# Pharmacomicrobiomics: The Frontier of Interindividual Variability in Drug Response

> **NIH NIH R35** · UNIV OF NORTH CAROLINA CHAPEL HILL · 2024 · $381,864

## Abstract

PROJECT SUMMARY
Many medications for diverse indications are modified by intestinal bacteria, positioning them as an emerging
and significant driver of overall drug response (efficacy and toxicity) beyond host factors e.g. ethnicity,
genetics, sex, and age. Considering the importance of bacterial drug metabolism during preclinical
development will uncover drug-induced toxicities in relevant tissues, prompting lead retooling, and precluding
adverse events in human trials. My career goal is to develop pharmacomicrobiomics, the emerging study of
drug-microbiota interactions that drive variable drug responses. My research goal is to develop a mechanistic
understanding of how bacterial enzymes mediate toxicity and adverse effects of various drugs in ethnically
diverse populations, and to devise strategies to mitigate, prevent, or treat microbe-mediated drug toxicities in
organs involved in drug disposition. Over the next five years, the Maximizing Investigators' Research Award for
Early Stage Investigators will support my efforts to utilize the bacterial enzyme β-glucuronidase (GUS) as a tool
to elucidate mechanisms by which bacterial drug metabolism alters host physiology. GUSs hydrolyze and
reactivate glucuronide-conjugated drugs formed by Phase II metabolism of host UGT enzymes. Deconjugated
aglycones are active and can be toxic to tissues involved in drug disposition, e.g. the intestines. Molecular and
structural features driving GUS' substrate preferences are elucidated, genetic manipulation of many GUS-
encoding bacteria is feasible, and selective GUS inhibitors are in preclinical development. Combining this
foundational postdoctoral work with high-throughput primary cell culture platforms, I propose two interrelated
research programs: Program 1 will test the hypothesis that inclusion of microbiota from diverse populations
will reveal the range of interindividual variability in bacteria reactivation of various drug-glucuronide conjugates.
Program 2 will test the hypothesis that drug disposition-associated tissues derived from diverse ethnic
populations vary in their susceptibility to bacterial drug metabolism. This proposal is the first systematic
analysis of bacterial metabolism of host Phase II conjugates, and their contribution to drug-induced injury in
diverse ethnic populations. This foundational work will facilitate addition of bacterial drug into future physiology-
based pharmacokinetic modeling that can aid in the accurate accurate prediction of drug side effects and
efficacy. The proposed research is significant as it will systematically interrogate the contribution of bacterial
drug metabolism to interindividual variability in drug responses. It will develop phenotypic biomarkers of
bacterial drug reactivation and resultant drug-induced injury, and serve as a primer for future
pharmacomicrobiomic studies. Importantly, this MIRA program will utilize samples from historically under- or
unstudied populations into this emerging and excitin...

## Key facts

- **NIH application ID:** 10941618
- **Project number:** 1R35GM155168-01
- **Recipient organization:** UNIV OF NORTH CAROLINA CHAPEL HILL
- **Principal Investigator:** Aadra Prashant Bhatt
- **Activity code:** R35 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $381,864
- **Award type:** 1
- **Project period:** 2024-07-15 → 2029-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10941618

## Citation

> US National Institutes of Health, RePORTER application 10941618, Pharmacomicrobiomics: The Frontier of Interindividual Variability in Drug Response (1R35GM155168-01). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10941618. Licensed CC0.

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