Interplay between bile acids and the gut microbiota promotes intestinal carcinogenesis

Abstract

The gut microbiota and the bile acid pool play pivotal roles in maintaining intestinal homeostasis. Bile acids are produced in the liver from cholesterol and metabolized in the intestine by the gut microbiota. Gut dysbiosis has been reported to be associated with colorectal cancer. However, the interplay between bile acid metabolism and the gut microbiota during intestinal carcinogenesis remains unclear. In the present study, we investigated the potential roles of bile acids and the gut microbiota in the cholic acid (CA; a primary bile acid)‐induced intestinal adenoma‐adenocarcinoma sequence. Apc min/+ mice, which spontaneously develop intestinal adenomas, were fed a diet supplemented with 0.4% CA for 12 weeks. Mice that were fed a normal diet were regarded as untreated controls. In CA‐treated Apc min/+ mice, the composition of the gut microbiota was significantly altered, and CA was efficiently transformed into deoxycholic acid (a secondary bile acid) by the bacterial 7α‐dehydroxylation reaction. The intestinal adenoma‐adenocarcinoma sequence was observed in CA‐treated Apc min/+ mice and was accompanied by an impaired intestinal barrier function and IL‐6/STAT3‐related low‐grade inflammation. More importantly, microbiota depletion using an antibiotic cocktail globally compromised CA‐induced intestinal carcinogenesis, suggesting a leading role for the microbiota during this process. Overall, our data suggested that the crosstalk between bile acids and the gut microbiota mediated intestinal carcinogenesis, which might provide novel therapeutic strategies against intestinal tumor development.

Insights into the Role of Human Gut Microbiota in Clostridioides difficile Infection

“…Lithocholic acid inhibits the germination of the spores, whereas deoxycholic acid fosters it, but it is toxic for the vegetative form of C. difficile [94,96]. When the gut microbiota is disrupted by the intake of antibiotics, the primary bile acids are not transformed into secondary ones [97], with an increase in the proportion of the cholic to chenodeoxycholic derivatives [97] due to faster absorption of the latter by the epithelium of the large intestine. This entire procedure causes the germination of the spores and the development of C. difficile [20].…”

The gut microbiota at the intersection of bile acids and intestinal carcinogenesis: An old story, yet mesmerizing

“…68 The abundance of Clostridia was increased after CA feeding and within the Clostridia, the genus Blautia was dominated. 69 Related studies have found that DCA is extremely toxic and can severely inhibit the growth of many intestinal bacteria, including B. fragilis, C. perfringens, bifidobacteria and lactobacilli. 68 Our published data showed that CA altered the composition of gut microbiota, and increased opportunistic pathogens such as Prevotella and Desulfovibrio, and decreased beneficial bacteria such as Ruminococcus, Lactobacillus and Roseburia, and in turn increased DCA production by 7α-dehydroxylation reaction, which promoted intestinal carcinogenesis.…”

“…68 Our published data showed that CA altered the composition of gut microbiota, and increased opportunistic pathogens such as Prevotella and Desulfovibrio, and decreased beneficial bacteria such as Ruminococcus, Lactobacillus and Roseburia, and in turn increased DCA production by 7α-dehydroxylation reaction, which promoted intestinal carcinogenesis. 69 Related studies have found that DCA is extremely toxic and can severely inhibit the growth of many intestinal bacteria, including B. fragilis, C. perfringens, bifidobacteria and lactobacilli. 70,71 Our previous study found that during DCA-induced intestinal carcinogenesis, the abundance of opportunistic pathogens including Ruminococcus, Escherichia-Shigella, Desulfovibrio and Dorea was increased, and the abundance of beneficial bacteria including Lactobacillus, Lactococcus and Roseburia was reduced.…”

MAIT cell activation in adolescents is impacted by bile acid concentrations and body weight

“…Bile acids (BAs) have received considerable interest due to their critical role in metabolic modulation. Dysregulated metabolism and signaling of BAs are suggested to play a role in several diseases, such as dyslipidemia, fatty liver disease, diabetes, obesity and atherosclerosis , as well as in inflammatory diseases . The two primary BAs, cholic acid (CA) and chenodeoxycholic acid (CDCA), are generated by the liver hepatocytes from cholesterol breakdown .…”