Berberine's Role in Modulating Gut Microbiota and Endocannabinoid System in Colitis‐Associated Colorectal Cancer

ABSTRACT

Colorectal cancer (CRC) linked to colitis is a major cause of cancer‐related deaths, highlighting the need for effective treatment options. This study aimed to investigate the effects of berberine (BRR) on gut microbiota and the endocannabinoid system (ECS) in a mouse model of colitis‐associated CRC, which was induced using azoxymethane (AOM) and dextran sulfate sodium (DSS). Through a combination of animal experiments, microbial sequencing, and biochemical assays, we discovered that BRR significantly inhibited tumor development. This was demonstrated by a dose‐dependent increase in body weight and a notable decrease in both the number and size of tumors. Histopathological examinations showed a reduction in aberrant crypt foci and inflammation. Additionally, BRR treatment led to lower levels of pro‐inflammatory cytokines, including TNF‐α, IL‐1β, and IL‐6, while increasing the levels of the anti‐inflammatory cytokine IL‐10, indicating a modulation of immune responses. Importantly, BRR altered gut microbial communities by promoting beneficial bacteria such as Akkermansia muciniphila , Bacteroides , Lachnoclostridium , Blautia , and Prevotellaceae_UCG‐001 , while reducing harmful species. We also observed improvements in intestinal barrier integrity, characterized by decreased permeability and lower levels of plasma lipopolysaccharides. Furthermore, BRR restored the expression of cannabinoid receptors CB2 and GPR55, suggesting that the ECS plays a role in mediating its effects. In summary, BRR shows significant promise in alleviating colitis‐associated CRC through various mechanisms, including the modulation of gut microbiota, regulation of immune responses, and enhancement of intestinal barrier function. Future studies should aim to validate these findings clinically and further explore the efficacy of BRR in the prevention and treatment of CRC.