Gut-brain communication in COVID-19: molecular mechanisms, mediators, biomarkers, and therapeutics

ABSTRACT

Introduction

Infection with COVID-19 results in acute respiratory symptoms followed by long COVID multi-organ effects presenting with neurological, cardiovascular, musculoskeletal, and gastrointestinal (GI) manifestations. Temporal relationship between gastrointestinal and neurological symptoms is unclear but warranted for exploring better clinical care for COVID-19 patients.

Areas covered

We critically reviewed the temporal relationship between gut-brain axis after SARS-CoV-2 infection and the molecular mechanisms involved in neuroinvasion following GI infection. Mediators are identified that could serve as biomarkers and therapeutic targets in SARS-CoV-2. We discussed the potential therapeutic approaches to mitigate the effects of GI infection with SARS-CoV-2.

Expert opinion

Altered gut microbiota cause increased expression of various mediators, including zonulin causing disruption of tight junction. This stimulates enteric nervous system and signals to CNS precipitating neurological sequalae. Published reports suggest potential role of cytokines, immune cells, B(0)AT1 (SLC6A19), ACE2, TMRSS2, TMPRSS4, IFN-γ, IL-17A, zonulin, and altered gut microbiome in gut-brain axis and associated neurological sequalae. Targeting these mediators and gut microbiome to improve immunity will be of therapeutic significance. In-depth research and well-designed large-scale population-based clinical trials with multidisciplinary and collaborative approaches are warranted. Investigating the temporal relationship between organs involved in long-term sequalae is critical due to evolving variants of SARS-CoV-2.

KEYWORDS:

• ACE-2 receptor
• COVID-19
• enteric nervous system
• gastrointestinal tract
• Gut-brain axis

Article highlights

• SARS-CoV-2 has acute and long-term neuropsychological sequalae.

• SARS-CoV-2 enters human body through respiratory and fecal-oral route.

• ACE-2 plays a critical role in the entry and pathogenesis.

• Gut-brain axis plays a crucial role in ensuing neurological symptoms.

• B^OAT1 (SLC6A19), ACE2, TMRSS2 and TMPRSS4 play a role in viral entry and IFN-γ, IL-17A and zonulin play a role in pathogenesis of symptoms associated with gut-brain axis.

• Targeting these mediators might be of therapeutic importance to reduce long-term neurological symptoms.

Declaration of interest

The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Author contributions

Conception and design: T Wais, M Hasan, V Rai, D Agrawal; literature search, collection of the scientific information, analysis, and interpretation of the data: T Wais, M Hasan, V Rai, D Agrawal; drafting of the article: T Wais, M Hasan; critical revision and editing of the article for important intellectual content: V Rai, D Agrawal; final approval of the submitted article: T Wais, M Hasan, V Rai, D Agrawal. All authors agree for the final version of the manuscript to be published.

Further information

The content of this critical review is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. The authors report no proprietary or commercial interest in any product mentioned or concept discussed in this article.

Data availability

Not applicable; all information is gathered from published articles.

Additional information

Funding

This research work was supported by research grants R01 HL144125 and R01 HL147662 to D Agrawal from the National Heart, Lung and Blood Institute, National Institutes of Health, USA.