Nutrition Research and Human Disease: A Critical Appraisal of Mechanistic Research, Cohort Studies, and Randomized Trials
Journal of Nutrition and Health Sciences
For many decades researchers have followed the strategy that in order to achieve a fuller understanding of nutrition, it is necessary to study the biochemical and physiological action of the huge numbers of chemicals in food, and thence learn the mechanisms by which they protect health or increase risk of disease    . This strategy, often known as reductionism, has revealed a great deal about the role played in the body by vitamins, minerals, and many other substances, and why
... s, and why deficiencies of them lead to specific symptoms. However, this mechanistic strategy has achieved little success in recent decades in terms of generating information that is of practical value with regard to nutrition and human health    . The reason for this is that because of the great complexity of the human body it is extraordinarily difficult to properly understand the exact details of the pathways leading to disease. Even with relatively "simple" disorders, such as hypertension, obesity, and type 2 diabetes, there are multiple pathways involved and the story of each disorder becomes steadily more complex as new discoveries are made. There is an additional reason for the poor success of mechanistic research as applied to nutrition: foods contain thousands of separate substances and this leads to vast numbers of possible interactions. A major part of nutrition research consists of the investigation of how food components affect the biochemical and physiological processes within the body. The rationale is that this mechanistic research will lead to a fuller understanding of disease etiology thereby generating information of practical value for the treatment and prevention of disease. More direct approaches to understanding dietdisease relationships are based on cohort studies and randomized controlled trials (RCTs). This paper critically examines examples of diet-disease relationships so as to determine which research approaches have been most productive. Areas covered include several foods (such as sugar-sweetened beverages, fish, meat, and fruit), several nutrients (such as fat, sodium, and selenium), and several diseases/disorders (hypertension, obesity, cancer, and coronary heart disease). This analysis reveals that most of our information of practical value has come from cohort studies and RCTs but relatively little has come from mechanistic research. It follows, therefore, that top priorities for nutrition research should be the carrying out of more cohort studies and RCTs. This is then discussed with reference to research on phytochemicals. However, mechanistic research has been of value in particular areas. This occurs where disease processes involve simple mechanisms; examples include several metabolic disorders with a genetic basis (such as lactose intolerance) and deficiencies of various vitamins and minerals. We can illustrate this with the example of olive oil and coronary heart disease (CHD). Much epidemiological (observational) evidence indicates an inverse association between consumption of a Mediterranean diet and risk of CHD. One component of this diet suspected of playing an important role is olive oil. A researcher decides to study the effects of olive oil on the body's biochemical and physiological processes focusing on those that may indicate whether olive oil affects the risk of CHD and, if it does, how this may occur. Her research team therefore investigates how the amount of olive oil in the diet affects a wide array of body mechanisms, including the following: the levels of various types of prostaglandins (and related substances), various mechanisms related to inflammatory processes, receptors on the cell surfaces of different tissues and how they respond to insulin (and other hormones), the processes related to atherogenesis within the artery wall, the mechanisms that regulate lipogenesis, and the control of energy balance (including the various hormones involved and their interactions with brain areas that regulate the appetite). Fully exploring how olive oil affects these processes will likely necessitate 20 or 30 years of total commitment by the 20 members of her research team (and tens of millions of dollars of NIH funding). However, major areas have not yet been touched, including: mechanisms involved in CHD that have not yet been discovered, interactions between olive oil and the many other components of the Mediterranean diet (such as the myriad phytochemicals present in wine and fruit), and the control systems operating at the genetic level that switch the systems off and on.