Anthraquinone laxative-altered gut microbiota induces colonic mucosal barrier dysfunction for colorectal cancer progression

Abstract

Background: The safety of anthraquinone laxatives has been debated. Previously, a few isolated studies have revealed that anthraquinones can cause damage to the structure of colonic epithelial tissue, and long-term intake of anthraquinone laxatives increases colorectal cancer risks. In this study, we focused on sennoside A, a primary purgative component in anthraquinone laxatives, and investigated the effects of sennoside A on intestinal inflammation and host metabolism, and we assessed whether it could exacerbate colitis-associated colon cancer in the AOM/DSS mouse model. Results: Initially, sennoside A disrupted the mucus layer and mechanical barrier of the colon. The dynamic effects of sennoside A on the community structure of gut microbiota were further analysed. We found that sennoside A significantly promoted the dominant growth of Akkermansia muciniphila after 56 days of continuous treatment, which was independent of the prototype of sennoside A and its metabolites, including the main host metabolite rhein and bacterial metabolites. Interestingly, sennoside A suppressed the growth of butyrate-producing bacteria, thereby decreasing butyrate levels. In addition, sennoside A directly inhibited the growth of Clostridium tyrobutyricum and Clostridium butyricum, which was not caused by the prototype of sennoside A but by the direct bacteriostatic effect produced from its metabolite rhein. Last, supplementation with butyrate prevented sennoside A-induced gut dysbiosis and mucus barrier impairment. Conclusions: Our work reveals that sennoside A can impair the integrity of the intestinal mucosal barrier, which is closely related to the disruption of the structural balance between mucus-degrading bacteria and exogenous fibro-degrading bacteria; this impaired imbalance can induce long-term low-grade inflammation and metabolic disorders associated with tumorigenesis, and it can consequently promote the progression of colonic carcinogenesis in the AOM/DSS mouse model.