Abstract
Elderly individuals infected with SARS-CoV-2 are at higher risk of developing cytokine storms and severe outcomes, yet specific biomarkers remain unclear. In this study, we investigated the alteration of primary bile acid metabolism in elderly patients with severe COVID-19 using untargeted metabolomics (n = 31), followed by targeted metabolomics to compare patients with disease progression (n = 16) to those without (n = 48). Significant reductions in chenodeoxycholic acid (CDCA) and glycochenodeoxycholic acid (GCDCA) levels were identified in severe cases, with GCDCA levels at admission correlating strongly with peak inflammatory markers. In vitro, CDCA, GCDCA, and their receptors, Farnesoid X Receptor (FXR) and Takeda G-protein-coupled receptor 5 (TGR5), effectively inhibited the inflammatory response induced by SARS-CoV-2. NOD-like receptor pathway, activated by SARS-CoV-2, may modulate inflammatory cytokines under the treatment of CDCA, GCDCA, and TGR5. CDCA and GCDCA levels at admission predicted disease progression, suggesting their potential as biomarkers for severe COVID-19 in the elderly and highlighting their regulatory role in inflammation, pointing to new therapeutic avenues.