Monitoring the Effects of Probiotic Supplementation in Immunocompromised Kidney Transplanted Subjects

Overview

In order to protect their new renal graft, post-transplant patients follow a rigorous immunosuppressive therapy combined with prophylactic antibiotic treatment. Kidney transplant recipients are prescribed long-term immunosuppression maintenance regimens that are the prophylaxis of organ rejection. The most frequently used are calcineurin inhibitors (tacrolimus or cyclosporine) combined with glucocorticoids (methylprednisolone, prednisone) and antiproliferative agents (mycophenolate mofetil, azathioprine). However, the use of immunosuppressive medication in transplanted patients have well-documented limitations. Recent studies reported major changes in microbiota composition as a result of immunosuppression use. A large majority of transplant patients develops severe GI problems, with the most common complication being post-transplant diarrhea. Several studies have assessed and confirmed negative effects of post-transplant diarrhea. According to (3, 4), post-transplant diarrhea affects 1 in 5 patients in the first year after kidney transplantation and is associated with decreased quality of life, allograft failure, and even death.

Challenges faced by patients after kidney transplantation prompted providers to look for additional strategies to improve their quality of life and decrease graft risks. In daily practice, investigators noted that a good percentage of transplant patients develops gastrointestinal (GI) symptoms, particularly diarrhea. In literature, this is known as Immunosuppression Acquired Diarrhea (IAD). These episodes are especially distressing and usually lead to immunosuppressive medication being reduced in dose or stopped. As a result of these actions, transplant patients become exposed to rejection, graft loss, and even death. Considering how the microbiota is altered during the post-transplant medication regimen, restoring the gut balance through the administration of probiotics presents a suitable solution. The proposed research would help increase knowledge on the beneficial effects and safety of probiotics in post-transplant patients. Diarrhea is a very common and severe complication in post-transplant patients. In the majority of the cases, it is categorized as unspecified noninfectious diarrhea (1, 3). Transplant physicians associate it with immunosuppressive drugs such as mycophenolate mofetil (MMF) (7) and other agents such as tacrolimus, azathioprine, and adrenal corticosteroids that are the prophylaxis of organ rejection in patients receiving allogenic renal transplants. The most common strategy to reduce post-transplant noninfectious diarrhea is the reduction of MMF dosing (4). Many times, the diarrhea events are so severe that the recipient's immunosuppressive medications are tapered, changed or stopped. As a result, patients become at risk of early acute rejection and graft loss. There is a large body of literature that offers information about the etiology of diarrhea for these patients. The main cause is an alteration in microbiota composition - a condition known as dysbiosis. Offering great insight, Swarat et al., (8) wrote, "the microbiota is able to induce disease (10, 12) and also able to regulate immunity or tolerance. An imbalance between pathogenic and protective microbes characterizes dysbiosis, a perturbation in the normal composition of commensal microbiota". In the post-transplant patient population, the immunosuppressive regimen and use of prophylactic antimicrobial treatments create new post-transplant microbiota communities. In literature, dysbiosis is associated with clinical conditions and systematic inflammation. Four main phyla found in the GI tract are known to contribute to human health and disease: Firmicutes, Bacteroidetes, Actinobacteria, and Proteobacteria, with the majority of species being non-pathogenic \[13\]. These commensal microbes play an important role in immune regulation, nutrition, and maintenance of host barriers against pathogens \[14, 15\]. It was reported that during diarrhea episodes (dysbiosis) in post-transplant patients, there is an increase in Proteobacteria and a decrease in Bacteroides, Ruminococcus, Coprococcus, and Dorea. Although there are clinical trials offering information about microbiota composition in patients with diarrhea, there is not much information that links it to probiotic use after kidney transplantation. The main objectives of this clinical trial are: 1. To investigate if daily use of low dose probiotics is effective in alleviating symptoms of diarrhea as well as lowering pro-inflammatory and inflammatory biomarkers and increasing anti-inflammatory biomarkers in renal transplant recipients. 2. To characterize microbiota in subjects with and without diarrhea and determine if there is any correlation between microbiota content and pro-inflammatory, inflammatory, and anti-inflammatory biomarkers.