Fever is a common symptom of influenza and COVID-19, yet its physiological role in host resistance to viral infection remains less clear. Increased susceptibility to influenza virus infection in older humans could be explained by the fact that older human monocytes have impaired signaling to induce type I interferons (IFNs) in response to influenza virus infection.
However, the role of other age-related changes of host factors in susceptibility to influenza virus infection remains unclear. Moreover, elderly individuals also have lower mean body temperatures. A team of researchers from The University of Tokyo conducted a study to discover the gap between body temperature and infection resistance by drawing inspiration from these clinical observations. According to research, a higher body temperature inhibits the replication of viruses and overactive inflammatory reactions.  Â
Through this study, scientists bridged the gap by linking higher body temperature with an increased infection-fighting capability of the gut microorganisms or “microbiota.”
The scientists exposed mice to 4°C, 22°C, or 36°C for a week before inoculating with the influenza virus for their tests. 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. On the other hand, the majority of the cold-exposed mice died from severe hypothermia after the viral infection was induced.
To boost host resistance to influenza virus infection, the scientists hypothesized that deoxycholic acid (DCA) signaling from the gut microbiota and its plasma membrane-bound receptor “Takeda G-protein-coupled receptor 5” (TGR5) was necessary. This was done by inhibiting viral reproduction and neutrophil-dependent tissue damage.
The team conducting these tests discovered that mice infected with the influenza virus had lower body temperatures nearly four days after the infection started and huddled up to stay warm.
After replacing the influenza virus with SARS-CoV-2, the scientists observed comparable results, and the study’s findings were further confirmed using a Syrian hamster model. According to their studies, body temperatures over 38°C may boost a host’s resistance to influenza and SARS-CoV-2 infections. Additionally, they discovered that such an elevation in body temperature accelerated critical gut microbial processes, which later produced secondary bile acids. These acids can modulate the immune system, protecting the host from viral infections.
Dr.Takeshi Ichinohe from the Division of Viral Infection at the University of Tokyo, Japan, said, “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 scientists then thoroughly analyzed the mechanisms underlying the host resistance to viral infections mediated by gut metabolites in heat-exposed animals. They also confirmed the function of bile acid receptors and secondary bile acids in preventing 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.”
To put it briefly, the presented study shows that the high-body-temperature-dependent activation of gut microbiota increases the blood and intestinal levels of bile acids. This inhibits the viral replication and inflammatory reactions that follow infections with influenza and SARS-CoV-2.
Journal Reference:
- Minami Nagai, Miyu Moriyama et al. High body temperature increases gut microbiota-dependent host resistance to influenza A virus and SARS-CoV-2 infection. Nature Communications. DOI: 10.1038/s41467-023-39569-0