The Gut Microbiome and Personalized Mediterranean Diet Interventions for Cardiometabolic Disease Prevention

项目摘要 许多权威机构建议地中海饮食（MedDiet）预防心脏代谢疾病。 这些饮食建议是基于人口的平均水平，可能不是最适合给定的 单独的.我们小组和其他人的初步数据支持，特定的饮食干预可能具有高度的 由于肠道微生物组的个体组成，不同个体的影响不同。而且我们 最近报道，自体粪便微生物群移植（aFMT）来源于最大的时间， 在一项随机对照试验中，体重减轻增强了MedDiet对维持心脏代谢健康的作用。这 背景支持我们的中心假设，即肠道微生物组可以改变MedDiet对 心脏代谢疾病风险。然而，没有研究利用从RCT纵向收集的数据来检验， 这个假设。大多数饮食微生物组研究受到16 S rRNA基因测序的限制， 非常一般的分类学分析，因此忽略了微生物的菌株特异性饮食相关的生化功能。到 获得更先进的机制见解，结合鸟枪宏基因组学和元转录组学， 综合框架中的代谢组学提供了一个独特的机会， 肠道微生物群落的功能。这项拟议的项目将利用两个长期的饮食RCT， 最近完成了为期18个月的DIRECT-PLUS试验，共有294名参与者，正在进行的为期3年的MIND试验，共有604名参与者。 参与者，检查是否个别肠道微生物特征修改MedDiet干预措施的影响， 心脏代谢风险和身体肥胖（目标1），并确定粪便中的代谢物和血浆中的代谢物， 肠道微生物来源可解释心脏代谢风险干预后变化的个体间差异 和肥胖症（目标2）。目标1和2的结果将在 MIND试验。在目标3中，我们将研究MedDiet和aFMT组合的长期干预后效果， 并在90名参与者的RCT中描述干预期间和干预后的肠道微生物变化。我们 该提案涉及2020-2030年战略计划中强调的一个主要研究重点，即精确营养 为NIH营养研究，并直接响应PAR-19-377：“OMIC指导的生物行为干预 改善健康结果：向前迈出的一步”作为前瞻性评估的首批努力之一， 肠道微生物组在解释个体间对饮食反应的异质性方面的功能作用 干预措施。基于现有的生物样本和在两项进行良好的长期随机对照试验中收集的数据， 最先进的多组学技术，我们的建议是一个高成本效益的机会，产生可翻译， 基于可重复生物机制的个性化饮食干预，有助于 向精确营养转变，以改善心脏代谢健康。

PROJECT SUMMARY Many authorities recommend the Mediterranean diet (MedDiet) for the prevention of cardiometabolic disease. These dietary recommendations are based on population averages and may not be best suited for a given individual. Preliminary data from our group and others support that a specific dietary intervention may have highly variable effects in different individuals due to the individual composition of the gut microbiome. Furthermore, we recently reported that autologous fecal microbiota transplantation (aFMT) derived from the time of maximal weight reduction enhanced the effects of MedDiet on maintaining cardiometabolic health in an RCT. This background supports our central hypothesis that the gut microbiome can modify the effects of MedDiet on cardiometabolic disease risk. However, no studies have utilized longitudinally collected data from RCTs to test this hypothesis. Most diet-microbiome studies are limited by the use of 16S rRNA gene sequencing yielding only very general taxonomic profiling, thus omitting strain-specific diet-related biochemical functions of microbes. To gain more advanced mechanistic insights, combining shotgun metagenomics and metatranscriptomics and metabolomics in an integrated framework presents a unique opportunity to probe both the composition and functionality of gut microbial communities. This proposed project will leverage two long-term dietary RCTs, the recently completed 18-month DIRECT-PLUS trial of 294 participants and the ongoing 3-year MIND trial of 604 participants, to examine whether individual gut microbial features modify the effects of MedDiet interventions on cardiometabolic risk and body adiposity (Aim 1) and identify metabolites in feces and metabolites in plasma of gut microbial origin that explain inter-individual differences in post-intervention changes in cardiometabolic risk and adiposity (Aim 2) in the DIRECT-PLUS trial. Findings from Aims 1 and 2 will be tested for replication in the MIND trial. In Aim 3, we will investigate long-lasting, post-intervention effects of combined MedDiet and aFMT, and characterize gut microbial changes during and after the interventions in an RCT of 90 participants. Our proposal addresses a major research priority, precision nutrition, emphasized in the 2020–2030 Strategic Plan for NIH Nutrition Research and is directly responsive to PAR-19-377: “Omics-guided Biobehavioral Interventions for Improved Health Outcomes: A Step Forward in Translation” as one of the first efforts to prospectively assess the functional role of gut microbiome in explaining inter-individual heterogeneity in response to dietary interventions. Built on existing biospecimen and data collected in two well-conducted long-term RCTs and state- of-the-art multi'omics technologies, our proposal is a highly cost-efficient opportunity to generate translatable, personalized dietary interventions grounded in reproducible biological mechanisms and contribute to the paradigm shift towards precision nutrition for improved cardiometabolic health.