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World J Gastroenterol. Dec 14, 2021; 27(46): 7925-7942
Published online Dec 14, 2021. doi: 10.3748/wjg.v27.i46.7925
COVID-19 and gut immunomodulation
Koushik Roy, Sidra Agarwal, Rajib Banerjee, Manash K Paul, Prabhat K Purbey
Koushik Roy, Microbiology and Immunology, Department of Pathology, School of Medicine, University of Utah, Salt Lake City, UT 84112, United States
Sidra Agarwal, Department of Gastroenterology, Shadan Institute of Medical Sciences, Peeramcheru 500086, Telangana, India
Rajib Banerjee, Department of Electronics and Communication Engineering, Dr. B. C. Roy Engineering College, Durgapur 713206, West Bengal, India
Manash K Paul, Division of Pulmonary and Critical Care Medicine, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA 90095, United States
Prabhat K Purbey, Department of Microbiology, Immunology and Molecular Genetics, University of California Los Angeles, Los Angeles, CA 90095, United States
Author contributions: Roy K and Agarwal S contributed equally; Roy K, Agarwal S, Banerjee R, Paul MK, and Purbey PK contributed to the draft preparation of the article; Paul MK and Purbey PK conceptualized and edited the article.
Conflict-of-interest statement: No Conflict-of-interest.
Open-Access: This article is an open-access article that was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution NonCommercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: https://creativecommons.org/Licenses/by-nc/4.0/
Corresponding author: Manash K Paul, PhD, Research Scientist, Division of Pulmonary and Critical Care Medicine, David Geffen School of Medicine, University of California Los Angeles, 700 Tiverton Ave (at Charles E. Young Dr. E.), Los Angeles, CA 90095, United States. manashp@ucla.edu
Received: February 18, 2021
Peer-review started: February 18, 2021
First decision: May 13, 2021
Revised: June 9, 2021
Accepted: November 29, 2021
Article in press: November 29, 2021
Published online: December 14, 2021
Processing time: 294 Days and 21.4 Hours
Abstract

The disease coronavirus disease 2019 (COVID-19) is a severe respiratory illness that has emerged as a devastating health problem worldwide. The disease outcome is heterogeneous, and severity is likely dependent on the immunity of infected individuals and comorbidities. Although symptoms of the disease are primarily associated with respiratory problems, additional infection or failure of other vital organs are being reported. Emerging reports suggest a quite common co-existence of gastrointestinal (GI) tract symptoms in addition to respiratory symptoms in many COVID-19 patients, and some patients show just the GI symptoms. The possible cause of the GI symptoms could be due to direct infection of the epithelial cells of the gut, which is supported by the fact that (1) The intestinal epithelium expresses a high level of angiotensin-converting enzyme-2 and transmembrane protease serine 2 protein that are required for the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) entry into the cells; (2) About half of the severe COVID-19 patients show viral RNA in their feces and various parts of the GI tract; and (3) SARS-CoV-2 can directly infect gut epithelial cells in vitro (gut epithelial cells and organoids) and in vivo (rhesus monkey). The GI tract seems to be a site of active innate and adaptive immune responses to SARS-CoV-2 as clinically, stool samples of COVID-19 patients possess proinflammatory cytokines (interleukin 8), calprotectin (neutrophils activity), and immunoglobulin A antibodies. In addition to direct immune activation by the virus, impairment of GI epithelium integrity can evoke immune response under the influence of systemic cytokines, hypoxia, and changes in gut microbiota (dysbiosis) due to infection of the respiratory system, which is confirmed by the observation that not all of the GI symptomatic patients are viral RNA positive. This review comprehensively summarizes the possible GI immunomodulation by SARS-CoV-2 that could lead to GI symptoms, their association with disease severity, and potential therapeutic interventions.

Keywords: COVID-19; Gastrointestinal symptoms; Pathogenesis; Innate immune response; Adaptive immune response; Gut microbiota; Dysbiosis; Therapeutics; Probiotic; Pre-existing diseases

Core Tip: Coronavirus disease 2019 (COVID-19) is a global pandemic. Many COVID-19 patients either present gastrointestinal (GI) symptoms in addition to respiratory symptoms or just GI symptoms. Syndrome coronavirus 2 (SARS-CoV-2) directly infects GI epithelial cells as they express significant levels of angiotensin-converting enzyme-2 and transmembrane protease serine 2 protein, required for SARS-CoV-2 entry. This article reviews gut infection and GI immunomodulation by SARS-CoV-2, leading to spectrum of GI symptoms and pathogenesis in COVID-19-patients. Special emphases are given on the innate and acquired immune responses in the GI tract due to intestinal and non-intestinal SARS-CoV-2 infection, COVID-19 severity in people with pre-existing intestinal diseases, role of gut microbiota, and possible therapeutic interventions are discussed.