Implications of SARS-CoV-2 infection for neurogastroenterology

Abstract

Background: Coronavirus disease 2019 (COVID-19) is associated with gastrointestinal and hepatic manifestation in up to one fifth of patients. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the etiologic agent of COVID-19, infects gastrointestinal epithelial cells expressing angiotensin-converting enzyme 2 (ACE2) receptors triggering a cascade of events leading to mucosal and systemic inflammation. Symptomatic patients display changes in gut microbiota composition and function which may contribute to intestinal barrier dysfunction and immune activation. Evidence suggests that SARS-CoV-2 infection and related mucosal inflammation impact on the function of the enteric nervous system and the activation of sensory fibers conveying information to the central nervous system, which, may at least in part, contribute symptom generation such as vomiting and diarrhea described in COVID-19. Liver and pancreas dysfunctions have also been described as non-respiratory complications of COVID-19 and add further emphasis to the common view of SARS-CoV-2 infection as a systemic disease with multiorgan involvement.

Purpose: The aim of this review was to highlight the current knowledge on the pathophysiology of gastrointestinal SARS-CoV-2 infection, including the crosstalk with the gut microbiota, the fecal-oral route of virus transmission, and the potential interaction of the virus with the enteric nervous system. We also review the current available data on gastrointestinal and liver manifestations, management, and outcomes of patients with COVID-19.

Keywords: ACE2; COVID-19; SARS-CoV-2; diarrhea; enteric nervous system; gastrointestinal; gut microbiota; pandemic.

FIGURE 1

Schematic representation of the putative interplay between SARS‐CoV‐2 and the gastrointestinal tract. (A) SARS‐CoV‐2 enters epithelial cells through ACE2 receptors with the participation of TMMPRSS2. (B) Virus‐related epithelial damage is associated with increased intestinal permeability, mucosal immune dysregulation, tissue inflammation (eg, mast cell activation, T‐cell lymphopenia, cytokine release), and dysbiosis. (C) A potential direct SARS‐CoV‐2 infection of enteric and afferent nerves and/or inflammation may contribute to (D) secretomotor dysfunction and (E) symptom perception

FIGURE 2

Panel 1: ACE2 expression in the human ENS of the large intestine. (A) Overview of the entire gut wall of a colon segment with immunofluorescence stainings for ACE2 (red), the glial marker S100b (green), and with the nuclear marker DAPI (blue). The white rectangles indicate the location of the high‐power magnification micrographs below showing a representative submucous and myenteric ganglion. (B, C) Show representative submucous and myenteric ganglia stained for ACE2 (red), DAPI (blue), and the neuronal markers PGP9.5 (B, red) or HuC/D (C, red). The ACE2 staining can be found in neurons and glial cells and is considerably stronger in the colon compared to the small intestine. The overview is a standard epifluorescence image; details are maximum intensity projections of optical sections by structured illumination. Scale bars: overview 250 mm; details 50 mm. Panel 2: TMPRSS2 expression in the human ENS. (A) Overview of the entire gut wall of a colon segment with immunofluorescence stainings for TMPRSS2 (red), the neuronal marker HuC/D (green), and the nuclear marker DAPI (blue). (B, C) Show representative large intestinal myenteric ganglia stained for TMPRSS2 (red), DAPI (blue), and the neuronal markers HuC/D (B, red) or PGP9.5 (C, red). (D) Representative myenteric ganglion in the small intestine stained for TMPRSS2 (red), the glial marker S100b (green), and the nuclear marker DAPI (blue). Note that TMPRSS2 stainings were markedly stronger in enteric ganglia in the colon (A–C) than in the small intestine (D). The overview is a standard epifluorescence image; details are maximum intensity projections of optical sections by structured illumination. Scale bars: (A) 250 mm; (B–D) 50 mm. Figure adapted with permission from Deffner F et al. Front Neuroanat 2020; 14:596439; Copyright © 2020 Deffner, Scharr, Klingenstein, Klingenstein, Milazzo, Scherer, Wagner, Hirt, Mack and Neckel

FIGURE 3

Gastrointestinal, hepatic, biliary, and pancreatic manifestation of COVID‐19