Obesity and Diabetes Increase SARS-CoV-2 Susceptibility Through Angiotensin-Converting Enzyme 2, Immunologic, and Gut...

Angiotensin-converting enzyme 2 (ACE2), the receptor for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is ubiquitously expressed and contributes to cardiovascular, metabolic, and gastrointestinal homeostasis. In this study, we observed ACE2 loss in organs of patients with COVID-19 and in SARS-CoV-2-infected cells. In aged, obese, and diabetic mice, SARS-CoV-2 infection caused greater morbidity, persistent pulmonary infection, intestinal and metabolic disruption, and impaired cardiac Wnt and interferon-γ signaling. ACE2-deficient obese-diabetic mice showed cardiovascular, intestinal, metabolic, and neurobehavioral abnormalities, providing a complementary model to examine ACE2-associated disruption in metabolic disease. Exploratory metabolic profiling identified shared disruptions in taurine, tryptophan, and microbiota-derived metabolites across clinical and preclinical samples. These findings identify metabolic disease as a modifier of SARS-CoV-2 susceptibility and support ACE2-associated dysregulation as one contributor to selected infection-related sequelae.