Gut microbiota-derived xanthohumol protects against heatstroke by inhibiting macrophage pyroptosis in mice

Heatstroke is a critical illness induced by heat stress, characterized by circulatory failure and multiple organ dysfunctions. Accumulating evidence suggests that the pathophysiology of various diseases is closely associated with the gut microbiome. However, the effects of gut microbiota and their metabolites on heatstroke remain largely unknown.

Our study aimed to understand how the gut microbiota and related metabolites regulate heatstroke-induced organ injury.

Heat stress was employed to establish heatstroke in mice. 16S rRNA gene sequencing and metabolite analysis were utilized to determine the composition and function of gut microbiota. Surface plasmon resonance-liquid chromatography-tandem mass spectrometry (SPR-LC-MS/MS), western blotting, cleavage under targets and tagmentation assay (Cut&Tag), and flow cytometry assay were employed to explore the impact of gut microbiota-derived metabolites on heatstroke.

We found that gut microbiota dysbiosis significantly exacerbated organ injury in heatstroke-induced mice. Reduced Lactobacillus murinus abundance during heatstroke led to decreased levels of xanthohumol (XN). Additionally, gut microbiota-derived XN supplements protected against heatstroke by inhibiting systemic inflammation and macrophage pyroptosis. Mechanistically, XN prevented macrophage pyroptosis by reducing nuclear accumulation of heterogeneous nuclear ribonucleoprotein K (hnRNPK) and its subsequent binding to the Nlrp3 promoter. Additionally, deletion of hnRNPK in macrophages provided protection against heatstroke.

Our findings suggest that gut microbiota and their associated metabolites play a critical role in heatstroke-induced organ injury. We provide evidence that XN acts as a novel hnRNPK inhibitor, effectively mitigating heatstroke-induced organ injury. Furthermore, gut microbiota-derived XN alleviates heatstroke-induced organ injury by suppressing hnRNPK-dependent macrophage pyroptosis, thereby identifying XN as a promising preventive strategy for heatstroke.