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In this issue, Oancea et al1 demonstrate for the first time that gut microbiota is able to convert the thiopurine drug thioguanine into therapeutically active thiopurine nucleotides (TGN). They thereby open new perspectives for an optimised use of thiopurines in the treatment of patients with IBD and inspire the vision of topical thiopurine delivery to the inflamed gut.
During the last years, our understanding of the molecular mechanisms, which underlie the well-known efficacy of thiopurines in IBD therapy, has been improved significantly. In order to allow potent therapeutic effects, classic thiopurine drugs including azathiopurine, mercaptopurine and thioguanine have to undergo metabolisation towards TGN. In particular, 6-thioguanine triphosphate (6-thio-GTP) could be identified as a crucial mediator of azathioprine-induced immunosuppressive effects in activated T cells and also in innate immune cells.2–4 Through its capacity to compete with endogenous GTP for the binding to the small GTPase Rac1 and subsequent inhibition of Rac1/Vav1 interaction, 6-thioGTP is able to efficiently block Rac1 signalling and thereby impact on immune cell function.2 ,3 Thiopurine-driven Rac1 blockade was shown to trigger apoptosis of stimulated T cells and to impair the capacity of T cells to form complexes with antigen-presenting cells (T cell/APC synapse formation).2 ,3 Regarding innate immune cells, thiopurine exposure of macrophages and subsequent inhibition of Rac1 signalling result in a significantly decreased inducible nitric oxide synthase (iNOS) expression and thus affect macrophage functions.5 Collectively, these findings highlight the concept that azathioprine-derived metabolites directly affect functions of …
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