key: cord-1040479-yidc3uw6 authors: Tsoukalas, Dimitris; Sarandi, Evangelia; Georgaki, Spyridoula title: The snapshot of metabolic health in evaluating micronutrient status, the risk of infection and clinical outcome of COVID-19 date: 2021-06-26 journal: Clin Nutr ESPEN DOI: 10.1016/j.clnesp.2021.06.011 sha: 686d445bee4a7c82527230d86574698210c236ca doc_id: 1040479 cord_uid: yidc3uw6 COVID-19 has re-established the significance of analyzing the organism through a metabolic perspective to uncover the dynamic interconnections within the biological systems. The role of micronutrient status and metabolic health emerge as pivotal in COVID-19 pathogenesis and the immune system’s response. Metabolic disruption, proceeding from modifiable factors, has been proposed as a significant risk factor, accounting for infection susceptibility, disease severity and risk for post-COVID complications. Metabolomics, the comprehensive study and quantification of intermediates and products of metabolism, is a rapidly evolving field and a novel tool in biomarker discovery. In this article, we propose that leveraging insulin resistance biomarkers, along with biomarkers of micronutrient deficiencies, will allow for a diagnostic window and provide functional therapeutic targets. Specifically, metabolomics can be applied as: a. At-home test to assess the risk of infection and propose nutritional support, b. A screening tool for high-risk COVID-19 patients to develop serious illness during hospital admission and prioritize medical support, c(i). A tool to match nutritional support with specific nutrient requirements for mildly ill patients to reduce the risk for hospitalization, and c(ii). for critically ill patients to reduce recovery time and risk of post-COVID complications, d. At-home test to monitor metabolic health and reduce post-COVID symptomatology. Metabolic rewiring offers potential virtues towards disease prevention, dissection of high-risk patients, taking actionable therapeutic measures, as well as shielding against post-COVID syndrome. natural killer cells (NKs) and macrophages (49). Importantly, concerning COVID- 19, zinc has been demonstrated to interfere with viral RNAs and to prevent their replication (50). This quality implies that zinc levels are associated with enhanced host responses against viral infections. Of note, zinc replenishment reversed NKs activity in patients with sickle cell anemia and improved T cell numbers in the elderly (51, 52) . Recent literature on respiratory tract infections shows that zinc supplementation correlates with lower mortality rates and lower incidence in adults and children (53, 54) . Magnesium is one of the most significant life-sustaining compounds, mainly required as a cofactor for the optimal function of numerous enzymes, for genomic integrity regulation, as well as for the regulation of secondary messaging and ion channels (55) . Deficiencies have been inherently associated with impaired immune responses, increasing the levels of proinflammatory molecules, such as TNF-α and depleting the anti-inflammatory cytokines (56) . Conversely, magnesium replenishment seems to also regulate the hemostasis cascade and tissue factor expression by decreasing NF-κB activation (57) . Recent literature demonstrates that adequacies in intracellular magnesium help to mediate NKs and CD8 + cytotoxic T lymphocytes activities (57) . Together, insufficient levels of magnesium promote cytokine storm mechanisms and increase the risk of intravascular thrombosis. Of note, the enzymes that promote vitamin D catabolism require magnesium as a cofactor (58). Thus, maintaining optimal levels of magnesium indirectly affects the above-mentioned monitoring of immune responses, coordinated by vitamin D. Data on a COVID-19 observational study have demonstrated the beneficial effect of magnesium, vitamin D and B12 supplementation in lung function deterioration and ICU admission (59). The immunomodulatory effects of omega-3 PUFAs have been extensively investigated in the area of inflammatory diseases, as they are negative regulators of pro-inflammatory compounds production, namely eicosanoids, cytokines and adhesion molecules (27) . Regarding COVID-19 data, in a recent pilot study of 100 patients, a tendency of reduced mortality risk was correlated with the levels of Eicosapentaenoic (EPA) and Docosahexaenoic (74) . With the advent of bioinformatics and spectrometric methodologies for metabolomics analysis, it is plausible to extract data on key metabolic processes, such as glycolysis and gluconeogenesis, fatty acid oxidation, oxidative stress, mitochondria function, as well as the metabolism of protein and carbohydrates, neurotransmitters and gut microbiota (73) . The afore-mentioned pathways are affected by nutritional delivery, metabolic perturbations, dysbiosis, disease and environmental pressure. Metabolomics has been applied in several clinical aspects for over three decades exceeding 19 .000 published articles in humans. From disease prediction to Pharmacometabolomics, metabolites can either predict the onset of a disease years before symptoms appear or reveal the most effective pharmacological drug, coupled with nutritional support against an acute or chronic disease (75) . This technology is not new, considering that biochemical analyses for disease risk assessment in cardiovascular complications and diabetes paradigms utilize the information derived from specific metabolites, such as cholesterol and glucose (76, 77) . In addition, inborn errors of metabolism have been diagnosed for decades through the quantification of metabolites (78) . Metabolomics comes to broaden our perspectives on health and disease dynamics by extracting informative biomarkers to illustrate the individual's metabolic health and reveal unnoticed micronutrient deficiencies. Malnutrition comprises one of the main reasons for ICU admission in cases of acute diseases, serving as a biomarker of disease progress and severity (79) . In addition, respiratory tract infections have been linked to key nutrient deficiencies, as well as an improved disease course upon nutrient replenishment (19, 20) . Collectively, the cytokine storm-induced ARDS J o u r n a l P r e -p r o o f indicates the similarities in pathogenesis that might be managed through nutritional restoration. For this reason, concerted efforts for the establishment of efficient nutrition support protocols in hospitalized patients have been made, as effective therapeutic ailments targeting disease causalities have not yet been discovered or validated (80, 81) . The presence of micronutrient deficiencies comprises a characteristic driver of metabolic disruption and disease (21) . Patients experience no symptoms until the severe deterioration of tissues or organs. Notably, recent literature describes that more than 20% of global mortality is attributed to poor nutritional habits, with chronic health complications, like cardiovascular disease, cancer and diabetes ranking as the leading causes of death (82) . The diagnosis of micronutrient inadequacies is challenging regarding the sensitivity of the biomarkers, the optimal levels of nutrient intake and the special populations being at risk. The paradigm of B12 deficiency assessment with the help of metabolomics represents an approach to overcome these barriers. The adequate intake for the essential nutrient, that is, vitamin B12 (chemically called cobalamin), relies solely on diet resources, as it cannot be synthesized by the human genome. The main causes of B12 inadequacy are suboptimal dietary intake and malabsorption. In order to be processed, vitamin B12 is transported into the cells via protein transporters, namely haptocorrin (HC), intrinsic factor (IF) and transcobalamin (TC). The functional role of B12 is the promotion of adenosylcobalamin and methylcobalamin-dependent enzymes for the production of succinyl-CoA from methylmalonyl-CoA and of methionine from homocysteine, respectively. The first reaction results in the replenishment of the Krebs's cycle, and as for the second, it yields to the production of tetrahydrofolate, which is a folic acid derivative vital for nucleic acid biosynthesis (83) . Metabolomics might be useful in the diagnosis of B12 deficiency, independently of the origin of the inadequacy, as suboptimal levels of B12 lead to the accumulation of methylmalonic acid and homocysteine in the blood, which can both be captured with sensitivity (84,85) before resulting to methylmalonic acidemia and J o u r n a l P r e -p r o o f hyperhomocystinemia (86) . Methylmalonic acidemia has been correlated with cognitive impairments, kidney disease, and pancreatic inflammation, whereas hyperhomocystinemia associates with elevated risk for developing acute coronary syndromes, peripheral vascular disease, myocardial infarction and stroke (87, 88) . Although conventional B12 deficiency is assessed via total serum levels, this method evades capturing the bioavailability of B12, as a large amount of B12 (~80%) is bound to HC (89), thus decreasing diagnostic reliability. The assessment of methylmalonic acid levels in human biofluids with metabolomic-based platforms captures B12 deficiency more efficiently, as the reaction catalyzed by the responsible enzyme (methylmalonyl-CoA synthase) and promoted by B12 does not require the presence of other vitamins (90, 91) . Increased methylmalonic acid may also be present in cases of renal dysfunction, requiring careful evaluation and discrimination of distinctive B12 deficiency (91). The diagnostic value of B12 deficiency increases with the assessment of Holo-TC, which is the bioactive form of B12 that, bound to TC, is furtherly dispensed to systemic circulation for processing. The accuracy increases when employing holo-TC analysis, owing to the ability to capture B12 insufficiencies in special populations (92). Therefore, combining the conceptions of metabolomics, paired with informative diagnostic algorithms, is of the essence in order to apply accurate, specific and sensitive diagnostics in the field of nutritional insufficiencies. A large number of metabolomic studies on T2D and metabolic syndrome patients have identified critical pathways that are implicated in the development of metabolic disease. BCAAs including valine, leucine, isoleucine and their downstream metabolites would be useful predictive biomarkers. It has been shown that BCAAs levels are useful to distinguish insulin-resistant from insulin-sensitive individuals, their levels are related to disease progression from pre-diabetes to diabetes, and they are accurate predictors of therapeutic interventions (15) . The proposed molecular mechanism by which BCAAs levels may reflect insulin resistance involves several aspects ( Figure 1 ); A. Insulin is a negative regulator of the enzymes that produce a-ketoacids or 2-ketoacids (2-ketoisocaproate, 2-ketoisovalerate, 2keto-3-methyl valerate), namely BCAA aminotransferase (BCAT) and branched-chain ketoacid dehydrogenase (BCKD) complex, thus disrupted levels of BCAAs in relation to their downstream metabolites might indicate insulin signaling disruption (94, 95) . Of note, these 2ketoacids are also markers of insufficiency for vitamins B1, B3, B5, which act as coenzymes for BCKD complex, B. BCAAs have been shown to activate the mammalian target of rapamycin1 (MTORC1), a known mechanism for insulin sensitivity regulation. Thus, increased levels of BCAAs may trigger insulin resistance (96), C. BCAAs levels have been shown to be affected in hyperlipidemic state, playing a key role in the development of insulin resistance. A proposed mechanism includes that, in overnutrition and obese state, glucose and lipids catabolism is promoted, with concurrent suppression of the metabolism of BCAAs in the liver and adipose tissue but not in the skeletal muscle. BCAAs accumulation in the skeletal muscle leads to increased generation of propionyl-CoA and succinyl-CoA, which supply the TCA cycle continuously, leading to a mitochondrial overload and defective fatty acid oxidation (97) . The accumulation of incomplete oxidized products, mitochondrial overload, cause mitochondrial stress, reduced insulin sensitivity and circulating glucose levels imbalances. D. Besides diet, BCAAs can be endogenously synthesized by gut bacteria suggesting that gut dysbiosis may contribute to the accumulation of BCAAs and insulin resistance. Taken together, BCAAs have been associated with insulin resistance via multiple pathways, and even though the exact etiological mechanism remains to be elucidated, their predictive value holds promise for clinical application. due to the complex mechanism of lipid metabolism, there are several challenges to understand whether free fatty acids changes occur due to specific dietary foods containing these fatty acids or due to increased intake of carbohydrates that result in de novo lipogenesis. Additional metabolites, such as 3-hydroxybutyric acid and acetoacetate, which are ketone bodies produced through the oxidation of fatty acids in cases of insufficient glucose uptake, might be able to validate insulin resistance. In addition, some reported that the enzymes metabolizing linolenic acid and DGLA, namely delta-6 and delta-5 desaturase, respectively, are regulated by insulin (101, 102) . DGLA is the precursor of the pro-inflammatory eicosanoids' mediator, arachidonic acid. Thus, high enzymatic activity, mediated by insulin signaling dysfunction, might cause excessive production of eicosanoids. Similarly, the enzyme converting myristoleic, palmitoleic and oleic, to myristic, palmitic and stearic, respectively, is delta-9 desaturase, and its activity has been shown to be affected upon insulin resistance, a state reflected by the mediated metabolites (103) . Thus, the evaluation of metabolite ratios with a dietary questionnaire might provide valuable insight on the hyperinsulinemia and/or insulin resistance state and as sensitive clinical diagnostic markers of insulin resistance but also for monitoring the efficacy of applied interventions. The afore-mentioned nutrient deficits, acting on the immune system's performance, require early identification by sensitive and reliable tools. Metabolomics focuses on the accumulation J o u r n a l P r e -p r o o f of specific metabolic intermediates, such as methylmalonic acid in the B12 paradigm, to assess the status of vital nutrients. The vitamin is endogenously produced by probiotic gastrointestinal bacteria and is required as a coenzyme to promote fatty acid biosynthesis, gluconeogenesis and amino acid metabolism. Biotin-dependent 3-methylcrotonyl-CoA carboxylase promotes leucine catabolism, and decreased enzymatic capacity is associated with the accumulation of 3-methyl crotonic acid and 3-hydroxyisovaleric acid in the biological fluids (105, 106) . Apart from the anti-inflammatory properties of Vitamin A, it also provides the cells with antioxidant protection. Lipid peroxidation is a sign of cell damage due to oxidative stress and leads to 8-Oxo-2'-deoxyguanosine (8-oxo-dG) formation (107) . Vitamin A insufficiencies cannot compensate for the toxic load of ROS, leading to increments in 8-oxo-dG levels. Maintaining redox balance to fight infections is in line with recent data, highlighting that mitochondria dysfunction is correlated with impaired immune responses (108) . Vitamin C acts as a reducing agent, therefore, restoring cellular antioxidant capacity. Together with 8oxo-dG analysis, vitamin C deficiency is defined by the presence of 4-hydroxyphenylpyruvic and p-hydroxyphenyllactate, which are intermediates of tyrosine metabolism and require J o u r n a l P r e -p r o o f ascorbic acid as a cofactor (109) . The measurement of intermediate metabolites in the blood is a more accurate diagnostic approach, as circulating vitamin C is highly degradable (110) . Another biomarker of vitamin C adequacy is adipic acid, a marker of carnitine biosynthesis. Vitamin C is a vital compound of the enzymatic reactions involved in carnitine biosynthesis for successful lipid oxidation in mitochondria (111) .Thus, the presence of adipic acid in the biofluids indicates that fatty acid oxidation is interrupted due to carnitine insufficiency, and omega oxidation occurs in the peroxisomes, leading to elevations of the compound in the periphery (112) . In this context, indirect metabolic biomarkers associated with increased oxidative stress are also employed to assess vitamin E levels, which is a natural antioxidant in the membranes of all cells. The information acquired from the presence of 8-oxo-dG, phydroxyphenyllactate and quinolinic acid is translated to increased demands of pro-oxidant scavengers, such as vitamin E (113, 114) . Vitamin D is distributed to the tissues and organs after being synthesized in the skin upon UV exposure, in the form of cholecalciferol or in the form of ergocalciferol, of dietary intake. At these stages, vitamin D is biologically inactive and requires two sequential hydroxylations; one in the liver, leading to the formation of 25-hydroxy-vitamin D and one taking place in the kidneys as well as in other cells such as T lymphocytes, to produce 1,25-dihydroxy vitamin D (115) . To exert its immunomodulatory effects, 1,25-dihydroxy vitamin D binds to DNA receptors to initiate protein synthesis (116) . Thus, 25-hydroxy-vitamin D measurement is the most accurate method to test vitamin D supplies in the body (117) . Zinc is involved as a cofactor in several biochemical reactions, enhancing the catalytic activity of enzymes and other proteins (118) . Apart from its role in antioxidant prophylaxis, it restores the metabolic imbalances of the TCA, thus promoting the normal function of mitochondria and oxidative phosphorylation, carbohydrate metabolism as well as fatty acids metabolism (119) . Intermediates of the TCA cycle, such as citrate, pyruvate or succinate, as well as a-linolenic acid of the omega-3 PUFAs catabolism, serve as sensitive indicators of zinc deficiency. Energy production in the form of ATP requires the presence of magnesium in J o u r n a l P r e -p r o o f order to be bioavailable, meaning that TCA intermediates including citrate, aconitate and succinate may serve as valuable compounds for the assessment of magnesium deficiency. Metabolomic-based platforms can directly identify, among others, the omega-3 PUFAs, namely EPA and DHA, the above-mentioned monounsaturated and omega-6 PUFAs, J o u r n a l P r e -p r o o f Although the role of metabolism has been relatively unvisited in the subject, severe metabolic imbalances, such as metabolic acidosis, have been directly linked to COVID-19 clinical manifestations (167, 168) . It has been demonstrated that elevations in serum lactic acid levels compromise T cell metabolism and function, leading to T cell reduction (169) . Taking into consideration that hyperlactatemia is a biomarker of hypoxia (170) , monitoring the levels of this particular metabolite might not only serve as a risk assessment strategy but also as a tool to minimize the potentials of autoimmunity appearance. WHO has reasonably established that individuals with underlying health complications, especially non-communicable diseases (NCDs), share elevated risks of developing a more severe infection and, for that reason, guidelines targeting high-risk populations were hyperinsulinemia and aberrant glucose uptake (175) (176) (177) . These long-term metabolic perturbations drive the development of chronic conditions, such as T2D, even years after recovery (178, 179) . The pathophysiology of these issues seems to implicate a combination of psychological, physiological and medical factors that compose the "metabolic unhealthy" phenotype. For instance, impaired metabolic health during the acute ARDS rehabilitation process may result in post-traumatic stress disorders and memory loss, which involve excessive eating habits, reduced motivation for exercise and outdoor activities, thus unfavorable metabolic outcomes. The underlying mechanism suggests that the prevalence of hypoxia and systemic inflammation, treated with ventilatory assistance and brain sedation during the ARDS rehabilitation, leads to post-traumatic stress syndrome and its associated complications (180) . Another potential metabolic burden in the recovery process concerns malnutrition and weight loss in patients exhibiting post-COVID stroke (181) . According to the literature, adipose tissue mass wasting, in an experimentally-induced stroke model, was directly correlated to alterations in lipid metabolism. Specifically, these changes included elevations of free fatty acids and triglycerides, which aggravate cardiovascular manifestations, such as atherosclerosis (182) . The resulting patterns combined offer information on drug-related individual variations. In this context, patients can be categorized as poor or good responders, according to their metabolic profile before and after drug dosing (185) . Overall, monitoring the levels of the above-mentioned metabolites, as well as integrating the assessment of metabolic health biomarkers in the preventive strategies against post-COVID syndrome, might be of the essence for restoring the metabolic characteristics of the pre-infection state. The utmost goal is to employ metabolomics in central healthcare stages to be implemented with current strategies. A. Metabolomics as a preventive measure for self-protection against infections. In most cases, clinical interventions in critical diseases evade curative effects, as symptoms occur upon advanced stages. In addition, in line with the above, healthcare systems are prompted to manage the symptomatology rather than the origin of disease, which is viruses in this setting. However, the reported inter-individuality in clinical manifestations arises from the diverse deregulations in the immune system function. The combination of metabolomics methodologies with wearable technologies, such as smartphones or smartwatches, could introduce self-testing and obtain real-time health results (186) . Biospecimens of minimal invasiveness, such as blood spots, saliva, urine and exhaled breath condensates, can be obtained with instructive test kits and collected at home or at the workplace to provide mechanistic information on metabolic health, micronutrient status and environmental cues (e.g., viruses). Particularly, breathomics emerges as a convenient and sensitive strategy in the COVID-19-associated diagnostic biomarkers discovery. The method is based on the identification of volatile organic compounds (VOCs) (e.g., acetone, acetic acid, alcohols, methylene chloride, ethylene glycol, carbon disulfides, formaldehyde) or non-volatiles J o u r n a l P r e -p r o o f (nucleic acid, DNA, eicosanoids, microbiota metabolites), as well as inorganic compounds (such as nitric oxide) in exhaled breath (187) . Thus, subjects with hidden metabolic disease and at high risk of developing serious illness upon infection will be identified (132) . These people will be instructed to change their lifestyle and diet to reduce the risk, ensure distancing and follow hygiene guidelines. B. Metabolomics as a tool to identify high-risk groups among infected individuals during hospital admission. In line with the above, metabolic biomarkers extracted from blood, urine or breath, along with predictive tools, such as machine learning technologies, will serve as a stratification method to discriminate high-risk patients to develop serious COVID-19 disease, even in the absence of comorbidities or old age (139) . The metabolic phenotypes will provide the benefit of a diagnostic window before disease progression, will be informative towards patients' allocation, as well as quantitative and representative of each patient's physiological state. C. Metabolomics in first-line treatment. Early detection of nutritional deficiencies through imbalances in metabolic networks will allow healthcare professionals to provide nutrientspecific guidelines on diet and supplements for low-risk and high-risk individuals. Each category, as well as each patient, will receive a personalized medical nutrition treatment targeting the enforcement of their immune system. Of note, it is essential to establish therapeutic supplement dosages, as special populations, like the elderly, pregnant women, and critically ill patients, usually present with larger-scale deficits, requiring to exceed the recommended dietary allowance in meeting nutritional ends (27, 188, 189) . In the same context, in the scientific report published by Dietary Guidelines Advisory Committee, it is recommended to increase the intake of certain nutrients whose deficiencies are associated with adverse health conditions (190) . The application of these strategies not only will deal with the acute health consequences from COVID-19 and improve patients' quality of life, but it will reduce hospital admissions in the overwhelmed healthcare systems. Rapid technological advancements have put metabolomics at the center of biomarker discovery of NCDs with proven utility in disorders with known metabolic hallmarks (e.g., cardiovascular disease, cancer, autoimmune diseases). There is strong evidence that COVID-19 should be handled as a disease with metabolic features, and metabolomics is the only tool that can comprehensively study metabolic networks (191) . Now, we are called to combine tools and knowledge from relatively unrelated fields, i.e., virology and biochemistry, to address the COVID-19 pandemic and be prepared for future outspreads. Despite that the assessment of metabolic health and micronutrient status is a widely studied field, COVID-19 is an evolving field that requires additional research. We need to set up a strategy in order to define those biomarkers that will provide the diagnostic advantage over disease progression and serve as therapeutic targets. In this article, we propose a panel of biomarkers ( Table 2) that are involved in central metabolic pathways, are related to early metabolic derangements, J o u r n a l P r e -p r o o f and some of them have been associated with the presence of COVID-19, which could be used as a starting point and be validated in clinical trials (Table 1) . However, there needs to be caution as the design of clinical trials is of the highest importance for the generation of conclusive results and the accurate comparability between trials. The ongoing ventures, evaluating nutritional deficits and COVID-19 risk, report considerable discrepancies due to poor study designs, lack of established methodologies and self-reported data (192) . Metabolomic profiling of selected biomarkers needs to be tested in a large number of COVID-19 patients and from different geographical regions, in addition to the medical and nutritional history and clinical laboratory parameters. Special attention should also be given to the methodological details given the sensitivity of metabolite concentrations on handling, storage and method. In addition, we need to establish how this metabolic profile is affected by the metabolic rewiring through medical nutrition treatment and relate it to the clinical phenotype. Thus, metabolite-based, artificial intelligence predictive models will be developed as decision-making tools that will match the metabolic fingerprint to a specific treatment. As described elsewhere, large-scale interventional metabolomic studies harnessing the information on nutritional habits, the optimal dosing of nutritional supplements, as well as the assessment of the synergistic effect of selected nutrients are crucial (72) . Overall, it is becoming apparent that we already have deciphered the scientific and technological background to target the host's metabolism and improve the immune system response; thus, we need to support their implementation in clinical practice. and nutrition guide. As more clinical trials report their findings, the complex interplay between the host's metabolism and COVID-19 progression will be unwound. From a clinical perspective, though, insulin resistance and micronutrient deficiencies are promising and viable targets as they represent early signs of metabolic deregulation and can be easily modulated through medical nutrition treatment. Tuned actions to establish a unified strategy will facilitate the realization of these goals and equip the healthcare system against the current and future pandemics. No external funding was received. WHO Coronavirus (COVID-19) Dashboard | WHO Coronavirus Siddiqi HK, Mehra MR. 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BCAT: Branchedchain amino acid aminotransferase, BCKADC: Branched-chain ketoacid dehydrogenase complex, 3-MCC: 3-methylcrotonyl-CoA carboxylase, PCC: Propionyl-CoA carboxylase, MCM: Methylmalonyl-CoA mutase The authors have a conflict of interest to declare. All authors contributed to the conception, literature search, figure design and writing of the manuscript.