Isotope Ratio Mass Spectrometer for Nutritional and Metabolic Studies

To fully understand how nutrients in our diet are metabolised and promote health or risk of disease, we need to trace molecules such as sugars and fats around the body. The gold-standard method for this is by using stable isotope tracers. These are molecules that have been modified so that one or more of their atoms is replaced with a less common form of the atom (a stable isotope). These tracers are not radioactive; they are safe to give to humans, including children and pregnant women, and they have really shaped our understanding of nutrition and metabolism. For example, if a person ingests a meal containing a specific type of fat that has been labelled with a stable isotope tracer, we can follow the movement of this fat in and out of the blood over the course of time, and independently of other types of fat in the body. We do this by measuring the stable isotope tracer in a series of timed blood samples, using mass spectrometry.
It is absolutely vital that we, and others, continue to use this technique to answer fundamental questions about how nutrition and physiology relate to human health, as outlined in the BBSRC's strategic plan. To this end, it is essential for us to update our old equipment (an isotope ratio mass-spectrometer, IRMS) with more reliable, next generation equipment. This will allow us to expand our analytical capability in the use of stable isotope tracer methodology at Surrey, and Nationwide. The more efficient software and hardware will allow us to operate the equipment in such a way as to maximise its use. This will involve widening access to the methodology, by increasing the available time on the machine, and by 'demystifying' the use of the technology through training and promotion. Our aim is train the next generation of undergraduate and postgraduate students, and visiting Fellows, in the use of stable isotope tracers. To help facilitate this aim, we have an industrial sponsor, LGC (The Laboratory of the Government Chemist), who will provide training on quality control procedures, and provide assurance that our measurements are of the highest standard.
A major biological challenge of modern life is to understand how the Western diet impacts on human health. We are currently applying stable isotope tracers to address this challenge in three multi-centred studies funded by the BBSRC, one MRC-funded project and two BBSRC doctoral training partnership PhD projects that relate to the UK eating patterns. The first BBSRC study has been designed to better understand why some people's blood cholesterol is very sensitive to changes in the intake of dietary saturated fat, while others people's blood cholesterol shows little or no effect. We will be giving stable isotope labelled saturated fat to 'cholesterol responders' and 'non-responders' to trace the differences in metabolic pathways that might explain this variation in cholesterol response to saturated fat. In another BBSRC DRINC funded project, we will use potatoes that have the starch pre-labelled with an isotope label. This will help us to understand how chilling and reheating a mashed potato meal improves the body's handling of a particular type of starch in the potato. In a third BBSRC study, we will provide new evidence for the health effects of 'inter-esterified' fats that are being introduced by the food industry as substitutes for unhealthy, hydrogenated trans fats. An MRC funded project will examine the impact of the balance of food eaten in the morning and evening on metabolic and behavioural regulation during weight loss. This study will help to understand how energy balance can be modulated by altering meal timing. Finally, our BBSRC DTP students are measuring the intestinal handling of fructose in vivo and in a cell model, and investigating the regulation of enzymes that mediate the conversion of alpha linolenic acid in cooking oils, into long chain polyunsaturated fatty acids. Both of these studies would employ the use of a new IRMS.

Stable isotope trace labelling is the gold-standard for measuring nutrient and metabolic flux in humans in vivo, and represents core technology for unravelling the complexity of the human metabolome. The applicant, BF, a world-leader in stable isotope tracer studies who established a mass-spectrometry facility at The University of Oxford, has transferred her expertise to the University of Surrey. The maintenance of Surrey as a centre of excellence in stable isotope tracer technology is of fundamental importance to one of the BBSRC's strategic priorities, to increase understanding of how nutrition relates to human health and wellbeing. Examples of how we have used stable isotope technology to address this priority include a study on the effects of high and low sugar diets on whole body lipid metabolism (BB/ G009899/1). A future study (one of 3 new BBSRC funded projects) will elucidate the mechanisms underlying variation in the blood cholesterol response to dietary saturated fat (BB/P010245/1). Our most sensitive equipment for tracer analysis is a gas chromatograph interfaced with a combustion isotope ratio mass spectrometer (GC-C-IRMS). While this equipment has been used extensively since its purchase in 2005, it is now outdated, and its maintenance is no longer fully supported. We therefore request funds to replace it with the 'next generation' equivalent. The greater analytical capability, improved automation, accuracy and reproducibility will increase the overall efficiency and analytical performance of the technique. It would also offer a wider range of measurements, improve efficiency of equipment use, and enhance our ability to share technical expertise with the UK research community and to train the next generation of scientists. Included in the commitment from our industrial sponsor LGC is training using their 'expertise in regulation, accreditation and standard setting'. This in turn highlights our commitment to maintaining the highest analytical standards.

The initial impacts of the work to be undertaken with the new equipment will be via our own funded studies within the BBSRC's Strategic Framework (2015-2020). These collaborative projects will offer new knowledge and insight into the mechanisms that underlie variation in the serum LDL-C response to dietary SFA (BB/P010245/1), the matrix effects of food structure (the effect of preparation of dietary starchy carbohydrate meals on the glycaemic response (BB/N021274/1), and how the inter-esterification of industrial fats influences the cardiovascular health of consumers (BB/N020987/1). Our work will exert multiple impacts by informing the formulation of dietary guidelines and transforming how they are applied, and by changing dietary practices so they exert the greatest impact on those most in need of dietary advice. From our strong track record in mechanistic nutrition and increased analytical capacity, we anticipate being able to extend our programmes of work to support other, more diverse collaborative projects in the future. Pathways to these impacts will be achieved through academics, dieticians, health care professionals and medics at the interface of public health and medicine, who can inform and educate the end users of our research outputs. These end users include:

Policy makers - These are academic and non-academic members of boards and panels who advise government and formulate policy on food and nutrition in relation to public health e.g. SACN, Public Health England, and the Department of Health. Many of our research collaborators also have a direct influence on these official bodies, as committee members, scientific advisers and consultants (see Pathways to Impact)

Charities, learned societies - these bodies exert significant impacts as active stakeholders of the role of nutrition on human health and risk of disease e.g. Nutrition Society, HEART UK, The British Nutrition Foundation, Association for Nutrition, British Heart Foundation. Applicants on this proposal also have a direct impact on these influential bodies as members, scientific advisers and consultants, including a planned workshop for members of the Nutrition Society (see Pathways to Impact).

Industry and commerce - Outputs from our studies will provide insight into the mechanisms of action of functional foods, thus creating opportunities in industry to design and reformulate foods to reduce cardiovascular risk by targeting such risk factors as blood cholesterol, postprandial glycaemia and lipaemia. For example, our work will provide a better understanding of what happens to starch during the processing of commercially available food products, and how processing translates to the health of consumers. This could ultimately be important for food labelling and health promotion. The study led by Dr Berry at Kings College, will provide an evidence base for industry to understand the potential role and impact of inter-esterified fats on human health. All of these programmes of work translate into economic and societal impacts through the production, marketing and commercial sales of new products.

Research funders - our mechanistic outputs would inform future research by featuring in the frameworks and strategic priorities of research funding bodies in the UK and Europe, creating employment and new knowledge. This process will produce highly trained young researchers capable of tackling contemporary challenges in both public and private sectors, and make a substantial contribution to the economic competitiveness of the UK.

General public - Our research will inform and educate consumers in an attempt to resolve mass confusion over the relationship between diet, lifestyle and health, and ultimately improve quality of life and wellbeing.