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Identifying Gut Microbiome Mediated Mechanisms for Diastolic Dysfunction Improvement After Bariatric Surgery

Award Number: R01HL158900
ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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Identifying Gut Microbiome Mediated Mechanisms for Diastolic Dysfunction Improvement After Bariatric Surgery - Project Summary Sleeve gastrectomy (SG), is a type of bariatric surgery, which improves obesity-related diastolic dysfunction, a hallmark finding of heart failure with preserved ejection fraction (HFpEF). As weight reduction through dieting and caloric restriction fails to improve cardiac function, this suggests a mechanism for diastolic function improvement initiated from the alteration in gastrointestinal anatomy after SG. The broad, long-term objective of this project is to explore if gut microbial changes after SG, lead to a bile acid pool rich in farnesoid X receptor (FXR) agonists, that mediate diastolic function improvements. In Specific Aim 1, we will test the hypothesis that the post-SG gut microbiome increases plasma bile acid FXR agonists as a mechanism for cardiac function improvement. Studies will be conducted utilizing fecal material transfer of SG mice as well as metagenomic sequence analysis of SG stool from rodents and humans to determine the transferable effect of the gut microbiome on the plasma BA pool and diastolic function. In Specific Aim 2, we will determine whether SG plasma decreases cardiomyocyte metabolic stress via FXR activation. Human and rodent cardiomyocyte cell lines will be engineered for regulated FXR expression to determine whether SG plasma reduces cardiac metabolic stress through FXR agonism. In Specific Aim 3, we will determine whether SG improves diastolic function through cardiomyocyte FXR signaling in vivo by performing surgery and assessing cardiac function in a cardiomyocyte-specific FXR knockout mouse model. We hypothesize that SG enhances FXR signaling through microbial-derived products to improve cardiac function. These findings will enhance our understanding of the mechanisms for diastolic recovery after bariatric surgery to develop novel surgical and non-surgical therapies for diastolic dysfunction and HFpEF which replicate the metabolic mechanisms generated by a SG.


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 = $396,578 )
2025	2025	THE MEDICAL COLLEGE OF WISCONSIN, INC.	8701 WATERTOWN PLANK RD	MILWAUKEE	WI	53226	MILWAUKEE	USA	Cardiovascular Diseases Research	000	4	5/1/2025	NON-COMPETING CONTINUATION	$396,578
														Subtotal = $396,578

Issue Date FY: 2024 ( Subtotal = $431,830 )
2024	2024	THE MEDICAL COLLEGE OF WISCONSIN, INC.	8701 WATERTOWN PLANK RD	MILWAUKEE	WI	53226	MILWAUKEE	USA	Cardiovascular Diseases Research	000	3	6/4/2024	NON-COMPETING CONTINUATION	$431,830
														Subtotal = $431,830

Issue Date FY: 2023 ( Subtotal = $440,642 )
2023	2023	THE MEDICAL COLLEGE OF WISCONSIN, INC.	8701 WATERTOWN PLANK RD	MILWAUKEE	WI	53226	MILWAUKEE	USA	Cardiovascular Diseases Research	000	2	4/12/2023	NON-COMPETING CONTINUATION	$440,642
														Subtotal = $440,642

Issue Date FY: 2022 ( Subtotal = $446,632 )
2022	2022	MEDICAL COLLEGE OF WISCONSIN, INC., THE	8701 WATERTOWN PLANK RD	MILWAUKEE	WI	53226	MILWAUKEE	USA	Cardiovascular Diseases Research	000	1	5/24/2022	NEW	$446,632
														Subtotal = $446,632

Grand Total All Awards = $1,715,682

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Identifying Gut Microbiome Mediated Mechanisms for Diastolic Dysfunction Improvement After Bariatric Surgery

Award Number: R01HL158900

ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

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