The Yin-Yang Pharmacomicrobiomics on Treatment Response in Inflammatory Arthritides: A Narrative Review

Abstract

(1) Background: Gut microbiota (GM) is the set of microorganisms inhabiting the gastroenteric tract that seems to have a role in the pathogenesis of rheumatic diseases. Recently, many authors proved that GM may influence pharmacodynamics and pharmacokinetics of several drugs with complex interactions that are studied by the growing field of pharmacomicrobiomics. The aim of this review is to highlight current evidence on pharmacomicrobiomics applied to the main treatments of Rheumatoid Arthritis and Spondyloarthritis in order to maximize therapeutic success, in the framework of Personalized Medicine. (2) Methods: We performed a narrative review concerning pharmacomicrobiomics in inflammatory arthritides. We evaluated the influence of gut microbiota on treatment response of conventional Disease Modifying Anti-Rheumatic drugs (cDMARDs) (Methotrexate and Leflunomide) and biological Disease Modifying Anti-Rheumatic drugs (bDMARDs) (Tumor necrosis factor inhibitors, Interleukin-17 inhibitors, Interleukin 12/23 inhibitors, Abatacept, Janus Kinase inhibitors and Rituximab). (3) Results: We found a great amount of studies concerning Methotrexate and Tumor Necrosis Inhibitors (TNFi). Conversely, fewer data were available about Interleukin-17 inhibitors (IL-17i) and Interleukin 12/23 inhibitors (IL-12/23i), while none was identified for Janus Kinase Inhibitors (JAKi), Tocilizumab, Abatacept and Rituximab. We observed that microbiota and drugs are influenced in a mutual and reciprocal way. Indeed, microbiota seems to influence therapeutic response and efficacy, whereas in the other hand, drugs may restore healthy microbiota. (4) Conclusions: Future improvement in pharmacomicrobiomics could help to detect an effective biomarker able to guide treatment choice and optimize management of inflammatory arthritides.

Keywords: gut microbiota; inflammatory arthritides; personalized medicine; pharmacomicrobiomics.

Figure 1

SCFA-producing bacteria generate butyrate, propionate and acetate in the gut. These compounds are able to inhibit histone deacetylase and nuclear factor-ƘB provoking a modification in gene expression. Through this mechanism, SCFAs promote T reg cells differentiation, downregulate Th17 activity and induce the production of anti-inflammatory cytokines such as IL-10. On the other hand, very high concentration of SCFAs may induce the production of IL-1, IL-6 and IL-8. An imbalance in SCFA-producing bacteria might be the cause of inflammatory status.

Figure 2

Once into cell, MTX is polyglutamated to MTX-PG by the enzyme folylpolyglutamate synthase (FPGS). This compound gains more affinity for the drug target, but it loses affinity for MTX-Transporter (T) hindering the release from the cell. Another enzyme, named glutamate carboxypeptidase (GCP), removes glutamate from MTX-PG permitting the transportation out of the cell. FPGS and GCP are enzymes expressed by many gut bacteria, suggesting a potential role in the efficacy of MTX.