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Mapping Xenobiotic Metabolism by the Human Gut Microbiome

Award Number: R00ES037746
ORGANIZATION: NATIONAL INSTITUTE OF ENVIRONMENTAL HEALTH SCIENCES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 08/25/2025
PERIOD OF PERFORMANCE END DATE: 06/30/2029

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Mapping Xenobiotic Metabolism by the Human Gut Microbiome - The gut microbiota is a key site to metabolize ingested xenobiotics, transforming hundreds of dietary molecules, drugs, and industrial chemicals into metabolites with altered or potentially toxic activities. Despite important discoveries on some microbial xenobiotic metabolites that affect health, gut microbial metabolism for most xenobiotics remains uncharacterized. Moreover, even when these metabolites are known, the information is often scattered across literature and not systematically organized for easy reuse in new data analyses. This lack of comprehensive characterization hinders understanding on the biological effects of xenobiotics tied to microbial transformation, limiting our ability to develop precision interventions. The objective of this proposal is to systematically map the gut microbial metabolites of xenobiotics with untargeted mass spectrometry (MS). During the K99 phase, we demonstrated with 140 drugs that a complex synthetic community of 111 human gut bacterial strains (hCom) can reproduce drug metabolites found in human feces. Building on this foundation, the R00 phase will advance three aims. In Aim 1, I will map the gut microbial metabolites of ~800 drugs through the high throughput hCom incubation combined with re-analysis of public untargeted metabolomics data from other large-scale screening studies on drug microbial metabolism. In Aim 2, I will investigate how these microbial transformations impact drug efficacy and toxicity. I will focus on antiretroviral (ARV) drugs used to treat human immunodeficiency virus (HIV), given that approximately 26 million people with HIV worldwide rely on daily ARV therapy. I have showed that the gut microbiota significantly transforms the ARVs. I will chemically synthesize microbial metabolites of the ARVs found in human samples, and functionally characterize them with in vitro bioassays relevant to HIV treatment and ARV-associated side effects. In Aim 3, I will expand this approach to dietary additives and environmental contaminants. I will inventory the gut microbial metabolites of these contaminants in large-scale, by mining public MS resources for reference spectra, and incubating them with the hCom. The resulting metabolites will be linked to disease phenotypes using public MS data, and key bioactivities will be validated with in vitro bioassays. The collected MS/MS spectra from Aim 1 and � will be organized into web-based tools that enable rapid query of xenobiotic-derived molecules in untargeted MS data, with links to their exposure sources, human occurrence, and potential health effects. The contribution of my proposal will be two-fold: (1) An untargeted MS/MS resource serving as the foundation for future discoveries on xenobiotic-derived health effects mediated by gut microbial metabolism; (2) An inventory of bioactive microbial metabolites with potential applications in precision disease prevention and treatment.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2026 ( Subtotal = $249,000 )
2026	2026	THE LELAND STANFORD JUNIOR UNIVERSITY	450 JANE STANFORD WAY	STANFORD	CA	94305	SANTA CLARA	USA	Environmental Health	000	2	7/22/2026	EXTENSION WITH OR WITHOUT FUNDS	$249,000
														Subtotal = $249,000

Grand Total All Awards = $249,000

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Mapping Xenobiotic Metabolism by the Human Gut Microbiome

Award Number: R00ES037746

ORGANIZATION: NATIONAL INSTITUTE OF ENVIRONMENTAL HEALTH SCIENCES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 08/25/2025

PERIOD OF PERFORMANCE END DATE: 06/30/2029

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