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

早期生活压力和心血管疾病风险：确定微生物代谢物的作用

• 批准号: 10739155
• 负责人: Keri Kemp
• 金额: $ 17.05万
• 依托单位: UNIVERSITY OF ALABAMA AT BIRMINGHAM
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-08-01 至 2025-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10739155
• 关键词: Address; Adolescence; Adolescent; Adolescent and Young Adult; Adult; Age; Aorta; Attenuated; Big Data; Bioinformatics; Biological Assay; Blood Vessels; Butyrates; Cardiovascular Diseases; Cardiovascular Physiology; Cardiovascular system; Cause of Death; Child; Chronic Disease; Chronic Kidney Failure; Clostridiaceae; Data; Development; Diet; Early Intervention; Early identification; Endogenous Factors; Exposure to; Family; Fermentation; Functional disorder; Future; Goals; Health; Household; Hypertension; Immune; Impairment; Individual; Intervention; Knowledge; Lactobacillaceae; Life; Link; Machine Learning; Measurement; Measures; Mediating; Mediation; Mediator; Mental disorders; Metabolic; Mus; Neurologic; Pathway interactions; Peripheral Resistance; Phase; Phenotype; Play; Production; Propionates; Publishing; Recording of previous events; Research; Risk; Risk Factors; Rodent Model; Role; Stressful Event; Superoxides; Supplementation; System; Techniques; Testing; Time-restricted feeding; Tissues; United States; Vascular Diseases; Volatile Fatty Acids; Woman; arterial stiffness; blood pressure control; cardiovascular disorder risk; cardiovascular risk factor; data integration; disorder risk; dysbiosis; early experience; early life stress; endothelial dysfunction; experience; fatty acid supplementation; gut microbiota; in vivo; mRNA Expression; maternal separation; metabolomics; metagenomic sequencing; microbial; mouse model; neglect; neonate; novel; offspring; pediatric trauma; protein expression; receptor; receptor expression; single-cell RNA sequencing; skills; stress reduction

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.

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