosis in tumor susceptibility. Analysis of duodenal samples from HFD-fed mice showed a significant reduction in host immune signaling pathways, including decreased expression of genes involved in antigen recognition, impaired antimicrobial function of Paneth cells, and diminished MHC class II presentation by dendritic cells. Systemic deletion of the immune adaptor protein myeloid differentiation primary response 88 (MYD88), antibiotic treatment, or supplementation with the short-chain fatty acid butyrate protected HFD-fed mice against tumor progression; the tumor-protective effect of butyrate was associated with a shift in microbiota composition to that of normal mice and partial restoration of immune function. Interestingly, colonization of healthy Kras-mutant mice with fecal samples from HFD-fed mutants resulted in intestinal tumor formation, suggesting that transfer of HFD-modulated microbiota is sufficient to transmit disease. Overall, these data support the hypothesis that diet-induced changes in gut microbiota composition play a major role in oncogene-driven intestinal tumor formation. Moreover, this study highlights the importance of personalized dietary intervention in genetically and environmentally susceptible patients, which may alter the gut microbiome to reduce the risk of intestinal tumorigenesis.

Schulz MD, Atay C, Heringer J, Romrig FK, Schwitalla S, Aydin B, et al. High-fat-diet-mediated dysbiosis promotes intestinal carcinogenesis independently of obesity. Nature 2014 Aug 31 [Epub ahead of print].

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