Tuesday, July 1, 2025 7/1/2025

Bile acid-dependent T cell regulation in the intestine

Award Number: R01AI143821
ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 01/24/2023
PERIOD OF PERFORMANCE END DATE: 01/31/2025

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Bile acid-dependent T cell regulation in the intestine - Project Summary Immune-mediated inflammation of the distal small intestine, or ileitis, is a common and debilitating feature of the inflammatory bowel disease, Crohn’s disease. However, the mechanisms governing local immune function and inflammation in the ileum remain poorly defined. This proposal interrogates a novel pathway by which circulating CD4+ T effector (Teff) cells—including IFN-producing Th1 and IL-17A-secreting Th17 cells— compensate for cytotoxic concentrations of bile acids (BAs) in the ileum to safeguard immune homeostasis. Long considered simple emulsifying agents that circulate between the liver and ileum and that facilitate absorption and elimination of dietary lipids, BAs have now emerged as pleiotropic signaling metabolites that regulate host metabolism and inflammation via dynamic interactions with both germline-encoded receptors and the intestinal microbiota. We have shown that Teff cells upregulate expression of the xenobiotic transporter, MDR1, in the ileum to limit oxidative stress, prevent pathogenic cytokine secretion and suppress ileitis in the presence of locally-reabsorbed BAs. We have also identified the constitutive androstane receptor (CAR)–a BA- sensing nuclear receptor with no known function in immune cells—as a driver of MDR1 (Abcb1a) gene expression in mucosal Teff cells. Loss or knockdown of either MDR1 or CAR in Teff cells precipitates severe ileitis upon transfer into immunodeficient Rag1-/- mice. Mechanistically, our data suggest that CAR responds to mucosa-associated BAs in the ileum by activating the expression of numerous drug-processing enzymes and transporters in mucosal Teff cells, including MDR1, to detoxify BAs and enforce local immune homeostasis. This mechanism is directly relevant to the understanding and treatment of Crohn’s disease, as: (i) MDR1 expression in human Teff cells is increased markedly in the intestinal mucosa; (ii) MDR1 loss-of-function is evident in a subset of Crohn’s disease patients; and (iii) cholestyramine, an FDA-approved bile acid sequestrant that blocks BA reabsorption into the ileal mucosa, attenuates ileitis in both T cell transfer and spontaneous mouse models of Crohn’s disease. In addition, this mechanism establishes an unexpected new regulatory function of BAs. Our proposed studies use genetic and pharmacologic approaches, as well as clinically-relevant mouse models of Crohn’s disease, to define the mechanisms by which CAR and its transcriptional targets interact with BAs to enforce immune homeostasis in the ileum. Together, these studies will bring to light an important new pathway underlying local immune homeostasis in the ileum, whilst having important implications for improving our understanding and treatment of human Crohn’s disease.


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 = -$6,297 )
2025	2023	DARTMOUTH-HITCHCOCK CLINIC	1 MEDICAL CENTER DR	LEBANON	NH	03756	GRAFTON	USA	Allergy and Infectious Diseases Research	000	6	5/23/2025	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	-$6,297
														Subtotal = -$6,297

Issue Date FY: 2023 ( Subtotal = $386,709 )
2023	2023	DARTMOUTH-HITCHCOCK CLINIC	ONE MEDICAL CENTER DR	LEBANON	NH	03756	GRAFTON	USA	Allergy and Infectious Diseases Research	004	6	9/19/2023	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$295,926
2023	2023	DARTMOUTH-HITCHCOCK CLINIC	ONE MEDICAL CENTER DR	LEBANON	NH	03756	GRAFTON	USA	Allergy and Infectious Diseases Research	001	6	3/10/2023	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$386,709
2023	2022	UNIVERSITY OF FLORIDA	1523 UNION RD RM 207	GAINESVILLE	FL	32611	ALACHUA	USA	Allergy and Infectious Diseases Research	003	5	9/19/2023	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	-$295,926
2023	2022	UNIVERSITY OF FLORIDA	1523 UNION RD RM 207	GAINESVILLE	FL	32611	ALACHUA	USA	Allergy and Infectious Diseases Research	002	5	3/14/2023	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$0
2023	2022	UNIVERSITY OF FLORIDA	1523 UNION RD RM 207	GAINESVILLE	FL	32611	ALACHUA	USA	Allergy and Infectious Diseases Research	000	5	3/9/2023	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$0
														Subtotal = $386,709

Issue Date FY: 2022 ( Subtotal = $454,714 )
2022	2022	UNIVERSITY OF FLORIDA	1523 UNION RD RM 207	GAINESVILLE	FL	32611	ALACHUA	USA	Allergy and Infectious Diseases Research	002	5	4/5/2022	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$325,529
2022	2022	UNIVERSITY OF FLORIDA	1523 UNION RD RM 207	GAINESVILLE	FL	32611	ALACHUA	USA	Allergy and Infectious Diseases Research	003	5	5/2/2022	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	-$11,141
2022	2022	SCRIPPS RESEARCH INSTITUTE, THE	130 SCRIPPS WAY	JUPITER	FL	33458	PALM BEACH	USA	Allergy and Infectious Diseases Research	004	4	8/29/2022	NON-COMPETING CONTINUATION	$0
2022	2022	SCRIPPS RESEARCH INSTITUTE, THE	130 SCRIPPS WAY	JUPITER	FL	33458	PALM BEACH	USA	Allergy and Infectious Diseases Research	000	4	3/8/2022	NON-COMPETING CONTINUATION	$140,326
2022	2022	SCRIPPS RESEARCH INSTITUTE, THE	130 SCRIPPS WAY	JUPITER	FL	33458	PALM BEACH	USA	Allergy and Infectious Diseases Research	001	4	4/5/2022	NON-COMPETING CONTINUATION	$0
														Subtotal = $454,714

Issue Date FY: 2021 ( Subtotal = $461,505 )
2021	2021	SCRIPPS RESEARCH INSTITUTE, THE	130 SCRIPPS WAY	JUPITER	FL	33458	PALM BEACH	USA	Allergy and Infectious Diseases Research	000	3	1/29/2021	NON-COMPETING CONTINUATION	$461,505
														Subtotal = $461,505

Issue Date FY: 2020 ( Subtotal = $461,311 )
2020	2020	SCRIPPS RESEARCH INSTITUTE, THE	130 SCRIPPS WAY	JUPITER	FL	33458	PALM BEACH	USA	Allergy and Infectious Diseases Research	001	2	3/13/2020	NON-COMPETING CONTINUATION	$0
2020	2020	SCRIPPS RESEARCH INSTITUTE, THE	130 SCRIPPS WAY	JUPITER	FL	33458	PALM BEACH	USA	Allergy and Infectious Diseases Research	000	2	1/17/2020	NON-COMPETING CONTINUATION	$461,311
														Subtotal = $461,311

Issue Date FY: 2019 ( Subtotal = $483,540 )
2019	2019	SCRIPPS RESEARCH INSTITUTE, THE	130 SCRIPPS WAY	JUPITER	FL	33458	PALM BEACH	USA	Allergy and Infectious Diseases Research	000	1	2/5/2019	NEW	$483,540
														Subtotal = $483,540

Grand Total All Awards = $2,241,482

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Bile acid-dependent T cell regulation in the intestine

Award Number: R01AI143821

ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 01/24/2023

PERIOD OF PERFORMANCE END DATE: 01/31/2025

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