Pathogenic Role of Loss of Butyrate Producing Bacteria in Immune Dysregulation and Development of Alcoholic Liver Disease (ALD)

本项目(项目2)将确定酒精引起的肠道生物失调的具体病原学特征，并调查 其在酒精性肝脏全身/肝脏免疫失调中的致病作用(及其机制) 疾病(ALD)。根据我们来自临床前和临床研究的令人信服的初步数据，我们假设 丁酸产生菌的丢失是ALD患者肠道生物失调的一个重要致病特征， 它在发展促炎T细胞-IL-17环境中发挥主要作用，导致 ALD的肠肝轴。该项目将利用一种高度创新的人类粪便微生物区系动物模型 从酒精性肝炎患者到传统小鼠的移植(FMT)概括了 人类ALD，以确定机制并开发有针对性的治疗干预措施。具体地说，该项目 将测试针对肠道生物失调的循证营养治疗策略的有效性，即(I) 三丁酸三丁酯(TB)，一种饮食丁酸酯前体药物和已知的HDAC抑制剂和(Ii)普氏杆菌 主要生产益生菌的人类丁酸盐。该提案利用了美国国立卫生研究院资助的现有资源 AlcHepNet临床联盟(U01AA026980)，包括大量ALD患者和 对照受试者、参与者招募、有效的人口学和临床数据、生物样品和生物标记物 在肝病方面的收集和临床专业知识。这项拟议的研究将为我们提供关于 ALD的潜在机制，并确定ALD治疗的新靶点，从而有助于ULARC 营养和酒精所致器官损伤的节目和主题。 该提案的具体目标是：目标1)确定丁酸酯的定性和定量损失 产生微生物群落作为酒精诱导的肠道生物失调的明确致病特征 以促炎T细胞-IL-17轴激活为代表的免疫失调 ALD，AIM 2)确定酒精诱导的丁酸产生菌的丧失对 促炎症T细胞/IL-17轴的激活和中性粒细胞在肝脏炎症/损伤中的募集 目的3)评价针对酒精所致肠道丁酸丢失的营养干预的效果。 产生菌和丁酸的产生减轻ALD肠肝轴的病原性变化。

This project (Project 2) will define specific pathogenic features of alcohol-induced gut dysbiosis and investigate its causative role (and underlying mechanisms) in systemic/hepatic immune dysregulation in alcoholic liver disease (ALD). Based on our compelling preliminary data from pre-clinical and clinical studies, we hypothesize that loss of butyrate producing bacteria is a significant pathogenic feature of gut dysbiosis in patients with ALD, which plays a major role in developing a pro-inflammatory T cell-IL-17 milieu leading to pathogenic changes in the gut-liver axis in ALD. This project will utilize a highly innovative animal model of human fecal microbiota transplant (FMT) from alcoholic hepatitis patients into conventional mice that recapitulates key features of human ALD, to identify mechanisms and develop targeted therapeutic interventions. Specifically, the project will test the efficacy of evidence-based nutritional therapeutic strategies that target gut dysbiosis, namely, (i) Tributyrin (Tb), a dietary butyrate pro-drug and known HDAC inhibitor and (ii) Faecalibacterium prausnitzi - a major human butyrate producing probiotic. The proposal leverages existing resources of the NIH funded AlcHepNet clinical consortium (U01AA026980) which include a large available cohort of ALD patients and control subjects, participant recruitment, validated demographic and clinical data, biospecimen and biomarker collection and clinical expertise in liver diseases. This proposed study will provide new insights into the mechanisms underlying ALD and identify new targets for ALD treatment, thereby contributing to the ULARC program and theme of nutrition and alcohol-induced organ injury. The specific aims of the proposal are: AIM 1) Determine the qualitative and quantitative loss of butyrate producing microbial communities as a defining pathogenic feature of alcohol-induced gut dysbiosis leading to immune dysregulation represented by the activation of the proinflammatory T cell-IL-17 axis in patients with ALD, AIM 2) Determine the causative role of alcohol-induced loss of butyrate producing bacteria on the activation of the proinflammatory T cell/IL-17 axis and neutrophil recruitment in hepatic inflammation/injury, and AIM 3) Evaluate the efficacy of nutritional interventions targeting the alcohol-induced loss of enteric butyrate producing bacteria and butyrate production in attenuating the pathogenic changes in the gut-liver axis in ALD.