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，而这两者都与未来的死亡率直接相关。患者接受胰酶替代疗法和高脂肪饮食的积极治疗，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 的体重和营养对临床治疗如此抵抗。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测定来检验这一假设。在囊性纤维化跨膜电导调节因子表达 G542X 突变的小鼠（CFTR-/- 小鼠）中，我们发现有缺陷的 FFA 穿过上皮进入肠细胞会导致乳糜微粒形成缺陷。此外，G542X 小鼠将小的、缺乏甘油三酯的乳糜微粒分泌到淋巴和血液中。这些有缺陷的乳糜微粒被清除到肠外组织的速度比 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，并且在用胶束脂质处理的原代小肠类器官中得以维持。这些研究表明，建议大多数 CF 患者遵循的超高脂肪饮食可能会使 CF 小肠的吸收能力超载，从而使脂肪泻和吸收不良缺陷变得更严重。版权所有 © 2024 作者。由爱思唯尔公司出版。保留所有权利。

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.Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.