Synbiosis and Berberine
Microbes in the gut play a central role in modulating immune responses, inflammation, and angiogenesis31. Microbial dysbiosis is an underlying factor in a variety of human disorders including metabolic diseases (obesity, type 2 diabetes mellitus), respiratory tract infections, appendicitis, and cardiovascular diseases34.The Gram-negative periodontal pathogen,Fusobacterium nucleatum plays an important role in promoting dysbiosis35. Alkalinized stomach contents due toHelicobacter pylori facilitate passage of microbes; likewise, cigarette smoking36 promotes the proliferation of anaerobic F. nucleatum which stimulates cells to produce proinflammatory cytokines, including IL-6, IL-8, and TNFα through TLRs37.
The actions of proinflammatory cytokines promote hypoxia, which results in the release HIF-1 that induces angiogenesis. Hypoxia itself leads to the production of proinflammatory cytokines via the NF-κB /COX-2 pathway and thereby exacerbates local inflammatory conditions38.
Patients with underlying disorders that are caused by or related to dysbiosis are more susceptible to COVID-19, as they are primed to exacerbate the cytokine storm produced by both dysbiosis and virus infection7. Therefore, I suggest that synbiotics might be combined with thalidomide and celecoxib to generate an effective therapeutic regimen.
The combination of thalidomide and celecoxib is important as it will serve to suppresses the production of vascular endothelial growth factor (VEGF), basic fibroblast growth factor (bFGF) and COX-2, the three key mediators of angiogenesis39.
Synbiosis promoted by berberine will serve to limit the production of proinflammatory cytokines and promote the secretion of short chain fatty acids that are beneficial toward positive systemic immunomodulation. Berberine is an isoquinoline alkaloid purified from Japanese herb,Phellodendron amurense (known as KIHADA in Japanese) that is used for the treatment of microbe-associated diarrhea40. The anti-inflammatory activity of berberine involves activation of AMP-activated protein kinase (AMPK)41 and inhibition of NF-κB and AP-1 signaling pathways42. Berberine-mediated inhibition of these pathways limits both inflammation and carcinogenesis due to down-regulation of cytokines and proinflammatory enzymes, including TNF-α, IL-1β, IL-6, monocyte chemoattractant protein-1 (MCP-1), inducible nitric oxide synthase (iNOS), and COX-243, 44. Patients with obesity, type 2 diabetes mellitus, hypertension, and/or a past history of acute appendicitis or H. pylori infection must be carefully observed while under this regimen.
Treatment
At present, there is no evidence from randomized controlled trials that supports the use of any specific drug regimen in patients with COVID-19. However, as I indicate here, there exist important common modalities that link the virus-induced cytokine storm to malignancies, notably, both conditions result in overexpression of proinflammatory cytokines and angiogenesis factors via the activation of NF-κB24.