419 Tsoukalas D, Sarandi E. bmjnph December 2020 Vol 3 No 2 Open access Micronutrient deficiencies in patients with COVID-19: how metabolomics can contribute to their prevention and replenishment Dear Editors, Reading the recent article by McAu- liffe et al, 1 we were interested in the approach presented to target the micronutrient deficiencies of the high-risk population for COVID-19 and empower their immune system against the infection. 1 The authors present evidence on the central role of selected nutrients on the immune system function against respiratory infections while showing clinical data from studies using prophylactic supplementation. However, clinical studies have not yielded conclusive results on the beneficial role of nutrient supple- mentation to the support of the immune system that can be translated into clinical practice. The authors report three main reasons that we will elaborate on in this letter: (1) poor study design; (2) lack of an estab- lished methodology for the assess- ment of the micronutrient status; and (3) unstandardised optimal dosing of the nutritional supplements. Clinical studies are usually designed to assess the role of a single nutrient on the immune system function. Although this approach facilitates close monitoring of the nutrient subtraction/supplementation effect, it does not reflect the biological system complexity. Thus, several inter- ventional studies report no effect of the nutrient supplementation, which contradicts others that demonstrate a positive impact, hampering the valida- tion of results. 2 It should also be noted that the primary role of nutrients, which is the facilitation of enzymatic reactions, is accomplished via the synergy of multiple nutrients. Thus, a combination of nutrients should be given as intervention instead of single nutrients. 3 In addition, a nutrient cocktail could be provided at base- line to cover some of the deficien- cies permitting the normal function of metabolic pathways, prior to the administration of a single nutrient in a dose–response manner to assess its effect on health and disease. A control group receiving the nutrient cocktail should also be included in these studies in addition to the no-in- take control group. Such study design might also reduce the interindi- vidual differences in response to the intervention, caused by the diverse nutrient requirements within the sample population. We propose both for human research studies but also for clinical practitioners to shift from single- nutrients assessment to the profiling of multiple nutrients at a given time for each person to have an overview of the micronutrient status and monitor the treatment efficacy. An obstacle towards this direction is that nutrients have markedly different chemical properties requiring other method- ological handles for their assessment in human biofluids. To overcome this complexity, we propose an analysis of the metabolic products of nutrients in line with others. 4 Recent evidence suggests that metabolomics could be an adjunct tool of identifying people with micro- nutrient deficiencies, and thus a high risk for COVID-19, and as a tool of monitoring progress after nutritional supplementation. Metabolomics has attracted the attention of health researchers because it is a sensitive method able to capture metabolic dysfunctions caused by or predicting the presence of a disease. 5 Their unique advantage is that it combines the genetic vari- ability of a person and the individual dietary and lifestyle preferences that affect the phenotype, which is metab- olites. Significant progress has been made for the identification of meta- bolic biomarkers in chronic diseases, 6 though the application of metabolo- mics as a tool of nutritional deficiency assessment is limited to few nutri- ents. Targeted metabolomics, which provides the absolute quantification of metabolites, can capture the func- tional adequacy of nutrients by measuring the metabolic interme- diates of enzymatic reactions regu- lated by the nutrients. For example, methylmalonic acid, a metabolite produced by methylmalonyl-CoA regulated by the bioavailability of B12, has been established in clinical prac- tice. It requires a multidisciplinary approach, including nutritionists, biologists, biochemists, biostatisti- cians and physicians, to implement metabolomics into clinical practice. 7 Lastly, it is important to note that the optimal dosing of micronutrients has not been established for clinical practice either for human studies. McAuliffe et al 1 mention that some groups may require doses higher than the Recommended Dietary Allowance (RDA) to meet the meta- bolic demands. Indeed, autoimmune diseases have been linked to vitamin D resistance, where higher amounts of that vitamin are required to exert its immunoregulatory effect. 8 Again, the profiling of metabolic products of micronutrients will provide a person- alised overview of nutrient needs. Now that we are facing the COVID-19 pandemic, actions must be taken so that practitioners are trained for the evaluation of the nutritional status using current methodologies but also promote measures for the validation of metabolomics nutri- tional biomarkers. Dimitris Tsoukalas, 1,2 Evangelia Sarandi 2,3 1 European Institute of Nutritional Medicine, Rome, Italy 2 Metabolomic Medicine, Athens, Greece 3 Laboratory of Toxicology and Forensic Sciences, Medical School of the University of Crete, Crete, Greece Correspondence to Dr Dimitris Tsoukalas, European Institute of Nutritional Medicine, Rome, Italy; dtsoukalas@einum.org Twitter Dimitris Tsoukalas @DrTsoukalas Contributors DT: conceptualisation, writing and overall responsibility of the content; ES: writing and review of the content. Funding The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors. Competing interests None declared. Patient consent for publication Not required. Provenance and peer review Not commissioned; externally peer reviewed. Letter on November 27, 2021 by guest. Protected by copyright. http://nutrition.bmj.com/ BMJNPH: first published as 10.1136/bmjnph-2020-000169 on 3 November 2020. 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