LONG COVID RESEARCH

Long COVID Pathophysiology 

​> spike protein of SARS-CoV-2 binds to ACE2 receptors on cells. Viral entry into the cell then initiates a cascade of inflammatory events.

> pro-inflammatory cytokines persist, causing immune dysregulation & autoimmunity. 

> neuroinflammation occurs directly via damage to neural tissue, and indirectly due to inflammatory molecules crossing the blood-brain barrier.

SARS-CoV-2 and Neuroinflammation 

​> mitochondria (in each cell) prompt interferon release and stimulate the death of infected cells.2 

> SARS-CoV-2 damages mitochondria by [1] creating oxidative stress which can damage the mitochondria directly, and [2] by disrupting lipid & glucose metabolism, resulting in systemic inflammation. 

 > high oxidative stress increases the demand for SAMe, resulting in [1] raised homocysteine levels (linked to mood and neurological disorders) and, [2] reduced glutathione. 

 > gut microbiota regulate immune response - when dysbiosis is present, intestinal permeability can ensue and promote immune dysregulation.2 

 > toxic byproducts (from gut) can translocate to brain, causing neuroinflammation.

 > lower abundance of good gut bacteria found in people with severe COVID-19.3 

Treatment Approaches 

1/ Vitamin C and L-Arginine

> l-arginine improve sendothelial function

> vitamin C reduces oxidative stress 

=> combining the two, reduces Long-COVID symptoms.

2/ Vitamin D and Glutathione

> glutathione deficiency -> increased oxidative stress

> epigenetically alters vitamin D regulatory genes => the suppressed gene expression decreases vitamin D biosynthesis -> vitamin D deficiency.

3/ Support Mitochondria

-> Acetyl-L-carnitine (ALC) supports mitochondrial and immune system health by [a] downregulating proinflammatory cytokines (IL-6) and TNF-alpha), [b] inhibiting NF-kB), and [c] reducing ACE1 levels. 

-> Flavonoids possess antiviral, antioxidant, and anti-inflammatory properties. In particular, quercetin, naringenin, and hesperidin provide mitochondrial protection against the effects of SARS-CoV-2.

[1] Quercetin inhibits the release of proinflammatory cytokines via suppression of the NLRP3 inflammasome. 

Foods high in quercetin include capers, red onions, buckwheat, radicchio, and dill.

[2] Naringenin inhibits NF-kB & ACE2 activity and [3] Hesperidin attenuates inflammatory responses by binding the spike protein of SARS-CoV-2. Both in citrus fruits.

[4] Sulforaphanes, curcumin, and EGCG provide antiviral & mitochondrial support.

4/ Methylation Support 

> B vitamins [a] prevent viral binding and replication, [b] lessen pro-inflammatory cytokines, [c] modulate the responses between the innate and adaptive immune system, and [4] reduce neuroinflammation.

> niacin protects lungs by reducing pro-inflammatory cytokines. 

> vitamin B6 prevents abnormal clot formation & maintains endothelial integrity, reducing the risk of strokes and myocardial infarctions. 

> folic acid prevents SARS-CoV-2 from binding to cells by inhibiting furin.

> vitamin B12 supports myelin synthesis and affects microbiota homeostasis. 

5/ Microbiome Support 

> probiotics support the immune system by: [a] upregulate interferon, T cell, and natural killer cell activity, [b] inhibit viral replication, [c] modulate cytokine responses, [d] influence ACE2,and [e] inhibit pathogen binding through mucin production. 

> probiotics increase Vitamin D absorption through enhancement of the VDR receptor.

> Lactobacillus plantarum, Lactobacillus rhamnosus, & Bifidobacterium longum improve COVID-19 symptoms, reduce severity,  & improve neurological and psychiatric health.

References

1. Izzo, R. Trimarco, V. Mone, P. et al. (2022). Combining L-Arginine with vitamin C improves long-COVID symptoms: The LINCOLN Survey. Pharmacological Research. www.sciencedirect.com/science/article/pii/S104366182200305X

2. Parsanathan, R. Jain, S. K. (2019) Glutathione deficiency induces epigenetic alterations of vitamin D metabolism genes in the livers of high-fat diet-fed obese mice. Sci. Rep. 9, 14784. 10.1038/s41598-019-51377-5.

3. Hunter P. Viral diseases and the brain: Long COVID puts the spotlight on how viral infections affect the brain: Long COVID puts the spotlight on how viral infections affect the brain. EMBO Rep. 2022;23(1):e54342.  

4. Hussain I, Cher GLY, Abid MA, et al. Role of Gut Microbiome in COVID-19: An Insight Into Pathogenesis and Therapeutic Potential. Front Immunol. 2021;12:765965. 

5. Reinold J, Farahpour F, Fehring C, et al. A Pro-Inflammatory Gut Microbiome Characterizes SARS-CoV-2 Infected Patients and a Reduction in the Connectivity of an Anti-Inflammatory Bacterial Network Associates With Severe COVID-19. Front Cell Infect Microbiol. 2021;11:747816. 

6. Scaturro D, Vitagliani F, DiBella VE, et al. The Role of Acetyl-Carnitine and Rehabilitation in the Management of Patients with Post-COVID Syndrome: Case-Control Study. Applied Sciences. 2022;12(8):4084. 

7. Kicinska A, Jarmuszkiewicz W. Flavonoids and Mitochondria: Activation of Cytoprotective Pathways? Molecules. 2020;25(13):3060. 

8. Saeedi-Boroujeni A, Mahmoudian-Sani MR. Anti-inflammatory potential of Quercetin in COVID-19 treatment. J Inflamm (Lond). 2021;18(1):3. 

9. Cheng FJ, et al. Hesperidin Is a Potential Inhibitor against SARS-CoV-2 Infection. Nutrients. 2021;13(8):2800. 

10. Ghidoli M,  et al. Food Containing Bioactive Flavonoids and Other Phenolic or Sulfur Phytochemicals With Antiviral Effect: Can We Design a Promising Diet Against COVID-19?. Front Nutr. 2021;8:661331. 

11. Ragan I, Hartson L, Pidcoke H, et al. Pathogen reduction of SARS-CoV-2 virus in plasma and whole blood using riboflavin and UV light. PLoS One. 2020;15(5):e0233947. 

12. Kurian SJ, Unnikrishnan MK, Miraj SS, et al. Probiotics in Prevention and Treatment of COVID-19: Current Perspective and Future Prospects. Arch Med Res. 2021;52(6):582-594. 

13. Gutiérrez-Castrellón P, et al. Probiotic improves symptomatic and viral clearance in Covid19 outpatients: a randomized, quadruple-blinded, placebo-controlled trial. Gut Microbes. 2022;14(1):2018899. 

14. Singh K, Rao A. Probiotics: potential immunomodulator in COVID-19 infection management. Nutr Res.2021;87.

15. Antunes AEC, Vinderola G, Xavier-Santos D, et al. Potential contribution of beneficial microbes to face the COVID-19 pandemic. Food Res Int. 2020;136:109577. 

16. Dolan KE, Finley HJ, Burns CM, et al. Probiotics and Disease: A Comprehensive Summary-Part 1, Mental and Neurological Health. Integr Med (Encinitas). 2016;15(5):46-58. 

 (Adapted from article by Yasaman Tasalloti, ND - https://ndnr.com/mindbody/addressing-long-covid/)