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

影响个人健康的唯一最重要的机会之一是通过持续改变饮食。尽管某些饮食模式在慢性病风险方面有明显的健康益处或危害，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。这项建议描述了一种循序渐进的战略，通过该战略，可将个别食物和饮食成分对健康的机制影响描述如下：步骤1)从典型的地中海式(MED)和西化饮食(WD)中确定饮食/食物组合的分子特征；步骤2)在人体生物标本(例如血浆、尿液、粪便)中确定MED和WD暴露的生物标记物；步骤3)将这些特征和生物标记物与健康指标，包括人体肠道微生物群；以及步骤4)在预期的临床试验中测试这些关联。这项建议利用了MED和WD的两个随机对照喂养试验中已有的样本(血液、尿液、粪便)。脂谱、血压、胰岛素敏感性、炎症和其他健康指标的测量是可用的，并将与本提案中产生的全面分子代谢谱相关联。中心假设是，不同的饮食模式(MED和WD)将产生不同的食物特有的分子特征，这些特征可以在人类生物样本中测量并与代谢健康指标联系起来。在强大的初步数据的指导下，我们的假设将在以下特定目标(SA)中进行验证：使用最先进的营养学、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/元基因组学方法来识别和验证食品中的分子签名和生物谱系中的生物标记物(SA 1和2)；通过将这些签名和生物标记物与健康指标和肠道微生物区系(SA 3)联系起来；以及通过在随机、前瞻性、受控喂养试验(SA 4)中测试目标1-3中确定的有益于代谢健康的特定食物或食品组(SA 4)。这项拟议的研究意义重大，因为它将首次使用循序渐进的方法，通过分子和代谢签名，将一大批个别食物和整体饮食与代谢和肠道健康指标直接联系起来。结果几乎可以立即用来为未来的研究提供信息。这种方法是创新的，因为它通过将营养代谢组作为更广泛的“暴露组”的一部分来检查营养代谢组，并确定单独食物、复合饮食和生物样本之间的重叠，从而大大偏离了现状。这项研究的结果将通过识别和联系独特的食物特征和生物代谢物来阐明饮食暴露和代谢健康之间的关系。这一知识将为制定有效和更精确的代谢性疾病预防饮食干预措施和促进健康的建议奠定基础。

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.