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

Minami Nagai, Miyu Moriyama, Chiharu Ishii, Hirotake Mori, Hikaru Watanabe, Taku Nakahara, Takuji Yamada, Dai Ishikawa, Takamasa Ishikawa, Akiyoshi Hirayama, Ikuo Kimura, Akihito Nagahara, Toshio Naito (), Shinji Fukuda () and Takeshi Ichinohe ()
Additional contact information
Minami Nagai: The University of Tokyo
Miyu Moriyama: The University of Tokyo
Chiharu Ishii: Keio University
Hirotake Mori: Juntendo University Faculty of Medicine
Hikaru Watanabe: Metagen Therapeutics, Inc.
Taku Nakahara: Metagen Therapeutics, Inc.
Takuji Yamada: Metagen Therapeutics, Inc.
Dai Ishikawa: Metagen Therapeutics, Inc.
Takamasa Ishikawa: Keio University
Akiyoshi Hirayama: Keio University
Ikuo Kimura: Kyoto University
Akihito Nagahara: Juntendo University Graduate School of Medicine
Toshio Naito: Juntendo University Faculty of Medicine
Shinji Fukuda: Keio University
Takeshi Ichinohe: The University of Tokyo

Nature Communications, 2023, vol. 14, issue 1, 1-13

Abstract: Abstract Fever is a common symptom of influenza and coronavirus disease 2019 (COVID-19), yet its physiological role in host resistance to viral infection remains less clear. Here, we demonstrate that exposure of mice to the high ambient temperature of 36 °C increases 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 °C 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 hamsters from lethal SARS-CoV-2 infection. Moreover, we demonstrate that certain bile acids are reduced in the plasma of COVID-19 patients who develop moderate I/II disease compared with the minor severity of illness group. These findings implicate a mechanism by which virus-induced high fever increases host resistance to influenza virus and SARS-CoV-2 in a gut microbiota-dependent manner.

Date: 2023
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DOI: 10.1038/s41467-023-39569-0

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