PRECISION NUTRITION
TO RESET
Iron (Fe)-Redox Dysregulation
Iron (Fe)-Redox Dysregulation (FeRD) is highly prevalent among both acute and chronic stages of viral-induced HMR/D. Serum levels of iron and hepcidin are low in COVID-19 patients, whereas erythropoietin (EPO) and haptoglobin levels significantly decline in critical and deceased patients. Other biomarkers of iron metabolism (i.e., ferritin, transferrin, lactoferrin, etc.) and haptoglobin could provide risk stratification strategies for HMR/D management, as initial anemia is strongly linked to increased mortality rates. Altered iron (Fe)-redox homeostasis (Fe-RH) with elevated ferritin/TF ratio predicts subsequent insufficient pulmonary oxygenation (with need for ICU admission) and mechanical ventilation. Serum transferrin (TF) levels decrease within the 1st week of hospitalization in many COVID-19 patients; however, a continuous decline is prominent among subjects with fatal outcomes. Therefore, nutritional strategies to reset FeRD with Fe-redox regulators and ferroptosis inhibitors is a critical and essential strategy for optimal recovery from viral-induced HMR/D.
Precision Nutrition to Reset Iron (Fe)-Redox Dysregulation
Iron (Fe)-Redox Regulators
In the human body, total iron content is ~3-g for women and ~4-g for men, distributed in two main forms as heme-iron, mostly found in the hemoglobin, myoglobin, and cytochromes (2 to 2.7-g); and as non-heme-iron, a cofactor for several enzymes. Free iron levels in human body fluids are regulated at <10⁻¹⁸M to avert microbial infections and to prevent precipitation of insoluble ferric hydroxides and formation of toxic free radicals. Innate Fe-Redox regulators such as lactoferrin (LF), heme oxygenase-1 (HO-1), erythropoietin (EPO), and hepcidin (HEP) serve as first innate barriers against free radical damage and hyper-immune responses during COVID-19 and PASC. In viral-induced HMR/D, the host iron (Fe)-redox homeostasis (Fe-RH) is disrupted for an extended period; while the hemoglobin, ferritin, and transferrin (TF) levels slowly restore back to normal after onset of initial FeRD, around a median of 122 days after hospital discharge.
Lactoferrin: Lactoferrin (LF), an iron-binding glycoprotein present in milk as well as several body fluids including saliva, tears, nasal secretions, gastric/cerebrospinal/synovial fluids, sperm, vaginal secretions, and neutrophils, is a key component of innate host defense. Due to iron-chelation and iron-transport properties, LF is considered an innate iron regulator with multifunctional role in scavenging iron-catalyzed free radicals (i.e., ROS, RNS) and maintain Fe-RH in the body. Free radical scavenging mechanisms of LF involve stimulated glycolysis, increased ATP generation to sustain ion gradient with membrane potential and morphology of the cell. As an innate regulator of Fe-RH, LF could combat OxS at cellular level, modulate inflammatory responses at tissue level and play a therapeutic role the reset of viral-induced HMR/D.
Furthermore, as a potent anti-inflammatory agent, LF modulates hepcidin and ferroportin (FPN) synthesis through down-regulation of IL-6; thereby inhibits intracellular iron overload. LF regulates both pro-inflammatory and anti-inflammatory responses and avert viral insult-induced cytokine storm. LF also activates plasminogen that regulates coagulation cascade and antithrombotic activity, a promising nutritional reset for viral-induced HMR/D. As normoxic mimetic of hypoxia, LF (in apo-form) could effectively stabilize redox-sensitive transcription factors (HIF-1α and HIF-2α) to provide synergistic protection via activation of the Keap1/Nrf2 signaling pathway. Also, LF could inhibit HIF-1α activity and provide therapeutic benefits to retinal neuronal cells during neuro-COVID. Taken together, milk LF could reverse iron overload and reduce inflammation, both considered as critical factors in the pathogenesis of viral-induced HMR/D; accordingly, LF could serve as a promising all-natural intervention to resolve FeRD and reset viral-induced HMR/D.
Heme Oxygenase-1: Heme Oxygenase-1 (HO-1), also known as the ‘heat shock protein-32’ (hsp32), is an inducible intracellular enzyme upregulated by >100-fold during viral-induced HMR/D. At cellular level, HO-1 exists in the endoplasmic reticulum, mitochondria, nucleus, and plasma membrane. HO-1 mediates catalytic breakdown of heme, a potent pro-oxidant and pro-inflammatory molecule. HO-1-regulates Fe-RH and provides cyto-protection via endogenous mechanisms to sustain body's antioxidant response against OxS. Human HO-1 binds to the SARS-CoV-2 ORF3a protein and inhibits viral-induced inflammation and tissue damage via the NLRP3 pathway. The ability of HO-1 to protect against SARS-CoV-2 is probably an emergency inducible defense mechanism to ameliorate OxS from heme-released oxidants. Thus, the cyto-protective function of HO-1 is a promising intervention strategy to alleviate cytokine release syndrome and the subsequent lung dysfunction in viral-induced HMR/D. In host response to inflammation and OxS, the activated HO-1 is also a powerful down-regulator of pro-coagulant factors to prevent thrombotic events, endothelial injury from vascular inflammation, resolve FeRD and reset viral-induced HMR/D.
Erythropoietin: Erythropoietin (EPO) is a hypoxia-inducible growth factor expressed in various organs and tissues of the body. Erythropoiesis is the single largest consumer of iron, quintessential for hemoglobin synthesis in the body. In COVID-19, both critical as well as deceased patients show significantly lower serum levels of EPO, haptoglobin, and hepcidin compared to survivors or mild cases. EPO treatment could restore Hb levels, increase red blood cell (RBC) count, and improve O₂ delivery to the tissues, thereby help in the recovery from viral-induced HMR/D.
EPO could potentially benefit neuro-COVID-19 patients with acute and chronic-progressive downstream sequelae of the CNS and peripheral nervous system (PNS). Therapeutic benefits of EPO in viral-induced HMR/D may include: i) respiratory improvement at several levels including lung, brainstem, spinal cord, and respiratory muscles; ii) counteract hyperinflammation caused by cytokine storm/inflammasome; iii) neuro-protection and neuro-regeneration in brain and peripheral nervous system. Thus, EPO could be a potential bio-replenishment to reverse FeRD and help reset viral-induced HMR/D in PASC patients.
Hepcidin (HEP) and HEP-Modulators: Hepcidin (HEP), a peptide hormone secreted by the liver, is a master regulator of iron intake and systemic Fe-RH. HEP regulates iron levels by binding to ferroportin (FPN), and the FPN/hepcidin regulatory axis allows precise control of iron at both systemic as well as cellular levels. HEP and HEP-modulators are potential candidates to reset FeRD and reverse iron-overload syndromes such as anemia and chronic kidney disease (CKD) in viral-induced HMR/D.
Ferroptosis Inhibitors: Ferroptosis is an iron-catalyzed, non-apoptotic form of regulated necrosis that causes oxidative lipid damage in cell membranes leading to m-Dys. Ferroptosis with characteristic accumulation of oxidized phospholipids (or their breakdown products) in myocardial and renal tissue is responsible for ischemia-reperfusion injury, which is a detrimental factor for cardiac damage and MODS in viral-induced HMR/D. Ferroptosis is more immunogenic than apoptosis and plays a detrimental role in hyper-inflammation such as the ‘cytokine storm’. Ferroptosis is also associated with ageusia and anosmia, the early clinical manifestations of COVID-19. Accordingly, ferroptosis might serve as a potential treatment target for viral-induced HMR/D management. Nuclear factor (erythroid-derived 2)-like 2 (Nrf2) could suppress ferroptosis and reset cellular Fe-RH in viral-induced HMR/D.
Precision Nutrition to Reset Hypoxia / ’Warburg’ Effect
Dysregulation of glucose metabolism with elevated serum glucose levels and upregulation of glycolytic intermediates is a prominent feature of COVID‐19. Glucose metabolism supports OXPHOS/TCA cycle (ATP synthesis) in mitochondria and generates malate, an indicator of mitochondrial activity. Interestingly, plasma malate levels dwindle after SARS‐CoV‐2 infection, which suggests mitochondrial dysfunction (m-Dys) due to hypoxia/Warburg effect in the pneumonia state. The SARS-CoV-2-induced hypoxia initiates the activation of gluconeogenesis and porphyrin (or iron) metabolism, thereby steers the clinical onset/progression of COVID-19. Furthermore, the hypoxia-mediated ‘Warburg’ effect also alters both TCA cycle as well as lipid metabolism through perturbation of tryptophan biosynthesis, aminoacyl-tRNA degradation, phenylalanine, and arachidonic metabolism. Dysregulated arachidonic acid metabolism and fatty acid β‐oxidation in tandem with platelet aggregation, and bile acid synthesis help identify SARS-CoV-2 infected asymptomatic individuals, the hidden drivers of COVID-19 pandemic as well as massive victims of PASC.
L-Arginine: Perturbations in arginine metabolism is prevalent among COVID-19 and PASC patients, across all disease stages. Arginine metabolism is vital for immune and vascular functions in the body. Its metabolic functions include conversion to nitric oxide (NO•) by NO synthase (NOS) or arginine catabolism to ornithine by arginase. NO• is master regulator of cardiovascular function, metabolism, neurotransmission, and immunity. Low availability of plasma arginine has been implicated in endothelial dysfunction, T cell dysregulation, and thrombocytopenia (coagulopathy) in acute respiratory distress syndrome (ARDS) patients, the most severe form of COVID-19. Thus, restoring optimum levels of arginine through oral supplementation could maintain immune homeostasis, particularly to reverse altered T cell activity and reset T cell/macrophage functions in viral-induced HMR/D. Oral supplementation of arginine could be a promising nutritional remedial to reset HMR/D-associated cardiovascular impairments and immune dysfunction in PASC patients.
L-Tryptophan metabolism is the most prominent pathway affected by viral-induced HMR/D, which alters kynurenine pathway, dysregulates host inflammatory and immune responses. The ‘tryptophan-kynurenine’ pathway is a regulatory ‘hub’ for canonical and non-canonical transcription, macrophage release of cytokines, which could trigger hyper-inflammation and cause poor clinical outcomes in COVID-19 and PASC. Major clinical manifestations in viral-induced HMR/D such as depression, fatigue, sleep disturbances, attention disorders, anxiety, muscle weakness, and dyspnea are directly linked to ‘kynurenine shunt’, which is known to increase tryptophan degradation towards kynurenine and away from serotonin (5-HT) synthesis. Tryptophan deficiency could also lower 5-HT levels and augment clinical manifestations such as anosmia, ageusia, and dysfunctional chemesthesis in COVID-19 and PASC. Furthermore, 5-HT deficiency could worsen silent hypoxemia, weaken hypoxic pulmonary vasoconstriction, and compromise recovery from viral-induced HMR/D.
Serotonin (5-HT) is a precursor for melatonin, a chrono-biotic pineal hormone, which may elicit potential adjuvant effects to combat viral-induced HMR/D. Melatonin could also reverse aerobic glycolysis in immune cells and inhibit viral-induced hyper-inflammatory response. Nutritional reset of tryptophan levels, and optimization of peripheral and central 5-HT levels could help alleviate neuro-cognitive dysfunction in viral-induced HMR/D.