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.

短肠综合症 (SGS) 是由成人和儿童的多种疾病治疗引起的。在儿童中，SGS 相关的死亡率约为 25%，使其成为婴儿期和儿童期最致命的疾病之一。幸存者的发病率很高，另外 25% 的儿童需要小肠移植。目前小肠移植后患者的 5 年生存率仍约为 58%。肠衰竭相关性肝病（IFALD）代表一系列肝损伤，包括脂肪变性、胆汁淤积、纤维化和肝硬化。 IFALD 是 SGS 儿童肠道和/或多脏器移植的主要适应症。在接受肠外营养 (PN) 的儿科患者中，IFALD 的发生率约为 50%。 IFALD 的发病机制很独特，因为 SGS 患者肠内饥饿、无胰岛素抵抗且不肥胖。使用不依赖 PN 的小肠切除 (SBR) 小鼠模型，我们证明了肠道屏障功能受到干扰，并且肠道脂质信号传导、严重肝炎、胆汁淤积、坏死和再生结节发生显着改变。在一只小鼠中，我们证实了 HCC 的发展。因此，我们的总体假设是，IFALD 反映了残余肠内的促炎环境以及肠和肝脏内脂质信号传导的深刻改变，从而引发肝损伤、纤维化并最终进展为晚期肝损伤。对于这个项目，我们制定了一项多 PI 提案，其中包含对大规模 SBR 的肠道适应反应 (Warner/Rubin)、肠道和肝脏脂质信号传导 (Davidson) 以及基因组学和代谢组学 (Ding) 方面的世界级专业知识。在第一个具体目标中，我们将重点关注肠道对肝损伤和纤维化的影响。首先，基因改造小鼠将接受 SBR，以确定肠道乳糜微粒组装受损、与脂质传感和信号传导有关的主要转录因子的肠道表达被破坏，以及与长链脂肪酸吸收有关的肠细胞胞质蛋白的表达扰乱对肝损伤的影响。然后我们将描述不同膳食脂肪对肝损伤、肠道通透性和门静脉细胞因子产生的影响。最后，我们将确定 Toll 样受体 4 (TLR4) 活性在肠道通透性改变和切除相关肝损伤发病机制中最重要的肠道位点。下一个具体目标将重点关注 SBR 后损伤、脂肪变性和纤维化的肝脏成分。我们将描绘 SBR 后多个时间点肝脏内脂质组和脂肪生成基因表达的时间概况。我们将确定 omega-6 与 omega-3 比例的改变以及脂质合成主要调节因子表达的破坏是否会导致晚期肝损伤。最后，我们将阐明小鼠以及终末期 IFALD 患者肝损伤演变过程中肝脏的基因组和代谢组学特征。这些发现可能为 IFALD 的病因学提供新的机制见解。