High body temperature increases gut microbiota-dependent host resistance to influenza A virus and SARS-CoV-2 infection PMID: 37391427

ADC Targets in Oncology

2026-04-10

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

Nat Commun. 2023 Jun 30;14(1):3863. doi: 10.1038/s41467-023-39569-0.

Minami Nagai ^# ¹ , Miyu Moriyama ^# ¹ , Chiharu Ishii ^# ² , Hirotake Mori ³ , Hikaru Watanabe ⁴ , Taku Nakahara ⁴ , Takuji Yamada ⁴ ⁵ , Dai Ishikawa ⁴ ⁶ ⁷ , Takamasa Ishikawa ² , Akiyoshi Hirayama ² , Ikuo Kimura ⁸ ⁹ , Akihito Nagahara ⁶ ⁷ , Toshio Naito ¹⁰ , Shinji Fukuda ¹¹ ¹² ¹³ ¹⁴ ¹⁵ , Takeshi Ichinohe ¹⁶

Affiliations

1. Division of Viral Infection, Department of Infectious Disease Control, International Research Center for Infectious Diseases, Institute of Medical Science, The University of Tokyo, Tokyo, Japan.
2. Institute for Advanced Biosciences, Keio University, Yamagata, Japan.
3. Department of General Medicine, Juntendo University Faculty of Medicine, Tokyo, Japan.
4. Metagen Therapeutics, Inc., Yamagata, Japan.
5. Department of Life Science and Technology, Tokyo Institute of Technology, Tokyo, Japan.
6. Laboratory for Regenerative Microbiology, Juntendo University Graduate School of Medicine, Tokyo, Japan.
7. Department of Gastroenterology, Juntendo University Faculty of Medicine, Tokyo, Japan.
8. Laboratory of Molecular Neurobiology, Graduate School of Biostudies, Kyoto University, Kyoto, Japan.
9. Department of Applied Biological Science, Graduate School of Agriculture, Tokyo University of Agriculture and Technology, Tokyo, Japan.
10. Department of General Medicine, Juntendo University Faculty of Medicine, Tokyo, Japan. [email protected].
11. Institute for Advanced Biosciences, Keio University, Yamagata, Japan. [email protected].
12. Metagen Therapeutics, Inc., Yamagata, Japan. [email protected].
13. Laboratory for Regenerative Microbiology, Juntendo University Graduate School of Medicine, Tokyo, Japan. [email protected].
14. Gut Environmental Design Group, Kanagawa Institute of Industrial Science and Technology, Kanagawa, Japan. [email protected].
15. Transborder Medical Research Center, University of Tsukuba, Ibaraki, Japan. [email protected].
16. Division of Viral Infection, Department of Infectious Disease Control, International Research Center for Infectious Diseases, Institute of Medical Science, The University of Tokyo, Tokyo, Japan. [email protected].
# Contributed equally.

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.