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

基本信息

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
项目类别：
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

项目摘要

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.

项目概要/摘要：暴露于早期生活压力（ELS），包括虐待、忽视和家庭功能失调，显着增加晚年患精神疾病、慢性肾病和心血管疾病 (CVD) 的风险。先前描述的 ELS 效应和成人慢性疾病的发展可能起源于 ELS- 对肠道微生物群的组成和功能的依赖性影响肠道微生物群直接相互作用。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具有调节作用我最近发表的使用 ELS 小鼠模型的研究表明，ELS 具有心血管功能。改变肠道微生物群，与母体遗传无关，这表明 ELS 治疗的内源性。后代内部的因素导致了 ELS 微生物表型，但目前仍不清楚。 ELS 介导的肠道微生物群变化是否在 CVD 的发生危险因素中发挥直接作用。该提案将通过识别 ELS 调节肠道的因子来解决这些知识差距微生物群并阐明导致 ELS 导致 CVD 风险增加的微生物介导途径。患有 ELS 的青少年和年轻人的动脉僵硬度和全身血管均增加使用已建立的涉及母体分离的 ELS 小鼠模型，我们的新数据表明。 ELS 还与青少年和成年小鼠的动脉僵硬度增加有关。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 诱发的 CVD 风险的重要介质，我们在小鼠中的新数据表明，ELS 会导致 CVD 风险。肠道微生物多样性减少、循环短链脂肪酸 (SCFA) 降低以及肠道屏障受损青春期肠道微生物多样性与女性动脉僵硬度呈负相关。 SCFA 的减少与高血压和肠道屏障功能受损有关，这表明它具有一定的作用。肠道微生物群在 ELS 诱导的血管功能障碍中的作用，但确切的机制仍不清楚。因此，该提案的总体目标是阐明微生物代谢产物的机制介导 ELS 诱导的主动脉硬化和内皮功能障碍，并检查早期饮食的潜力 CVD风险的干预。