# Understanding and Controlling Drug Metabolism by the Gut Microbiota to Improve Human Health

> **NIH NIH R01** · UNIV OF NORTH CAROLINA CHAPEL HILL · 2022 · $304,654

## Abstract

PROJECT SUMMARY
The human factors involved in drug metabolism are well understood, but the microbial enzymes that play
important roles in this process remain largely uncharacterized. Here we seek to fill this knowledge gap by
focusing on the gut microbial β-glucuronidase (GUS) proteins. GUS enzymes remove the glucuronic acid
moiety that is placed on a wide range of drugs and xenobiotics by human phase II drug metabolizing UDP-
glucuronosyltransferase proteins in the liver and other key metabolic tissues. The conjugation of a glucuronide
to a xenobiotic or drug nearly always inactivates it and very often marks it for elimination via the
gastrointestinal (GI) tract. Gut microbial GUS enzymes can reverse this process and reactivate drugs in the
intestines; as such, they are important drug metabolism enzymes. The reactivation of drug-glucuronides in the
intestines is known to cause the dose-limiting GI toxicity of therapeutics and is suspected to produce inter-
individual variabilities in drug responses. In the last few years, my group has begun to unravel the diversity,
function, and structure of gut microbial GUS enzymes and has developed initial microbiome-targeted inhibitors.
Through these efforts, we are beginning to elucidate the crucial roles these enzymes play in responding to the
xenobiotic- and drug-glucuronides that reach the gut. This proposal focuses on three drugs: the anticancer
chemotherapeutic irinotecan and two non-steroidal anti-inflammatory drugs, diclofenac and indomethacin.
Each is inactivated by glucuronidation and sent to the GI tract for excretion, each is reactivated within the
lumen of the GI tract by gut microbial GUS enzymes, and each reactivated drug causes dose-limiting gut
toxicities. Importantly, we have developed microbiome-targeted inhibitors that reduce, but do not eliminate, the
gut toxicity of these drugs. Considerably more work remains to realize the potential promise of this new
approach to improve human health through targeting the gut microbiome. To enable our success in these
efforts, we have developed a new activity-based probe-enabled proteomics pipeline to identify the gut microbial
GUS enzymes present in mouse and human fecal material. We will use this novel technology to understand at
the protein level how GUS enzymes change upon drug treatment or targeted inhibition. Our overarching
hypothesis is that gut microbial GUS enzymes reactivate a range of structurally distinct drug glucuronide
conjugates and cause GI toxicity, and that these proteins can be inhibited to prevent intestinal damage. We will
test this hypothesis by completing three focused in vitro, proteomics, and in vivo aims. Taken together, the
data we collect will significantly expand our understanding of drug metabolism by the gut microbiota, and will
potentially lead to novel therapeutics to improve human health.

## Key facts

- **NIH application ID:** 10401799
- **Project number:** 5R01GM137286-03
- **Recipient organization:** UNIV OF NORTH CAROLINA CHAPEL HILL
- **Principal Investigator:** Matthew R Redinbo
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $304,654
- **Award type:** 5
- **Project period:** 2020-05-01 → 2024-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10401799

## Citation

> US National Institutes of Health, RePORTER application 10401799, Understanding and Controlling Drug Metabolism by the Gut Microbiota to Improve Human Health (5R01GM137286-03). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10401799. Licensed CC0.

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