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Vitamin A metabolism at the host-microbiome interface

Award Number: R01DK113265
ORGANIZATION: NATIONAL INSTITUTE OF DIABETES & DIGESTIVE & KIDNEY DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 06/01/2018
PERIOD OF PERFORMANCE END DATE: 06/30/2029

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Vitamin A metabolism at the host-microbiome interface - PROJECT SUMMARY: In the context of the gut barrier, Vitamin A metabolite retinoic acid (RA) is central to immune homeostasis in the gut, coordinating both innate and adaptive immunity. Vitamin A directly regulates proliferation and differentiation in the intestinal epithelium, which is crucial for maintaining optimal gut barrier. Our work in the last funding cycle revealed that gut bacteria are crucial in regulating how dietary vitamin A is processed in the intestinal mucosa. Specifically, we showed for the first time that commensal bacteria suppress RA synthesis in the gut by modulating the intestinal epithelium’s vitamin A metabolic gene rdh7. Our findings delineated the previously unknown impact of commensal bacteria on the vitamin A homeostasis, thus opening up questions regarding the role of microbially regulated RA synthesis on mucosal immunity and epithelial regeneration. Using a mouse model that constitutively expresses rdh7 gene in IECs we now show that dysregulated epithelium intrinsic RA synthesis is detrimental to host and results in increased number of IFNγ producing T-cells and enhanced susceptibility to experimental colitis. We find that overexpressing Rdh7 gene in IECs results in decreased proliferation and repair upon damage compared to control mice. Additionally, our work establishes that commensal bacteria in the gut possess vitamin A metabolic activity and significantly increase RA concentration in the gut lumen. Precise role of bacteria derived RA on epithelial barrier and intestinal immune homeostasis remains to be discovered. We hypothesize that the host and bacteria collaborate to generate an RA gradient that supports optimal intestinal epithelium renewal and immune homeostasis. In this grant proposal we will:1) determine the mechanism by which IEC intrinsic RA regulates T-cell effector responses and whether impact of IEC intrinsic RA is restricted to T-cells residing in close proximity to IECs. Additionally, we will evaluate the role of IEC intrinsic rdh7 expression in regulating IFNγ dependent immunity against intestinal pathogens and infection burden (Aim1), 2) delineate the mechanism by which RA regulates stem cells and assess the role of rdh7 expression in remodeling stem cell niche during infection via interactions with underlying immune cells (Aim2), and 3) metabolic difference in ability of gut bacteria to produce RA from pro-form vs pre-form vitamin A to probe the exclusive role of gut-bacteria sourced RA on host physiology(Aim3). Our work will deliver an unprecedented and comprehensive understanding of the role of bacterially regulated vitamin A homeostasis in the host. Our Aims will generate new paradigms for investigating and understanding vitamin A-mediated ISC remodeling. Our work will provide microbial and dietary interventions that could be therapeutic for diseases with an underlying defect in ISC regeneration and mucosal immunity.


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: 2024 ( Subtotal = $599,127 )
2024	2024	BROWN UNIVERSITY	1 PROSPECT ST	PROVIDENCE	RI	02912	PROVIDENCE	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	6	8/30/2024	COMPETING CONTINUATION	$599,127
2024	2022	BROWN UNIVERSITY	1 PROSPECT ST	PROVIDENCE	RI	02912	PROVIDENCE	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	5	7/3/2024	NON-COMPETING CONTINUATION	$0
														Subtotal = $599,127

Issue Date FY: 2022 ( Subtotal = $448,470 )
2022	2022	BROWN UNIVERSITY	1 PROSPECT ST	PROVIDENCE	RI	02912	PROVIDENCE	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	5	3/30/2022	NON-COMPETING CONTINUATION	$44,849
2022	2022	BROWN UNIVERSITY	1 PROSPECT ST	PROVIDENCE	RI	02912	PROVIDENCE	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	5	3/1/2022	NON-COMPETING CONTINUATION	$403,621
														Subtotal = $448,470

Issue Date FY: 2021 ( Subtotal = $448,470 )
2021	2021	BROWN UNIVERSITY IN PROVIDENCE IN THE STATE OF RHODE ISLAND AND PROVIDENCE PLANTATIONS	1 PROSPECT ST	PROVIDENCE	RI	02912	PROVIDENCE	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	4	3/25/2021	NON-COMPETING CONTINUATION	$448,470
														Subtotal = $448,470

Issue Date FY: 2020 ( Subtotal = $448,470 )
2020	2020	BROWN UNIVERSITY IN PROVIDENCE IN THE STATE OF RHODE ISLAND AND PROVIDENCE PLANTATIONS	1 PROSPECT ST	PROVIDENCE	RI	02912	PROVIDENCE	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	3	3/16/2020	NON-COMPETING CONTINUATION	$448,470
														Subtotal = $448,470

Issue Date FY: 2019 ( Subtotal = $448,470 )
2019	2019	BROWN UNIVERSITY IN PROVIDENCE IN THE STATE OF RHODE ISLAND AND PROVIDENCE PLANTATIONS	1 PROSPECT ST	PROVIDENCE	RI	02912	PROVIDENCE	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	2	3/12/2019	NON-COMPETING CONTINUATION	$448,470
														Subtotal = $448,470

Issue Date FY: 2018 ( Subtotal = $462,531 )
2018	2018	BROWN UNIVERSITY IN PROVIDENCE IN THE STATE OF RHODE ISLAND AND PROVIDENCE PLANTATIONS	1 PROSPECT ST	PROVIDENCE	RI	02912	PROVIDENCE	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	1	5/14/2018	NEW	$462,531
														Subtotal = $462,531

Grand Total All Awards = $2,855,538

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Vitamin A metabolism at the host-microbiome interface

Award Number: R01DK113265

ORGANIZATION: NATIONAL INSTITUTE OF DIABETES & DIGESTIVE & KIDNEY DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 06/01/2018

PERIOD OF PERFORMANCE END DATE: 06/30/2029

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