Intestinal Resection Associated Liver Injury and Fibrosis

短肠综合征（SGS）是由成人和儿童多种疾病的治疗引起的。在儿童中，与SGS相关的死亡率约为25%，使其成为婴儿和儿童最致命的疾病之一。幸存者的死亡率很高，另有25%的儿童需要小肠移植。目前，小肠移植后5年的患者生存率仍约为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的发病机制是独特的，因为SGS患者是肠饥饿的，没有胰岛素抵抗，也不肥胖。使用PN-独立的小鼠模型小肠切除术（SBR），我们表现出肠道屏障功能紊乱和肠道脂质信号，严重肝炎，胆汁淤积，坏死和再生结节的显着改变。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反映了残留肠沿着肠和肝内脂质信号传导的深刻改变的促炎环境，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，我们已经开发了一个多PI的建议，包括世界一流的专业知识，肠道适应反应，大规模SBR（华纳/鲁宾），肠道和肝脏脂质信号（戴维森）和基因组学和代谢组学（丁）。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贡献。首先，基因改变的小鼠将经历SBR以确定受损的肠乳糜微粒组装、参与脂质传感和信号传导的主要转录因子的破坏的肠表达以及参与长链脂肪酸吸收的肠细胞胞质蛋白的扰动表达对肝损伤的影响。然后，我们将描述不同的膳食脂肪对肝损伤，肠通透性，和门静脉细胞因子的生产的影响。最后，我们将确定Toll样受体4（TLR 4）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部位。下一个具体目标将集中在SBR后损伤，脂肪变性和纤维化的肝脏成分。我们将描述SBR后多个时间点肝脏内脂质组学和脂肪生成基因表达的时间分布。我们将确定ω-6与ω-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有助于晚期肝损伤。最后，我们将阐明基因组学和代谢组学在肝脏中的演变肝损伤小鼠以及人类患者的终末期IFALD。这些发现可能为IFALD的病因学提供新的机制见解。

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.