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.

Keywords: corticosteroids; cyclosporine; everolimus; methylprednisolone; microbiota; mycophenolic acid; prednisolone; prednisone; sirolimus; tacrolimus.

Figure 1

Flowchart of the systematic review. The figure shows the flowchart of this study prepared according to Page et al., 2021 [107]. For more information, visit: http://www.prisma-statement.org/ (accessed on 15 January 2023).

Figure 2

Risk of bias in the human observational studies examined. The chart reports the risk of bias in the reviewed human observational studies estimated for each of the GRADE categories and expressed as percentage of studies with “low”, “unclear” or “high” risk score.

Figure 3

Risk of bias of observational human studies [21,22,24,27,28,29,32,33,35,38,40,41,54,55,56,60,64,65]. The chart reports the risk of bias for each of the individually estimated GRADE categories in all the reviewed human observational studies and classified as “low”, “unclear” or “high”. na: not applicable.

Figure 4

Comprehensive view of the effect of cIMDs on bacterial composition of the intestinal microbiota in animal studies [34,42,43,44,45,46,47,48,49,50,51,52,53,57,61,62,63,66,67,68,69,70]. The chart shows the main alterations in the composition of the intestinal microbiota at the genus level as identified in the text and/or tables of the respective papers. The black upward and the red downward arrows indicate respectively an increase or a decrease in the relative abundance of the respective bacterial genus. For reasons of space and to make the chart readable, we could not include all the data reported in each paper or in their supplementary information, but we have focused on those on which the authors of each publication emphasized. The study by Lyons et al., 2018 [59] was not included since no change in the composition of the intestinal microbiota was observed upon treatment of mice with SIR. * Whenever available in the original publications, the data reported are related to changes observed at the genus level. When this information was not available, we reported the data at the closest classification level (order or family).

Figure 5

Comprehensive view of the effect of cIMDs on bacterial composition of the intestinal microbiota in human studies [33,41,54,55,56,59,60,64,65]. The chart shows the main alterations in the composition of the intestinal microbiota at the genus level as identified in the text and/or tables of the respective papers. The black upward and the red downward arrows indicate respectively an increase or a decrease in the relative abundance of the respective bacterial genus. For reasons of space and to make the chart readable, we could not include all the data reported in each paper or in their supplementary information, but we have focused on those on which the authors of each publication emphasized.

Figure 6

Comprehensive view of the effect of TAC, SIR, GCs and MMF bacterial composition of the intestinal microbiota [34,42,43,44,45,46,47,48,49,51,52,53,54,55,57,59,60,61,62,63,66,67,68,69,70]. The different panel show the main findings of the studies performed with each of the indicated cIMDs given alone to either experiment animals or human patients. The black upward and the red downward arrows indicate respectively an increase or a decrease in the relative abundance of the respective bacterial genus. No data have been reported for the other two cIMDs, CyA and EVERO since only one study was available for each of them. * Whenever available in the original publications, the data reported are related to changes observed at the genus level. When this information was not available, we reported the data at the closest classification level (order or family).