RESUMO
BACKGROUND: Patients with prolonged inflammatory bowel disease (IBD) can develop into colorectal cancer (CRC), also called colitis-associated cancer (CAC). Studies have shown the association between gut dysbiosis, abnormal bile acid metabolism, and inflammation process. Here, we aimed to investigate these two factors in the CAC model. METHODS: C57BL/6 mice were randomly allocated to two groups: azoxymethane/dextran sodium sulfate (AOM/DSS) and control. The AOM/DSS group received AOM injection followed by DSS drinking water. Intestinal inflammation, mucosal barrier, and bile acid receptors were determined by real-time PCR and immunohistochemistry. Fecal microbiome and bile acids were detected via 16S rRNA sequencing and liquid chromatography-mass spectrometry. RESULTS: The AOM/DSS group exhibited severe mucosal barrier impairment, inflammatory response, and tumor formation. In the CAC model, the richness and biodiversity of gut microbiota were decreased, along with significant alteration of composition. The abundance of pathogens was increased, while the short-chain fatty acids producing bacteria were reduced. Interestingly, Clostridium XlV and Lactobacillus, which might be involved in the bile acid deconjugation, transformation, and desulfation, were significantly decreased. Accordingly, fecal bile acids were decreased, accompanied by reduced transformation of primary to secondary bile acids. Given bile acid receptors, the ileum farnesoid X receptor-fibroblast growth factor 15 (FXR-FGF15) axis was downregulated, while Takeda G-protein receptor 5 (TGR5) was overexpressed in colonic tumor tissues. CONCLUSION: Gut dysbiosis might alter the metabolism of bile acids and promote CAC, which would provide a potential preventive strategy of CAC by regulating gut microbiota and bile acid metabolism.
RESUMO
BACKGROUND: Accumulating evidence points to a close relationship between gut dysbiosis and colorectal cancer (CRC). As >90% of CRC develop from adenoma, we aimed to investigate the crucial role of imbalanced gut microbiota on the progression of intestinal adenoma. METHODS: The Apcmin/+ mice gavage with phosphate-buffered saline (PBS), feces from healthy controls or CRC patients after antibiotic cocktails. The intestinal tissues were isolated for histopathology, western blotting, and RNA-seq. The microbiota of feces and short-chain fatty acids (SCFAs) were analysed by 16S rDNA Amplicon Sequencing and gas chromatography. FINDINGS: The Apcmin/+mice gavaged by feces from CRC patients had more intestinal tumours compared with those fed with feces from healthy controls or PBS. Administration of feces from CRC patients increased tumour proliferation and decreased apoptosis in tumour cells, accompanied by impairment of gut barrier function and up-regulation the pro-inflammatory cytokines profile. The up-regulated the expression of ß-catenin and cyclinD1 further indicating the activation of Wnt signalling pathway. The abundance of pathogenic bacteria was increased after FMT, while producing SCFAs bacteria and SCFAs production were decreased. INTERPRETATION: Gut microbiota of CRC patients disrupted intestinal barrier, induced low-grade inflammation and dysbiosis. The altered gut microbiota enhanced the progression of intestinal adenomas in Apcmin/+mice, suggesting that a new strategy to target gut microbiota against CRC could be noted. FUND: The study was supported by the National Natural Science Foundation of China, Tianjin Research Programme of Application Foundation and Advanced Technology of China, and China Postdoctoral Science Foundation.
