The gut microbiota-brain axis has been associated with the pathogenesis of numerous disorders, but the mechanism(s) underlying these links are generally poorly understood. Accumulating evidence indicates the involvement of gut microbe-derived metabolites. Circulating levels of the gut microbe/host co-metabolite p-cresol sulfate (pCS) correlate with cerebrovascular event risk in individuals with chronic kidney disease (CKD), but whether this relationship is mechanistic is unclear. We hypothesized that pCS would impair the function of the blood-brain barrier (BBB), the primary brain vasculature interface. We report that pCS exposure impairs BBB integrity in human cells in vitro and both acutely (≤6 hours) and chronically (28 days) in mice, enhancing tracer extravasation, disrupting barrier-regulating tight junction components and ultimately exerting a suppressive effect upon whole-brain transcriptomic activity. In vitro and in vivo mechanistic studies showed that pCS activated epidermal growth factor receptor (EGFR) signaling, sequentially activating the intracellular signaling proteins annexin A1 and STAT3 to induce mobilization of matrix metalloproteinase MMP-2/9 and disruption to the integrity of the BBB. This effect was confirmed as specific to the EGFR through the use of both pharmacological and RNA interference approaches. Confirming the translational relevance of this work, exposure of the cerebromicrovascular endothelia to serum from hemodialysis patients in vitro led to a significant increase in paracellular permeability, with the magnitude of permeabilization closely correlating with serum pCS, but not most other uremic toxin, content. Notably, this damaging effect of hemodialysis patient serum was prevented by pharmacological blockade of the EGFR. Our results define a pathway linking the co-metabolite pCS with BBB damage and suggest that targeting the EGFR may mitigate against cerebrovascular damage in CKD. This work further provides mechanistic evidence indicating the role of gut microbe-derived metabolites in human disease.

中文翻译：

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由肠道微生物/宿主共代谢物硫酸对甲酚引起的脑血管损伤可通过阻断 EGF 受体来防止。


肠道菌群-脑轴与许多疾病的发病机制有关，但这些联系背后的机制通常知之甚少。越来越多的证据表明肠道微生物衍生的代谢物参与其中。肠道微生物/宿主共代谢物硫酸对甲酚 （pCS） 的循环水平与慢性肾病 （CKD） 个体的脑血管事件风险相关，但这种关系是否是机制性的尚不清楚。我们假设 pCS 会损害血脑屏障 （BBB） 的功能，BBB 是主要的脑血管界面。我们报道，pCS 暴露在体外以及小鼠急性 （≤6 小时） 和慢性 （28 天） 都会损害人细胞中 BBB 的完整性，增强示踪剂外渗，破坏屏障调节紧密连接成分，并最终对全脑转录组活性产生抑制作用。体外和体内机制研究表明，pCS 激活表皮生长因子受体 （EGFR） 信号传导，依次激活细胞内信号蛋白膜联蛋白 A1 和 STAT3 以诱导基质金属蛋白酶 MMP-2/9 的动员并破坏 BBB 的完整性。通过使用药理学和 RNA 干扰方法，这种效应被证实为 EGFR 的特异性。证实了这项工作的转化相关性，脑微血管内皮细胞在体外暴露于血液透析患者的血清中导致细胞旁通透性显着增加，透化程度与血清 pCS 密切相关，但与大多数其他尿毒症毒素含量无关。值得注意的是，血液透析患者血清的这种破坏性作用是通过 EGFR 的药物阻断来防止的。 我们的结果定义了将共代谢物 pCS 与 BBB 损伤联系起来的途径，并表明靶向 EGFR 可能会减轻 CKD 中的脑血管损伤。这项工作进一步提供了机制证据，表明肠道微生物衍生的代谢物在人类疾病中的作用。