Phenotypic flexibility as a measure of health: the optimal nutritional stress response test

Abstract

Nutrition research is struggling to demonstrate beneficial health effects, since nutritional effects are often subtle and long term. Health has been redefined as the ability of our body to cope with daily-life challenges. Physiology acts as a well-orchestrated machinery to adapt to the continuously changing environment. We term this adaptive capacity "phenotypic flexibility." The phenotypic flexibility concept implies that health can be measured by the ability to adapt to conditions of temporary stress, such as physical exercise, infections or mental stress, in a healthy manner. This may offer a more sensitive way to assess changes in health status of healthy subjects. Here, we performed a systematic review of 61 studies applying different nutritional stress tests to quantify health and nutritional health effects, with the objective to define an optimal nutritional stress test that has the potential to be adopted as the golden standard in nutrition research. To acknowledge the multi-target role of nutrition, a relevant subset of 50 processes that govern optimal health, with high relevance to diet, was used to define phenotypic flexibility. Subsequently, we assessed the response of biomarkers related to this subset of processes to the different challenge tests. Based on the obtained insights, we propose a nutritional stress test composed of a high-fat, high-caloric drink, containing 60 g palm olein, 75 g glucose and 20 g dairy protein in a total volume of 400 ml. The use of such a standardized nutritional challenge test in intervention studies is expected to demonstrate subtle improvements of phenotypic flexibility, thereby enabling substantiation of nutritional health effects.

Fig. 1

Physiological processes involved in phenotypic flexibility. Thirty-five different physiological processes that may be influenced by food and nutrition have been defined. The optimal nutritional stress challenge should trigger all these physiological processes, so that it allows the broad quantification of nutritional health effects

Fig. 2

Graphical representation of a single-marker response profile during homeostasis and upon challenge test before and after intervention. The challenge test evokes a response in concentration of a biomarker that is representative of a physiological system of interest which returns to homeostatic levels after a period of time. The intervention should ideally lead to an improved challenge response in terms of amplitude and duration

Fig. 3

Ratio of carbohydrate, fat and protein in combination challenge tests used in reported studies. The studies are organized from high carbohydrate content on the left to low carbohydrate content on the right (1 Esposito and Nappo, 2 Zwirska-Korczala, 3 Ramos-Roman, 4 Casas-Agustench, 5 Phillips, 6 Scheffer, 7 Wopereis, 8 Pellis, 9 Krug, 10 Thomsen, 11 Coutinho, 12 Derosa, 13 Cheng, 14 Mortensen, 15 Saxena, 16 Mahdu, 17 Iraklianou)