Gut Microbiota Metabolism of Azathioprine: A New Hallmark for Personalized Drug-Targeted Therapy of Chronic Inflammatory Bowel Disease

Abstract

Despite the growing number of new drugs approved for the treatment of inflammatory bowel disease (IBD), the long-term clinical use of thiopurine therapy and the well-known properties of conventional drugs including azathioprine have made their place in IBD therapy extremely valuable. Despite the fact that thiopurine S-methyltransferase (TPMT) polymorphism has been recognized as a major cause of the interindividual variability in the azathioprine response, recent evidence suggests that there might be some yet unknown causes which complicate dosing strategies causing either failure of therapy or toxicity. Increasing evidence suggests that gut microbiota, with its ability to release microbial enzymes, affects the pharmacokinetics of numerous drugs and subsequently drastically alters clinical effectiveness. Azathioprine, as an orally administered drug which has a complex metabolic pathway, is the prime illustrative candidate for such microbial metabolism of drugs. Comprehensive databases on microbial drug-metabolizing enzymes have not yet been generated. This study provides insights into the current evidence on microbiota-mediated metabolism of azathioprine and systematically accumulates findings of bacteria that possess enzymes required for the azathioprine biotransformation. Additionally, it proposes concepts for the identification of gut bacteria species responsible for the metabolism of azathioprine that could aid in the prediction of dose-response effects, complementing pharmacogenetic approaches already applied in the optimization of thiopurine therapy of IBD. It would be of great importance to elucidate to what extent microbiota-mediated metabolism of azathioprine contributes to the drug outcomes in IBD patients which could facilitate the clinical implementation of novel tools for personalized thiopurine treatment of IBD.

Unraveling interindividual differences and functional consequences of gut microbial metabolism of immunosuppressants

“…To identify bacteria-produced drug metabolites we leveraged insights from our prior high-throughput screen (7 ) and existing literature (16, 17 ). Mining untargeted metabolomics data, we identified a total of 18 different drug metabolites for 16 different drugs (Table S11 and Fig 3A).…”

Mechanisms and Clinical Implications of Human Gut Microbiota-Drug Interactions in the Precision Medicine Era

“…Specific gut bacteria have the capacity to produce SCFAs, such as acetate, propionate, and butyrate. These SCFAs can modulate the expression and activity of hepatic cytochrome P450 (CYP) enzymes through various mechanisms, such as activation of peroxisome proliferator-activated receptor (PPAR), inhibition of histone deacetylases (HDACs), or alteration of redox status [32]. Similarly, certain gut bacteria can generate indole derivatives through tryptophan metabolism, which can either inhibit CYP enzymes or induce phase II conjugation reactions [33,34].…”

Precision medicine in inflammatory bowel disease

“…Besides genetic markers, the roles of gut microbiota in predicting thiopurine treatment response should also be noted. Available data demonstrated that gut microbiota affect thiopurine biotransformation by releasing microbial enzymes [ 182 ]. Liu et al .…”