Gut microbiota prevents small intestinal tumor formation due to bile acids in gnotobiotic mice

The gut microbiota is implicated in the development of intestinal tumors. Furthermore, Western diet is a risk factor for colorectal cancer and induces alterations in both, the microbiota and bile acid metabolism. Here, we performed fecal microbiota transfer experiments by inoculating germfree Apc1368N/+ mice with stool from genetically engineered APC1311/+ pigs to test the causal role of Western diet-induced changes in the microbiota and secondary bile acid production, which were linked to disease exacerbation in APC1311/+ pigs. The recipient mice were fed a control diet, or the same diet supplemented with the primary bile acid cholic acid (CA) to stimulate secondary bile acid production. Unexpectedly, the germfree mice fed CA had a high number of lesions in the upper small intestine, which was reduced by the colonization with microbes. The same mice (germfree, CA diet) were characterized by a remarkable lengthening of the small intestine (approximately +10 cm on average). Colonic lesions were rare and only observed in the mice that received stool from control pigs and fed the CA diet. Diversity and composition analyses showed that the microbiota transfer was incomplete. Nevertheless, mice receiving the Western diet-associated microbiota clustered separately from control animals. The effects of CA in diet on the microbiota were less pronounced and were observed primarily in the mice that received stool from control pigs. Bile acid analysis in the recipient mice revealed associations between the phenotype and specific bile acid species in bile and cecum. These findings highlight the importance of diet-microbiota-BA interactions in intestinal morphogenesis and tumorigenesis.