Nonalcoholic fatty liver disease (NAFLD), largely studied as a condition of overnutrition, also presents in undernourished populations. Like NAFLD, undernutrition disrupts systemic metabolism and has been linked to gut microbiota dysbiosis. Indeed, chronic exposures to fecal microbes contribute to undernutrition pathology in regions with poor sanitation. Despite a growing prevalence of fatty liver disease, the influence of undernutrition and the gut microbiota remain largely unexplored. Here, we utilize an established murine model (C57BL/6J mice placed on a malnourished diet that received iterative Escherichia coli/Bacteroidales gavage [MBG mice]) that combines a protein/fat-deficient diet and iterative exposure to specific, fecal microbes. Fecal-oral contamination exacerbates triglyceride accumulation in undernourished mice. MBG livers exhibit diffuse lipidosis accompanied by striking shifts in fatty acid, glycerophospholipid, and retinol metabolism. Multiomic analyses revealed metabolomic pathways linked to the undernourished gut microbiome and hepatic steatosis, including phenylacetate metabolism. Intriguingly, fatty liver features were observed only in the early-life, but not adult, MBG model despite similar liver metabolomic profiles. Importantly, we demonstrate that dietary intervention largely mitigates aberrant metabolomic and microbiome features in MBG mice. These findings indicate a crucial window in early-life development that, when disrupted by nutritional deficiency, may significantly influence liver function. Our work provides a multifaceted study of how diet and gut microbes inform fatty liver progression and reversal during undernutrition.

中文翻译：

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饮食干预在生命早期营养不良期间逆转脂肪肝和改变肠道微生物群。

非酒精性脂肪性肝病 (NAFLD) 主要作为营养过剩的一种情况进行研究，也出现在营养不良的人群中。与 NAFLD 一样，营养不良会破坏全身代谢，并与肠道微生物群失调有关。事实上，在卫生条件差的地区，长期接触粪便微生物会导致营养不良。尽管脂肪肝的患病率越来越高，但营养不良和肠道微生物群的影响在很大程度上仍未得到探索。在这里，我们利用已建立的小鼠模型（C57BL/6J 小鼠置于营养不良的饮食中，接受迭代的大肠杆菌/拟杆菌灌胃 [MBG 小鼠])，它结合了蛋白质/脂肪缺乏的饮食和反复接触特定的粪便微生物。粪口污染加剧了营养不良小鼠的甘油三酯积累。MBG 肝脏表现出弥漫性脂质沉积，伴随着脂肪酸、甘油磷脂和视黄醇代谢的显着变化。多组学分析揭示了与营养不良的肠道微生物群和肝脏脂肪变性相关的代谢组学途径，包括苯乙酸酯代谢。有趣的是，尽管肝脏代谢组学特征相似，但仅在生命早期而非成年 MBG 模型中观察到脂肪肝特征。重要的是，我们证明饮食干预在很大程度上减轻了 MBG 小鼠的异常代谢组学和微生物组特征。这些发现表明生命早期发展的一个关键窗口，当因营养缺乏而中断时，可能会显着影响肝功能。我们的工作提供了一项关于饮食和肠道微生物如何影响营养不良期间脂肪肝进展和逆转的多方面研究。