PRECISION NUTRITION
TO RESET
New 'Onset' System Disorders
Precision Nutrition to Reset New 'Onset' System Disorders
RESET: Immune Impairment
SARS-CoV-2 infection triggers immune response, a regular host defense strategy to restrain viral entry and constrain disease progression. However, when immune system exhausts and/or compromised, the viral infection become aggressive in vulnerable hosts and evolves into a severe pathophysiological state with hyper- inflammation, extensive tissue damage, and MODS. Such hyper-inflammatory state could lead to loss of appetite, altered intestinal absorption, impaired gut permeability, and malnutrition. Malnutrition in turn could aggravate inflammatory pathways, compromise the immune system, onset dysbiosis, increase risks of new microbial infection(s) as well as reactivate latent pathogens. Therefore, nutritional resolution of immune dysfunction is an important aspect of recovery from severe inflammation, malnutrition, and sarcopenia during clinical rehabilitation from viral-induced HMR/D.
Vitamin D3: Vitamin D3 (Vit-D) is a lipid-soluble seco-steroid produced by human skin with conversion of 7- dehydro-cholesterol to cholecalciferol via exposure to sunlight. Circulatory vit-D is initially transported to liver by vit-D binding protein. Vit-D is mainly known to regulate calcium/ phosphate homeostasis and bone metabolism. However, vit-D is also vital for several biological pathways including modulation of innate and adaptive immune responses. Immuno-modulatory role of vit-D could be categorized into 3 essential functions: i) physical barrier, ii) natural cellular immunity, and iii) adaptive immunity. Vit-D could activate the release of cathelicidin and defensins to inhibit viral replication, down-regulate release of proinflammatory Th1 cytokines (i.e., TNF-α and IFN-γ) and stimulate macrophages to generate anti-inflammatory cytokines to minimize the risk of ARDS in COVID-19. Vit-D could also inhibit NF-κB activation to down-regulate proinflammatory cytokine synthesis and other key activators of cell-mediated immunity. Vit-D can modulate both innate and adaptive immune responses, and vit-D deficiency is linked to increased autoimmunity as well as increased susceptibility to microbial infections. Vit-D is a negative regulator for expression of renin and interacts with the RAAS/ACE/ ACE2 signaling axis, therefore could affect SARS-CoV-2 infection process as well as host cardiovascular and circulatory function.
In COVID-19 patients, vit-D deficiency was reported in 41.7% cases, vit-D insufficiency in 46.0%, and the remaining 12.3% of cases with normal vit-D levels. The odds of severe COVID-19 outcomes increase by 38.1 and 5.6 times for vit-D-deficiency and -insufficiency patients, respectively. Low vit-D levels are associated with elevated inflammatory cytokines with increased risk of pneumonia and viral upper respiratory tract infections. Vit-D deficiency is also associated with an increase in thrombotic episodes, frequently reported in COVID-19. Severe cases of COVID-19 demonstrate 64% more vit-D deficiency than mild cases, while vit-D insufficiency could significantly increase hospitalization and case fatality rate (CFR). Vit-D deficiency is a risk factor for unregulated cytokine storm and hyper-inflammation in COVID-19. Also, individuals with viral-induced HMR/D show lower 25(OH)D levels, where Vit-D deficiency refers to serum levels of 25-hydroxyvitamin D, 25(OH)D, <20 ng/mL (50 nmol/L). There is mounting evidence that optimal 25(OH)D levels are associated with reduced risk of viral-induced HMR/D. Reactivation of latent Epstein–Barr virus (EBV) is an emerging risk factor with adverse outcomes in HMR/D. Vit-D supplementation could significantly reduce humoral immune responses against latent EBV antigen in relapsing-remitting multiple sclerosis. Vit-D deficiency is cost-effective, safe, and readily available reset for viral-HMR/D management.
Omega-3 Polyunsaturated Fatty Acids: Omega-3 or n-3 PUFAs, eicosapentaenoic acid (EPA), docosa-pentaenoic acid (DPA), and docosahexaenoic acid (DHA), are broad-spectrum anti-inflammatory compounds that modulate several pathways of inflammation including leukocyte chemotaxis, adhesion molecule expression, and leukocyte-endothelial adhesive interactions, inflammatory cytokine synthesis and T cell reactivity. As potent antioxidants, omega-3 PUFAs upregulate Nrf2, mitogen-activated protein kinase (MAPK) phosphatases, GSH and HO-1 genes. Metabolites of omega-3 PUFAs are vital for synthesis of several inflammatory mediators including prostaglandins (PG), leukotrienes (LT), thromboxanes (TX), protectins, and resolvins. Omega-3 PUFAs modulate both innate and acquired immune systems through activation of macrophages, neutrophils, T-cells, B-cells, dendritic cells, NK cells, mast cells, basophils, and eosinophils. As an integral part of the cellular membrane, omega-3 PUFAs regulate membrane fluidity and complex assembly in lipid rafts. PUFAs could help alleviate mitochondrial ROS production in T cells to combat SARS-CoV-2 infection. Viral-induced HMR/D of host lipid metabolism may persist as chronic inflammatory condition in PASC patients. Palmitoylethanolamide (PEA), a lipid-derived peroxisome proliferator-activated receptor-α (PPAR-α), is shown to dismantle lipid droplets via β-oxidation and restore innate cellular defenses.
Omega-3 PUFAs may interact at different stages of SARS-CoV-2 infection, particularly during viral entry and replication phases where persistence of viral antigens may lead to sustained inflammatory state in PASC patients. Omega-3 PUFAs, particularly EPA, are potential remedials to reduce pro-inflammatory cytokines, alter the HPA axis, modulate neurotransmission via lipid rafts, and alleviate neurocognitive complications in viral-induced HMR/D. Furthermore, omega-3 PUFAs and their metabolites (i.e., specialized pro-resolvin mediators), could effectively ameliorate uncontrolled inflammatory responses, reduce OxS, mitigate coagulopathy, and restore tissue homeostasis. Besides antioxidant and anti-inflammatory activities, omega-3 PUFAs could regulate platelet homeostasis and lower the risk of thrombosis, which indicates its potential to reset viral-induced HMR/D. Therefore, the nutritional status of omega-3 PUFAs is particularly important for the overall immune response, tissue inflammation and repair, which may be an effective nutritional strategy to recover from HMR/D.
RESET: Gut Dysbiosis
SARS-CoV-2 infection alters gut microflora composition and function, which leads to gut barrier dysfunction and immune activation. Epithelial tight junction is a critical gut barrier, and its disruption could leak toxic substances from the gut into blood circulation and cause systemic injury. The maintenance of intestinal epithelial tight junctions is closely related to energy homeostasis and mitochondrial function. Such viral-induced dysbiosis triggers cytokine release with NF-κB-mediated hyperinflammatory response, and ensuing immune dys-regulation could worsen the clinical outcomes of viral-induced HMR/D. Gut microbiota plays a multi-functional role in the GI tract, including energy extraction from the diet, immune-modulation, synthesis of vitamins and short-chain fat acids (SCFAs). A complex equilibrium exists among prebiotics (i.e., fructo-oligosaccharides), probiotics (i.e., LAB), and postbiotics (i.e., bacteriocins, SCFAs), with involvement of several networks between gut microflora and other organ systems through different axes (i.e., Gut-Lung, Gut-Liver, Gut-Brain axes) that affect a plethora of pathways in health and disease.
Gut dysbiosis could persist for at least 6 months in COVID-19 patients after hospital discharge, and this chronic inflammatory condition may onset a wide range of neurological and neuropsychiatric symptoms leading to severe HMR/D. Accordingly, several gut metabolic dysfunctions could contribute to long-term neuro-cognitive impairments, including: i) perturbed ‘gut-brain’ axis due to loss of SCFA producing intestinal flora, which may cause neuropsychiatric disorders; ii) cytokine storm-induced immune-metabolic reprogramming, which could elevate ‘kynurenine : tryptophan’ ratio and trigger chronic depression syndrome; and iii) ACE2 activation in the gut could alter L-DOPA production and neurotransmitter synthesis, thereby inflict neurological complications including chronic fatigue syndrome (CFS).
Probiotics: Lactic Acid Bacteria (LAB) regulate cytokine secretion and affect both non-specific as well as specific immune responses. Bacteriocins produced by LAB are antimicrobial compounds known to inhibit adhesion and invasion of microbial pathogens in the GI epithelia. Probiotics could block SARS-CoV-2 proliferation in host cells, via potential immuno-modulation, and inhibit NLRP3 inflammasome activation. Re-balancing of healthy gut microbiota through probiotics, prebiotics, and immune nutrients, could reduce inflammation, promote anti-inflammatory mechanisms, and reset a functional ‘gut-brain’ axis to recover from viral-induced HMR/D.
RESET: Viral-Induced Metabolic Disorders
Viral-induced HMR/D in tandem with chronic metabolic syndromes could result in more severe clinical outcomes. A meta-analysis of 120 studies (n=125,446 patients) reported that most prevalent comorbidities for SARS-CoV-2 infection include: hypertension (32%), obesity (25%), T2DM (18%), and CVD (16%). COVID-19 in conjunction with diabetes and obesity (both characterized by severe insulin resistance) has severe clinical consequences. Therefore, restriction of dietary lipid and sugar intake could potentially benefit COVID-19 and PASC patients with T2DM, obesity or other metabolic syndromes.
‘New Onset’ Diabetes: Viral-Induced Metabolic Disorder – ‘New Onset’ Diabetes: T2DM is a progressive metabolic disorder due to insulin resistance with underlying chronic inflammation as well as endothelial and β-cell dysfunction. SARS-CoV-2 infection could trigger hyper-inflammation, exacerbate insulin resistance, worsen endothelial dysfunction and lead to new-onset diabetes. Viral-induced aberrant glycol-metabolic dysregulation could persist even after COVID-19 recovery. In a cohort of hospitalized COVID-19 patients (n=551) about 46% of cases showed long-term hyper-glycemia (who were normo-glycemic prior to infection). Therefore, not only patients with metabolic and endocrine dysfunction are predisposed to risks of severe COVID-19; but also, SARS-CoV-2 infected normal population could potentially develop ‘new-onset’ diabetes or aggravation of pre-existing metabolic syndromes. The hyperglycemia in non-diabetic COVID‐19 patients could result from impaired pancreatic islet function as well as viral inflammation-induced insulin resistance and abnormal β cell activation. Superoxide dismutase (SOD), the antioxidant enzyme, could reduce OxS in the intestinal barrier and ameliorate the vicious circle between hyperglycemia and the oxidative damage. Therefore, targeting the intestinal barrier with dietary bioactive SOD could be a promising glucose-lowering approach to reset HMR/D- induced new onset diabetes.
Obesity: Viral-Induced Metabolic Disorder – Obesity: Body mass index (BMI) strongly correlates with immune signatures that predict severity of viral-induced HMR/D. Obesity is recognized as a high‐risk factor in HMR/D, and high-fat diet promotes ACE2 expression on adipocytes. The lipid-rich adipocytes facilitate lipid raft formation on cell membranes to support viral entry, as well as provide building blocks to assemble viral capsules. Viral-mediated adipocyte infection (cellular entry, invasion, and propagation) processes could inflict severe adipose tissue dysfunction and insulin resistance. Interestingly, SARS‐CoV‐2 has been detected in the adipose tissue of overweight males but not in females. Inhibition of lipase‐mediated breakdown of body fat could effectively block viral propagation in adipocytes. Thus, cellular metabolic state and overall nutrition status are key determinants in the onset and progression of viral-induced HMR/D.