High Body Temperature Increases Resistance to Pathogenic Viral Infections, New Study Finds

July 14, ​2023

Viral infections affect the elderly more frequently than the younger population. Moreover, elderly individuals also have lower mean body temperatures. Taking cues from these clinical observations, a team of researchers from The University of Tokyo undertook a study to find the missing link between body temperature and infection resistance. Findings indicate that increased body temperature suppresses virus replication and excessive inflammatory responses.     
 
Clinical evidence suggests that elderly individuals are at a higher risk of contracting viral infections. Quite notably, the older people also have lower mean body temperatures. However, the effects of increased body temperature on fighting viral infections remain largely unexplored.

A team of Japanese researchers has now been able to bridge the gap by linking higher body temperature with an increased infection-fighting capability of the gut microorganisms or "microbiota." Their study was published in Volume 14 Issue 3863 of Nature Communications in June 2023 and made available online on 30 June 2023.      
 
To conduct their experiments, the team used mice which were heat- or cold-exposed at 4°C, 22°C, or 36°C a week before influenza virus infection. After the viral infection was induced, the cold-exposed mice mostly died due to severe hypothermia, whereas the heat-exposed mice were highly resistant to the infection even at increasing doses of the virus. "High-heat-exposed mice raise their basal body temperature above 38°C, allowing them to produce more bile acids in a gut microbiota-dependent manner,” remarks Dr.Takeshi Ichinohe from the Division of Viral Infection, The University of Tokyo, Japan.
 
The authors speculated that signaling of deoxycholic acid (DCA) from the gut microbiota and its plasma membrane-bound receptor "Takeda G-protein-coupled receptor 5" (TGR5) increased host resistance to influenza virus infection by suppressing virus replication and neutrophil-dependent tissue damage.
 
While working on these experiments, the team noticed that mice infected with the influenza virus showed decreased body temperatures nearly four days after the onset of the infection, and they snuggled together to stay warm!
 
The team noticed similar results after switching the influenza virus with SARS-CoV-2 and the study results were also validated using a Syrian hamster model. Their experiments revealed that body temperature over 38°C could increase host resistance to influenza virus and SARS-CoV-2 infections. Moreover, they also found that such increase in body temperature catalyzed key gut microbial reactions, which in turn, led to the production of secondary bile acids. These acids can modulate immune responses and safeguard the host against viral infections.
 
Dr.Ichinohe explains, “The DCA and its nuclear farnesoid X receptor (FXR) agonist protect Syrian hamsters from lethal SARS-CoV-2 infection. Moreover, 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.”
 
The team then performed extensive analysis to gain insight into the precise mechanisms underlying the gut-metabolite-mediated host resistance to viral infections in heat-exposed rodents. Besides, they also established the role of secondary bile acids and bile acid receptors in mitigating viral infections.   
 
 “Our finding that reduction of certain bile acids in the plasma of patients with moderate I/II COVID-19 may provide insight into the variability in clinical disease manifestation in humans and enable approaches for mitigating COVID-19 outcomes,” concludes Dr. Ichinohe.
 
To briefly summarize, the published study reveals that the high-body-temperature-dependent activation of gut microbiota boosts the serum and intestinal levels of bile acids. This suppresses virus replication and inflammatory responses that follow influenza and SARS-CoV-2 infections. 
 
A heartfelt appreciation to the Japanese researchers for placing their trust in their intuition and gut instincts!
 

 Reference

DOI：
10.1038/s41467-023-39569-0 

Authors：
Minami Nagai¹, Miyu Moriyama¹, Chiharu Ishii², Hirotake Mori³, Hikaru Watanabe⁴, Taku Nakahara⁴, Takuji Yamada^4,5, Dai Ishikawa^4,6,7, Takamasa Ishikawa², Akiyoshi Hirayama², Ikuo Kimura^8,9, Akihito Nagahara^6,7, Toshio Naito¹⁰, Shinji Fukuda ^{11,12,13,14,15}, Takeshi Ichinohe¹⁶

Affiliations：

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

 
 

About Dr. Takeshi Ichinohe

Dr. Takeshi Ichinohe serves as an Associate Professor at The Institute of Medical Science, The University of Tokyo. He is a well-cited researcher with over 45 publications to his credit including some in Scientific Reports, Nature Communications, and PNAS. Prof. Ichinohe obtained his Ph.D. from Tokyo University of Science in 2007. He has also won numerous awards including the Takahashi Incentive Award of the Japanese Society for Vaccinology in recognition of his outstanding research. Prof. Ichinohe’s research group primarily focuses on the regulation of adaptive immune responses to influenza A virus by microbiota and inflammasomes.  

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Dr. ICHINOHE Takeshi
 

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