Microbiota-derived lysophosphatidylcholine alleviates Alzheimer’s disease pathology via suppressing ferroptosis

IF 27.7 1区生物学 Q1 CELL BIOLOGY

Cell metabolism Pub Date : 2024-11-06 DOI:10.1016/j.cmet.2024.10.006

Xu Zha, Xicheng Liu, Mengping Wei, Huanwei Huang, Jiaqi Cao, Shuo Liu, Xiaomei Bian, Yuting Zhang, Fenyan Xiao, Yuping Xie, Wei Wang, Chen Zhang

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Abstract

Alzheimer’s disease (AD) is a pervasive neurodegenerative disorder, and new approaches for its prevention and therapy are critically needed. Here, we elucidate a gut-microbiome-brain axis that offers actionable perspectives for achieving this objective. Using the 5xFAD mouse model, we identify increased Clostridium abundance and decreased Bacteroides abundance as key features associated with β-amyloid (Aβ) burden. Treatment with Bacteroides ovatus, or its associated metabolite lysophosphatidylcholine (LPC), significantly reduces Aβ load and ameliorates cognitive impairment. Mechanistically, LPC acts through the orphan receptor GPR119, inhibiting ACSL4 expression, thereby suppressing ferroptosis and ameliorating AD pathologies. Analysis of fecal and serum samples from individuals with AD also reveals diminished levels of Bacteroides and LPC. This study thus identifies a B.ovatus-triggered pathway regulating AD pathologies and indicates that the use of single gut microbiota, metabolite, or small molecule compound may complement current prevention and treatment approaches for AD.

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源于微生物群的溶血磷脂酰胆碱通过抑制铁蛋白沉积缓解阿尔茨海默病的病理变化

阿尔茨海默病（AD）是一种普遍存在的神经退行性疾病，亟需新的预防和治疗方法。在这里，我们阐明了肠道-微生物-大脑轴，为实现这一目标提供了可行的视角。利用 5xFAD 小鼠模型，我们发现梭状芽孢杆菌丰度的增加和乳杆菌丰度的降低是与β淀粉样蛋白（Aβ）负担相关的关键特征。使用卵形乳杆菌或其相关代谢产物溶血磷脂酰胆碱（LPC）治疗可显著降低Aβ负荷并改善认知障碍。从机理上讲，LPC通过孤儿受体GPR119发挥作用，抑制ACSL4的表达，从而抑制铁变态反应，改善AD的病理变化。对注意力缺失症患者的粪便和血清样本进行分析后发现，乳酸杆菌和 LPC 的水平也有所降低。因此，这项研究确定了一种由巴氏乳杆菌触发的AD病理调节途径，并表明使用单一的肠道微生物群、代谢物或小分子化合物可能会对目前的AD预防和治疗方法起到补充作用。

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来源期刊

Cell metabolism 生物-内分泌学与代谢

CiteScore

48.60

自引率

1.40%

发文量

173

审稿时长

2.5 months

期刊介绍： Cell Metabolism is a top research journal established in 2005 that focuses on publishing original and impactful papers in the field of metabolic research.It covers a wide range of topics including diabetes, obesity, cardiovascular biology, aging and stress responses, circadian biology, and many others. Cell Metabolism aims to contribute to the advancement of metabolic research by providing a platform for the publication and dissemination of high-quality research and thought-provoking articles.