The role of intestine in metabolic dysregulation in murine Wilson disease.
The role of intestine in metabolic dysregulation in murine Wilson disease.
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DOI：
10.1097/hc9.0000000000000247
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发表时间：
2023-10-01
影响因子：
5.1
通讯作者：
中科院分区：
文献类型：
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肝豆状核变性(WD)的临床表现与铜在肝脏和脑中的蓄积有关，但对WD中其他组织的代谢变化知之甚少。体外研究表明，肠道ATP7B的缺失影响WD的代谢失调。我们通过评估两种WD小鼠模型的肠道微生物区系和脂体，以及通过在肠道中靶向缺失ATP7B的新小鼠模型的特征来验证这一假设。对杰克逊实验室毒奶和ATP7B基因敲除WD小鼠模型的盲肠内容物、16S测序、非靶向肝脏和血浆脂体分析进行了分析和整合。建立了肠道特异的ATP7B基因敲除小鼠(ATP7BΔIEC)，并在高脂饮食挑战后进行了靶向脂体分析。在WD动物模型中，肠道微生物区系多样性降低。比较预测分析揭示了WD肠道微生物元基因组中氨基酸、碳水化合物和脂肪代谢功能的失调。在WD模型中，肝脏和血浆脂代谢谱显示甘油三酯和二甘油三酯、磷脂和鞘磷脂代谢紊乱。然而，与野生型相比，ATP7BΔIEC小鼠没有表现出肠道微生物群的差异。当受到高脂饮食刺激时，ATP7BΔIEC小鼠表现出脂肪酸去饱和度和鞘脂代谢途径的深刻变化，以及肠上皮细胞APOB48分布的改变。肠道微生物群和类脂体是WD小鼠全身代谢表现的基础。肠道特异性ATP7B缺乏影响了肠道和全身对高脂肪挑战的反应，但不影响微生物组，至少在早期阶段是这样。WD是一种全身性疾病，肠道特异性ATP7B缺失和饮食影响表型和脂体分布。
The clinical manifestations of Wilson disease (WD) are related to copper accumulation in the liver and the brain, but little is known about other tissue involvement regarding metabolic changes in WD. In vitro studies suggested that the loss of intestinal ATP7B affects metabolic dysregulation in WD. We tested this hypothesis by evaluating the gut microbiota and lipidome in 2 mouse models of WD and by characterizing a new mouse model with a targeted deletion of Atp7b in the intestine. Cecal content 16S sequencing and untargeted hepatic and plasma lipidome analyses in the Jackson Laboratory toxic-milk and the Atp7b null global knockout mouse models of WD were profiled and integrated. Intestine-specific Atp7b knockout mice (Atp7bΔIEC) were generated and characterized using targeted lipidome analysis following a high-fat diet challenge. Gut microbiota diversity was reduced in animal models of WD. Comparative prediction analysis revealed amino acid, carbohydrate, and lipid metabolism functions to be dysregulated in the WD gut microbial metagenome. Liver and plasma lipidomic profiles showed dysregulated triglyceride and diglyceride, phospholipid, and sphingolipid metabolism in WD models. However, Atp7bΔIEC mice did not show gut microbiome differences compared to wild type. When challenged with a high-fat diet, Atp7bΔIEC mice exhibited profound alterations to fatty acid desaturation and sphingolipid metabolism pathways as well as altered APOB48 distribution in intestinal epithelial cells. Gut microbiome and lipidome underlie systemic metabolic manifestations in murine WD. Intestine-specific ATP7B deficiency affected both intestinal and systemic response to a high-fat challenge but not the microbiome profile, at least at early stages. WD is a systemic disease in which intestinal-specific ATP7B loss and diet influence the phenotype and the lipidome profile.
DOI：
10.1016/j.jcmgh.2021.05.020
发表时间：
2021
影响因子：
7.2
作者：
Sarode GV;Neier K;Shibata NM;Shen Y;Goncharov DA;Goncharova EA;Mazi TA;Joshi N;Settles ML;LaSalle JM;Medici V
通讯作者：
Medici V