Monday, June 30, 2025 6/30/2025

The role of bile acid metabolomics in graft-versus-host disease

Award Number: R01CA228308
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 03/15/2024
PERIOD OF PERFORMANCE END DATE: 03/31/2028

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The role of bile acid metabolomics in graft-versus-host disease - Allogeneic hematopoietic cell transplantation (allo-HCT) is a therapy with curative intent for a variety of malignant and non-malignant diseases. One of the major complications after allo-HCT is graft-versus-host disease (GVHD), especially of the gastrointestinal tract. Our group was one of the first to explore the role of the intestinal microbiome in allo-HCT in patients and preclinical models by combining next-generation sequencing with immunological, microbial and metabolomic approaches. We found relationships between the intestinal microbiome and GVHD, relapse, infections, engraftment, and immune reconstitution. The clinical and preclinical studies we performed in the previous funding period resulted in 19 manuscripts (including NEJM, Nature, Science, and Nature Med). We observed in large multi-center studies that higher diversity of intestinal microbiota was associated with better overall survival, reconstitution of CD4, mucosal-associated invariant and V2 T cells. Expansion of particular Enterococci was not only associated with GVHD in patients but exacerbated disease in mice. We showed that loss of Clostridia was associated with the onset of acute GVHD, whereas lower serum levels of butyrate were associated with an increased risk for chronic GVHD. In addition to their role in digestive physiology, bile acids (BAs) exert wide-ranging biological effects, including antimicrobial activity, intestinal epithelial homeostasis, and modulation of immunity. Primary BAs (PBA) are synthesized in the liver and transformed by the intestinal microbiota into a diverse pool of secondary bile acids (SBAs) with unique biochemical properties. BAs can bind to Farnesoid X Receptor (FXR), a nuclear receptor that is a critical regulator of BA homeostasis, inflammation, and GI barrier function. Our preliminary preclinical studies demonstrate that allo-HCT recipients with GVHD have: a) a decrease in unconjugated BAs and SBAs in cecal contents and plasma, b) a reduced abundance of bile salt hydrolase genes (critical for SBA transformation) in the intestinal microbiome, and c) decreased BA synthesis in the liver. In addition, we found that a) most BAs can counteract FXR activation by the PBA chenodeoxycholic acid and b) donor T cells deficient of FXR induce less GVHD. Our preliminary clinical studies corroborate the experimental results in that fecal α-diversity is associated with increased abundance of SBAs, which are in turn correlated to less acute GVHD and better overall survival. Based on studies demonstrating that BAs can inhibit Th17 polarization and enhance Treg generation and our preliminary data in mouse models and allo-HCT patients, we hypothesize that BA metabolism is an important modulator of alloreactive donor T cells and GVHD in allo-HCT recipients. All our research is performed through perpetual dialogue between investigation in mice and humans. Therefore, we propose to study the role of bile acids in GVHD after allo-HCT in preclinical models (Aim 1) and allo-HCT patients (Aim 2) and to develop strategies to improve GVHD by targeting BA metabolism (Aim 3). Our major goal is to ameliorate outcomes after allo-HCT by developing BA-based therapies.


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: 2025 ( Subtotal = $585,843 )
2025	2025	BECKMAN RESEARCH INSTITUTE OF THE CITY OF HOPE	1500 DUARTE RD	DUARTE	CA	91010	LOS ANGELES	USA	Cancer Biology Research	000	8	3/31/2025	NON-COMPETING CONTINUATION	$527,259
2025	2025	BECKMAN RESEARCH INSTITUTE OF THE CITY OF HOPE	1500 DUARTE RD	DUARTE	CA	91010	LOS ANGELES	USA	Cancer Biology Research	002	8	6/4/2025	NON-COMPETING CONTINUATION	$58,584
2025	2025	BECKMAN RESEARCH INSTITUTE OF THE CITY OF HOPE	1500 DUARTE RD	DUARTE	CA	91010	LOS ANGELES	USA	Cancer Biology Research	001	8	5/6/2025	NON-COMPETING CONTINUATION	$0
														Subtotal = $585,843

Issue Date FY: 2024 ( Subtotal = $555,619 )
2024	2024	BECKMAN RESEARCH INSTITUTE OF THE CITY OF HOPE	1500 DUARTE RD	DUARTE	CA	91010	LOS ANGELES	USA	Cancer Biology Research	004	7	9/9/2024	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$276,000
2024	2024	BECKMAN RESEARCH INSTITUTE OF THE CITY OF HOPE	1500 DUARTE RD	DUARTE	CA	91010	LOS ANGELES	USA	Cancer Biology Research	001	7	5/6/2024	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$555,619
2024	2023	SLOAN-KETTERING INSTITUTE FOR CANCER RESEARCH	1275 YORK AVE	NEW YORK	NY	10065	NEW YORK	USA	Cancer Biology Research	003	6	9/9/2024	COMPETING CONTINUATION	-$276,000
2024	2023	SLOAN-KETTERING INSTITUTE FOR CANCER RESEARCH	1275 YORK AVENUE	NEW YORK	NY	10065	NEW YORK	USA	Cancer Biology Research	002	6	5/22/2024	COMPETING CONTINUATION	$0
2024	2022	SLOAN-KETTERING INSTITUTE FOR CANCER RESEARCH	1275 YORK AVE	NEW YORK	NY	10065	NEW YORK	USA	Cancer Cause and Prevention Research	000	5	5/2/2024	NON-COMPETING CONTINUATION	$0
														Subtotal = $555,619

Issue Date FY: 2023 ( Subtotal = $584,482 )
2023	2023	SLOAN-KETTERING INSTITUTE FOR CANCER RESEARCH	1275 YORK AVE	NEW YORK	NY	10065	NEW YORK	USA	Cancer Biology Research	000	6	3/7/2023	COMPETING CONTINUATION	$584,482
														Subtotal = $584,482

Issue Date FY: 2022 ( Subtotal = $580,450 )
2022	2022	SLOAN-KETTERING INSTITUTE FOR CANCER RESEARCH	1275 YORK AVE	NEW YORK	NY	10065	NEW YORK	USA	Cancer Biology Research	001	5	3/11/2022	SUPPLEMENT FOR EXPANSION	$37,924
2022	2022	SLOAN-KETTERING INSTITUTE FOR CANCER RESEARCH	1275 YORK AVE	NEW YORK	NY	10065	NEW YORK	USA	Cancer Biology Research	003	5	5/10/2022	SUPPLEMENT FOR EXPANSION	$3,372
2022	2022	SLOAN-KETTERING INSTITUTE FOR CANCER RESEARCH	1275 YORK AVE	NEW YORK	NY	10065	NEW YORK	USA	Cancer Cause and Prevention Research	000	5	3/9/2022	NON-COMPETING CONTINUATION	$495,137
2022	2022	SLOAN-KETTERING INSTITUTE FOR CANCER RESEARCH	1275 YORK AVE	NEW YORK	NY	10065	NEW YORK	USA	Cancer Cause and Prevention Research	002	5	5/9/2022	NON-COMPETING CONTINUATION	$44,017
														Subtotal = $580,450

Issue Date FY: 2021 ( Subtotal = $673,952 )
2021	2021	SLOAN-KETTERING INSTITUTE FOR CANCER RESEARCH	1275 YORK AVE	NEW YORK	NY	10065	NEW YORK	USA	Cancer Cause and Prevention Research	000	4	3/17/2021	NON-COMPETING CONTINUATION	$550,156
2021	2021	SLOAN-KETTERING INSTITUTE FOR CANCER RESEARCH	1275 YORK AVE	NEW YORK	NY	10065	NEW YORK	USA	Cancer Biology Research	001	4	4/27/2021	SUPPLEMENT FOR EXPANSION	$123,796
														Subtotal = $673,952

Issue Date FY: 2020 ( Subtotal = $550,156 )
2020	2020	SLOAN-KETTERING INSTITUTE FOR CANCER RESEARCH	1275 YORK AVE	NEW YORK	NY	10065	NEW YORK	USA	Cancer Cause and Prevention Research	000	3	4/1/2020	NON-COMPETING CONTINUATION	$550,156
														Subtotal = $550,156

Issue Date FY: 2019 ( Subtotal = $533,651 )
2019	2019	SLOAN-KETTERING INSTITUTE FOR CANCER RESEARCH	1275 YORK AVE	NEW YORK	NY	10065	NEW YORK	USA	Cancer Cause and Prevention Research	000	2	3/25/2019	NON-COMPETING CONTINUATION	$533,651
														Subtotal = $533,651

Issue Date FY: 2018 ( Subtotal = $525,957 )
2018	2018	SLOAN-KETTERING INSTITUTE FOR CANCER RESEARCH	1275 YORK AVE	NEW YORK	NY	10065	NEW YORK	USA	Cancer Cause and Prevention Research	000	1	3/20/2018	NEW	$525,957
														Subtotal = $525,957

Grand Total All Awards = $4,590,110

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The role of bile acid metabolomics in graft-versus-host disease

Award Number: R01CA228308

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 03/15/2024

PERIOD OF PERFORMANCE END DATE: 03/31/2028

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