Exploring Drug Metabolism by the Gut Microbiota: Modes of Metabolism and Experimental Approaches

Abstract

Increasing evidence uncovers the involvement of gut microbiota in the metabolism of numerous pharmaceutical drugs. The human gut microbiome harbours 10-100 trillion symbiotic gut microbial bacteria that utilize drugs as substrates for enzymatic processes to alter host metabolism. Thus, microbiota-mediated drug metabolism can change the conventional drug action course and cause inter-individual differences in efficacy and toxicity, making it vital for drug discovery and development. This review focuses on drug biotransformation pathways and discusses different models for evaluating gut microbiota role in drug metabolism.

Human Gut Microbiota and Drug Metabolism

“…The two broad mechanisms by which gut microbiota mediates drug metabolism: direct biotransformation mechanism where metabolism of drugs is performed by microbial enzymes, while indirect biotransformation mechanism suggests the impact of microbial metabolites on host receptors and signaling pathways. The gut microbiota can directly influence a person’s response to a specific drug through directly interacting or by producing enzymes and inducing major or minor biochemical transformations in the drug to make it either more or less active/inactive or produce toxic metabolites [ 47 – 50 ] (Table 1 ). Besides this, microbiota indirectly interact with administered drugs by inducing reactivation of secreted inactive drug metabolites [ 51 ], producing metabolites to compete with drugs for the same host-metabolizing enzymes [ 52 ], modulating immune cell dynamics during immunomodulatory interventions like conditioning [ 53 ], and altering the levels of metabolizing enzymes in the intestine and liver [ 54 – 56 ].…”

Unusual Biotransformation Reactions of Drugs and Drug Candidates

“…(Fullerton et al, 2018) Formation of benzene sulfinic acid (confirmed by comparison with an authentic standard) as a major metabolite of SAM-760 in human hepatocytes has been attributed potentially to a thiol-mediated reductive cleavage of Gut microbiota can play an important role in particular in the reductive metabolism of drugs. (Dhurjad et al, 2022) Several examples of these reductions have been reviewed previously (Guo et al, 2020) and a recent example was reported by Guo et al for tacrolimus, (Guo et al, 2019) a commonly used immunosuppressant for kidney transplant recipients. Metabolite M1 formed by the reduction of the ketone moiety (Fig.…”

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

“…Lately, the investigation of factors that cause interpersonal variability has shifted the focus from the human genome analysis to the role of gut microbiota in drug response and toxicity. Various models have been applied to study gut microbiota-drug interactions ( Liu et al, 2017 ; Oancea et al, 2017 ; Xu et al, 2018 ; Dhurjad et al, 2022 ). In a recently published study, Zimmermann et al ( Zimmermann et al, 2019 ) showed that even two-thirds of 271 studied drugs have been metabolized by at least one strain of human gut bacteria, confirming that the link between the gene content and metabolic activity of gut bacteria directly reflects on interindividual differences in therapeutic outcome.…”