Department of Health and Human Services, National Institutes of Health, Eunice Kennedy Shriver National Institute of Child Health and Human Development, Bethesda, MD, 20892, USA.
Department of Health and Human Services, National Institutes of Health, National Institute of Arthritis and Musculoskeletal and Skin Diseases, Bethesda, MD, 20892, USA.
Dig Dis Sci. 2018 Apr;63(4):870-880. doi: 10.1007/s10620-018-4914-x. Epub 2018 Jan 22.
Niemann-Pick disease, type C (NPC) is a rare lysosomal storage disorder characterized by progressive neurodegeneration, splenomegaly, hepatomegaly, and early death. NPC is caused by mutations in either the NPC1 or NPC2 gene. Impaired NPC function leads to defective intracellular transport of unesterified cholesterol and its accumulation in late endosomes and lysosomes. A high frequency of Crohn disease has been reported in NPC1 patients, suggesting that gastrointestinal tract pathology may become a more prominent clinical issue if effective therapies are developed to slow the neurodegeneration. The Npc1 mouse model on a BALB/c background replicates the hepatic and neurological disease observed in NPC1 patients. Thus, we sought to characterize the gastrointestinal tract pathology in this model to determine whether it can serve as a model of Crohn disease in NPC1.
We analyzed the gastrointestinal tract and isolated macrophages of BALB/cJ cNctr-Npc1m1N/J (Npc1) mouse model to determine whether there was any Crohn-like pathology or inflammatory cell activation. We also evaluated temporal changes in the microbiota by 16S rRNA sequencing of fecal samples to determine whether there were changes consistent with Crohn disease.
Relative to controls, Npc1 mutant mice demonstrate increased inflammation and crypt abscesses in the gastrointestinal tract; however, the observed pathological changes are significantly less than those observed in other Crohn disease mouse models. Analysis of Npc1 mutant macrophages demonstrated an increased response to lipopolysaccharides and delayed bactericidal activity; both of which are pathological features of Crohn disease. Analysis of the bacterial microbiota does not mimic what is reported in Crohn disease in either human or mouse models. We did observe significant increases in cyanobacteria and epsilon-proteobacteria. The increase in epsilon-proteobacteria may be related to altered cholesterol homeostasis since cholesterol is known to promote growth of this bacterial subgroup.
Macrophage dysfunction in the BALB/c Npc1 mouse is similar to that observed in other Crohn disease models. However, neither the degree of pathology nor the microbiota changes are typical of Crohn disease. Thus, this mouse model is not a good model system for Crohn disease pathology reported in NPC1 patients.
尼曼-匹克病 C 型（NPC）是一种罕见的溶酶体贮积症，其特征为进行性神经退行性变、脾肿大、肝肿大和早亡。NPC 由 NPC1 或 NPC2 基因突变引起。NPC 功能受损导致未酯化胆固醇的细胞内转运缺陷，并在晚期内体和溶酶体中蓄积。NPC1 患者中经常报告克罗恩病，这表明如果开发出有效的治疗方法来减缓神经退行性变，那么胃肠道病理学可能成为更突出的临床问题。在 BALB/c 背景下的 Npc1 小鼠模型复制了 NPC1 患者中观察到的肝和神经疾病。因此，我们试图对该模型的胃肠道病理学进行表征，以确定其是否可以作为 NPC1 中克罗恩病的模型。
我们分析了 BALB/cJ cNctr-Npc1m1N/J（Npc1）小鼠模型的胃肠道和分离的巨噬细胞，以确定是否存在类似克罗恩病的病理学或炎症细胞激活。我们还通过粪便样本的 16S rRNA 测序评估了微生物组的时间变化，以确定是否存在与克罗恩病一致的变化。
与对照组相比，Npc1 突变小鼠的胃肠道炎症和隐窝脓肿增加；然而，观察到的病理变化明显小于其他克罗恩病小鼠模型。Npc1 突变巨噬细胞分析表明对脂多糖的反应增加和杀菌活性延迟；这两者都是克罗恩病的病理特征。细菌微生物组的分析与人类或小鼠模型中报告的克罗恩病都不相似。我们确实观察到蓝细菌和 epsilon-变形菌的显著增加。epsilon-变形菌的增加可能与胆固醇稳态的改变有关，因为胆固醇已知可促进该细菌亚群的生长。
BALB/c Npc1 小鼠中的巨噬细胞功能障碍与其他克罗恩病模型观察到的相似。然而，无论是病理学的程度还是微生物组的变化都不是克罗恩病的典型特征。因此，这种小鼠模型不是 NPC1 患者报告的克罗恩病病理学的良好模型系统。
