SARS-CoV-2 causes secretory diarrhea with an enterotoxin-like mechanism, which is reduced by diosmectite

Marco Poeta; Valentina Cioffi; Vittoria Buccigrossi; Francesco Corcione; Roberto Peltrini; Angela Amoresano; Fabio Magurano; Maurizio Viscardi; Giovanna Fusco; Antonietta Tarallo; Carla Damiano; Andrea Lo Vecchio; Eugenia Bruzzese; Alfredo Guarino

doi:10.1016/j.heliyon.2022.e10246

SARS-CoV-2 causes secretory diarrhea with an enterotoxin-like mechanism, which is reduced by diosmectite

Heliyon. 2022 Aug;8(8):e10246. doi: 10.1016/j.heliyon.2022.e10246. Epub 2022 Aug 18.

Affiliations

¹ Department of Translational Medical Science, Section of Pediatrics, University of Naples Federico II, Naples, Italy.
² Department of Public Health, University of Naples Federico II, Naples, Italy.
³ Department of Chemical Sciences, University of Naples Federico II, Naples, Italy.
⁴ Department of Infectious Diseases, National Institute of Health, Rome, Italy.
⁵ Istituto Zooprofilattico Sperimentale Del Mezzogiorno, Portici, Naples, Italy.

Abstract

Background and aims: The pathophysiology of SARS-CoV-2-associated diarrhea is unknown. Using an experimental model validated for rotavirus-induced diarrhea, we investigated the effects of SARS-CoV-2 on transepithelial ion fluxes and epithelial integrity of human intestinal cells. The effect of the antidiarrheal agent diosmectite on secretion was also evaluated following its inclusion in COVID-19 management protocols.

Methods: We evaluated electrical parameters (intensity of short-circuit current [Isc] and transepithelial electrical resistance [TEER]) in polarized Caco-2 cells and in colonic specimens mounted in Ussing chambers after exposure to heat-inactivated (hi) SARS-CoV-2 and spike protein. Spectrofluorometry was used to measure reactive oxygen species (ROS), a marker of oxidative stress. Experiments were repeated after pretreatment with diosmectite, an antidiarrheal drug used in COVID-19 patients.

Results: hiSARS-CoV-2 induced an increase in Isc when added to the mucosal (but not serosal) side of Caco-2 cells. The effect was inhibited in the absence of chloride and calcium and by the mucosal addition of the Ca²⁺-activated Cl^- channel inhibitor A01, suggesting calcium-dependent chloride secretion. Spike protein had a lower, but similar, effect on Isc. The findings were consistent when repeated in human colonic mucosa specimens. Neither hiSARS-CoV-2 nor spike protein affected TEER, indicating epithelial integrity; both increased ROS production. Pretreatment with diosmectite inhibited the secretory effect and significantly reduced ROS of both hiSARS-CoV-2 and spike protein.

Conclusions: SARS-CoV-2 induces calcium-dependent chloride secretion and oxidative stress without damaging intestinal epithelial structure. The effects are largely induced by the spike protein and are significantly reduced by diosmectite. SARS-CoV-2 should be added to the list of human enteric pathogens.

Keywords: COVID-19; Diosmectite; Gastroenteritis; Oxidative stress.