Commensal bacteria promote azathioprine-therapy-failure in inflammatory bowel disease via decreasing 6-mercaptopurine bioavailability. Mus musculus

Azathioprine (AZA) therapy failure is one of many (not the major) causes of disease relapse and progression in Inflammatory bowel disease (IBD). However, the role of gut microbiota in AZA therapy failure has not been well understood. Here, we found that B.wexlerae were abundant in fecal samples with AZA therapy failure, and associated with poor disease flares survival time in IBD patients. Administration of B. wexlerae significantly increased the amount of inflammatory macrophages and decreased the therapeutic effect of AZA. B. wexlerae colonization decreased the bioavailability of 6-Mercaptopurine (6-MP) via enhancing the enzyme activity of selenium-dependent xanthine dehydrogenase (sd-XDH). Sd-XDH was responsible for catalyzing 6-MP to 6-thioxanthine (6-TX), which is the inactive metabolite of 6-MP and could not inhibit the inflammation of IBD. Supplementation of hypoxanthine phosphoribosyltransferase (HPRT)-enriched Bacillus (B.) subtilis effectively ameliorated B. wexlerae-induced AZA treatment failure in intestinal colitis mouse. Differentially management of patients with different levels of B. wexlerae is necessary.