Lymphatic remodeling and transport of dietary fats in short gut syndrome

摘要 短肠综合征（SGS）是由于手术切除了相当长的小肠， 治疗成人和儿童的多种疾病。在儿童中，与SGS相关的死亡率约为25%， 它是婴儿和儿童时期最致命的疾病之一。手术后，残余肠道的重塑 节段可以发生以达到更有利于吸收功能和存活的状态。尽管重要性 虽然淋巴管系统在脂肪吸收中的作用是非常重要的，但对于淋巴转运在SGS中如何受到影响却知之甚少。 我们的初步数据表明，淋巴管的完整性受到损害，在SGS。因为， 中央参与运输的脂肪营养物质进入主机，这是有关考虑如何淋巴管 SGS的变化可能会影响受试者的健康。脂肪肝进展为肝衰竭，或 肠衰竭相关性肝病（IFALD）是SGS患者在肠衰竭后存活的主要发病率。 切除术虽然IFALD的潜在机制尚不清楚，但实验SGS的数据表明， 微生物组和宿主TLR 4在驱动IFALD中的作用。众所周知，肠道的淋巴管系统 是长链脂肪酸以甘油三酯形式通过大分子（~1 µm）吸收到体内的途径 由肠上皮细胞包装和分泌的称为乳糜微粒的特殊脂蛋白。是 不太广泛认识到，HDL从肠道运输也可作为一种替代手段， 胆固醇和脂溶性维生素，如生育酚（维生素E），以吸收。通常，HDL 与代谢依赖性乳糜微粒途径相比，吸收途径是次要的。但这可能 疾病环境的变化。此外，尚不清楚HDL在吸收过程中如何进入宿主，但数据 强烈表明它通过非血管性途径传播，可能通过门静脉途径。如果是这样的话， 高密度脂蛋白可以作为一个关键的替代车辆的脂肪吸收期间受损的淋巴运输。 因为肝脏的大部分血液供应来自门静脉而不是肝动脉， 预期门静脉中的货物会强烈影响肝脏生理学。除了携带脂溶性 营养素、HDL和其他脂蛋白是转运微生物脂质（如TLR 4配体）的主要载体 脂多糖（LPS）。我们的初步数据表明，在SGS期间，LPS在更大程度上穿梭于 而不是淋巴。我们假设这种穿梭发生在HDL上，并驱动TLR 4依赖性的 SGS中的IFALD。如果是这样，那么一个长期的目标可能是将其路由回乳糜微粒和功能性淋巴管 网络保护肝脏为了验证肠道HDL绕过动脉进入门脉的假设， 静脉和携带LPS到肝脏，以促进IFALD，我们将利用小鼠SGS的实验模型， 解决（i）HDL是否通常绕过代谢物以动员脂溶性营养素和微生物脂质， 门静脉血（目的1），（ii）该途径是否在SGS中升高，因为淋巴完整性和运输 （iii）HDL是否是SGS中LPS运输至肝脏的关键载体（目的3）。

ABSTRACT Short gut syndrome (SGS) results from the surgical removal of a significant length of small intestine required to treat multiple conditions in adults and children. In children, the mortality associated with SGS is ~25%, making it one of the most lethal conditions in infancy and childhood. After surgery, remodeling of the remaining bowel segment can occur to reach a state more favorable to absorptive function and survival. Despite the importance of the lymphatic vasculature in fat absorption, little is known about how lymphatic transport is affected in SGS. Our preliminary data suggest that lymphatic vessel integrity is compromised in SGS. Since lymphatics are centrally involved in transport of fat nutrients into the host, it is relevant to consider how lymphatic vessel changes in SGS might affect the subject's health. The development of fatty liver progressing to liver failure, or intestinal failure-associated liver disease (IFALD), is the major morbidity in SGS patients that survive bowel resection. While mechanisms underlying IFALD remain unclear, data in experimental SGS indicate a pivotal role for the microbiome and host TLR4 in driving IFALD. It is well known that the bowel's lymphatic vasculature is the route through which long chain fatty acids are absorbed as triglycerides into the body via large (~1 µm) specialized lipoproteins called chylomicrons that are packaged and secreted by intestinal epithelial cells. It is less widely recognized that HDL trafficking from the intestine also serves as an alternative means for cholesterol and fat soluble vitamins, such as tocopherol (vitamin E), to be absorbed. Typically, the HDL pathway of absorption is minor compared to the lymphatic-dependent chylomicron pathway. However, this may change in disease settings. Moreover, it is not known how HDL enters the host during absorption, but data strongly suggest that it travels via a lymphatic-independent route, perhaps via the portal venous route. If so, HDL may serve as a key alternative vehicle for fat absorption during times of impaired lymphatic transport. Because the liver receives the majority of its blood supply from the portal vein rather than the hepatic artery, the cargo in the portal vein would be expected to strongly impact liver physiology. Besides carrying fat-soluble nutrients, HDL and other lipoproteins are major vehicles for transport of microbial lipids like the TLR4 ligand lipopolysaccharide (LPS). Our preliminary data indicate that during SGS, LPS is shuttled to a greater extent to the portal vein than to lymph. We hypothesize that this shuttling occurs on HDL and drives TLR4-dependent IFALD in SGS. If so, then a long term goal may be to route it back to chylomicrons and a functional lymphatic network to protect the liver. To test the hypothesis that intestinal HDL bypasses lymphatics to enter the portal vein and carry LPS to the liver to promote IFALD, we will utilize an experimental model of SGS in mice to address (i) whether HDL normally bypasses lymphatics to mobilize fat-soluble nutrients and microbial lipids to the portal blood (aim 1), (ii) whether this pathway is elevated in SGS because lymphatic integrity and transport is compromised (aim 2), and (iii) whether HDL is a crucial vehicle for LPS to traffic to the liver in SGS (aim 3).