Gut Microbiota And Post-Transplant Complications In Kidney Transplant Recipients

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Abstract
The gut microbiota is now considered to have a role in regulating the immune system and in drug metabolism. Little, however, is known about its role in infectious and immunological complications and in metabolism of immnosuppressive medications in kidney transplantation. In this pilot study, we prospectively collected fecal specimens in 26 kidney transplant recipients and characterized the changes in the gut microbiota during the first 3 months after kidney transplantation. We utilized 16S rRNA deep sequencing of the V4-V5 hypervariable region to comprehensively characterize the gut microbiota in the fecal specimens. We characterized the changes in the gut microbiota from pre-transplantation to post-transplantation and we evaluated whether the gut microbiota was associated with post-transplant diarrhea, urinary tract infections, acute rejection, and tacrolimus dosing requirements. We report a significant increase in the phylum, Proteobacteria, from pre-transplantation to post-transplantation (0.9% vs. 4.1%, respectively, P=0.04, Wilcoxon signed-rank test) in the 5 kidney transplant recipients who had available pre-transplant fecal specimens. Recipients with post-transplant diarrhea had a lower microbial diversity as measured by the Shannon diversity index than those who did not develop post-transplant diarrhea (2.5±0.3 vs. 3.4±0.8, respectively, P = 0.02, Wilcoxon rank-sum test). Using linear discriminant analysis effect size (LEfSe) method, we determined that post-transplant diarrhea fecal specimens were associated with a significantly lower abundance of Bacteroides, Ruminococcus, Coprococcus, and Dorea. 3 kidney transplant recipients developed Enterococcus urinary tract infections (UTI) and the 3 fecal specimens associated with Enterococcus UTI had a significantly higher median Enterococcus fecal abundance than the 23 time-matched fecal specimens from the kidney transplant recipients who did not develop Enterococcus UTI (24% vs. 0%, respectively, P=0.005, Wilcoxon rank-sum test). The same 3 kidney transplant recipients developed acute rejection and the fecal specimens associated with acute rejection had a lower abundance of Bacteroidetes (P=0.02, Wilcoxon rank-sum test), Clostridiales (P=0.01), and Bacteroidales (P=0.03) and a higher abundance of Lactobacillales (P=0.04) than the 23 time-matched fecal specimens from the kidney transplant recipients who did not develop acute rejection. In a subset of 19 kidney transplant recipients who were maintained on tacrolimus and who had available fecal specimens in the first week of transplantation, we evaluated whether the gut microbiota in the first week of transplantation was associated with a dose escalation of tacrolimus at 1 month (Dose Escalation Group, ?50% increase in initial tacrolimus dosing by 1 month, > 6 mg/day) or with no dose escalation (Dose Stable Group, <50% increase in initial tacrolimus dosing by 1 month, ? 6 mg/day). The fecal abundance of Faecalibacterium prausnitzii was significantly higher in the Dose Escalation Group (N=5) than in the Dose Stable Group (N=14) (11.8% vs. 0.8%, P=0.002, Wilcoxon rank-sum test). There was a positive linear correlation between the fecal abundance of Faecalibacerium prausnitzii at week 1 post-transplantation and future 1 month tacrolimus dosing (R=0.57, P=0.01). In this pilot study, we report one of the first characterizations of the gut microbiota after kidney transplantation and we report novel associations with post-transplant diarrhea, Enterococcus UTI, acute rejection, and tacrolimus dosing requirements in kidney transplantation.
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2016
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acute rejection; diarrhea; gut microbiota; kidney transplantation; tacrolimus dosing; urinary tract infections
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Clinical & Translational Investigation
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Master of Science
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Government Document
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Attribution-NonCommercial-NoDerivatives 4.0 International
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dissertation or thesis
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