Copyright
©The Author(s) 2021. Published by Baishideng Publishing Group Inc. All rights reserved.
Therapeutic implications of SARS-CoV-2 dysregulation of the gut-brain-lung axis
Samuel D Johnson, Omalla A Olwenyi, Namita Bhyravbhatla, Michellie Thurman, Kabita Pandey, Elizabeth A Klug, Morgan Johnston, Shetty Ravi Dyavar, Arpan Acharya, Anthony T Podany, Courtney V Fletcher, Mahesh Mohan, Kamal Singh, Siddappa N Byrareddy
Samuel D Johnson, Omalla A Olwenyi, Kabita Pandey, Elizabeth A Klug, Department of Pathology and Microbiology, University of Nebraska Medical Center, Omaha, NE 68198, United States
Samuel D Johnson, Omalla A Olwenyi, Namita Bhyravbhatla, Michellie Thurman, Kabita Pandey, Elizabeth A Klug, Morgan Johnston, Arpan Acharya, Siddappa N Byrareddy, Department of Pharmacology and Experimental Neuroscience, University of Nebraska Medical Center, Omaha, NE 68198, United States
Shetty Ravi Dyavar, Anthony T Podany, Courtney V Fletcher, Antiviral Pharmacology Laboratory, University of Nebraska Medical Center (UNMC) Center for Drug Discovery, Omaha, NE 68198, United States
Mahesh Mohan, Southwest National Primate Research Center, Texas Biomedical Research Institute, San Antonio, TX 78227, United States
Kamal Singh, Department of Molecular Microbiology and Immunology and Bond Life Sciences Center, University of Missouri, Columbia, MO 65212, United States
Siddappa N Byrareddy, Department of Genetics, Cell Biology and Anatomy, University of Nebraska Medical Center, Omaha, NE 68198, United States
Siddappa N Byrareddy, Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE 68198, United States
Author contributions: Johnson SD and Olwenyi OA contributed equally to the conception, review of literature, and drafting of the manuscript; all authors contributed to the writing and editing of the manuscript and approved the final version of the manuscript.
Supported by National Institutes of Health grants, No. R01AI129745, No. R21MH113455, No. R01DA052845, and No. R01AI113883 (to Byrareddy SN).
Conflict-of-interest statement: Authors declare no conflict of interests for this article.
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 Non Commercial (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:
http://creativecommons.org/Licenses/by-nc/4.0/ Corresponding author: Siddappa N Byrareddy, PhD, Associate Professor, Department of Pharmacology and Experimental Neuroscience, University of Nebraska Medical Center, 42nd Street and Emile Street, Omaha, NE 68198, United States. sid.byrareddy@unmc.edu
Received: February 18, 2021
Peer-review started: February 18, 2021
First decision: May 1, 2021
Revised: May 10, 2021
Accepted: July 20, 2021
Article in press: July 20, 2021
Published online: August 7, 2021
The emergence and rapid spread of novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has caused over 180 million confirmed cases resulting in over 4 million deaths worldwide with no clear end in sight for the coronavirus disease 19 (COVID-19) pandemic. Most SARS-CoV-2 exposed individuals experience mild to moderate symptoms, including fever, cough, fatigue, and loss of smell and taste. However, many individuals develop pneumonia, acute respiratory distress syndrome, septic shock, and multiorgan dysfunction. In addition to these primarily respiratory symptoms, SARS-CoV-2 can also infiltrate the central nervous system, which may damage the blood-brain barrier and the neuron's synapses. Resultant inflammation and neurodegeneration in the brain stem can further prevent efferent signaling to cranial nerves, leading to the loss of anti-inflammatory signaling and normal respiratory and gastrointestinal functions. Additionally, SARS-CoV-2 can infect enterocytes resulting in gut damage followed by microbial dysbiosis and translocation of bacteria and their byproducts across the damaged epithelial barrier. As a result, this exacerbates pro-inflammatory responses both locally and systemically, resulting in impaired clinical outcomes. Recent evidence has highlighted the complex interactions that mutually modulate respiratory, neurological, and gastrointestinal function. In this review, we discuss the ways SARS-CoV-2 potentially disrupts the gut-brain-lung axis. We further highlight targeting specific responses to SARS-CoV-2 for the development of novel, urgently needed therapeutic interventions. Finally, we propose a prospective related to the individuals from Low- and Middle-Income countries. Here, the underlying propensity for heightened gut damage/microbial translocation is likely to result in worse clinical outcomes during this COVID-19 pandemic.
Core Tip: Severe acute respiratory syndrome coronavirus 2 has spread rapidly, infecting and killing millions worldwide. In addition to respiratory symptoms, coronavirus disease 19 (COVID-19) is associated with enterocyte infection leading to intestinal inflammation, gut barrier damage, and microbial dysbiosis exacerbating the systemic inflammatory response. Viral infiltration to the central nervous system from cranial nerve innervation of the lungs and gut can also cause neuroinflammation and degeneration, which further dysregulates gut and lungs. This review summarizes recent findings on COVID-19 pathogenesis in the gut-brain-lung axis and offers therapeutic interventions to improve clinical outcomes.
