Drug-microbiota interactions and treatment response: Relevance to rheumatoid arthritis

Ellie Sayers, Alex MacGregor, Simon R Carding, Ellie Sayers, Alex MacGregor, Simon R Carding

Abstract

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.

Keywords: drug response; intestinal microbiota; metabolism; methotrexate.

Conflict of interest statement

Conflict of interest: The authors declare no conflicts of interest in this paper.

Figures

Figure 1.. Mechanisms for drug-microbiota interactions. There…
Figure 1.. Mechanisms for drug-microbiota interactions. There are several known mechanisms for drug-microbiota interaction that may affect treatment outcomes. Of course, it is not always the case that there will be interactions. For example, some drugs may bypass the intestinal microbiota altogether (e). However, others will be enzymatically activated (b) or inactivated (a) by certain microbes or be converted into potentially toxic substances (f). More recently, the composition of the microbiota has been linked to treatment outcomes, either in association with taking a drug (c) or in response to the existence of certain microbes prior to its use (d). ICI = immune checkpoint inhibitor; SCFA = short chain fatty acid.
Figure 2.. Transport and metabolism of methotrexate…
Figure 2.. Transport and metabolism of methotrexate in humans. Methotrexate (MTX) is transported into cells via the reduced folate transporter (RFT) or proton-coupled folate transporter (PCFT). On entry, MTX is polyglutamated to MTX-PG by the enzyme folylpolyglutamate synthase (FPGS), which retains the drug inside the cell and increases its affinity for the drug target. MTX-PG may then have glutamate entities removed by glutamate carboxypeptidase (GCP), and the single-glutamate MTX may be transported out of the cell and re-enter circulation.

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