Climate change has a strong effect on respiratory health, the effects of extreme temperatures on the lung-gut axis remains unclear. This study investigates the impact of extreme temperatures on the lung-gut microbiome and its associated biological pathways in mice. <i>B6.Sftpc^CreERT2/+ ROSA26Sor^CAG-tdTomato</i> mice were exposed to normal (22 °C), low (10 °C), high (40 °C), or fluctuating (40 °C 2 hrs to 10 °C 2 hrs; 40-10 °C) temperatures at 65 % relative humidity, 4hrs/day for 7days. Lung and gut microbiota were analyzed by 16S rDNA sequencing, short-chain fatty acids (SCFAs) were quantified using gas chromatography-mass spectrometry. Intestinal LDH, IL-6, and KC levels were measured. Liquid chromatography-tandem mass spectrometry was used to characterized proteins. Significant beta diversity was observed among groups in the both lung and gut microbiomes. In the lung, Deferribacterota and Desulfobacterota increased at 10 °C and 40-10 °C, while Firmicutes and Verrucomicrobiota decreased under the same conditions. Desulfobacterota and Patescibacteria were enriched at 40-10 °C, whereas Verrucomicrobiota and Firmicutes increased at 40 °C and 10 °C in mice stool, respectively. 40 °C elevated intestinal KC levels, while 10 °C reduced serum butyric and pentanoic acids in mice serum. Significant correlations between lung and stool microbiota, SCFAs, inflammatory markers, and LDH were observed. Proteomic profiling makes available unique temperature-dependent expression patterns, involving: metabolic regulation, immune response, cellular stress, and injury pathways. Extreme temperature exposure induced lung-gut dysbiosis, intestinal inflammation, Serum SCFAs imbalance, and proteomic alterations in mice. These findings revealed the adverse effects of extreme temperature events in disrupting the host-microbiome homeostasis, which potentially increase the susceptibility to temperature-sensitive adverse health outcomes.