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.

项目摘要/摘要： 暴露于早期生活压力(ELS)，包括虐待、忽视和家庭功能障碍 增加精神疾病、慢性肾脏疾病和心血管疾病(CVD)的风险。这个 先前表征的ELS效应和成人慢性病的发展可能起源于ELS- 对肠道微生物区系组成和功能的依赖效应。肠道微生物区系直接与 宿主的免疫和神经系统以及微生物衍生的代谢物已被证明是 心血管功能。我最近发表的一项使用ELS小鼠模型的研究确定ELS 改变肠道微生物区系，独立于母体遗传。这表明ELS药物是内源性的 后代体内的因素是ELS微生物表型的原因。然而，它仍然是未知的 ELS介导的肠道微生物区系变化是否在CVD的发生风险因素中起直接作用。这 一项提案将通过确定调节肠道的ELS药物因子来解决这些知识差距 微生物区系和阐明导致ELS导致心血管疾病风险增加的微生物介导的途径。 患有ELS的青少年和年轻人动脉僵硬和全身血管增加 抵抗。使用建立的涉及母体分离的ELS小鼠模型，我们的新数据表明 ELS还与青春期和成年小鼠动脉僵硬增加有关。此外，ELS 诱导成年小鼠产生超氧化物和内皮功能障碍。这表明血管 功能障碍是ELS诱发心血管疾病风险的重要中介因素。我们在老鼠身上的新数据显示ELS导致 肠道微生物多样性降低，循环短链脂肪酸(SCFA)减少，肠道屏障受损 在青春期起作用。女性肠道微生物多样性与动脉僵硬呈负相关 而SCFAs减少与高血压和肠道屏障功能受损有关。这暗示着一种角色 对于ELS诱导的血管功能障碍中的肠道微生物区系，尽管确切的机制仍不清楚。 因此，这项提议的总体目标是阐明微生物代谢物 早期干预ELS诱导的主动脉硬化和内皮功能障碍并检测饮食的潜力 心血管疾病风险的干预。