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Phenotypic flexibility: a breakthrough in health-claim substantiation

Published: 06-09-2016, | Member: TNO

Measuring phenotypic flexibility – how individual bodies adapt to changing circumstances – could be a breakthrough tool in health-claim substantiation. However, applying this approach to the general population remains a challenge, say Nard Clabbers and Suzan Wopereis from research organization TNO: “Our goal is a more-personalized approach.”

The European Food Safety Authority (EFSA) guidelines for health claims require cause-effect and dose-response relationships to be established in apparently-healthy consumers. With conventional single biomarkers, such as LDL-cholesterol and blood pressure, measuring the subtle, multiple and long-term effects of nutrition is very difficult.

“Health-claim approvals will need combinations of biomarkers that represent early-stage physiological changes, when individuals still appear healthy”, explains Nard Clabbers, Senior Business Development Manager, Personalized Nutrition and Health, at TNO  in Zeist. “This requires a paradigm shift in which health and disease are considered as two points on a continuum, not as polar opposites.”

PhenFlex and NutriTech
Based on this philosophy, TNO initiated the PhenFlex project (2012-2015) , a precompetitive collaboration co-financed by five food-multinationals. The aim was to develop and assess objective approaches for quantifying optimal health – defined by TNO as the “capability to adapt under changing circumstances” – and to substantiate dietary benefits to health. At the same time, the EC-funded, TNO-coordinated project NutriTech (2012-2015)  was launched: 23 research organizations and universities, across the globe, working to standardize nutrition-research methodologies. PhenFlex and NutriTech ‘fed’ each other via scientific boards, joint meetings and the guidance and support of the International Life Sciences Institute (ILSI).

In the two projects, phenotypic flexibility was measured by applying a dietary challenge milkshake containing high levels of sugar, fat and protein. This was followed by assessing the response profiles of around 160 classical and novel biomarkers over a period of several hours after the challenge was consumed. These biomarkers represent health-related processes throughout the body and include “classical” biomarkers like cholesterol, glucose and triglyceride levels but also metabolomics parameters (such as amino acids or ketone bodies) and ‘exposure biomarkers’, using items like a food frequency questionnaire.

Sensitive measure
“We concluded that phenotypic flexibility is highly-sensitive, making it a valuable, measure for health assessment; one that allows quantification of subtle differences in health status”, says TNO scientist Suzan Wopereis.

“In the PhenFlex project we demonstrated substantial differences in phenotypic flexibility between healthy people and diabetes patients”, she illustrates. “We also found, within the healthy range of the population, that the higher a person’s age or body-fat percentage, the lower their phenotypic flexibility.”

In the NutriTech project, the main aim was to show that using caloric restriction as an intervention would demonstrate a change in phenotypic flexibility. “This was, indeed, shown, although it was more difficult than expected”, Wopereis continues. “Subgroups of volunteers appeared to respond differently, as measured by modern nutrigenomics technology.” The research team concluded that when you want to substantiate health effects, it is important to get up close and personal, by segmenting the population.

The PhenFlex challenge-approach has been adopted by several international research groups and TNO has started a follow-up project, PhenFlex Phase 2 (January 2016 – September 2017). “The goal is a proof-of-concept that the new biomarkers, identified in PhenFlex 1 and validated in NutriTech, can be used to substantiate health effects in nutritional-intervention studies”, says Clabbers.

How to deal with segmentation, and the challenges inherent in personalized nutritional recommendations, will be part of PhenFlex Phase 2. “The project is intended to prove that our phenotypic flexibility toolbox can substantiate the health effects of food and nutrition in a sensitive and clinically-relevant manner”, he continues.

The project will also include self-measuring, by volunteers in their own homes. “We will investigate the value of a more-personalized approach to nutritional intervention, one that combines individual health assessments with tailor-made nutrition advice”, illustrates Clabbers. The research outcomes will be shared with the Public-Private Partnership Personalized Nutrition and Health, a collaboration of TNO with Wageningen UR and several industry partners.

Personalized approach
Clabbers and Wopereis expect that, within a few years, the food industry will have made major advances in health-claim substantiation. “More-sensitive, validated tools for measuring phenotypic flexibility will become available, facilitating robust health-claim substantiation and including study designs that support consumer self testing”, says Wopereis. These developments will bring new opportunities for product development and nutrition advice, says Clabbers: “Generic health claims will be superseded by specific claims for specific individuals in specific situations. This should make a real difference to people’s health.”

Interested in participating to PhenFlex Phase 2 or in the PPP Personalized Nutrition and Health? Contact Nard Clabbers or Suzan Wopereis at TNO: or