Is butyrate a natural alternative to dexamethasone in the management of CoVID-19?

Abstract

Coronavirus disease 2019 (CoVID-19) caused by Severe Acute Respiratory Syndrome Coronavirus 2 has affected more than 100 million lives. Severe CoVID-19 infection may lead to acute respiratory distress syndrome and death of the patient, and is associated with hyperinflammation and cytokine storm. The broad spectrum immunosuppressant corticosteroid, dexamethasone, is being used to manage the cytokine storm and hyperinflammation in CoVID-19 patients. However, the extensive use of corticosteroids leads to serious adverse events and disruption of the gut-lung axis. Various micronutrients and probiotic supplementations are known to aid in the reduction of hyperinflammation and restoration of gut microbiota. The attenuation of the deleterious immune response and hyperinflammation could be mediated by short chain fatty acids produced by the gut microbiota. Butyric acid, the most extensively studied short chain fatty acid, is known for its anti-inflammatory properties. Additionally, butyric acid has been shown to ameliorate hyperinflammation and reduce oxidative stress in various pathologies, including respiratory viral infections. In this review, the potential anti-inflammatory effects of butyric acid that aid in cytokine storm depletion, and its usefulness in effective management of critical illness related to CoVID-19 have been discussed.

Keywords: Butyrate; Butyric acid; CoVID-19; Cytokine storm; Dexamethasone; Gut microbiota; Hyperinflammation; Probiotics.

Figure 1.. Proinflammatory Angiotensin II, Interleukins, Tumour necrosis factor-α and Triggering receptor expressed on myeloid cells 1 (TREM-1) mediates the activation of Mitogen-activated protein kinase (MAPK), Extracellular signal-regulated kinase (ERK1/2) and Phosphatidylinositol 3-kinase (PI3K)/protein kinase B (AKT) intracellular signalling pathways.

The downstream activators of these pathways induces the reactive oxygen species (ROS) generation and transcription factor, NF-κB dependent expression of proinflammatory molecules. HDACs, which deacetylates Signal transducer and activator of transcription 1 (STAT1), and promotes the nuclear translocation and subsequent activity of NF-κB. Target genes of NF-κB, inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 increases the NF-κB activity via positive feedback loop. Histone deacetylase (HDAC) inhibitor, butyrate mediates its effects through GPCRs: Free fatty acid receptors 2/3 and GPCR 109A or by directly binding to HDAC active sites. Inhibition of NF-κB activity by butyrate attenuates inflammation and oxidative stress associated with various pathologies including CoVID-19. Butyrate also activates the transcription factor B lymphocyte-induced maturation protein-1 (BLIMP-1) and enhances the production of anti-inflammatory cytokines.

Figure 2.

A. SARS-CoV-2 transmitted through aerosols reach the lungs via respiratory tract and enters the host cell by binding to its receptor, ACE2 present on the surface of pneumocytes. Followed by endosome mediated internalization, SARS-CoV-2 causes cell injury and subsequent hyperinflammation and cytokine storm, resulting in fibrosis of lungs. These cytokines reach the gut via blood and lymphatic vessels that instigates local inflammation in gut, ushering to leaky gut and gut dysbiosis, resulting in diarrhoea and malabsorption together with reduced production of short chain fatty acids. B. Dexamethasone a synthetic broad-spectrum immunosuppressant can inhibit cytokine storm associated with CoVID-19. As an alternative, oral administration of probiotics or gut microbiome metabolite, SCFAs may ameliorate gut inflammation, restore gut integrity, and gut microbiome. This enhances the production of endogenous SCFAs and reaches the lungs via blood and lymphatic vessels, and may inhibit hyperinflammation and cytokine storm along with induction of anti-inflammatory cytokines production which recovers the lung from injury and the acute respiratory distresses associated with CoVID-19.