Gut microbial diversity, inflammation, and oxidative stress are associated with tacrolimus dosing requirements early after heart transplantation

Douglas L. Jennings, Bruno Bohn, Amelia Zuver, Duygu Onat, Maureen Gaine, Eugene Royzman, Jonathan Hupf, Danielle Brunjes, Farhana Latif, Susan Restaino, Arthur R. Garan, Veli K. Topkara, Hiroo Takayama, Koji Takeda, Yoshifumi Naka, Maryjane Farr, Renu Nandakumar, Anne Catrin Uhlemann, Paolo C. Colombo, Ryan T. DemmerMelana Yuzefpolskaya

Research output: Contribution to journalArticlepeer-review

10 Scopus citations


INTRODUCTION: Effective tacrolimus (TAC) dosing is hampered by complex pharmacokinetics and significant patient variability. The gut microbiome, a key mediator of endotoxemia, inflammation and oxidative stress in advanced heart failure (HF) patients, is a possible contributor to interindividual variations in drug efficacy. The effect of alterations in the gut microbiome on TAC dosing requirements after heart transplant (HT) has not been explored.

METHODS: We enrolled 24 patients (mean age = 55.8 ±2.3 years) within 3 months post-HT. Biomarkers of endotoxemia ((lipopolysaccharide (LPS)), inflammation (tumor necrosis factor-α (TNF-α)) and oxidative stress (8,12-iso-Isoprostane F-2alpha-VI) were measured in 16 blood samples. 22 stool samples were analyzed using 16S rRNA sequencing. TAC dose and serum trough level were measured at the time of stool and blood collection. TAC doses were reported in mg/kg/day and as level-to-dose (L/D) ratio, and categorized as ≤ vs. > median.

RESULTS: The median TAC dose was 0.1 mg/kg/day and L/D ratio was 100.01. Above the median daily weight-based TAC dose was associated with higher gut microbial alpha diversity (p = 0.03); similarly, TNF-α and 8,12-iso-Isoprostane F-2alpha-VI levels were lower and LPS levels were higher in the above median TAC group, although these findings were only marginally statistically significant and dependent on BMI adjustment. We observed n = 37 taxa to be significantly enriched among patients with > median TAC dose (all FDR<0.05), several of which are potential short-chain fatty acid producers with anti-inflammatory properties, including taxa from the family Subdoligranulum.

CONCLUSIONS: Our pilot study observed gut microbial alpha diversity to be increased while inflammation and oxidative stress were reduced among patients requiring higher TAC doses early after HT.

Original languageEnglish (US)
Article numbere0233646
JournalPloS one
Issue number5
StatePublished - May 2020

Bibliographical note

Publisher Copyright:
© 2020 Public Library of Science. All rights reserved.


  • Cross-Sectional Studies
  • Dose-Response Relationship, Drug
  • Female
  • Gastrointestinal Microbiome/drug effects
  • Heart Transplantation
  • Humans
  • Immunosuppressive Agents/administration & dosage
  • Inflammation/drug therapy
  • Male
  • Middle Aged
  • Oxidative Stress/drug effects
  • Tacrolimus/administration & dosage

PubMed: MeSH publication types

  • Research Support, Non-U.S. Gov't
  • Journal Article
  • Research Support, N.I.H., Extramural


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