The role of intestinal gp130 in alcohol-associated liver disease

项目摘要/摘要 酒精使用障碍最突出的后果是酒精相关性肝病(ALD)。酒精 滥用与肠道生物失调、细菌过度生长、肠道通透性增加和细菌 移位到肝脏，促进肝脏炎症。这对肝脏的侮辱，加剧了ALD。内脏-肝脏 AXIS在ALD的发病机制中起着至关重要的作用。在这个轴线内，肠道微生物区系组成， 粘膜免疫系统和肠道特化细胞是最基本的调节细胞。这些组件是 在阿尔茨海默病期间受到干扰。饮酒减少白介素22先天分泌型3型 淋巴样细胞(ILC3)。IL-22导致抗菌再生胰岛衍生蛋白3(REG3)的产生 凝集素介导的信号转导和转录激活因子3(STAT3)信号转导通路 肠子。抗菌剂REG3凝集素调节肠道微生物组成和预防细菌 易位。乙醇喂养小鼠小肠和十二指肠中REG3凝集素的表达减少 酒精使用障碍(AUD)患者的比例。因此，我们假设恢复表达的 肠道REG3凝集素是治疗ALD的有效药物。 STAT3-REG3轴的磷酸化也通过激活IL-6信号转导而发生 (IL6ST/gp130)共受体。我们初步确定了过度活跃的肠道gp130对小鼠的保护作用。 乙醇诱导的小鼠肝病。Gp130信号通路通过四种不同的信号转导途径 途径，其中最突出的是gp130-STAT3途径。因此，我们的目标是定义准确的 Gp130对酒精性肝病预防作用的信号转导盒 并将工程gp130受体配体的使用定义为一种新的翻译干预策略 来预防ALD。 为了探索提出的假设，目标1将调查gp130-STAT3-REG3信号盒是否 参与预防酒精性肝病。这一方法建议使用乙醇喂养的 小鼠过表达活跃的肠道gp130，但具有肠道STAT3的特异性缺失。它将评估这一角色 Gp130-STAT3-REG3轴在预防乙醇介导的微生物区系组成失调中的作用 肠道通透性、细菌移位至肝脏和脂肪性肝炎。目标2将定义是否使用 一种新的工程嵌合gp130配体作为预防酒精性肝病的有效疗法 在小鼠中进行临床前试验，并在来自AUD患者的人小肠有机化合物中测试其肠道效应。 这项拟议的研究将表征gp130-STAT3-REG3轴在乙醇临床前模型中的作用。 在酒精使用障碍患者中使用尖端微生物学和最新研究进展 艺术技术。拟议的干预措施将找到预防酒精相关性肝脏的创新策略 病人中的疾病。

Project Summary/Abstract The most prominent consequence of alcohol use disorder is alcohol-associated liver disease (ALD). Alcohol abuse is associated with intestinal dysbiosis, bacterial overgrowth, increased gut permeability, and bacterial translocation to the liver, promoting liver inflammation. This insult to the liver, exacerbates ALD. The gut-liver axis plays a crucial role on the pathogenesis of ALD. Within this axis the intestinal microbiota composition, the mucosal immune system and intestinal specialized cells are fundamental regulators. These components are disturbed during ALD. Alcohol consumption decreases the pool of interleukin (IL)-22 secreting type 3 innate lymphoid cells (ILC3). IL-22 leads to the production of antimicrobial regenerating islet-derived protein 3 (REG3) lectins mediated by activation of the signal transducer and activator of transcription 3 (STAT3) signaling in the intestine. Antimicrobial REG3 lectins regulate the intestinal microbial composition and prevent from bacterial translocation. Expression of REG3 lectins is reduced in small intestines of ethanol-fed mice and in the duodenum of patients with alcohol use disorder (AUD). Therefore, we hypothesize that restoring the expression of intestinal REG3 lectins would be an effective therapy for patients with ALD. Phosphorylation of STAT3-REG3 axis also occurs through activation of the IL-6 signal transducer (IL6ST/gp130) coreceptor. We preliminarily determined the protective role of overactive intestinal gp130 in ethanol-induced liver disease in mice. gp130 pathway signals through four different signaling transduction pathways, among them the most prominent is gp130-STAT3 pathway. Hence, we aim to define the exact signaling transduction cassette involved in the preventive role of gp130 in ethanol-induced liver disease and define the use of an engineered gp130 receptor ligand as a novel translational interventional strategy to prevent ALD. To explore the proposed hypothesis, aim 1 will investigate whether gp130-STAT3-REG3 signaling cassette is involved in the prevention against ethanol-induced liver disease. This approach proposes to use ethanol-fed mice overexpressing active intestinal gp130 but with specific deletion of intestinal STAT3. It will assess the role of gp130-STAT3-REG3 axis in the prevention of ethanol-mediated dysregulation of microbiota composition, intestinal permeability, bacterial translocation to the liver, and steatohepatitis. Aim 2 will define whether the use of a novel engineered chimeric gp130 ligand is effective as a therapy to prevent ethanol-induced liver disease preclinically in mice and test its intestinal effects in human small intestinal organoids from AUD patients. The proposed study will characterize the role of gp130-STAT3-REG3 axis in preclinical models of ethanol- induced liver disease and in patients with alcohol use disorder using cutting edge microbiomics and state-of-the- art technology. The proposed intervention will find innovative strategies to prevent alcohol-associated liver disease in patients.