Role of intestinal microbiota, obesity and inherited predisposition in colorectal carcinogenesis

Colorectal cancer (CRC) has a multifactorial etiology, involving genetic, environmental, and life-style factors, gut microbiota and metabolites. To evaluate the role of various CRC risk factors, we stratified patients according to the grade of dysplasia of their polyps, to their body mass index and waist circumference, or to their genetic background. Both lumen- and mucosa-associated microbiota (MAM) were analyzed. We have devised a new technique to collect MAM and metabolites from the polyp's surface without jeopardizing tissue integrity. Firstly, we analyzed MAM and mucosa-associated metabolome in 78 patients. According to the driver- passenger model, the driver bacterium Bacteroides fragilis was enriched on low-grade polyps. We also found different metabolite signatures associated to tumor stage. A microbiota-metabolome integrated analysis showed positive or negative correlations between bacteria and metabolites. These results support the involvement of mucosa-associated microbiota and metabolome in CRC initiation and progression. Secondly, we analyzed 120 patients divided in normal-weight or obese. Dietary habits data revealed a higher consumption of processed meat for obese patients. Moreover, mucosal and luminal microbiota and metabolome signatures distinguished the two groups. These data support the hypothesis that different risk factors concur in tumorigenesis of obese or normal-weight patients. Thirdly, we identified 26 of 242 patients carrying germline pathogenic variants, and classified them as mutated. Then, we performed MAM shotgun sequencing analysis to compare 154 patients with or without inherited predisposition to cancer (i.e. mutated vs sporadic) and identified different bacterial signatures in the two groups. We speculate that mucosa-associated bacteria concur with the genetic defect to promote cancer. Overall, our data show that different mechanisms and risk factors are involved in colorectal carcinogenesis in specific groups of patients.