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

Azathioprine (AZA) therapy failure, though not the primary cause, contributes to disease relapse and progression in inflammatory bowel disease (IBD). However, the role of gut microbiota in AZA therapy failure remains poorly understood. We found a high prevalence of Blautia wexlerae in patients with IBD with AZA therapy failure, associated with shorter disease flare survival time. Colonization of B. wexlerae increased inflammatory macrophages and compromised AZA’s therapeutic efficacy in mice with intestinal colitis. B. wexlerae colonization reduced 6-mercaptopurine (6-MP) bioavailability by enhancing selenium-dependent xanthine dehydrogenase (sd-XDH) activity. The enzyme sd-XDH converts 6-MP into its inactive metabolite, 6-thioxanthine (6-TX), thereby impairing its ability to inhibit inflammation in mice. Supplementation with Bacillus ( B .) subtilis enriched in hypoxanthine phosphoribosyltransferase (HPRT) effectively mitigated B. wexlerae -induced AZA treatment failure in mice with intestinal colitis. These findings emphasize the need for tailored management strategies based on B. wexlerae levels in patients with IBD. • B. wexlerae could predict AZA therapy failure in patients with inflammatory bowel disease • B. wexlerae weakened AZA’s effect on macrophages in DSS-induced colitis mice • The sd-XDH gene harbored by B.wexlerae may impact 6-mercaptopurine biotransformation • B. subtilis reverses B. wexlerae -induced AZA failure in colitis mice Identification of B. wexlerae by Yan et al. provides potential biomarkers for predicting response to azathioprine (AZA) therapy in inflammatory bowel disease (IBD). B. wexlerae inhibits 6-mercaptopurine biotransformation and attenuates the inhibition of AZA on inflammatory macrophages. Supplementation of HPRT-enriched probiotics shows potential in mitigating the intestinal colitis of mice.