Intestinal Resection Associated Liver Injury and Fibrosis

小肠切除相关的肝损伤和纤维化

• 批准号: 10366528
• 负责人: Nicholas O. Davidson
• 金额: $ 58.72万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-30 至 2025-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10366528
• 关键词: Adult; Child; Child Mortality; Childhood; Cholestasis; Chylomicrons; Cirrhosis; Comprehensive Health Care; Cytoplasmic Protein; Development; Dietary Fats; Dyslipidemias; Enteral; Enteral Feeding; Enterocytes; Etiology; Excision; Failure; Fibrosis; Gene Expression; Generations; Genomics; Goals; Hepatic; Hepatitis; Human; Impairment; Incidence; Inflammation; Injury; Insulin Resistance; Intestinal permeability; Intestines; Length; Lipids; Liver; Liver Fibrosis; Liver diseases; Membrane; Metabolic syndrome; Morbidity - disease rate; Mus; Necrosis; Nodule; Non-Insulin-Dependent Diabetes Mellitus; Nonesterified Fatty Acids; Obesity; Omega-3 Fatty Acids; Omega-6 Fatty Acids; Parenteral Nutrition; Pathogenesis; Pathway interactions; Patients; Primary carcinoma of the liver cells; Procedures; Production; Proteins; Reactive Oxygen Species; Resected; Role; Sepsis; Short Bowel Syndrome; Signal Transduction; Signaling Molecule; Site; Small Intestines; Structure; Survivors; TLR4 gene; Time; Transplantation; Venous; absorption; cytokine; economic impact; endoplasmic reticulum stress; infancy; insight; lipid biosynthesis; lipidomics; liver injury; long chain fatty acid; metabolomics; mitochondrial dysfunction; mortality; mouse model; non-alcoholic fatty liver disease; nonalcoholic steatohepatitis; novel; novel therapeutics; pediatric patients; regenerative; response; transcription factor

Short gut syndrome (SGS) results from the treatment of multiple conditions in adults and children. In children, the mortality associated with SGS is roughly 25%, making it one of the most lethal conditions in infancy and childhood. Morbidity among survivors is high with another 25% of children requiring a small bowel transplant. The current 5-year patient survival following a small bowel transplant is still roughly 58%. Intestinal failure associated liver disease (IFALD) represents a spectrum of liver injury including steatosis, cholestasis, fibrosis, and cirrhosis. IFALD is the leading indication for intestinal and/or multivisceral transplantation in children with SGS. The incidence of IFALD is roughly 50% in pediatric patients who receive parenteral nutrition (PN). The pathogenesis of IFALD is unique because SGS patients are enterally starved, have no insulin resistance, and are not obese. Using a PN-independent murine model of small bowel resection (SBR), we demonstrate perturbed gut barrier function and significant alterations in intestinal lipid signaling, severe hepatitis, cholestasis, necrosis, and regenerative nodules. In one mouse, we confirmed the development of HCC. Accordingly, our overarching hypothesis is that IFALD reflects a proinflammatory milieu within the remnant bowel along with profound alterations in lipid signaling within both intestine and liver to initiate hepatic injury, fibrosis, and ultimate progression to advanced liver injury. For this project, we have developed a multiple-PI proposal embracing world class expertise in intestinal adaptation responses to massive SBR (Warner/Rubin), intestinal and hepatic lipid signaling (Davidson) and genomics and metabolomics (Ding). In the first Specific Aim, we will focus on the intestinal contribution to liver injury and fibrosis. First, genetically altered mice will undergo SBR to determine the effect of impaired intestinal chylomicron assembly, disrupted intestinal expression of a major transcription factor involved with lipid sensing and signaling, and perturbed expression of an enterocyte cytoplasmic protein involved with absorption of long chain fatty acids on liver injury. We will then delineate the effects of varied dietary fat on liver injury, intestinal permeability, and portal venous cytokine production. Finally, we will determine the most important intestinal site of toll-like receptor 4 (TLR4) activity in the pathogenesis of altered gut permeability and resection-associated liver injury. The next Specific Aim will focus on the hepatic component of injury, steatosis, and fibrosis after SBR. We will delineate a temporal profile of lipidomic and lipogenic gene expression within the liver at multiple time points after SBR. We will determine whether alteration of the omega-6 to omega-3 ratio as well as disrupted expression of a major regulator of lipid synthesis contributes to advanced liver injury. Finally, we will elucidate a genomic and metabolomic profile in the liver of evolving liver injury in mice as well as in human patients with end stage IFALD. These findings may provide novel mechanistic insight into the etiology of IFALD.

短肠道综合征（SGS）是由于对成人和儿童多种疾病的治疗而产生的。在儿童中，与SG相关的死亡率约为25％，使其成为婴儿期和童年最致命的状况之一。幸存者的发病率很高，另外25％的儿童需要小肠移植。小肠移植后目前的5年患者存活率仍然约为58％。肠道衰竭相关的肝病（Ifald）代表了一系列肝损伤，包括脂肪变性，胆汁淤积，纤维化和肝硬化。 ifald是SGS儿童的肠道和/或多人移植的主要指标。接受肠胃外营养（PN）的小儿患者的IFALD的发生率约为50％。 Ifald的发病机理是独一无二的，因为SGS患者始终饿死，没有胰岛素抵抗，也不肥胖。使用无独立的小肠切除鼠模型（SBR），我们证明了肠道屏障功能的扰动和肠脂质信号传导，严重的肝炎，胆汁淤积，坏死和再生结节的显着改变。在一只鼠标中，我们确认了HCC的发展。因此，我们的总体假设是，ifald反映了残留肠内的促炎环境，以及肠道和肝脏内脂质信号的深刻变化，以引发肝损伤，纤维化，纤维化，最终向晚期肝损伤发展。对于这个项目，我们开发了一项多重PI建议，该建议在对大规模SBR（Warner/Rubin），肠道和肝脂质信号（Davidson）以及基因组学和代谢组学（DING）方面的肠道适应反应方面提供了世界一流的专业知识。在第一个特定目的中，我们将重点关注对肝损伤和纤维化的肠道贡献。首先，遗传改变的小鼠将经历SBR，以确定肠道乳糜微粒构成受损的影响，肠道传感和信号传导涉及的主要转录因子的肠道表达破坏，以及与长链脂肪酸吸收对植物脂肪损伤的吸收有关的肠细胞细胞质蛋白所涉及的表达。然后，我们将描述各种饮食脂肪对肝损伤，肠道渗透性和门静脉细胞因子产生的影响。最后，我们将确定肠道渗透性改变和与切除相关的肝损伤的发病机理中，类似受体4（TLR4）活性的最重要的肠部位。下一个特定目标将集中于SBR后损伤，脂肪变性和纤维化的肝脏成分。我们将在SBR后多个时间点描绘肝脏中脂质组和脂肪生成基因表达的时间谱。我们将确定omega-6与omega-3比的改变以及脂质合成主要调节剂的表达是否有助于晚期肝损伤。最后，我们将阐明小鼠肝损伤以及IFALD终阶段患者的肝损伤肝脏的基因组和代谢组学特征。这些发现可能会提供对Ifald病因的新机械洞察力。