Gut Microbial Tryptophan Metabolism Is Involved in Post-Cardiac Arrest Brain Injury via Pyroptosis Modulation

IF 4.8 1区医学 Q1 NEUROSCIENCES

CNS Neuroscience & Therapeutics Pub Date : 2025-04-22 DOI:10.1111/cns.70381

Chenghao Wu, Mengyuan Diao, Shuhang Yu, Shaosong Xi, Zhipeng Zheng, Yang Cao, Shuai Wang, Ying Zhu, Mao Zhang, Wei Hu

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Abstract

Aims

Post-cardiac arrest brain injury (PCABI) is a leading cause of death in cardiac arrest/cardiopulmonary resuscitation (CA/CPR) victims and long-term disability in CA/CPR survivors. Despite previous evidence indicating that the microbiota-gut-brain axis is critically involved in many neurological disorders, no research has hitherto established a connection between the gut microbiota and PCABI through this axis. This study aims to explore the biological roles of microbial tryptophan metabolites in the progression of PCABI.

Methods

To achieve this, we pretreated rats with a cocktail of broad-spectrum antibiotics (Abx) to eradicate the gut microbiota before establishing a 7-min asphyxia-CA/CPR model.

Results

Remarkably, the 24-h survival rate and neurological outcomes improved in Abx/CPR rats. Fecal 16s rDNA sequencing and PICRUSt2 analysis revealed that Abx reshaped the microbial community and elevated the proportion of microbial tryptophan metabolism in rats. Metabolomic profiling suggested that Abx shifted the phenotype of microbial tryptophan metabolism from the indole pathway to the kynurenine pathway, thereby increasing the levels of the neuroprotective metabolite kynurenine in the feces, circulation, and ultimately the brain. Furthermore, the hippocampal expression of aryl hydrocarbon receptor (AhR), an endogenous receptor of kynurenine, was upregulated in Abx/CPR rats. In vitro experiments further demonstrated that the neuroprotective effects of kynurenine are AhR-dependent and that AhR activation could negatively regulate the NLRP3 protein expression. Supporting this, results from qRT–PCR, immunohistochemistry, and immunofluorescence in the rat cerebral cortex exhibited that L-kynurenine inhibited NLRP3-induced pyroptosis.

Conclusions

Our study provides a direct clue to the essential participation of the microbiota-gut-brain axis in the progression of PCABI. It demonstrates that kynurenine might attenuate PCABI by inhibiting NLRP3-induced pyroptosis.

Abstract Image

查看原文本刊更多论文

肠道微生物色氨酸代谢通过焦亡调节参与心脏骤停后脑损伤

心脏骤停后脑损伤（PCABI）是心脏骤停/心肺复苏（CA/CPR）患者死亡和CA/CPR幸存者长期残疾的主要原因。尽管先前的证据表明微生物群-肠-脑轴与许多神经系统疾病密切相关，但迄今为止还没有研究通过该轴建立肠道微生物群与PCABI之间的联系。本研究旨在探讨微生物色氨酸代谢物在PCABI进展中的生物学作用。为了实现这一目标，我们在建立7分钟窒息- ca /CPR模型之前，用广谱抗生素（Abx）鸡尾酒预处理大鼠，以根除肠道微生物群。结果Abx/CPR大鼠的24小时存活率和神经预后显著改善。粪便16s rDNA测序和PICRUSt2分析显示，Abx重塑了大鼠的微生物群落，提高了微生物色氨酸代谢的比例。代谢组学分析表明，Abx将微生物色氨酸代谢的表型从吲哚途径转移到犬尿氨酸途径，从而增加了粪便、循环和最终大脑中神经保护代谢物犬尿氨酸的水平。此外，Abx/CPR大鼠海马中内源性犬尿氨酸受体芳烃受体（AhR）的表达上调。体外实验进一步证明犬尿氨酸的神经保护作用是依赖AhR的，AhR的激活可以负向调节NLRP3蛋白的表达。大鼠大脑皮层的qRT-PCR、免疫组织化学和免疫荧光结果表明，l -犬尿氨酸抑制nlrp3诱导的焦亡。结论我们的研究为微生物-肠-脑轴在PCABI进展中的重要参与提供了直接线索。这表明犬尿氨酸可能通过抑制nlrp3诱导的焦亡来减轻PCABI。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

CNS Neuroscience & Therapeutics 医学-神经科学

CiteScore

7.30

自引率

12.70%

发文量

240

审稿时长

2 months

期刊介绍： CNS Neuroscience & Therapeutics provides a medium for rapid publication of original clinical, experimental, and translational research papers, timely reviews and reports of novel findings of therapeutic relevance to the central nervous system, as well as papers related to clinical pharmacology, drug development and novel methodologies for drug evaluation. The journal focuses on neurological and psychiatric diseases such as stroke, Parkinson’s disease, Alzheimer’s disease, depression, schizophrenia, epilepsy, and drug abuse.