High body temperature increases gut microbiota-dependent host resistance to influenza A virus and SARS-CoV-2 infection

While a common symptom of influenza and coronavirus disease 2019 (COVID-19) is fever, its physiological role on host resistance to viral infection remains less clear. Here, we demonstrate that exposure of mice to the high ambient temperature of 36 degrees Celsius increase host resistance to viral pathogens including influenza virus and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). High heat-exposed mice increase basal body temperature over 38 degrees Celsius to enable more bile acids production in a gut microbiota-dependent manner. The gut microbiota-derived deoxycholic acid (DCA) and its plasma membrane-bound receptor Takeda G-protein-coupled receptor 5 (TGR5) signaling increase host resistance to influenza virus infection by suppressing virus replication and neutrophil-dependent tissue damage. Furthermore, the DCA and its nuclear farnesoid X receptor (FXR) agonist protect Syrian hamster from lethal SARS-CoV-2 infection. Moreover, we demonstrate that certain bile acids are reduced in the plasma of COVID-19 patients who developed moderate I/II disease compared with minor illness group. These findings uncover an unexpected mechanism by which virus-induced high fever increases host resistance to influenza virus and SARS-CoV-2 in a gut microbiota-dependent manner.