# Predicting and preventing drug metabolism by the human gut microbiome

> **NIH NIH R01** · UNIVERSITY OF CALIFORNIA, SAN FRANCISCO · 2022 · $649,975

## Abstract

PROJECT SUMMARY
The human microbiome is an underappreciated contributor to drug disposition and treatment outcomes,
supported by associations in human cohorts, controlled studies in preclinical models, and high-throughput in
vitro screens. However, despite considerable recent progress in this emerging area of study there are still
major gaps in knowledge regarding the fundamental mechanisms through which human gut microbes impact
pharmacology. Research in the Turnbaugh lab over the past 5 years (supported by 1R01HL122593-01A1) was
focused on understanding the role of the prevalent human gut Actinobacterium Eggerthella lenta in drug
metabolism and disposition. While we began by focusing on the gut bacterial inactivation of the cardiac drug
digoxin, used to treat heart failure and cardiac arrythmias, our results together with the broader scientific
literature have further implicated E. lenta as a key bacterial species for the metabolism of diverse drugs,
dietary small molecules, and host metabolites. We established a robust comparative genomics toolkit for
studying E. lenta that could be readily extended to other genetically intractable gut bacterial species. In the
coming years we will continue to leverage E. lenta as a test case, with a focus on two general challenges at the
interface of microbiome research and pharmacology. In Aim 1, we will study the endogenous substrates for gut
bacterial enzymes involved in drug metabolism, building on the surprising observation that the same enzyme
responsible for digoxin metabolism is also necessary and sufficient to activate pro-inflammatory Th17 cells in
the murine gut, exacerbating mouse models of colitis. Then, in Aim 2, we will determine the mechanism
through which E. lenta inhibits the activity of the key intestinal drug efflux transporter P-glycoprotein, providing
the first step towards a more comprehensive view of the role of the microbiome in drug disposition that
accounts for microbiome-dependent changes in absorption, distribution, metabolism, and elimination. Together,
these studies emphasize the utility and feasibility of hypothesis-driven mechanistic studies, meant to
complement the wealth of data from large-scale clinical cohort studies and high-throughput screens. Our
results have already provided multiple insights that both inform and complicate our model of how the
microbiome impacts drugs, emphasizing the numerous challenges that lie ahead prior to translating this work
to achieve our long-term goal of microbiome-based precision medicine.

## Key facts

- **NIH application ID:** 10461860
- **Project number:** 5R01HL122593-07
- **Recipient organization:** UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
- **Principal Investigator:** Peter James Turnbaugh
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $649,975
- **Award type:** 5
- **Project period:** 2016-03-01 → 2025-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10461860

## Citation

> US National Institutes of Health, RePORTER application 10461860, Predicting and preventing drug metabolism by the human gut microbiome (5R01HL122593-07). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10461860. Licensed CC0.

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