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 micro biota 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 glu curonidase, may be transformed into the inactive product.

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

Figure 1

Factors affecting the intestinal microbiota after kidney transplantation.

Figure 2

Impact of glucocorticoids on the gut microbiota. MUC: Mucin; RegIII: Regenerating protein; Muc2: Mucine 2; GC: Glucocorticoids; TNF-α: Tumor necrosis factor α; MLCK: Myosin light chain kinase; MLC2: Myosin light chain 2.

Figure 3

Impact of Tacrolimus on the gut microbiota. SCFA: Short chain fatty acids.

Figure 4

Impact of mycophenolate mofetil on the gut microbiota. MMF: Mycophenolate mofetil; MPA: Mycophenolic acid; MPAG: Mycophenolic acid glucuronated; LPS: Lipopolysaccherides; MLCK: Myosin light chain kinase; MLC2: Myosin light chain 2; MLC2P: Myosin light chain 2 phosphorilated; KT: Kidney transplantation.