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; Gut-brain axis; enteric nervous system; gastrointestinal tract.

Figure 1:

Flow Chart of the Literature Search.

Figure 2.

The schematic diagram showing the underlying mechanism of the development of neurologic symptoms via gut in SARS-CoV-2. The SARS-CoV-2 enters the body through the nasopharynx down the esophagus into the GI system. Figure 2A: SARS-CoV-2 activation and membrane priming in the gut and brain are dependent on ACE-2 and TMPRSS2 membrane proteins on the intestinal epithelium and blood-brain barrier. Figure 2B: ACE2 activates B(0) AT1, a tryptophan transporter. Tryptophan is metabolized to form metabolites such as kynurenine (Kyn) and nicotinamide, both dependent on the rate-limiting enzyme indole 2,3-dioxygenase (IDO1). Nicotinamide activates the mTOR pathway to transcribe antimicrobial peptide agents. Kyn activates the aryl hydrocarbon receptor (AhR) found on immune cells, including CD4+ T-cells, innate immune cells, and natural killer cells. The activation of AhR leads to these immune cells secreting IL-22 cytokines to bind and activate IL-22 receptors to phosphorylate STAT3 on paneth cells in the intestinal epithelium to secrete beta-defensins and cathelicidins. Kyn also affects the microglial cells and astrocytes in the CNS to maintain the BBB and clear waste products. SARS-CoV-2 affects the whole tryptophan pathway leading to antimicrobial changes in the gut and neuroinflammation. Figure 2C: SARS-CoV-2 binds to TLR4 on intestinal epithelium to activate MYD88 to produce proinflammatory cytokines and zonulin. Zonulin is released back into the intestinal lumen to bind to protease-activated receptors-2 (PAR2). When activated, PAR2 disrupts the tight junctions in between the intestinal epithelial cells, allowing SARS-CoV-2 to enter the bloodstream. SARS-CoV-2 reaches the blood vessels in the brain to act on the TLR4 on the BBB to create more zonulin. This zonulin binds to a special zonulin receptor in the BBB that disrupts the TJ, allowing SARS-CoV-2 to enter the CNS to cause neuroinflammation.

Figure 3.

The mechanisms of different treatment options to help prevent severe SARS-CoV-2 infection. Figure 3A: TMPR22 inhibitors such as camostat mesylate and nafamostat mesylate block the action of TMPRSS2, preventing viral activation and membrane binding. This prevents SARS-CoV-2 replication in the intestinal epithelium and prevents SARS-CoV-2 from reaching the bloodstream to reach the CNS. Figure 3B: Nicotinamide supplements replenish the levels caused by the decreased tryptophan absorption from SARS-CoV-2 leading to transcription of antimicrobial agents. With decreased Kyn from SARS-CoV-2, AhR agonists such as pelargonidin, FICZ, and OMP can be used to activate AhR receptors on the immune cells to secrete IL-22. This allows increased secretion of beta-defensins and cathelicidins from paneth cells on the intestinal epithelium. Nicotinamide and AhR agonists both maintain the gut microbial composition preventing a cytokine storm of proinflammatory markers. Figure 3C: SARS-CoV-2 increases the zonulin levels leading to tight junction (TJ) disruption. Larazotide acetate (AT1001) is used to prevent the binding of zonulin from PAR2 in the intestinal epithelium, blocking the disruption of the TJ that zonulin causes. This prevents SARS-CoV-2 from entering the bloodstream.