Predicting Health Outcomes of Mediterranean Diet via Metabolomics of Foods and Biospecimens

影响个人健康的一个最重要的机会是通过持续的饮食调整。虽然某些饮食模式对慢性疾病风险有明显的健康益处或损害，但将这种饮食模式与健康影响联系起来的生化和代谢基础尚不清楚。该建议描述了一种循序渐进的策略，通过这种策略，单个食物和饮食成分对健康的机制影响可以描述如下：步骤1)从典型的地中海式（MED）和西化饮食（WD）中识别饮食/食物复合物的分子特征；步骤2)确定人类生物标本（如血浆、尿液、粪便）中MED和WD暴露的生物标志物；步骤3)将这些特征和生物标志物与人类受试者的健康指标（包括肠道微生物组）联系起来；步骤4)在前瞻性临床试验中检验这些关联。本建议利用了两项随机对照喂养试验中已有的标本（血液、尿液、粪便）。脂质谱、血压、胰岛素敏感性、炎症和其他健康指标的测量是可用的，并将与本提案中生成的综合分子代谢谱相关联。核心假设是，不同的饮食模式（MED vs. WD）将产生不同的食物特异性分子特征，这些特征可以在人类生物标本中测量，并与代谢健康指标相关联。在强有力的初步数据的指导下，我们的假设将在以下特定目标（SA）中进行测试，通过使用最先进的食品组学，血浆/尿液代谢组学，已知营养素的靶向分析以及粪便代谢组学/宏基因组学方法来识别和验证食品中的分子特征和生物标本中的生物标志物（SA 1和2）；通过将这些特征和生物标志物与健康指标和肠道微生物群联系起来（SA 3）；并在一项随机、前瞻性、对照喂养试验中测试目标1-3中确定的有利于代谢健康的特定食物或食物组（SA 4）。这项拟议中的研究意义重大，因为它将首次采用逐步的方法，通过分子和代谢特征，直接将大量个体食物和整个饮食与代谢和肠道健康指标联系起来。结果几乎可以立即用于未来的研究。这种方法是创新的，因为它通过检查营养代谢组作为更广泛的“暴露体”的一部分，并确定个体食物、复合饮食和生物标本之间的重叠，代表了对现状的重大背离。这项研究的结果将通过识别和连接独特的食物特征和生物代谢物来阐明饮食暴露与代谢健康之间的关系。这方面的知识将有助于制定有效和更精确的饮食干预措施，以预防代谢性疾病，并提出促进健康的建议。

One of the single most important opportunities to influence an individual's health is through sustained modification of diet. Although certain dietary patterns have clear health benefits or detriments with respect to chronic disease risk, the biochemical and metabolic underpinnings linking such dietary patterns with health effects are not clear. This proposal describes a step-wise strategy whereby the mechanistic effects of individual foods and dietary components on health can be delineated as follows: Step 1) identify molecular signatures of diet/food composites from typical Mediterranean-style (MED) and Westernized diets (WD); Step 2) identify biomarkers of MED and WD exposures in human biospecimens (e.g., plasma, urine, stool); Step 3) connect these signatures and biomarkers with health indicators, including gut microbiome, in human subjects; and Step 4) test these associations in a prospective clinical trial. This proposal leverages already available specimens (blood, urine, stool) from two randomized, controlled feeding trials of MED and WD. Measures of lipid profile, blood pressure, insulin sensitivity, inflammation, and other health indicators are available and will be associated with the comprehensive molecular metabolic profiles generated in this proposal. The central hypothesis is that different dietary patterns (MED vs. WD) will generate distinct food-specific molecular signatures that can be measured in human biospecimens and linked to metabolic health indicators. Guided by strong preliminary data, our hypotheses will be tested in the following specific aims (SA) by using state-of-art foodomics, plasma/urine metabolomics, targeted analysis of known nutrients, and fecal metabolomic/metagenomic approaches to identify and validate molecular signatures in foods and biomarkers in biospecimens (SA 1 and 2); by linking these signatures and biomarkers with health indicators and the gut microbiota (SA 3); and by testing the specific foods or food groups identified in Aims 1-3 that are beneficial to metabolic health in a randomized, prospective, controlled feeding trial (SA 4). The proposed research is significant because, for the first time, it will use a step-wise approach to directly connect a large panel of individual foods and whole diets to metabolic and intestinal health indicators through molecular and metabolic signatures. Results can be used almost immediately to inform future studies. The approach is innovative because it represents a substantial departure from the status quo by examining the nutritional metabolome as part of the broader “exposome” and identifying the overlap between individual foods, composite diets, and biospecimens. Findings from this research will elucidate relationships between dietary exposures and metabolic health by identifying and connecting unique food signatures and biological metabolites. This knowledge will underpin the development of effective and more precise dietary interventions for metabolic disease prevention and recommendations to promote health.