Advances in the implications of the gut microbiota on the treatment efficacy of disease-modifying anti-rheumatic drugs in rheumatoid arthritis

Abstract

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. Thus, considering its wide range of metabolic capabilities, the gut microbiota is a promising target for pharmacological modulation. Furthermore, drugs can alter the microbiota and the mechanisms by which they interact with their host. Individual variances in microbial profiles can also contribute to the different host responses to various drugs. However, the influence of interactions between the gut microbiota and drugs on treatment efficacy remains poorly elucidated. In this review, we will discuss the impact of microbiota dysbiosis in the pathogenesis of rheumatoid arthritis (RA), and we will attempt to elucidate the crosstalk between the gut microbiota and disease-modifying anti-rheumatic drugs (DMARDs), with an emphasis on how drug-microbiota interactions affect the treatment efficacy in RA. We speculate that improved knowledge of these critical interactions will facilitate the development of novel therapeutic options that use microbial markers for predicting or optimizing treatment outcomes.

Keywords: DMARDs; dysbiosis; gut microbiota; immune response; rheumatoid arthritis.

Figure 1

Interactions between the gut microbiota and disease-modifying anti-rheumatic drugs: implications for treatment efficacy in rheumatoid arthritis. The gut microbiota plays a critical role in the pathogenesis of rheumatoid arthritis (RA). The dynamic gut microbiota composition helps regulating host autoimmunity. Expansion of some opportunistic commensal bacteria may influence RA development by modifying the host’s microbiome, metabolic profile, and immune responses. The microbiota and its metabolite-associated signals are responsible for the activation and function of different immune cells. Autoreactive cells (e.g., Th1 and Th17 cells) are activated in lymphoid tissues, leading to inflammatory cytokine responses and production of autoantibodies. Certain disease-modifying anti-rheumatic drugs (DMARDs), such as methotrexate (MTX), sulfasalazine (SSZ), and etanercept (ETN), can directly affect the growth of gut microbiota. Furthermore, alteration of the gut microbiota may also contribute to the treatment efficacy of DMARDs by various mechanisms. CPDG2, carboxypeptidase-G2; DAMPA, 2,4-diamino-N(10)-methylpteroic acid; ETN, etanercept; MTX, methotrexate; SSZ, sulfasalazine; Th1, T helper 1 cells; Th17, T helper 17 cells.