Ramping up the heat: Induction of systemic and pulmonary immune responses and metabolic adaptations in mice

Abstract

Heatwaves are an increasing public health concern, yet most animal studies use sudden extreme heat exposure that poorly reflects real‐world conditions. This study examined the effects of gradual exposure to extreme heat on mice. Adult male and female C57Bl/6 mice were randomly assigned to heat‐exposed, control, or pair‐fed experimental groups. Heat‐exposed mice underwent a single 8‐h temperature ramp from 20°C to 38°C; control and pair‐fed mice remained at ambient temperature. Multi‐omics analyses after heat exposure included cytokine profiling in serum and lung, cecal microbiome characterization, lung transcriptomics, and serum metabolomics. Heat exposure altered several serum and lung cytokines (IL‐17α, MIP‐1α, MIP‐1β, IL‐1α, IL‐12(p40), and RANTES). Random forest analysis identified microbial taxa that distinguished experimental groups, with a reduction in Lactobacillus observed in males; however, these effects were not statistically significant. Lung transcriptomics revealed changes in immune‐related gene expression, particularly in pathways associated with B‐cell activation. Serum metabolomics indicated modest disruptions in amino acid and energy metabolism, with enrichment of the glycine, serine, and threonine metabolism pathway. Integrated analyses identified associations among cytokines, gene expression, and bile acid‐related metabolites. These findings demonstrate that gradual exposure to extreme heat triggers systemic and pulmonary responses in mice.