Secondary bile acid-induced dysbiosis promotes intestinal carcinogenesis

Abstract

The gut microbiota plays an important role in maintaining intestinal homeostasis. Dysbiosis is associated with intestinal tumorigenesis. Deoxycholic acid (DCA), a secondary bile acid increased by a western diet, correlates with intestinal carcinogenesis. However, evidence relating bile acids, intestinal microbiota and tumorigenesis are limited. In our study, we investigated the effect of DCA on induction of intestinal dysbiosis and its roles in intestinal carcinogenesis. Alteration of the composition of the intestinal microbiota was induced in DCA-treated APC mice, which was accompanied by impaired intestinal barrier, gut low grade inflammation and tumor progression. The transfer of fecal microbiota from DCA-treated mice to another group of Apc mice increased tumor multiplicity, induced inflammation and recruited M2 phenotype tumor-associated macrophages. Importantly, the fecal microbiota transplantation activated the tumor-associated Wnt/β-catenin signaling pathway. Moreover, microbiota depletion by a cocktail of antibiotics was sufficient to block DCA-induced intestinal carcinogenesis, further suggesting the role of dysbiosis in tumor development. Our study demonstrated that alteration of the microbial community induced by DCA promoted intestinal carcinogenesis.

Influence of Bile Acids on Colorectal Cancer Risk: Potential Mechanisms Mediated by Diet-Gut Microbiota Interactions

“…Importantly, in most experimental studies the increased fecal bile acid levels alone were not sufficient to induce intestinal tumor formation, but required increased susceptibility of the rodent model mediated by chemical treatment or genetic disposition [23, 24, 27•, 29]. One study found an inherent tumor-inducing effect for DCA in wild-type mice when this secondary bile acid was added to the diet [25], but tumor formation was only observed after a comparatively long time frame (8–10 months).…”

“…Similarly, lower fecal levels of CA observed in cirrhosis patients coincided with reduced abundance of 7α-dehydroxylating bacteria in the feces [33]. In contrast, a recent study detected different compositional shifts of the gut microbiota after adding DCA to the diet of Apc min+ mice [29]: at phylum level, the administration of DCA triggered an increased abundance of Bacteroidetes and decreased numbers of Firmicutes compared to Apc min+ mice that received a diet without additional DCA. However, this may be not surprising, since DCA was shown to have more potent antimicrobial activity than CA [36] and Apc min+ mice are likely to have an altered gut microbiota compared to wild-type mice.…”

“…Similar evidence was demonstrated in a second study by Cao et al , who used Apc min+ mice, a model for tumor formation in the small intestine. The addition of exogenous DCA to the diet of Apc min+ mice resulted in accelerated tumorigenesis in the small intestine compared to Apc min+ mice that received no additional DCA [29]. The transfer of the fecal microbiota from DCA-treated Apc min+ mice to Apc min+ mice, which were treated before with antibiotics, transmitted the increased tumor-promoting activity.…”

Novel insights into microbiome in colitis and colorectal cancer

“…For example, IEC-derived SIRT1, a NAD+-dependent protein deacetylase downregulated in UC patients, prevents age-dependent reduction of Bacilli/ Lactobacillus partially via regulating bile acid metabolism (29). In addition, DCA administration accelerates tumorigenesis by inducing microbiota dysbiosis and inflammation in Apc min/+ mice (30*). Fecal transfer of DCA-treated but not untreated Apc min/+ mice induced low grade inflammation and activated M2 tumor-associated macrophages and the WNT/β-catenin pathway in recipient Apc min/+ mice (30*).…”

“…In addition, DCA administration accelerates tumorigenesis by inducing microbiota dysbiosis and inflammation in Apc min/+ mice (30*). Fecal transfer of DCA-treated but not untreated Apc min/+ mice induced low grade inflammation and activated M2 tumor-associated macrophages and the WNT/β-catenin pathway in recipient Apc min/+ mice (30*). …”