Lymphatic remodeling and transport of dietary fats in short gut syndrome

短肠综合征中的淋巴重塑和膳食脂肪运输

• 批准号: 10579922
• 负责人: Gwendalyn J Randolph
• 金额: $ 43.65万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-03-01 至 2024-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10579922
• 关键词: ATP binding cassette transporter 1; Address; Adult; Affect; Apolipoprotein A-I; Automobile Driving; Back; Blood; Bypass; Cannulations; Cells; Child; Childhood; Cholesterol; Chylomicrons; Complement; Data; Development; Diet; Dietary Fats; Disease; Epithelial Cells; Excision; Experimental Models; Failure; Fat-Soluble Vitamin; Fatty Liver; Fatty acid glycerol esters; Goals; Health; Hepatic artery; High Density Lipoproteins; Infant; Interruption; Intestinal Secretions; Intestines; Length; Ligands; Light; Link; Lipids; Lipopolysaccharides; Lipoproteins; Liver; Liver Failure; Liver diseases; Lymph; Lymphatic; Lymphatic System; Mesentery; Metabolic; Minor; Molecular; Morbidity - disease rate; Movement; Mus; Necrotizing Enterocolitis; Nutrient; Operative Surgical Procedures; Outcome; Pathway interactions; Patients; Physiology; Portal vein structure; Production; Publishing; Rest; Role; Route; Short Bowel Syndrome; Shunt Device; Signal Transduction; Site; Small Intestines; Structure; TLR4 gene; Testing; Tissues; Tocopherols; Travel; Triglycerides; Vascular blood supply; Venous; absorption; fatty liver disease; follow-up; improved; infancy; long chain fatty acid; lymphatic circulation; lymphatic dysfunction; lymphatic vasculature; lymphatic vessel; meter; microbial; microbiome; mortality; novel; response; trafficking

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).

摘要 短肠综合征(SGS)是由外科手术切除的大量小肠引起的 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%，使 这是婴儿期和儿童期最致命的疾病之一。手术后，剩余的肠管重塑 节段可出现更有利于吸收功能和生存的状态。尽管重要的是 在脂肪吸收的淋巴管系统中，关于淋巴运输在SGS中是如何受到影响的，我们知之甚少。 我们的初步数据表明，SGS患者淋巴管完整性受损。因为淋巴管是 中枢参与脂肪营养物质的运输进入宿主，考虑淋巴管是如何相关的 SGS的变化可能会影响受试者的健康。脂肪肝进展为肝功能衰竭，或 肠衰竭相关性肝病(IFALD)是存活于肠道的SGS患者的主要发病率。 切除手术。虽然IFALD背后的机制尚不清楚，但实验性SGS的数据表明， 微生物组和宿主TLR4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的形式通过大(~1微米)吸收进入体内的途径 被称为乳糜粒的特殊脂蛋白由肠道上皮细胞包装和分泌。它是 不太广泛地认识到，从肠道运输高密度脂蛋白也是一种替代手段 胆固醇和脂溶维生素，如生育酚(维生素E)，需要吸收。通常，高密度脂蛋白 与淋巴依赖的乳糜粒途径相比，吸收途径较小。然而，这可能会 疾病环境的变化。此外，目前还不知道高密度脂蛋白在吸收过程中是如何进入宿主的，但数据 强烈提示它是通过淋巴不依赖的途径传播的，可能是门静脉途径。如果是的话， 在淋巴运输受损的时期，高密度脂蛋白可能是脂肪吸收的关键替代载体。 因为肝脏的大部分血液供应来自门静脉，而不是肝动脉， 预计门静脉中的货物将对肝脏生理产生强烈影响。除了携带脂溶的 营养素、高密度脂蛋白和其他脂蛋白是微生物脂类的主要运输工具，如TLR4配体 脂多糖(LPS)。我们的初步数据表明，在SGS期间，内毒素在更大程度上穿梭于 门静脉比淋巴多。我们假设这种穿梭发生在高密度脂蛋白上并驱动依赖于TLR4的驱动器 SGS中的IFALD。如果是这样的话，那么一个长期的目标可能是把它送回乳糜粒和功能正常的淋巴管 保护肝脏的网络。为了验证肠道高密度脂蛋白绕过淋巴管进入门静脉的假设 静脉和携带内毒素到肝脏促进IFALD，我们将利用SGS的小鼠实验模型来 解决(I)高密度脂蛋白是否通常绕过淋巴管动员脂溶营养素和微生物脂类来 门静脉血液(目标1)，(Ii)这一途径在SGS中是否升高，因为淋巴的完整性和运输 是否受到损害(目标2)，以及(Iii)高密度脂蛋白是否是脂多糖在SGS中进入肝脏的关键载体(目标3)。