Dietary Etiologies of Heart Disease

冠心病(CHD)仍然是美国的主要健康威胁。 预防措施，如饮食和生活方式干预措施，因人而异，可能是 部分归因于肠道微生物群组成和功能的差异。这项拟议的研究旨在 阐明人类微生物组可能参与冠心病病因学的关键代谢途径 并解释了人与人之间对饮食和生活方式选择的反应。具体地说，我们的目标是评估 前瞻性地，估计暴露于内毒素(LPS)的关联，内毒素是 革兰氏阴性菌膜，对冠心病风险。我们还将检查饮食、生活方式和微生物 并建立“经验性代谢性内毒素血症指数”。人内毒素输注 实验清楚地表明，暴露于脂多糖可诱导强大的先天免疫反应，包括 炎症和白细胞向内皮细胞的募集，并使人类患上 发展为动脉粥样硬化。在大规模人体中测量循环内毒素浓度是具有挑战性的 由于半衰期较短而进行的总体研究，以及由于每日波动和变化而导致的分析效果的变异性 血液样本中蛋白质的干扰。更可靠的生物标志物，包括内毒素结合蛋白(LBP)和 可溶性分化簇14(SCD14)是内毒素暴露的特征，但尚未系统化 在有记录的冠心病事件的前瞻性流行病学研究中进行检查。进一步的知识差距 包括对与内毒素有关微生物组成和功能潜力的综合评价 曝光。为了直接解决这些科学差距，我们的目标是1)评估LBP和sCD14与CHD的关系 风险，2)检查LBP/sCD14的饮食和生活方式预测因素，得出经验性代谢性内毒素血症 这些生物标志物的指数，3)建立经验指数的变化与变化的时间关系 在LBP/sCD14水平，以及CHD发病率，以及4)调查微生物组在决定 循环中LBP/sCD14水平及其对调节饮食/生活方式关联的影响。这些目标将是 在参与卫生专业人员后续研究(HPFS)的男性和女性中实现 护士健康研究II(NHSII)，提供了多种血液和粪便样本。除了存储 这些研究还提供了丰富的现有数据，包括肠道元基因组和元转录组。 数据，通过7天饮食记录进行的饮食评估，以及对饮食、生活方式和CHD的30年随访 这使我们能够以有效和全面的方式审查目标。要生成的数据 将提供新的证据来阐明两者之间复杂的相互关系 饮食/生活方式、微生物组成和功能潜力、脂多糖暴露和冠心病发病率。证据 还将有助于开发更个性化的方法来预防和管理冠心病 疾病。

Coronary heart disease (CHD) remains the major health threat in the U.S. The effectiveness of CHD prevention measures, such as dietary and lifestyle interventions vary greatly between individuals and may be ascribed partly to differences in gut microbiome composition and function. The proposed research aims to elucidate a critical metabolic pathway through which human microbiome may contribute to the CHD etiology and account for the between-person responses to diet and lifestyle choices. Specifically, we aim to evaluate, prospectively, the association of the estimated exposure to lipopolysaccharide (LPS), a major component of the Gram-negative bacteria membrane, on CHD risk. We will also examine dietary, lifestyle, and microbial predictors of LPS exposure and create an “empirical metabolic endotoxemia index”. Human LPS-infusion experiments clearly demonstrate that LPS exposure induces potent innate immune reactions, including inflammation and recruitment of leukocytes to endothelium, and predisposes humans to an elevated risk of developing atherosclerosis. Circulating LPS concentrations are challenging to measure in large-scale human population studies due to a short half-life and variability in assay effectiveness due to daily fluctuations and interference from proteins in blood samples. More reliable biomarkers, including LPS binding protein (LBP) and soluble cluster of differentiation 14 (sCD14), characterize LPS exposure, but have yet to be systematically examined in prospective epidemiological studies with documented incident CHD. Further knowledge gaps include a comprehensive evaluation of microbial composition and functional potential in relation to LPS exposure. To address these scientific gaps directly, we aim to 1) evaluate LBP and sCD14 in relation to CHD risk, 2) examine dietary and lifestyle predictors of LBP/sCD14 and derive an empirical metabolic endotoxemia index of these biomarkers, 3) establish temporal relationships of changes in the empirical index with changes in LBP/sCD14 levels, as well as CHD incidence, and 4) investigate the role of the microbiome in determining circulating levels of LBP/sCD14 and their impact on mediating diet/lifestyle associations. These aims will be realized among men and women participating in the Health Professionals Follow-up Study (HPFS) and the Nurses’ Health Study II (NHSII), who provided multiple blood and fecal samples. In addition to stored biospecimens, these studies also offer rich, existing data, including gut metagenome and metatranscriptome data, dietary assessments by 7-day diet records, and three decades of follow-up of diet, lifestyle, and CHD incidence, that allow us to examine the aims in an efficient and comprehensive manner. Data to be generated from this project will provide novel evidence that elucidates the complex inter-relationships between diet/lifestyle, microbial composition and functional potential, LPS exposure, and CHD incidence. The evidence will also inform the development of a more personalized approach to preventing and managing coronary heart disease.