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

Award Number: R01AT010271
ORGANIZATION: CENTER FOR DRUG EVALUATION AND RESEARCH, NIH
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 09/21/2018
PERIOD OF PERFORMANCE END DATE: 08/31/2025

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


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 = $0 )
2026	2021	OREGON STATE UNIVERSITY	1500 SW JEFFERSON AVE	CORVALLIS	OR	97331	BENTON	USA	Research and Training in Complementary and Integrative Health	000	4	12/16/2025	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2025 ( Subtotal = $0 )
2025	2021	OREGON STATE UNIVERSITY	1500 SW JEFFERSON AVE	CORVALLIS	OR	97331	BENTON	USA	Research and Training in Complementary and Integrative Health	000	4	11/1/2024	NON-COMPETING CONTINUATION	$0
2025	2021	OREGON STATE UNIVERSITY	1500 SW JEFFERSON AVE	CORVALLIS	OR	97331	BENTON	USA	Research and Training in Complementary and Integrative Health	001	4	11/4/2024	SUPPLEMENT FOR EXPANSION	$0
														Subtotal = $0

Issue Date FY: 2023 ( Subtotal = $0 )
2023	2021	OREGON STATE UNIVERSITY	1500 SW JEFFERSON ST	CORVALLIS	OR	97331	BENTON	USA	Research and Training in Complementary and Integrative Health	001	4	8/7/2023	SUPPLEMENT FOR EXPANSION	$0
2023	2021	OREGON STATE UNIVERSITY	1500 SW JEFFERSON ST	CORVALLIS	OR	97331	BENTON	USA	Research and Training in Complementary and Integrative Health	000	4	8/4/2023	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2021 ( Subtotal = $516,964 )
2021	2021	OREGON STATE UNIVERSITY	1500 SW JEFFERSON ST	CORVALLIS	OR	97331	BENTON	USA	Research and Training in Complementary and Integrative Health	003	4	8/25/2021	SUPPLEMENT FOR EXPANSION	$27,120
2021	2021	OREGON STATE UNIVERSITY	1500 SW JEFFERSON ST	CORVALLIS	OR	97331	BENTON	USA	Research and Training in Complementary and Integrative Health	000	3	12/7/2020	SUPPLEMENT FOR EXPANSION	$95,082
2021	2021	OREGON STATE UNIVERSITY	1500 SW JEFFERSON ST	CORVALLIS	OR	97331	BENTON	USA	Research and Training in Complementary and Integrative Health	002	4	8/24/2021	NON-COMPETING CONTINUATION	$394,762
2021	2020	OREGON STATE UNIVERSITY	1500 SW JEFFERSON ST	CORVALLIS	OR	97331	BENTON	USA	Research and Training in Complementary and Integrative Health	001	3	8/23/2021	NON-COMPETING CONTINUATION	$0
														Subtotal = $516,964

Issue Date FY: 2020 ( Subtotal = $524,656 )
2020	2020	OREGON STATE UNIVERSITY	1500 SW JEFFERSON ST	CORVALLIS	OR	97331	BENTON	USA	Research and Training in Complementary and Integrative Health	000	2	12/11/2019	SUPPLEMENT FOR EXPANSION	$139,600
2020	2020	OREGON STATE UNIVERSITY	1500 SW JEFFERSON ST	CORVALLIS	OR	97331	BENTON	USA	Research and Training in Complementary and Integrative Health	001	3	8/12/2020	NON-COMPETING CONTINUATION	$385,056
														Subtotal = $524,656

Issue Date FY: 2019 ( Subtotal = $365,163 )
2019	2019	OREGON STATE UNIVERSITY	1500 SW JEFFERSON ST	CORVALLIS	OR	97331	BENTON	USA	Research and Training in Complementary and Integrative Health	002	2	8/13/2019	NON-COMPETING CONTINUATION	$365,163
2019	2018	OREGON STATE UNIVERSITY	1500 SW JEFFERSON ST	CORVALLIS	OR	97331	BENTON	USA	Research and Training in Complementary and Integrative Health	001	1	6/5/2019	NEW	$0
2019	2018	OREGON STATE UNIVERSITY	1500 SW JEFFERSON ST	CORVALLIS	OR	97331	BENTON	USA	Research and Training in Complementary and Integrative Health	000	1	12/31/2018	NEW	$0
														Subtotal = $365,163

Issue Date FY: 2018 ( Subtotal = $399,697 )
2018	2018	OREGON STATE UNIVERSITY	1500 SW JEFFERSON ST	CORVALLIS	OR	97331	BENTON	USA	Research and Training in Complementary and Integrative Health	000	1	9/21/2018	NEW	$399,697
														Subtotal = $399,697

Grand Total All Awards = $1,806,480

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

Award Number: R01AT010271

ORGANIZATION: CENTER FOR DRUG EVALUATION AND RESEARCH, NIH

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 09/21/2018

PERIOD OF PERFORMANCE END DATE: 08/31/2025

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