Cerebral cavernous malformation (CCM) is a genetic, cerebrovascular disease. Familial CCM is caused by genetic mutations in KRIT1, CCM2, or PDCD10 Disease onset is earlier and more severe in individuals with PDCD10 mutations. Recent studies have shown that lesions arise from excess mitogen-activated protein kinase kinase kinase 3 (MEKK3) signaling downstream of Toll-like receptor 4 (TLR4) stimulation by lipopolysaccharide derived from the gut microbiome. These findings suggest a gut-brain CCM disease axis but fail to define it or explain the poor prognosis of patients with PDCD10 mutations. Here, we demonstrate that the gut barrier is a primary determinant of CCM disease course, independent of microbiome configuration, that explains the increased severity of CCM disease associated with PDCD10 deficiency. Chemical disruption of the gut barrier with dextran sulfate sodium augments CCM formation in a mouse model, as does genetic loss of Pdcd10, but not Krit1, in gut epithelial cells. Loss of gut epithelial Pdcd10 results in disruption of the colonic mucosal barrier. Accordingly, loss of Mucin-2 or exposure to dietary emulsifiers that reduce the mucus barrier increases CCM burden analogous to loss of Pdcd10 in the gut epithelium. Last, we show that treatment with dexamethasone potently inhibits CCM formation in mice because of the combined effect of action at both brain endothelial cells and gut epithelial cells. These studies define a gut-brain disease axis in an experimental model of CCM in which a single gene is required for two critical components: gut epithelial function and brain endothelial signaling.

中文翻译：

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PDCD10 的不同细胞作用定义了脑海绵状血管畸形中的肠-脑轴。

脑海绵状血管畸形 (CCM) 是一种遗传性脑血管疾病。家族性 CCM 是由 KRIT1、CCM2 或 PDCD10 中的基因突变引起的 在具有 PDCD10 突变的个体中，疾病发作更早且更严重。最近的研究表明，病变是由来自肠道微生物组的脂多糖刺激 Toll 样受体 4 (TLR4) 下游的过量丝裂原活化蛋白激酶激酶激酶 3 (MEKK3) 信号引起的。这些发现提示肠-脑 CCM 疾病轴，但未能对其进行定义或解释 PDCD10 突变患者的不良预后。在这里，我们证明肠道屏障是 CCM 病程的主要决定因素，与微生物组配置无关，这解释了与 PDCD10 缺乏相关的 CCM 疾病的严重程度增加。在小鼠模型中，用葡聚糖硫酸钠化学破坏肠道屏障会增强 CCM 的形成，肠道上皮细胞中 Pdcd10 而非 Krit1 的遗传缺失也是如此。肠道上皮 Pdcd10 的缺失会导致结肠粘膜屏障的破坏。因此，Mucin-2 的缺失或暴露于降低粘液屏障的膳食乳化剂会增加 CCM 负担，类似于肠道上皮细胞中 Pdcd10 的缺失。最后，我们表明，由于对脑内皮细胞和肠上皮细胞的联合作用，地塞米松治疗可有效抑制小鼠 CCM 的形成。这些研究在 CCM 的实验模型中定义了肠-脑疾病轴，其中两个关键成分需要单个基因：肠上皮功能和脑内皮信号传导。