Altered SIgA-targeting of gut microbiota is associated with long-term dysbiosis in pediatric solid organ transplant recipients

The composition of the gut microbiota (GM) is altered in solid organ transplantation (SOT) recipients, where the degree of dysbiosis is associated with long-term survival and is believed to be influenced by immunosuppression therapy. At the interface stands secretory (S)IgA, however, little is known about its role in governing dysbiosis in the context of SOT. We performed quantitative metagenomic analyses of the GM accompanied by SIgA sequencing in 48 pediatric SOT recipients (age = 10.6 ± 4.7 y) receiving either heart (<i>n</i> = 11), kidney (<i>n</i> = 10) or liver transplantation (<i>n</i> = 27), and compared the results to age-matched healthy controls (HC, <i>n</i> = 16). We confirmed compositional and functional dysbiosis in SOT recipients, with the degree of dysbiosis being associated with tacrolimus (TAC) levels. Overall, SOT recipients exhibited higher SIgA levels than HC, along with an increased percentage of bacteria targeted and altered target spectra. Furthermore, altered SIgA responses were associated with the degree of dysbiosis. A mechanistic model connecting immunosuppression, GM composition and SIgA-targeting is proposed, suggesting that GM dysbiosis in SOT recipients is mediated by the immune system through the SIgA response; direct drug-mediated effects on fecal communities were not observed in <i>in vitro</i> experiments. Our study provides new insights into factors that contribute to persisting dysbiosis in SOT recipients.