Title: Assessing metabolic profiling strategies for nutritional management of cardiovascular disease risk
Funder: Department of Health and Social Care

Abstract: A cornerstone of governments' policies to reduce cardiovascular disease (CVD) risk is to encourage population change towards healthier diet and lifestyle. However, monitoring dietary changes in response to policy recommendations is based on self-reported dietary assessment tools, which are known to have high misreporting rates. This makes it difficult to understand if poor response to policy recommendations is due to lack of physiological effect of a diet, poor compliance to recommendations and/or variation in individuals' response to dietary changes. I previously developed an analytical pipeline to accurately classify metabolic profiles in healthy individuals according to dietary type and to assess adherence to diet, independently of dietary recording based on NMR urine spectra. I now want to focus on developing a method that effectively reflects adherence and variability in response to dietary changes in people at risk of CVD in order to implement metabolically-personalised nutritional advice to increase participants' compliance to dietary recommendations that will result in reducing CVD-risk factors (e.g. high cholesterol, BMI, blood pressure). I will achieve this by expanding coverage of the metabolome to incorporate plasma lipids and urine/plasma markers of gut bacterial modulation, using a multiplatform (NMR, LC-MS, GC-MS) approach.Research question Can metabolically-informed personalised dietary advice be used to more effectively change dietary habits of CVD-risk participants in comparison to traditional dietary advice? Specifically I aim to: - Build a multiplatform mathematical model to establish the level of adherence of individuals to dietary recommendations based on comprehensive molecular phenotyping of urine and blood plasma and to ascertain whether metabolic patterns at baseline are predictive of an individual's response to diet in terms of changes in metabolism. (Study 1) - Establish the response of free-living individuals at risk of CVD to dietary interventions by determining the relationship of the metabolic profiles with traditional CVD-risk metrics including cholesterol, BMI and blood pressure and evaluate the clinical benefit of incorporating this information into nutritional management programs compared to standardised clinical advice (Study 2). A further objective is to establish whether metabolically-tailored strategies can improve compliance to dietary recommendations and reduce misreporting.Investigation planStudy 1: 1H-NMR-spectroscopy, lipidomics and mass-spectrometry of urine and plasma will be used to generate a comprehensive metabolic profile of volunteers at risk of CVD based on an in-patient randomised cross-over clinical trial (CCT) to follow either a healthy dietary intervention, compliant with current dietary guidelines for risk reduction of CVD or a diet associated with high risk of CVD according to current UK dietary intake. Study 2: Mathematical models from the in-patient study will be used to objectively assess dietary intake, monitor adherence to diet and responses to dietary changes in free-living people at risk of CVD. Participants will follow a randomized CCT for 12-weeks, in which a dietitian will provide personalised dietary advice based on knowledge of urine and plasma metabolic profiles from samples collected at clinic every 2-weeks in addition to 24-h food diaries. A control group will mirror the intervention group but will receive standard NICE-guideline dietary recommendations. The changes in CVD-risk factors will be compared between the intervention and the control group.Furthermore, the 24-h food diaries of the intervention and the control groups will be assessed against objective measurements of their dietary habits using the metabolic profiles and the mathematical models from the in-patient study. The success of this project will facilitate improved measurement and monitoring of dietary intake in free-living people. This Fellowship will support a major step forward in improving British clinical nutritional practice by introducing new strategies to provide personalised advice, patient education and improve compliance to dietary advice for people at risk of CVD.

Lay abstract: Cardiovascular diseases (CVD) account for approximately a third of the total deaths worldwide and cost the NHS approximately 7 billion per year (https://www.ncbi.nlm.nih.gov). Although genetic predisposition plays a role in CVD, lifestyle, particularly diet, is known to modify disease risk. Healthy diets such as the Mediterranean diet have been shown to improve CVD risk factors (blood pressure, obesity, cholesterol) and are critical to the UK government's policies to reduce CVD-risk. However, it is known that people respond differently to dietary changes and in order to find the best strategy for an individual it is necessary to identify objective measures of dietary intake, dietary adherence and dietary effect. It has been estimated that 50% of the self-reported food diaries within the 2000 cohort of the National Diet and Nutrition Survey significantly under-reported, which makes these national data impossible to interpret.The premise of this proposal is that metabolic profiling can be used to improve the accuracy of monitoring dietary intake, behaviour and adherence to diet guidelines for people at risk of CVD and can be a useful tool for establishing inter-individual variation in response to diet. Thus the overarching goal of this project is to evaluate the applicability of providing a metabolically-informed personalised dietary advice to help people at risk of CVD to change their dietary habits within their own environment. This will be achieved by using metabolic profiles of blood and urine to build a model for predicting adherence and response to diet. In the first phase of the project, a group of people at risk of developing CVD will be housed in a clinical unit. Their response to a healthy and an unhealthy diet over a 5-day period will be monitored through NMR and MS spectroscopic analysis of urine and blood which will map the levels of many different molecules including lipids, amino acids and gut bacterial metabolites. The profiles and knowledge acquired from this closely controlled study will be used to build a model for predicting whether patients are following a healthy diet, with specific molecules representing intake of individual foods or nutrients. In the second phase of the project, the model will be tested on a larger number of individuals at risk of CVD, in their home environment and the viability of using these metabolic profiles as an adjunct to nutritional management in a clinical setting will be evaluated. Here, the intervention group will receive advice based on measurements of their urinary metabolic profiles and the effect of metabolically-informed personalised dietary advice on reducing CVD risk factors will be compared with a control group receiving standard dietary advice provided by the dietician. A secondary aim of the study is to explore whether misreporting declines when free-living patients are aware that reliable information is obtained by monitoring their profiles. Patients will be encouraged to provide feedback on effectiveness of personalised dietary advice and on the efficiency, ease of implementation and added benefit of the process. This fellowship grant will support a major step forward in British clinical nutritional practice by bringing together state-of-art technologies and cutting edge nutritional research in order to introduce new strategies to provide personalised advice, educate patients, improve compliance and will facilitate improved measurement and monitoring of dietary intake and the downstream effect on cardiovascular health. In addition to publishing the methods and results in high quality journals, a patient/public facing website will be created to explain the scientific basis of the research and to share findings in a timely manner. The topic is timely as governments battle with the increasing burden of non-communicable diseases, with obesity and poor diet as significant aetiological factors. Ultimately, the project will result in improved efficacy of dietary modification in CVD risk-reduction with accompanying socioeconomic benefits.

Research activity codes: 4.2 EVALUATION OF MARKERS AND TECHNOLOGIES
Health categories: CANCER AND NEOPLASMS;CARDIOVASCULAR;METABOLIC AND ENDOCRINE;ORAL AND GASTROINTESTINAL;STROKE