Gut microbiota mediates the effect of diet on the risk of developing colon cancer: comparison between meat-based diet and pesco-vegetarian diet in an experimental carcinogenesis model

Colorectal cancer (CRC) is strongly affected by diet, with red and processed meat increasing risk. To understand the role of microbiota in this phenomenon and to identify specific microbiota/metabolomics profiles associated with CRC risk, we studied colon tumorigenesis and gut microbiota profiles (metagenomics and metabolomics) in two validated models of CRC: Pirc rats, mutated in the Apc gene and thus developing spontaneous colon tumours and Azoxymethane (AOM)-induced wt rats developing preneoplastic lesions such as Aberrant Crypt Foci (ACF) and Mucin Depleted Foci (MDF). Both models were fed for 3 months with high-CRC risk diet (meat-based MBD), a normalized CRC risk diet (MBD plus alpha-tocopherol, MBD-T), a low-CRC risk diet (pesco-vegetarian, PVD) and a control diet (CTRL). Pirc rats fed the PVD diet, showed a significantly lower number of colon tumors than rats fed all the other diets. In the AOM-treated rats, MDF from PVD and CTRL diets were smaller than with the two meat-based diets, while no differences were observed in the number of ACF or MDF. Lipid peroxidation parameters such as fecal TBARS, urinary DHN-MA and urinary 8-iso-PGF 2a were lower in PVD than in Meat-based diets-fed rats (both models, more or less). AOM-treated rats in the PVD group showed a significantly lower number of colon macrophagic infiltration (CD_68 positive cells) than in MBD group, while in the PVD-fed Pirc rats apoptosis in both the colon mucosa and tumours was higher than the MBD-group. To prove that the microbiota contributes to the different cancer risk associated with the different diets, we performed a fecal microbial transplantation (FMT) from Pirc rat feces fed the 4 diets into AOM-induced germ-free rats fed a standard control diet for three months. Strikingly, rats transplanted with the MBD-feces had the highest number of MDF compared with all the other diets. Fecal metagenomic analysis showed that bacterial communities significantly differed on the basis of diet, with the exception of MBD and MBD-T samples which were similar. Metabolite profiles were also impacted by the different diets. In conclusion, these results demonstrate the protective properties of PVD diet and confirm the carcinogenetic activity of MBD-diets. Our results further demonstrate that these impacts of the different diets on carcinogenicity are, at least in part, mediated by the intestinal microbiota.