title: Gut microbiota and tacrolimus dosing in kidney transplantation.
abstract: Tacrolimus dosing to establish therapeutic levels in recipients of organ transplants is a challenging task because of much interpatient and intrapatient variability in drug absorption, metabolism, and disposition. In view of the reported impact of gut microbial species on drug metabolism, we investigated the relationship between the gut microbiota and tacrolimus dosing requirements in this pilot study of adult kidney transplant recipients. Serial fecal specimens were collected during the first month of transplantation from 19 kidney transplant recipients who either required a 50% increase from initial tacrolimus dosing during the first month of transplantation (Dose Escalation Group, n=5) or did not require such an increase (Dose Stable Group, n=14). We characterized bacterial composition in the fecal specimens by deep sequencing of the PCR amplified 16S rRNA V4-V5 region and we investigated the hypothesis that gut microbial composition is associated with tacrolimus dosing requirements. Initial tacrolimus dosing was similar in the Dose Escalation Group and in the Stable Group (4.2 ± 1.1 mg/day vs. 3.8 ± 0.8 mg/day, respectively, P=0.61, two-way between-group ANOVA using contrasts) but became higher in the Dose Escalation Group than in the Dose Stable Group by the end of the first transplantation month (9.6 ± 2.4 mg/day vs. 3.3 ± 1.5 mg/day, respectively, P<0.001). Our systematic characterization of the gut microbial composition identified that fecal Faecalibacterium prausnitzii abundance in the first week of transplantation was 11.8% in the Dose Escalation Group and 0.8% in the Dose Stable Group (P=0.002, Wilcoxon Rank Sum test, P<0.05 after Benjamini-Hochberg correction for multiple hypotheses). Fecal Faecalibacterium prausnitzii abundance in the first week of transplantation was positively correlated with future tacrolimus dosing at 1 month (R=0.57, P=0.01) and had a coefficient ± standard error of 1.0 ± 0.6 (P=0.08) after multivariable linear regression. Our novel observations may help further explain inter-individual differences in tacrolimus dosing to achieve therapeutic levels.
authors: Department of Medicine, Division of Nephrology and Hypertension, Weill Cornell Medical College, New York, New York, United States of America; Department of Transplantation Medicine, New York Presbyterian Hospital-Weill Cornell Medical Center, New York, New York, United States of America.
authors: John R
authors: JR
authors: Lee
authors: Department of Medicine, Division of Nephrology and Hypertension, Weill Cornell Medical College, New York, New York, United States of America; Department of Transplantation Medicine, New York Presbyterian Hospital-Weill Cornell Medical Center, New York, New York, United States of America.
authors: Thangamani
authors: T
authors: Muthukumar
authors: Department of Medicine, Division of Nephrology and Hypertension, Weill Cornell Medical College, New York, New York, United States of America; Department of Transplantation Medicine, New York Presbyterian Hospital-Weill Cornell Medical Center, New York, New York, United States of America.
authors: Darshana
authors: D
authors: Dadhania
authors: Department of Medicine, Infectious Diseases Services, Memorial Sloan Kettering Cancer Center, New York, New York, United States of America; Lucille Castori Center for Microbes, Inflammation and Cancer, Memorial Sloan Kettering Cancer Center, New York, New York, United States of America; Weill Cornell Medical College, New York, New York, United States of America.
authors: Ying
authors: Y
authors: Taur
authors: Lucille Castori Center for Microbes, Inflammation and Cancer, Memorial Sloan Kettering Cancer Center, New York, New York, United States of America; Weill Cornell Medical College, New York, New York, United States of America; Department of Medicine, Adult Bone Marrow Transplant Service, Memorial Sloan Kettering Cancer Center, New York, New York, United States of America.
authors: Robert R
authors: RR
authors: Jenq
authors: Department of Medicine, Infectious Diseases Services, Memorial Sloan Kettering Cancer Center, New York, New York, United States of America.
authors: Nora C
authors: NC
authors: Toussaint
authors: Lucille Castori Center for Microbes, Inflammation and Cancer, Memorial Sloan Kettering Cancer Center, New York, New York, United States of America.
authors: Lilan
authors: L
authors: Ling
authors: Department of Medicine, Infectious Diseases Services, Memorial Sloan Kettering Cancer Center, New York, New York, United States of America; Lucille Castori Center for Microbes, Inflammation and Cancer, Memorial Sloan Kettering Cancer Center, New York, New York, United States of America; Weill Cornell Medical College, New York, New York, United States of America.
authors: Eric
authors: E
authors: Pamer
authors: Department of Medicine, Division of Nephrology and Hypertension, Weill Cornell Medical College, New York, New York, United States of America; Department of Transplantation Medicine, New York Presbyterian Hospital-Weill Cornell Medical Center, New York, New York, United States of America.
authors: Manikkam
authors: M
authors: Suthanthiran
mesh_terms: D000328:Adult; D000368:Aged; D001419:Bacteria / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D005243:Feces / Q000382:microbiology; D005260:Female; D000069196:Gastrointestinal Microbiome / Q000235:genetics*; D006084:Graft Rejection / Q000188:drug therapy* / Q000235:genetics / Q000382:microbiology; D006801:Humans; D016030:Kidney Transplantation; D008297:Male; D008875:Middle Aged; D012336:RNA, Ribosomal, 16S / Q000235:genetics; D016559:Tacrolimus / Q000008:administration & dosage*; D066027:Transplant Recipients
chemical_list: D012336:RNA, Ribosomal, 16S; D016559:Tacrolimus