# Discovery and Biological Signatures of Microbiome-Derived Xanthohumol Metabolites and their Role in Ameliorating Inflammatory Bowel Disease

> **NIH NIH R01** · OREGON STATE UNIVERSITY · 2021 · $27,120

## Abstract

The limitations of current therapies for treatment of inflammatory bowel disease (IBD) underscore the need for
new therapeutic modalities that both target the inflamed gut and the microbial dysbiosis causing the
inflammation. Our published and preliminary data demonstrate that xanthohumol (XN), the principal
prenylflavonoid found in hops (Humulus lupulus), exerts anti-inflammatory effects in vitro and in vivo by
stimulating the anti-inflammatory Keap1-Nrf2 pathway while inhibiting the pro-inflammatory NFκB pathway.
Furthermore, our studies show that mouse and human gut microbiota extensively metabolize XN and that the
metabolites' bioactivities differ qualitatively and quantitatively from the parent XN. Overall, there is strong
support for a mitigating impact of XN and its gut microbiota-derived metabolites on gut inflammation and IBD.
We hypothesize that we can identify a biological signature of XN exposure and effect on IBD mitigation. Our
corollary hypothesis is that specific gut microbiota alter the biological signature of XN exposure through
metabolic transformations and that the resulting XN metabolites uniquely contribute to normalizing the IBD-
associated microbial dysbiosis and inflammation. We define three specific aims:
1. Identify the interactions among XN, human gut microbiota species, and the inflamed intestine. Sub-aims: a)
 Identify gut microbiota-derived metabolites of XN in a fecal incubation system, b) Identify the molecular
 interactions of XN and its metabolites with gut microbial proteins at the species level by using activity-based
 proteomics, and c) Determine the anti-inflammatory and gut barrier-improving effects of XN and its
 metabolites in a 3D-cell culture model of the inflamed gut.
2. Identify biological signatures of longer-term oral treatment with XN in healthy and IBD subjects. We will
 conduct two prospective, randomized, triple-masked clinical trials, one with 24 adults diagnosed with IBD
 and one with 24 healthy control subjects. Participants will be randomized to either: 24 mg XN orally per day
 or daily placebo for 12 weeks. We will quantitatively determine established fecal and plasma markers of
 IBD, XN metabolite profiles, gut microbiome profiles, and fecal/plasma metabolome and lipidome profiles.
3. Generate a conceptual model for the understanding of the interactions between XN and the gut microbiome,
 and how the interactions benefit IBD mitigation. Based on computational integration of statistically
 processed multi-omics data from 16S rRNA gene sequencing, metagenome sequencing, metabolomics,
 and activity-based proteomics measurements, we will be able to predict which gut microbe species are
 responsible for which biotransformations of XN and its metabolites. The outcome of this aim will be a
 conceptual model of how these species interact at a community level to produce levels of XN and
 metabolites that ameliorate the dysbiosis and inflammation associated with IBD.

## Key facts

- **NIH application ID:** 10472280
- **Project number:** 3R01AT010271-04S1
- **Recipient organization:** OREGON STATE UNIVERSITY
- **Principal Investigator:** Ryan D Bradley
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $27,120
- **Award type:** 3
- **Project period:** 2018-09-21 → 2025-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10472280

## Citation

> US National Institutes of Health, RePORTER application 10472280, Discovery and Biological Signatures of Microbiome-Derived Xanthohumol Metabolites and their Role in Ameliorating Inflammatory Bowel Disease (3R01AT010271-04S1). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10472280. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*