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Early Life Stress and Cardiovascular Disease Risk: Identifying the Role of Microbial Metabolites

Award Number: R00HL165091
ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 07/01/2025
PERIOD OF PERFORMANCE END DATE: 06/30/2028

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Early Life Stress and Cardiovascular Disease Risk: Identifying the Role of Microbial Metabolites - PROJECT SUMMARY/ABSTRACT: Exposure to early life stress (ELS), including abuse, neglect, and household dysfunction, significantly increases the risk of mental illness, chronic kidney disease, and cardiovascular disease (CVD) later in life. The previously characterized effects ELS and chronic disease development in adults may have their origins in ELS- dependent effects on composition and functions of the gut microbiota. The gut microbiota interact directly with the host’s immune and neurological systems and microbial derived metabolites have been shown to mediation cardiovascular function. My recently published research using a mouse model of ELS has determined that ELS alters the gut microbiota independent of maternal inheritance. This suggests ELS-medicated endogenous factors within the offspring are responsible for the ELS microbial phenotype. However, it remains unknown whether ELS-mediated changes in the gut microbiota play a direct role in the genesis risk factors for CVD. This proposal will address these knowledge gaps by identifying ELS-medicated factors that regulate the gut microbiota and elucidating microbial-mediated pathways that lead to increased CVD risk due to ELS. Adolescents and young adults with ELS have increased arterial stiffness and systemic vascular resistance. Using an established mouse model of ELS involving maternal separation, our novel data indicate that ELS is also associated with increased arterial stiffness in adolescent and adult mice. Furthermore, ELS induces superoxide production and endothelial dysfunction in adult mice. This suggests that vascular dysfunction is an important mediator of ELS-induced CVD risk. Our new data in mice show that ELS leads to reduced gut microbial diversity, lower circulating short-chain-fatty acids (SCFAs), and impaired gut barrier function during adolescence. Gut microbial diversity is negatively associated with arterial stiffness in women and reduced SCFAs are associated with hypertension and impaired gut barrier function. This suggests a role for the gut microbiota in ELS-induced vascular dysfunction, though exact mechanisms remain undefined. Therefore, the overall goal of this proposal is to elucidate mechanisms by which microbial metabolites mediate ELS-induced aortic stiffening and endothelial dysfunction and examine the potential of diet in the early intervention of CVD risk.


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	2025	UNIVERSITY OF ALABAMA AT BIRMINGHAM	701 S 20TH STREET	BIRMINGHAM	AL	35294	JEFFERSON	USA	Cardiovascular Diseases Research	000	3	12/3/2025	EXTENSION WITH OR WITHOUT FUNDS	$0
														Subtotal = $0

Issue Date FY: 2025 ( Subtotal = $249,000 )
2025	2025	UNIVERSITY OF ALABAMA AT BIRMINGHAM	701 S 20TH STREET	BIRMINGHAM	AL	35294	JEFFERSON	USA	Cardiovascular Diseases Research	000	3	7/1/2025	EXTENSION WITH OR WITHOUT FUNDS	$249,000
														Subtotal = $249,000

Grand Total All Awards = $249,000

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Early Life Stress and Cardiovascular Disease Risk: Identifying the Role of Microbial Metabolites

Award Number: R00HL165091

ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 07/01/2025

PERIOD OF PERFORMANCE END DATE: 06/30/2028

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