Knowledge about associations between changes in the structure and/or function of intestinal microbes (the microbiota) and the pathogenesis of various diseases is expanding. However, interactions between the intestinal microbiota and different pharmaceuticals and the impact of these on responses to treatment are less well studied. Several mechanisms are known by which drug-microbiota interactions can influence drug bioavailability, efficacy, and/or toxicity. This includes direct activation or inactivation of drugs by microbial enzymes which can enhance or reduce drug effectiveness. The extensive metabolic capabilities of the intestinal microbiota make it a hotspot for drug modification. However, drugs can also influence the microbiota profoundly and change the outcome of interactions with the host. Additionally, individual microbiota signatures are unique, leading to substantial variation in host responses to particular drugs. In this review, we describe several known and emerging examples of how drug-microbiota interactions influence the responses of patients to treatment for various diseases, including inflammatory bowel disease, type 2 diabetes and cancer. Focussing on rheumatoid arthritis (RA), a chronic inflammatory disease of the joints which has been linked with microbial dysbiosis, we propose mechanisms by which the intestinal microbiota may affect responses to treatment with methotrexate which are highly variable. Furthering our knowledge of this subject will eventually lead to the adoption of new treatment strategies incorporating microbiota signatures to predict or improve treatment outcomes.
Elucidation of the role of gut microbiota in the metabolism of orally administered drugs may improve therapeutic effectiveness and contribute to the development of personalized medicine. In this study, ten different artificial gut microbiota (AGM), obtained by culturing fecal samples in a continuous fermentation system, were challenged for their metabolizing capacity on a panel of six glucocorticoids selected from either prodrugs or drugs. Data from metabolic stability assays highlighted that, while the hydrolysis-mediated conversion of prodrugs to drugs represented only a minor metabolic pathway, significant differences in the stability of parent compounds and in their conversion rates to multiple reductive metabolites were obtained for the selected drugs.
The drug response phenotype is determined by a combination of genetic and environmental factors. The high clinical conversion failure rate of gene-targeted drugs might be attributed to the lack of emphasis on environmental factors and the inherent individual variability in drug response (IVDR). Current evidence suggests that environmental variables, rather than the disease itself, are the primary determinants of both gut microbiota composition and drug metabolism.
Autoimmune (or rheumatic) diseases are increasing in prevalence but selecting the best therapy for each patient proceeds in trial-and-error fashion. This strategy can lead to ineffective therapy resulting in irreversible damage and suffering; thus, there is a need to bring the promise of precision medicine to patients with autoimmune disease. While host factors partially determine the therapeutic response to immunosuppressive drugs, these are not routinely used to tailor therapy.
Alterations in the composition or function of the gut microbiota are associated with the etiology of human diseases. Drug-microbiota interactions can affect drug bioavailability, effectiveness, and toxicity through various routes. For instance, the direct effect of microbial enzymes on drugs can either boost or diminish their efficacy.
