Exploiting the gut microbiome's trialogue with microRNAs and host gene expression to treat Covid-19 related cardiac hypertension Deepansh Mody1 and Vibha Rani1* 1Department of Biotechnology, Jaypee Institute of Information Technology (Noida)
ABSTRACT
ORIGINAL HYPOTHESIS
The human gastrointestinal (GI) tract hosts trillions of microbial inhabitants involved in maintaining intestinal homeostasis, dysbiosis of which provokes a motley of pathogenic and autoimmune disorders. While the mechanisms by which the microbiota modulates human health are manifold, their liberated metabolites from ingested dietary supplements play a crucial role by bidirectionally regulating the expression of micro-ribonucleic acids (miRNAs). MiRNAs are small endogenous non-coding RNAs (ncRNAs) which have been confirmed to be involved in an interplay with microbiota to regulate host gene expression. The outbreak of SARS-CoV-2 virus, causative of Covid-19 pandemic, has been linked with increased cardiac hypertension co-morbidities, attributed to the use of ACE- inhibitors as a line of treatment for the latter. Present research proposes to augment the production of hsa-miR-27b, a defensive antiviral miRNA produced by host which targets the spike protein of Covid-19 virus, while also regulating ACE enzyme activity and myocardin differentiation in cardiac hypertension. We hypothesize and attempt to elucidate a novel mechanism to treat Covid-19 and related hypertension by targeting gut microbial species which modulate levels of miR-27b via metabolism of dietary supplements, eliminating the use of ACE inhibitors.
Increase in levels of miR-27b should post-transcriptionally silence the expression of ACE and myocardin, resolving cardiac hypertension. Since miR-27b is a fecal miRNA, its expression levels can be modulated by metabolites liberated by gut microbiota on metabolizing dietary supplements. We propose to augment the production of hsa-miR-27b, a defensive antiviral miRNA produced by host which targets the spike protein of Covid-19 virus, while also regulating ACE enzyme activity and myocardin differentiation in cardiac hypertension. We hypothesize a novel mechanism to treat Covid-19 and related hypertension by targeting gut microbial species which modulate levels of miR-27b via metabolism of dietary supplements, eliminating the use of ACE inhibitors.
OUR SUPPORTIVE FINDINGS Targets of miR-27b • Web Server: TargetScanHuman (v7.2) • miR-27b regulates myocardin gene expression by binding to 3’UTR mRNA. Role of Gut Microbiota • Web Database: miRbase • Directed to previous report on production of miR-27b by gut microbes, and a positive correlation with genus Enterococcus.
PILLARS OF RATIONALE Gut microbiome is a controller of wellness and disease1. Fecal miRNAs shape gut microbiome2. Microbiota- miRNA crosstalk to influence gene expression by hormonelike dissemination of miRNAs in endothelial vesicles2. External supplements can influence Microbiota- miRNA interplay3.
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Dietary Supplements that enhance Enterococcus in the gut • Dairy products, Fermented vegetables, Meat products, Probiotics (Cernivet® and FortiFlora®)
Figure 1: Modulating gut microbiome- miRNA and host gene expression trialogue with dietary supplements to treat various human diseases. (Source: Mody D., Verma V., & Rani V. (2020). Exploiting the gut microbiome- miRNA and host gene expression trialogue to treat pathogenic and autoimmune disorders. Critical Reviews of Microbiology. (Under Review))
Figure 2: TargetScan Analysis of miR-27b revealed 3’UTR of myocardin mRNA as a target.
PROBLEM AT HAND • •
FUTURE DIRECTIONS
Co-morbidities between hypertension (cardiovascular disease) amongst patients with COVID-19, with >7% of cases of myocardial injury. Patients are treated with ACE inhibitors, which are being discovered to facilitate SARS-CoV-2 binding to promote their entry in lung cells. Need for alternative therapies4.
• Wet-lab experiments to study the interplay between miR-27b expression and gut microbiota. • Identification of species and liberated metabolites involved in miR-27b expression • Effectual-analysis of miR-27b expression on ACE and myocardin expression. • Formulation studies on economic and natural therapeutic dietary supplements to prevent Covid-19 and related cardiac hypertension.
EDIFYING STUDIES • • • • • •
hsa-miR-27b is a human antiviral miRNA, uniquely targeting the Indian SARS-CoV2 due to a unique A930V mutation identified in the spike surface glycoprotein5. Abnormal Angiotensin Converting Enzyme (ACE) is a causative of vasoconstriction leading to hypertension. ACE Inhibitor infusions decrease ACE but increase ACE-2 receptors, to which SARS-CoV2 binds on cells of lungs and blood vessels. Upregulation of miR-27b hypomethylates CpG islands in the promoter regions of ACE gene, regulate ACE mRNA translation5. ACE efficiency depends on fibrillar collagen formation mediated by myocardial infarction. Myocardin is a key Transcription Factor for SMC differentiation and expression, for contractility
KEY REFERENCES Kho, Z. Y., & Lal, S. K. (2018). The human gut microbiome–a potential controller of wellness and disease. Frontiers in microbiology, 9, 1835. 2 Liu, Shirong, et al. "The host shapes the gut microbiota via fecal microRNA." Cell host & microbe 19.1 (2016): 32-43. 3 Fan, Y., & Zhang, J. (2019). Dietary modulation of intestinal microbiota: future opportunities in experimental autoimmune encephalomyelitis and multiple sclerosis. Frontiers in Microbiology, 10, 740. 4 Singh, A. K., Gupta, R., & Misra, A. (2020). Comorbidities in COVID-19: Outcomes in hypertensive cohort and controversies with renin angiotensin system blockers. Diabetes & Metabolic Syndrome: Clinical Research & Reviews. 5 Sardar, R., Satish, D., Birla, S., & Gupta, D. (2020). Comparative analyses of SAR-CoV2 genomes from different geographical locations and other coronavirus family genomes reveals unique features potentially consequential to host-virus interaction and pathogenesis. bioRxiv. 1