Department of Internal Medicine, Division of Gastroenterology and Hepatology, UC Davis, Sacramento, California, USA.
Department of Community Health Sciences - Clinical Nutrition, College of Applied Medical Sciences, King Saud University, Riyadh, Saudi Arabia.
Hepatol Commun. 2023 Sep 11;7(10). doi: 10.1097/HC9.0000000000000247. eCollection 2023 Oct 1.
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.
Wilson 病（WD）的临床表现与铜在肝脏和大脑中的积累有关，但对于 WD 代谢变化相关的其他组织受累知之甚少。体外研究表明，肠 ATP7B 的丧失会影响 WD 中的代谢失调。我们通过评估 2 种 WD 小鼠模型中的肠道微生物组和脂质组，并通过表征一种在肠道中靶向缺失 Atp7b 的新型小鼠模型来测试这一假设。
对 Jackson 实验室有毒牛奶和 Atp7b 全局敲除小鼠模型中的回肠内容物 16S 测序和非靶向肝和血浆脂质组分析进行了分析，并进行了整合。使用靶向脂质组分析生成并表征了具有肠道特异性 Atp7b 敲除（Atp7bΔIEC）的小鼠，随后对其进行高脂肪饮食挑战。
WD 动物模型中的肠道微生物多样性降低。比较预测分析显示，WD 肠道微生物宏基因组中的氨基酸、碳水化合物和脂质代谢功能失调。肝和血浆脂质组谱显示 WD 模型中的甘油三酯和二甘油酯、磷脂和鞘脂代谢失调。然而，与野生型相比，Atp7bΔIEC 小鼠的肠道微生物组没有差异。当用高脂肪饮食挑战时，Atp7bΔIEC 小鼠表现出脂肪酸去饱和和鞘脂代谢途径的显著改变以及肠上皮细胞中 APOB48 分布的改变。
肠道微生物组和脂质组是 WD 中系统性代谢表现的基础。肠道特异性 ATP7B 缺乏会影响高脂肪挑战对肠道和全身的反应，但至少在早期阶段不会影响微生物组谱。WD 是一种全身性疾病，其中肠道特异性 ATP7B 丧失和饮食会影响表型和脂质组谱。
