COVID-19 pathophysiology: interactions of gut microbiome, melatonin, vitamin D, stress, kynurenine and the alpha 7 nicotinic receptor: Treatment implications

Abstract

As data emerges on the pathophysiological underpinnings of severe acute respiratory syndrome coronavirus (SARS-CoV)-2, it is clear that there are considerable variations in its susceptibility and severity/fatality, which give indications as to its pathophysiology and treatment. SARS-CoV-2 modulatory factors include age, vitamin D levels, cigarette smoking, gender and ethnicity as well as premorbid medical conditions, including diabetes, cancer, obesity, cardiovascular disease, and immune-compromised conditions. A complex picture is emerging, with an array of systemic physiological processes interacting including circadian, immune, intestinal, CNS and coagulation factors. This article reviews data on SARS-CoV-2 pathoetiology and pathophysiology. It is proposed that a decrease in pineal and systemic melatonin is an important driver of SARS-CoV-2 susceptibility and severity, with the loss of pineal melatonin's induction of the alpha 7 nicotinic acetylcholine receptor (α7nAChR) in pulmonary epithelial cells and immune cells being a powerful regulator of susceptibility and severity, respectively. Stress, including discrimination stress, and decreased vitamin D also regulate SARS-CoV-2, including via gut dysbiosis and permeability, with a resultant decrease in the short-chain fatty acid, butyrate, and increase in circulating lipopolysaccharide. Stress and cytokine induction of the kynurenine pathways, leads to aryl hydrocarbon receptor activation, which primes platelets for heightened activity, coagulation and thrombin production, thereby driving elevations in thrombin that underpin many SARS-CoV-2 fatalities. On the basis of these pathophysiological changes, prophylactic and symptomatic treatments are proposed, including the use of melatonin and α7nAChR agonism.

Targeting Host Defense System and Rescuing Compromised Mitochondria to Increase Tolerance against Pathogens by Melatonin May Impact Outcome of Deadly Virus Infection Pertinent to COVID-19

“…Melatonin is a naturally occurring molecule assumed to be present in every species [ 19 ]. Due to its antioxidant, anti-inflammatory, as well as other properties [ 20 , 21 , 22 , 23 , 24 , 25 ], it has been speculated to be a promising molecule for treating COVID-19 patients [ 18 , 26 , 27 , 28 , 29 , 30 , 31 , 32 , 33 , 34 , 35 , 36 , 37 , 38 , 39 , 40 , 41 , 42 , 43 , 44 , 45 , 46 , 47 ], and also other deadly viral infectious diseases [ 48 , 49 , 50 , 51 ]. A small scale clinical trial has also shown promising results [ 52 ].…”

Nitric oxide (NO) and nanoparticles – Potential small tools for the war against COVID-19 and other human coronavirus infections

“…Although positive biological effects have been reported for the administration of NO donors, further studies are required to better evaluate the levels of inflammatory mediators and the activity of important heme-containing enzymes, such as indoleamine 2,3–dioxygenase (IDO), directly involved in the inflammatory responses in respiratory viral infections ( Anderson and Reiter, 2020 ). During virus infection, a significant increase in the levels of inflammatory mediators can be observed, known as a “cytokine storm”, associated with endothelial and platelet activation; this can lead to vascular permeability, thrombocytopenia, shock (observed in severe cases), pulmonary hypertension and pneumonia ( Belladona and Orabona, 2020 ).…”

Aryl Hydrocarbon Receptor Role in Co-Ordinating SARS-CoV-2 Entry and Symptomatology: Linking Cytotoxicity Changes in COVID-19 and Cancers; Modulation by Racial Discrimination Stress

“…Alterations in metabolism are crucial to immune cell function. All immune cells have to upregulate glycolytic metabolism in order to become activated whilst also maintaining their levels of OXPHOS [ 5 ]. As such, factors acting to regulate OXPHOS and glycolytic metabolism can dramatically influence immune cell function.…”

“…Although the importance of the initial rise in pro-inflammatory cytokines have been widely emphasized, there has been relatively little investigation of the common consequences arising, including (1) cytokine suppression of pineal gland melatonin and circadian dysregulation; (2) cytokine-induced gut permeability and dysbiosis with consequences for alterations in immune regulation and activation; and (3) cytokine induction of indoleamine 2,3-dioxygenase (IDO), thereby increasing kynurenine and kynurenine activation of the aryl hydrocarbon receptor (AhR) [ 5 ]. The current article reviews such processes and their implications for the understanding and treatment of SARS-CoV-2 pathophysiology.…”

“…As IDO utilizes tryptophan to produce kynurenine, there is a decrease in tryptophan availability for serotonin, N-acetylserotonin (NAS), and melatonin synthesis [ 5 ]. Consequently, an increase in kynurenine production and activation of the AhR is associated with a decrease in serotonin and melatonin.…”