The objective of this study was to investigate whether juvenile Iberian pigs with diet-induced non-alcoholic fatty liver disease (NAFLD), cholestasis and gut dysbiosis would develop histological and metabolic markers of neurodegeneration in the frontal cortex (FC), and whether supplementing probiotics would influence the response to the diet. Twenty-eight juvenile Iberian pigs were fed for 10 weeks either a control (CON) or high-fructose high-fat diet (HFF) with or without a commercial probiotic mixture. Compared with CON, HFF-fed pigs had decreased number of neurons and an increase in reactive astrocytes in FC tissue. We found also a decrease in one-carbon metabolites choline and betaine, and a marked accumulation of bile acids, cholesteryl esters, and polyol-pathway intermediates in FC of HFF-fed pigs, which were associated with markers of neurodegeneration and accentuated with the severity of NAFLD. Betaine depletion in FC tissue was negatively correlated with choline-derived phospholipids in colon content, whereas primary conjugated bile acids in FC were associated with cholestasis. Plasma kynurenine-to-tryptophan quotient, as a marker of indoleamine 2,3-dioxygenase activity, and intestinal dysbiosis were also correlated with neuronal loss and astrogliosis. Recognition memory test, and FC levels of amyloid β and phosphorylated Tau did not differ between diets, while probiotics increased amyloid β and memory loss in HFF-fed pigs. In conclusion, our results show evidence of neurodegeneration in FC of juvenile Iberian pigs, and establish a novel pediatric model to investigate the role of gut-liver-brain axis in diet-induced NAFLD.

中文翻译：

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患有饮食诱导的非酒精性脂肪性肝病的幼年伊比利亚猪的神经变性。

本研究的目的是调查患有饮食诱导的非酒精性脂肪性肝病 (NAFLD)、胆汁淤积和肠道菌群失调的伊比利亚幼猪是否会出现额叶皮层 (FC) 神经变性的组织学和代谢标志物，以及是否补充益生菌会影响对饮食的反应。将 28 头伊比利亚幼猪喂食对照 (CON) 或高果糖高脂肪饮食 (HFF) 10 周，添加或不添加商业益生菌混合物。与 CON 相比，HFF 喂养的猪的神经元数量减少，FC 组织中反应性星形胶质细胞增加。我们还发现 HFF 喂养的猪的 FC 中一碳代谢物胆碱和甜菜碱的减少，以及胆汁酸、胆固醇酯和多元醇途径中间体的显着积累，这与神经退行性疾病的标志物相关，并随着 NAFLD 的严重程度而加剧。FC 组织中甜菜碱的消耗与结肠内容物中的胆碱衍生磷脂呈负相关，而 FC 中的初级结合胆汁酸与胆汁淤积有关。血浆犬尿氨酸-色氨酸商，作为吲哚胺 2,3-双加氧酶活性的标志物，肠道生态失调也与神经元丢失和星形胶质细胞增生相关。识别记忆测试以及 β 淀粉样蛋白和磷酸化 Tau 的 FC 水平在饮食之间没有差异，而益生菌增加了 HFF 喂养猪的淀粉样蛋白 β 和记忆力丧失。总之，我们的结果显示了幼年伊比利亚猪 FC 神经变性的证据，并建立了一种新的儿科模型来研究肠-肝-脑轴在饮食诱导的 NAFLD 中的作用。