# Longitudinal Effects of Diet and the Gut Microbiome on Immunosuppressive Drug Metabolism

> **NIH NIH R03** · WASHINGTON UNIVERSITY · 2020 · $6,230

## Abstract

Project Summary
 The primary purpose of this study is to investigate mechanisms by which commensal gut microbes (gut
microbiome) might modulate interindividual differences in tacrolimus metabolism. Tacrolimus is commonly used
for immunosuppression after renal transplantation. Its dosing requirements vary widely from person to person,
and have proved difficult to predict. This unpredictability has significant clinical implications due to tacrolimus'
narrow therapeutic index: subtherapeutic levels increase risk of allograft rejection and supratherapeutic levels
increase risk of drug toxicity. Thus, understanding the mechanisms for interindividual differences in tacrolimus
metabolism could significantly reduce post-transplant morbidity and mortality.
 We hypothesize that the gut microbiome influences tacrolimus pharmacokinetics, and might account
for interindividual differences in tacrolimus metabolism not explained by existing models. We propose to
test this hypothesis by accomplishing two independent and complementary specific aims:
I. Identify gut microbial taxa and functions correlating with differences in tacrolimus metabolism
 through longitudinal surveillance of renal allograft recipients post-transplant.
II. Experimentally validate genetic and molecular mechanisms for microbial metabolism of
 tacrolimus in vitro using functional metagenomic assays, culture, and cloning techniques.
 In our first Aim, we will follow renal allograft transplants from their pre-transplant evaluation up to one year
post-transplant, collecting clinical data, dietary information, and stool samples at monthly intervals. We will use
whole-metagenome sequencing to interrogate fecal microbiome taxa and functions at each time point, and
identify microbial genes statistically associated with variation in tacrolimus pharmacokinetics. This Aim is
innovative because, to our knowledge, no prior studies of the gut microbiome and tacrolimus metabolism have
included community encoded microbial functions and host dietary patterns in their analysis. Integrating
microbiome functions with clinical and dietary data will ensure the robustness and relevance of our results.
 In our second Aim, we will functionally screen a large set of previously constructed fecal metagenomic
libraries to select for genes involved in tacrolimus metabolism or tolerance. This Aim is innovative because,
although direct metabolism of tacrolimus by bacteria has been documented, the molecular mechanisms of
microbial tacrolimus metabolism remain unknown. The molecular mechanisms found in our functional
metagenomic assays will inform the results of the longitudinal study in Aim 1, and keep them grounded in
physiology. Neither Aim depends on the success of the other, but they will work synergistically to provide insight
into the molecular mechanisms by which gut bacteria might mediate interindividual differences in tacrolimus
metabolism. Understanding the physiology of gut microbiome contributions to tacrolimus ...

## Key facts

- **NIH application ID:** 9957453
- **Project number:** 1R03DK124739-01
- **Recipient organization:** WASHINGTON UNIVERSITY
- **Principal Investigator:** Aimee M Moore
- **Activity code:** R03 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $6,230
- **Award type:** 1
- **Project period:** 2020-04-06 → 2020-09-15

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9957453

## Citation

> US National Institutes of Health, RePORTER application 9957453, Longitudinal Effects of Diet and the Gut Microbiome on Immunosuppressive Drug Metabolism (1R03DK124739-01). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/9957453. Licensed CC0.

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