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

Abstract

Gut microbiota is often modified after kidney transplantation. This principally happens in the first period after transplantation. Antibiotics and, most of all, immunosuppressive drugs are the main responsible. The relationship between immunosuppressive drugs and the gut microbiota is bilateral. From one side immunosuppressive drugs modify the gut microbiota, often generating dysbiosis; from the other side microbiota may interfere with the immunosuppressant pharmacokinetics, producing products more or less active with respect to the original drug. These phenomena have influence over the graft outcomes and clinical consequences as rejections, infections, diarrhea may be caused by the dysbiotic condition. Corticosteroids, calcineurin inhibitors such as tacrolimus and cyclosporine, mycophenolate mofetil and mTOR inhibitors are the immunosuppressive drugs whose effect on the gut microbiota is better known. In contrast is well known how the gut microbiota may interfere with glucocorticoids, which may be transformed into androgens. Tacrolimus may be transformed by microbiota into a product called M1 that is 15-fold less active with respect to tacrolimus. The pro-drug mycophenolate mofetil is normally transformed in mycophenolic acid that according the presence or not of microbes producing the enzyme glucuronidase, may be transformed into the inactive product.

Keywords: Immunosuppressive therapy; Kidney transplantation; Gut microbiota; Dysbiosis; Pathobionts; Graft outcomes

Core Tip: Gut dysbiosis frequently occurs in the first period after kidney transplantation. Among the different causes, immunosuppressive drugs play a relevant role. There is a reciprocal effect between immunosuppressive drugs and the gut microbiota. Indeed, immunosuppressive drugs may change the gut microbiota composition causing dysbiosis as related side effects as rejection and infections. In contrast, the gut microbiota may alter the pharmacokinetic of immunosuppressive drugs determining modification in their metabolism and favoring the presence of substances with lower or higher immunosuppressant effect with respect to the original compound. Physicians should pay particular attention to these possibilities and carefully control both changes in the gut microbiota and the correct level of immunosuppressive drugs.