Gut Microbiota from Colorectal Cancer Patients Enhances the Progression of Intestinal Adenoma in Apc min/+ Mice

Background: Accumulating evidence points to a close relationship between gut dysbiosis and colorectal cancer (CRC). As more than 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 analyzed by 16S rDNA Amplicon Sequencing and gas chromatography. Results: The Apcmin/+ mice gavaged by feces from CRC patients had more intestinal tumors compared with those fed with feces from healthy controls or PBS. Administration of fecal from CRC patients increased tumor proliferation and decreased apoptosis in tumor cells, accompanied by impairment of gut barrier function and up-regulation the pro-inflammatory cytokines profile. Abnormal expression of genes related to Wnt-protein binding and lipid metabolic process was observed. The upregulated the expression of β-catenin and cyclinD1 further indicating the activation of Wnt signaling pathway. The abundance of pathogenic bacteria was increased after FMT, while SCFAs producing bacteria and SCFAs production were decreased. Conclusion: 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. Funding Statement: This study is supported by the grants (81741075, 81570478, and 81700456) from the National Natural Science Foundation of China, the grants (17JCYBJC24900, 17ZXMFSY00210) from Tianjin Research Program of Application Foundation and Advanced Technology of China, the grant (2019M651049) from China Postdoctoral Science Foundation. Declaration of Interests: The authors state: "No potential conflicts of interest." Ethics Approval Statement: All experimental procedures have been approved by the Ethics Committee of Tianjin Medical University.