Public Database-Driven Insights Into Aging Stress-Associated Defective Gut Barrier With Low SARS-CoV-2 Receptors

The novel coronavirus disease (COVID-19), caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has led to a global pandemic, and resulted in high case-fatality rate in the elderly. In addition to typical respiratory responses, ~50% of clinical cases include gastrointestinal symptoms such as diarrhea, vomiting, abdominal pain, and persistent fecal shedding of the virus even after its clearance from the pulmonary system. In the present study, we assessed aging-associated gut transcriptomic responses considering the gastrointestinal symptoms contributing to COVID-19 severity. Intestinal expression of SARS-CoV-2 receptors and defense biomarkers decreased with increasing age. Moreover, aging-associated integrated stress responses (ISR) and mTOR-linked cell metabolic stress signals counteracted gut defense biomarkers. However, SARS-CoV-2 receptor expression was positively associated with gut barrier integrity potently via downregulation of the two stress-responsive signals. Gut transcriptome-based mechanistic prediction implicates that high susceptibility to COVID-19 in the elderly with low SARS-CoV-2 receptors is due to aging stress-associated defective gut defense, providing a new avenue for viral entry receptor-independent interventions.