When we try to pick out anything by itself, we find it hitched to everything else in the universe! – John Muir
Sars-Cov-2 has literally taken the world by storm with hundreds of thousands of deaths, numerous complications of COVID-19 still ongoing, and now renewed interest in the ‘vaccines’ used to prevent or mute this disease that may be less effective than we originally thought. We are now learning about significant complications not only of the disease itself, but of the use of experimental ‘vaccines’ based on mRNA to viral spike protein. As the pandemic declines, the virus remains persistent will likely become more of an endemic condition. Meanwhile, we have learned much about SARS-COV-2 virus. Most viruses have a receptor or receptors that allow them to connect with and penetrate human cells. Li and others first described a receptor that allows binding, and the spike protein receptor binding domain that allows attachment to ACE2. ACE2 was initially identiﬁed in 2000 as a homolog of the ACE receptor. Since the beginning of the COVID-19 pandemic, hypertension and diabetes have been correlated with higher risk of mortality. Initial reports speculated that angiotensin converting enzyme inhibitors (ACEi) and angiotensin receptor blockers (ARBs), which are commonly used therapeutic agents, would up-regulate ACE2 expression, thus increasing the risk of severe illness. Recent evidence has challenged this hypothesis, demonstrating both mechanistically and in large cohort studies that ACEi and ARBs do not up-regulate ACE2 and are not associated with an increased mortality. Studies on ACE2 up-regulation have shown that patient sex, various diseases and a number of drugs have often given confusing and even contradictory results. ,
Recently, the bile acid receptor farnesoid X receptor (FXR) has been shown to be a strong up-regulator of ACE2 expression by binding directly to the ACE2 promoter. The FXR nuclear receptor family of transcriptional regulators has been shown to be upregulated or downregulated by various conditions, and is known to play a critical role in the regulation of bile acid synthesis, lipoprotein metabolism, glucose metabolism, and protection of the liver from toxins to mention to mention just a few of its actions. FXR activity is affected by the balance of unconjugated bile salts and those that are conjugated. One factor that has been shown to up-regulate FXR has been the presence of microbial bile salt hydrolases that break down various bile salt conjugates that suppress FXR activity. Ursodeoxycholate (UDC; Ursodiol) is one of those conjugated bile salts. It was approved for the treatment of gallstones in 1987, and has been a mainstay of the treatment of primary biliary cholangitis and cirrhosis. UDC reduces FXR stimulation of ACE2 by reducing the presence of FXR on the ACE2 promoter. Bacterial bile salt hydrolases break down these inhibitory conjugated bile salts thus reducing their inhibitory effect on the FXR/ACE2 axis. In the human gut, a number of organisms can produce bile salt hydrolases. Among bacteria producing bile salt hydrolases the genus Bacteroides are the most abundant. Sun, et. al. studied the effects of metformin on the gut microbiota and found that the genus Bacteroides was substantially reduced in individuals given just 3 days of therapeutic doses of metformin. Metformin has been a first-line antidiabetic medication for more than 60 years because of its distinct glucose-lowering effect and safety profile, Metformin administered orally reaches high concentrations in the intestine with much lower serum concentrations; thus, the possibility cannot be excluded that its metabolic benefits might be due in part to actions in the intestine. Metformin was recently shown to alter the gut microbiome of individuals with T2D and has a number of effects on gut bacteria including suppression of Bacteroides spp,, enhancement of the presence of short chain fatty acid (SCFA) producing organisms as well as a substantial increase in the mucin degrading organism Akkermansia muciniphila. 
Thus these two ‘old drugs’ (ursodeoxycholate and metformin) have effects on one or more of the ancient species of the gut microbiota to reduce the FXR effect on up-regulating ACE2 activity. This could be one of the mechanisms whereby metformin has been associated with a reduced severity of COVID-19 infections. Sharma et al first proposed metformin’s beneficial effects occur through the activation of AMP-activated protein kinase (AMPK) in hepatocytes, and postulated that would lead to ACE-2 conformational and functional changes, resulting in decreased binding with SARS-CoV-2 and subsequently to a reduction in its infectivity. Sun et. al., however, showed that metformin inhibits intestinal FXR signaling via the gut microbiota in an AMPK-independent manner. Thus the effect of metformin on suppression of some gut bacteria may be the mechanism at play for its beneficial effects in COVID-19 infections.
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