# Gut Microbiota and Effect on Immune Suppressants in Transplantation

> **NIH NIH R01** · HENNEPIN HEALTHCARE RESEARCH INSTITUTE · 2020 · $716,882

## Abstract

Myocphenolate mofetil (MMF) and tacrolimus are the main immune suppressants used in over 90% of kidney
transplants (tx). Several studies have shown an association between low mycophenolic acid (MPA, active
metabolite of MMF) exposure as measured by 12 hour area-under-the-curve (AUC) and acute allograft
rejection. However, significant inter-individual variation in the pharmacokinetics (PK) of MMF exists with as
much as a 10-fold variation in AUC with the same dose. Elevated MPA concentrations have been associated in
some studies with toxicities such as diarrhea, leukopenia and anemia. PK studies show a second peak of MPA
6-8 hours after oral MMF from enterohepatic recycling (EHR) of MPA due to biliary excretion of its phenolic
glucuronide (MPAG, major inactive metabolite of MPA). EHR occurs by hydrolysis of the glucuronide by β-
glucuronidases produced by gut bacteria and reabsorption of MPA. Extensive EHR greatly increases systemic
exposure to MPA and likely enhances immunosuppression and toxicity. β-glucuronidases are produced by the
gut microbes Streptococcus agalactiae, Clostridium perfringens, and E. coli and are known to influence drug
substrates and potentially the extent of EHR. In a pilot study of stool from tx patients, Bacteroides,
Ruminococcus, Coprococcus, and Dorea were significantly lower in tx patients with diarrhea. The specific
hypothesis is that certain patterns of stool microbiota lead to increased EHR, greater MPA systemic exposure
and toxicities. Therefore, we will determine the association of microbiome with: MPA and metabolite PK posttx
and EHR (Aim 1) and MPA associated toxicities such as anemia and leukopenia posttx (Aim 2). Lastly we will
determine the association of microbiome diversity with diarrhea in tx recipients on MPA posttx (Aim 3). A
prospective cohort of new kidney txs with serial stool microbiome samples will be developed and MPA and
metabolite PK and EHR measured (Aim 1), and subsequent assessment of leukopenia and anemia (Aim 2).
We will measure serial stool microbiome for association with diarrhea posttx (Aim 3). All subjects will be
followed for 12 months posttx for estimated glomerular filtration rate which is associated with long-term kidney
outcomes. The microbiome will be determined using innovative, shotgun sequencing for all aims, along with
Internal Transcribed Spacer 2 (ITS2) gene sequencing for fungi for Aim 3. We will use metatranscriptomics of
microbial β-glucuronidases, using RNAseq, to elucidate the mechanism through which the microbiome
influences MPA exposure, and MPA associated leukopenia and anemia, and posttx diarrhea. We will collect
patient centered outcomes of diarrhea using text messaging. By the end of the study, we will have developed
microbiota patterns that could be utilized as a predictive test for when MPA PK assessment is needed, for
selection of MPA dose to minimize toxicities. This study can lead to future use of select antibiotics or fecal
transplants to restore the microbio...

## Key facts

- **NIH application ID:** 9856980
- **Project number:** 5R01AI140303-02
- **Recipient organization:** HENNEPIN HEALTHCARE RESEARCH INSTITUTE
- **Principal Investigator:** AJAY K ISRANI
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $716,882
- **Award type:** 5
- **Project period:** 2019-02-01 → 2024-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9856980

## Citation

> US National Institutes of Health, RePORTER application 9856980, Gut Microbiota and Effect on Immune Suppressants in Transplantation (5R01AI140303-02). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9856980. Licensed CC0.

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