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.