The Imbalance Of Gut Microbiota On The Development Of Colorectal Cancer And The Intervention Of Berberine

AIMS: Colorectal cancer (CRC) is a disease which involving multiple factorsand multiple stages. Intestinal homeostatic, dietary structure, cigarette smoking andalcohol consumption are the main environmental factors. The correlation andmechanism between host gut microbiota and colorectal carcinoma have become thenewest research hot dots. In this study, we will explore the correlation between gutmicrobiota imbalance and colorectal cancer and the mechanism of berberineintervention, via cohort study, in vivo and in vitro experiments. Further, we willprovide new ideas about regulation of micro ecological for the prevention andtreatment of CRC.METHODS: We firstly detected the difference of fecal gut microbiota betweenhealthy controls and advanced colorectal adenoma (A-CRA) patients viahigh-throughput pyrosequencing technique, and analyze the correlation with dietaryfiber and fecal short-chain fatty acids (SCFAs). Then we analyzed the fecal gutmicrobiota from healthy controls, colorectal adenoma patients and CRC patients, toexplore the key bacteria in the occurrence and development process of CRC. On theone hand, we clarified that Fusobacterium nucleatum could induce the occurrence ofcolon tumor via both wild type C57BL/6mice and APC(Min/+) mice experiment, andanalyzed their fecal gut microbiota and mucosal immune factors. On the other hand,we also compared the gene expression status in the colorectal cancer HT29cells aftertreated with Fusobacterium nucleatum through gene expression profiling. Finally, weobserved the generation of colon tumor, the structure of gut microbiota and thesecretion of mucosal immune factors in the mice after treated with berberin. RESULTS: Patients with A-CRA had lower dietary fiber intake and loweryields of fecal SCFAs than healthy subjects. The structural imbalance in the patientswith A-CRA was highlight by the significant decrease of butyrate-producing bacteria(Clostridium、Roseburia、Eubacterium spp.) and by the increase in a variety ofopportunistic pathogens (Enterococcus and Streptococcus spp.)(all P＜0.05). Wealso found that the abundance of Fusobacteria and Fusobacterium increasedgradually from healthy controls, colorectal adenoma (CRA) to CRC. Fusobacteriumnucleatum could promote the generation of colon tumor in the mice intestine andchange the structure of fecal gut microbiota and secretion of mucosal immune factors,which also involved multiple genes expression and signal pathway. Finally, we foundthat berberine could inhibit the generation induced by Fusobacterium nucleatum, andregulate their gut microbiota and secretion of mucosal immune factors.CONCLUSIONS: The gut microbiota imbalance has a close correlation withthe occurrence and development of colorectal cancer. Some intestinal bacteria, suchas Fusobacterium nucleatum, might play a key role in the occurrence anddevelopment of CRC. Berberine could inhibit the colon tumor generation induced byFusobacterium nucleatum. In addition, high fiber dietary and their fermentationSCFAs might contribute to a healthy intestinal micro ecology environment, whichwould reduce the risk of colon cancer.