High-fat-diet-mediated dysbiosis promotes intestinal carcinogenesis independently of obesity

A high-fat diet promotes intestinal tumorigenesis independently of obesity in a mouse model with oncogene activation, by changing the composition of the gut microbiota and altering immune regulation. Fatty diets and cancer Western diets, particularly those high in fats, have been linked to gastrointestinal cancers. In a mouse model, Manon Schulz et al . now show that a high-fat diet can promote intestinal tumorigenesis independently of obesity, by changing the composition of the gut microbiota and altering the immune environment. While antibiotics can prevent tumour promotion by dietary fat, the transfer of faeces from mice on a high-fat diet to mice genetically predisposed to intestinal cancer but fed with a normal diet is sufficient to promote tumorigenesis. These findings highlight the complex interactions between diet, microbiota, the immune response and cancer, and may offer new avenues for cancer prevention. Several features common to a Western lifestyle, including obesity and low levels of physical activity, are known risk factors for gastrointestinal cancers 1 . There is substantial evidence suggesting that diet markedly affects the composition of the intestinal microbiota 2 . Moreover, there is now unequivocal evidence linking dysbiosis to cancer development 3 . However, the mechanisms by which high-fat diet (HFD)-mediated changes in the microbial community affect the severity of tumorigenesis in the gut remain to be determined. Here we demonstrate that an HFD promotes tumour progression in the small intestine of genetically susceptible, K-ras G12Dint , mice independently of obesity. HFD consumption, in conjunction with K- ras mutation, mediated a shift in the composition of the gut microbiota, and this shift was associated with a decrease in Paneth-cell-mediated antimicrobial host defence that compromised dendritic cell recruitment and MHC class II molecule presentation in the gut-associated lymphoid tissues. When butyrate was administered to HFD-fed K-ras G12Dint mice, dendritic cell recruitment in the gut-associated lymphoid tissues was normalized, and tumour progression was attenuated. Importantly, deficiency in MYD88, a signalling adaptor for pattern recognition receptors and Toll-like receptors, blocked tumour progression. The transfer of faecal samples from HFD-fed mice with intestinal tumours to healthy adult K-ras G12Dint mice was sufficient to transmit disease in the absence of an HFD. Furthermore, treatment with antibiotics completely b