Abstract
Recently it has been demonstrated that the gut microbiome has the ability to metabolize thioguanine into pharmacological active 6-thioguanine nucleotides (6-TGN). Incubation of representative gut bacteria with thioguanine led to the formation of 6-TGN and hypoxanthine phosphoribosyl transferase (HPRT)-deficient mice with a dextran sulphate sodium–induced colitis, rapidly improved after treatment with oral thioguanine and 6-TGN metabolites were detected in their feces. This suggests a mechanism of action by thioguanine conversion via gut bacteria, as the required HPRT is absent in host cells of HPRT-deficient mice. Moreover, after treating Winnie mice (a mouse with spontaneous colitis due to a variant polymorphism in Muc2) with rectally administrated thioguanine, a rapid and significant improvement of the colitis appeared in the treated parts of the colon. Based on these observations, we present, for the first time, 16 cases of ulcerative colitis patients who were treated either with thioguanine suppositories or enemas as off-label rescue treatment.