Intestinal Resection Associated Liver Injury and Fibrosis

短肠综合征(SGS)是成人和儿童多种疾病治疗的结果。在儿童中，与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，另有25%的儿童需要小肠移植。目前，小肠移植后患者的5年存活率仍约为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、纤维化和肝硬变。IFALD是SGS患儿进行肠道和/或多脏器移植的主要适应症。在接受肠外营养(PN)的儿童患者中，IFALD的发生率约为50%。IFALD的发病机制是独特的，因为SGS患者是肠道饥饿的，没有胰岛素抵抗，也不肥胖。使用非PN依赖的小鼠小肠切除(SBR)模型，我们发现肠道屏障功能受到干扰，肠道脂质信号发生显著变化，出现重型肝炎、胆汁淤积、坏死和再生结节。在一只小鼠身上，我们证实了肝细胞癌的发生。因此，我们的总体假设是，IFALD反映了残肠内的促炎环境以及肠和肝脏内脂质信号的深刻变化，从而启动了肝损伤、纤维化，并最终发展为晚期肝损伤。对于这个项目，我们开发了一个多PI方案，包含了大规模SBR(Warner/Rubin)、肠道和肝脏脂质信号转导(Davidson)以及基因组和代谢组学(Ding)的肠道适应反应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贡献。首先，转基因小鼠将接受SBR，以确定肠道乳糜粒组装受损、与脂质感应和信号转导有关的主要转录因子在肠道中的表达受到干扰，以及与长链脂肪酸吸收有关的肠细胞质蛋白在肝脏损伤中的表达受到干扰。然后，我们将描述不同饮食脂肪对肝脏损伤、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上。我们将描绘SBR后多个时间点肝脏内脂类和成脂基因表达的时间分布。我们将确定omega-6和omega-3比率的改变以及脂质合成的主要调节因子的表达中断是否有助于进展性肝损伤。最后，我们将阐明小鼠和人类终末期IFALD患者肝脏进行性肝损伤的基因组和代谢概况。这些发现可能为IFALD的病因提供新的机制洞察力。

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.