肠道微生物群衍生的黄腐酚通过抑制小鼠巨噬细胞焦亡来预防中暑。

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

作者信息

Huang Wei, Xie Weidang, Liu Haixia, Chen Hui, Ling Yaping, Ma Qiang, Huang Qiaobing, Chen Zhongqing, Zhong Hanhui, Liu Yanan

机构信息

Department of Critical Care Medicine, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China; Department of Critical Care Medicine, Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou 510282, China.

Department of Critical Care Medicine, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China.

出版信息

J Adv Res. 2025 Jul 19. doi: 10.1016/j.jare.2025.07.031.

DOI:10.1016/j.jare.2025.07.031

PMID:40691986

Abstract

BACKGROUND

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.

OBJECTIVES

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

METHODS

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.

RESULTS

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.

CONCLUSIONS

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.

摘要

背景

中暑是一种由热应激引起的危重病，其特征为循环衰竭和多器官功能障碍。越来越多的证据表明，各种疾病的病理生理学与肠道微生物群密切相关。然而，肠道微生物群及其代谢产物对中暑的影响在很大程度上仍不清楚。

目的

我们的研究旨在了解肠道微生物群及其相关代谢产物如何调节中暑诱导的器官损伤。

方法

采用热应激建立小鼠中暑模型。利用16S rRNA基因测序和代谢产物分析来确定肠道微生物群的组成和功能。采用表面等离子体共振-液相色谱-串联质谱（SPR-LC-MS/MS）、蛋白质免疫印迹法、靶向切割和标签化分析（Cut&Tag）以及流式细胞术分析，以探究肠道微生物群衍生的代谢产物对中暑的影响。

结果

我们发现肠道微生物群失调显著加剧了中暑诱导小鼠的器官损伤。中暑期间鼠乳杆菌丰度降低导致黄腐酚（XN）水平下降。此外，肠道微生物群衍生的XN补充剂通过抑制全身炎症和巨噬细胞焦亡来预防中暑。机制上，XN通过减少异质性核糖核蛋白K（hnRNPK）的核积累及其随后与Nlrp3启动子的结合来防止巨噬细胞焦亡。此外，巨噬细胞中hnRNPK的缺失提供了对中暑的保护作用。

结论

我们的研究结果表明，肠道微生物群及其相关代谢产物在中暑诱导的器官损伤中起关键作用。我们提供的证据表明，XN作为一种新型hnRNPK抑制剂，可有效减轻中暑诱导的器官损伤。此外，肠道微生物群衍生的XN通过抑制hnRNPK依赖性巨噬细胞焦亡来减轻中暑诱导的器官损伤，从而将XN确定为一种有前景的中暑预防策略。