肠道菌群耗竭通过对香豆酸促进Treg分化加速脑出血后血肿消退和神经系统恢复。

IF 12.4 1区 医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL
Theranostics Pub Date : 2025-06-09 eCollection Date: 2025-01-01 DOI:10.7150/thno.113764
Yonghe Zheng, Yin Li, Xuchao He, Yuhan Zhu, Shiyu Xu, Yirong Feng, Yirui Kuang, Huaijun Chen, Linfeng Fan, Huaping Huang, Libin Hu, Xian Yu, Jianan Wu, Lingji Jin, Junwen Hu, Xiongjie Fu, Hanhai Zeng, Shenglong Cao, Lin Wang
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引用次数: 0

摘要

血肿体积对脑出血患者预后有显著影响。通过增强清除机制和减少血肿溶解来有效解决血肿是脑出血后神经恢复的必要条件。调节性T细胞(Tregs)以其抗炎特性而闻名,在各种中枢神经系统疾病中发挥神经保护作用。此外,肠道菌群通过多种调控途径深刻影响Treg的发育。尽管如此,Tregs和肠道微生物群在促进脑出血后血肿消退中的确切作用仍不清楚。因此,本研究旨在探讨Tregs和肠道微生物群在ich后血肿消退中的作用及其潜在机制。方法:在小鼠脑出血诱导前,采用抗生素鸡尾酒(ABX)灌胃,评估肠道微生物群消耗对神经功能缺损和血肿消退(包括红细胞吞噬和红细胞溶解)的影响。采用流式细胞术分析和靶向细胞耗尽技术来鉴定外周免疫细胞群,这些免疫细胞群介导肠道微生物群耗尽对神经恢复和血肿消退的有益影响。通过过继性Treg转移实验,研究Treg在红细胞吞噬、红细胞溶解及相关下游分子信号通路中的功能作用。利用质谱技术对ICH小鼠血清和粪便代谢产物进行多组学分析,并利用16S rRNA测序技术对粪便微生物组成进行分析,探讨ICH小鼠微生物群耗竭后Treg种群扩增的机制。此外,还评估了对香豆酸(PCA)灌胃和克林霉素介导的PCA代谢肠道微生物群耗竭对脑出血后Treg丰度、血肿消退和神经恢复的影响。结果:ABX灌胃减少肠道微生物群,增加脑Treg种群,从而增强红细胞吞噬,抑制红细胞溶解,最终促进血肿消退和神经系统恢复。过继性Treg转移实验进一步证实Treg促进清道夫途径介导的红细胞吞噬,抑制补体介导的红细胞溶解。这些作用是通过胞吐受体(MERTK和AXL)、配体(Gas6和C1q)和血红蛋白清除率受体CD163的上调,以及补体C3表达的下调和膜攻击复合物(MACs)形成的减少而发生的。多组学分析表明,灌胃ABX消除了代谢PCA的微生物群,从而增加了血清和粪便中的PCA浓度。升高的PCA水平通过抑制pck θ- akt - foxo1 /3a信号通路促进外周Treg分化,导致脑Treg数量增加。PCA灌胃和克林霉素治疗同样增强脑Treg群,加速血肿消退,改善脑出血后神经恢复。结论:肠道菌群减少通过pca介导的Treg分化促进血肿消退和神经系统恢复。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Gut microbiota depletion accelerates hematoma resolution and neurological recovery after intracerebral hemorrhage via p-coumaric acid-promoted Treg differentiation.

Hematoma volume significantly influences the prognosis of patients with intracerebral hemorrhage (ICH). Effective resolution of hematoma through enhanced clearance mechanisms and reduced hematoma lysis is essential for neurological recovery following ICH. Regulatory T cells (Tregs), known for their anti-inflammatory properties, exert neuroprotective effects in various central nervous system disorders. Additionally, gut microbiota profoundly impacts Treg development through multiple regulatory pathways. Nonetheless, the precise roles of Tregs and gut microbiota in facilitating hematoma resolution after ICH remain unclear. This study, therefore, aimed to investigate the contributions of Tregs and gut microbiota to hematoma resolution post-ICH, as well as the underlying mechanisms. Methods: The impact of gut microbiota depletion on neurological deficits and hematoma resolution, including erythrophagocytosis and erythrocyte lysis, was assessed using antibiotic cocktail (ABX) gavage administered prior to ICH induction in mice. Flow cytometry analysis and targeted cell depletion techniques were employed to identify peripheral immune cell populations mediating the beneficial effects of gut microbiota depletion on neurological recovery and hematoma resolution. The functional roles of Tregs in erythrophagocytosis, erythrocyte lysis, and associated downstream molecular signaling pathways were investigated through adoptive Treg transfer experiments. The mechanisms underlying Treg population expansion post-microbiota depletion in ICH mice were explored using multi-omics analysis of serum and fecal metabolites via mass spectrometry and fecal microbial composition using 16S rRNA sequencing. Additionally, the effects of p-coumaric acid (PCA) gavage and clindamycin-mediated depletion of PCA-metabolizing gut microbiota on Treg abundance, hematoma resolution, and neurological recovery post-ICH were assessed. Results: Gut microbiota depletion by ABX gavage increased brain Treg populations, thereby enhancing erythrophagocytosis, suppressing erythrocyte lysis, and ultimately promoting hematoma resolution and neurological recovery. Adoptive Treg transfer experiments further established that Tregs facilitate scavenger pathway-mediated erythrophagocytosis and suppress complement-mediated erythrocyte lysis. These effects occurred via upregulation of efferocytosis receptors (MERTK and AXL), ligands (Gas6 and C1q), and the hemoglobin scavenger receptor CD163, alongside downregulation of complement C3 expression and reduced formation of membrane attack complexes (MACs). Multi-omics analysis demonstrated that ABX gavage eliminated PCA-metabolizing microbiota, thereby increasing PCA concentrations in serum and feces. Elevated PCA levels promoted peripheral Treg differentiation by inhibiting the PKCθ-AKT-FoxO1/3a signaling pathway, leading to higher brain Treg numbers. PCA gavage and clindamycin treatment similarly enhanced brain Treg populations, accelerated hematoma resolution, and improved neurological recovery following ICH. Conclusion: Gut microbiota depletion facilitates hematoma resolution and neurological recovery through PCA-mediated induction of Treg differentiation.

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来源期刊
Theranostics
Theranostics MEDICINE, RESEARCH & EXPERIMENTAL-
CiteScore
25.40
自引率
1.60%
发文量
433
审稿时长
1 months
期刊介绍: Theranostics serves as a pivotal platform for the exchange of clinical and scientific insights within the diagnostic and therapeutic molecular and nanomedicine community, along with allied professions engaged in integrating molecular imaging and therapy. As a multidisciplinary journal, Theranostics showcases innovative research articles spanning fields such as in vitro diagnostics and prognostics, in vivo molecular imaging, molecular therapeutics, image-guided therapy, biosensor technology, nanobiosensors, bioelectronics, system biology, translational medicine, point-of-care applications, and personalized medicine. Encouraging a broad spectrum of biomedical research with potential theranostic applications, the journal rigorously peer-reviews primary research, alongside publishing reviews, news, and commentary that aim to bridge the gap between the laboratory, clinic, and biotechnology industries.
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