PDF(Pubmed)
Abstract：
Intestinal disease is one of the earliest manifestations of cystic fibrosis (CF) in children and is closely tied to deficits in growth and nutrition, both of which are directly linked to future mortality. Patients are treated aggressively with pancreatic enzyme replacement therapy and a high-fat diet to circumvent fat malabsorption, but this does not reverse growth and nutritional defects. We hypothesized that defects in chylomicron production could explain why CF body weights and nutrition are so resistant to clinical treatments. We used gold standard intestinal lipid absorption and metabolism approaches, including mouse mesenteric lymph cannulation, in vivo chylomicron secretion kinetics, transmission electron microscopy, small intestinal organoids, and chylomicron metabolism assays to test this hypothesis. In mice expressing the G542X mutation in cystic fibrosis transmembrane conductance regulator (CFTR-/- mice), we find that defective FFA trafficking across the epithelium into enterocytes drives a chylomicron formation defect. Furthermore, G542X mice secrete small, triglyceride-poor chylomicrons into the lymph and blood. These defective chylomicrons are cleared into extraintestinal tissues at ∼10-fold faster than WT chylomicrons. This defect in FFA absorption resulting in dysfunctional chylomicrons cannot be explained by steatorrhea or pancreatic insufficiency and is maintained in primary small intestinal organoids treated with micellar lipids. These studies suggest that the ultrahigh-fat diet that most people with CF are counselled to follow may instead make steatorrhea and malabsorption defects worse by overloading the absorptive capacity of the CF small intestine.
摘要：
肠道疾病是儿童囊性纤维化（CF）的最早表现之一，与生长和营养缺陷密切相关。两者都与未来的死亡率直接相关。患者积极接受胰酶替代疗法和高脂肪饮食以避免脂肪吸收不良，但这并不能逆转生长和营养缺陷。我们假设乳糜微粒产生的缺陷可以解释为什么CF体重和营养对临床治疗如此耐药。我们使用金标准肠道脂质吸收和代谢方法，包括小鼠肠系膜淋巴插管,体内乳糜微粒分泌动力学，透射电子显微镜,小肠类器官，和乳糜微粒代谢试验来检验这一假设。在囊性纤维化跨膜传导调节因子（CFTR-/-小鼠）中表达G542X突变的小鼠中，我们发现，有缺陷的FFA通过上皮进入肠上皮细胞驱动乳糜微粒形成缺陷。此外，G542X小鼠分泌小，缺乏甘油三酯的乳糜微粒进入淋巴和血液。这些有缺陷的乳糜微粒在肠外组织中的清除速度比WT乳糜微粒快10倍。这种导致功能失调的乳糜微粒的FFA吸收缺陷不能用脂肪泻或胰腺功能不全来解释，并且在用胶束脂质治疗的原发性小肠类器官中得以维持。这些研究表明，建议大多数CF患者遵循的超高脂饮食可能会使CF小肠的吸收能力过重，从而使脂肪泻和吸收不良恶化。
