Pharmacomicrobiomics of Classical Immunosuppressant Drugs: A Systematic Review

Abstract

The clinical response to classical immunosuppressant drugs (cIMDs) is highly variable among individuals. We performed a systematic review of published evidence supporting the hypothesis that gut microorganisms may contribute to this variability by affecting cIMD pharmacokinetics, efficacy or tolerability. The evidence that these drugs affect the composition of intestinal microbiota was also reviewed. The PubMed and Scopus databases were searched using specific keywords without limits of species (human or animal) or time from publication. One thousand and fifty five published papers were retrieved in the initial database search. After screening, 50 papers were selected to be reviewed. Potential effects on cIMD pharmacokinetics, efficacy or tolerability were observed in 17/20 papers evaluating this issue, in particular with tacrolimus, cyclosporine, mycophenolic acid and corticosteroids, whereas evidence was missing for everolimus and sirolimus. Only one of the papers investigating the effect of cIMDs on the gut microbiota reported negative results while all the others showed significant changes in the relative abundance of specific intestinal bacteria. However, no unique pattern of microbiota modification was observed across the different studies. In conclusion, the available evidence supports the hypothesis that intestinal microbiota could contribute to the variability in the response to some cIMDs, whereas data are still missing for others.

Mechanisms and Clinical Implications of Human Gut Microbiota-Drug Interactions in the Precision Medicine Era

“…Immunosuppressive drugs have the potential to modify the composition of the gut microbiota, subsequently impacting both drug metabolism and the immune system of transplantation recipients. For instance, mycophenolic acid (MPA), an immunosuppressive agent inhibiting T and B lymphocyte proliferation associated with organ rejection [55], has been found to induce gut microbiota dysbiosis [56]. The dysbiosis not only disrupts the enterohepatic recirculation (EHR) of MPA, which leads to alterations of pharmacokinetic and pharmacodynamic profiles of MPA [57], but also elevates the risk of infections, inflammation, and graft-versus-host disease (GvHD) in transplant patients [58,59].…”

Update on the reciprocal interference between immunosuppressive therapy and gut microbiota after kidney transplantation

“…The clinical response to classical immunosuppressant drugs is highly variable among individuals and this may be asc ribed to the variety of gut microorganisms[ 60 ].…”