Temporal Correlation Between Neurological and Gastrointestinal Symptoms of SARS-CoV-2

Abstract

Severe Acute Respiratory Syndrome Coronavirus-2 (SAR-CoV-2) has been shown to invade brain tissue. Based on the evolutionary similarity with SARS-CoV, researchers propose that SARS-CoV-2 can invade the olfactory bulb and gastrointestinal (GI) system through angiotensin-converting enzyme 2. However, how SARS-CoV-2 causes neurological or GI symptoms is not clear. Many suggested intestinal and neural inflammations, caused by viral invasion, as the most likely reason for the GI and neurological symptoms; however, the patients with coronavirus disease 2019 (COVID-19) without neurological or GI symptoms indicate that this is not the case. The gut-brain axis could explain the reason for why some with COVID-19 do not have these symptoms. COVID-19 patients mostly show respiratory distress first, then diarrhea, anorexia, stroke, or loss of consciousness comes into view. Obviously, GI invasion is a mechanical process that begins with oral invasion and, therefore, most probably exists before the brain invasion, as indicated in case reports. However, when the GI tract is invaded, the virus may enter the central nervous system through vascular and lymphatic systems or the vagal nerve. SARS-CoV-2 can infect leukocytes and migrate with them into the brain, or the viral particles can be directly transported across the blood-brain barrier to the brain. Also, more recent research has revealed that SARS-CoV-2 can invade the peripheral lymphatic vessels connecting with the glymphatic system of the brain. The temporal correlation between neurological and gastrointestinal symptoms suggests the lymph vessels around the GI tract, the vascular system, or the gut-brain axis (enteric nervous system) as the most likely entry route for SARS-CoV-2 to the brain.

SARS-CoV-2 and nervous system: From pathogenesis to clinical manifestation

“…While SARS-CoV-2 involves lung and gastrointestinal tract very commonly, neuro-invasion through retrograde neuronal transport within vagal nerve afferents ( Li et al, 2020 ; Toljan, 2020 ) has been postulated. Local peripheral nerves located in the enteric nervous system, may also get infected by other cells in the gastrointestinal tract ( Bostancıklıoğlu, 2020 ; Lima et al, 2020 ; Wong et al, 2020b ). Experimental studies have demonstrated this retrograde route for the influenza virus ( Matsuda et al, 2004 ) and hemagglutinating encephalomyelitis virus (HEV) ( Andries and Pensaert, 1980b ).…”

“…Hematogenous spread, through the destruction of the blood-brain barrier (BBB), has been proposed as yet another pathway of viral invasion to the brain, as found in influenza and other coronaviruses ( Desforges et al, 2019 ; Koyuncu et al, 2013 ; Wang et al, 2010 ). This can be through the direct invasion of the CNS by SARS-CoV-2 or infected leukocytes entering the CNS ( Bostancıklıoğlu, 2020 ). Additionally, SARS-CoV-2 can attack angiotensin-converting enzyme 2 (ACE-2) receptors that are present in the endothelial cells of blood vessels in the brain, disrupting the BBB and increasing the BBB permeability ( Hamming et al, 2004 ), which ultimately encourages penetration into the CNS.…”

Neurological consequences of COVID-19: what have we learned and where do we go from here?

“…The gastrointestinal (GI) tract is directly infected by SARS-CoV-2 and up to a quarter of COVID-19 patients display GI issues, including nausea, anorexia, vomiting, and diarrhea [72,73]. A temporal correlation exists between GI and neurological symptoms, and it is postulated that anorexia and nausea may be caused, at least in part, by infection of the lateral hypothalamic nuclei [73,74]. Toward this end, SARS-CoV-2 may enter the CNS via the vagus nerve, a cranial nerve that regulates parasympathetic control of the heart, lungs, and GI tract.…”

Molecular and cellular mechanisms of central nervous system alteration in COVID-19

“…Путь легкие-кишечник-мозг может быть дополнительным направлением проникновения SARS-CoV-2 в ЦНС [2,11]. Возможным механизмом может служить ретроградное распространение вируса в ЦНС через волокна блуждающего нерва, которые иннервируют нижние дыхательные пути и большую часть желудочно-кишечного тракта.…”