Metagenomic analysis characterizes stage-specific gut microbiota in Alzheimer’s disease

IF 9.6 1区 医学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY
Longhao Jia, Yize Ke, Shuo Zhao, Jinxin Liu, Xiaohui Luo, Jixin Cao, Yujia Liu, Qihao Guo, Wei‑Hua Chen, Feng Chen, Jiao Wang, Hao Wu, Jing Ding, Xing‑Ming Zhao
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Abstract

Alzheimer’s disease (AD) is a progressive neurodegenerative disorder with a decade-long preclinical pathological period that can be divided into several stages. Emerging evidence has revealed that the microbiota-gut-brain axis plays an important role in AD pathology. However, the role of gut microbiota in different AD stages has not been well characterized. In this study, we performed fecal shotgun metagenomic analysis on a Chinese cohort with 476 participants across five stages of AD pathology to characterize stage-specific alterations in gut microbiota and evaluate their diagnostic potential. We discovered extensive gut dysbiosis that is associated with neuroinflammation and neurotransmitter dysregulation, with over 10% of microbial species and gene families showing significant alterations during AD progression. Furthermore, we demonstrated that microbial gene families exhibited strong diagnostic capabilities, evidenced by an average AUC of 0.80 in cross-validation and 0.75 in independent external validation. In the optimal model, the most discriminant gene families are primarily involved in the metabolism of carbohydrates, amino acids, energy, glycan and vitamins. We found that stage-specific microbial gene families in AD pathology could be validated by an in vitro gut simulator and were associated with specific genera. We also observed that the gut microbiota could affect the progression of cognitive decline in 5xFAD mice through fecal microbiota transplantation, which could be used for early intervention of AD. Our multi-stage large cohort metagenomic analysis demonstrates that alterations in gut microbiota occur from the very early stages of AD pathology, offering important etiological and diagnostic insights.

Abstract Image

宏基因组分析表征了阿尔茨海默病的阶段特异性肠道微生物群
阿尔茨海默病(AD)是一种进行性神经退行性疾病,其临床前病理期长达十年,可分为几个阶段。新出现的证据表明,微生物-肠-脑轴在阿尔茨海默病病理中起着重要作用。然而,肠道微生物群在不同AD阶段的作用尚未得到很好的表征。在这项研究中,我们对中国的476名参与者进行了粪便鸟枪宏基因组分析,涵盖了阿尔茨海默病的5个病理阶段,以表征肠道微生物群的特异性改变,并评估其诊断潜力。我们发现广泛的肠道生态失调与神经炎症和神经递质失调有关,超过10%的微生物物种和基因家族在阿尔茨海默病的进展中表现出显著的改变。此外,我们证明微生物基因家族具有很强的诊断能力,交叉验证的平均AUC为0.80,独立外部验证的平均AUC为0.75。在最优模型中,最具区别性的基因家族主要参与碳水化合物、氨基酸、能量、聚糖和维生素的代谢。我们发现阿尔茨海默病病理的阶段特异性微生物基因家族可以通过体外肠道模拟器进行验证,并且与特定属相关。我们还通过粪便菌群移植观察到肠道菌群可以影响5xFAD小鼠认知能力下降的进展,可用于AD的早期干预。我们的多阶段大队列宏基因组分析表明,肠道微生物群的改变发生在阿尔茨海默病病理的早期阶段,为病因学和诊断提供了重要的见解。
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来源期刊
Molecular Psychiatry
Molecular Psychiatry 医学-精神病学
CiteScore
20.50
自引率
4.50%
发文量
459
审稿时长
4-8 weeks
期刊介绍: Molecular Psychiatry focuses on publishing research that aims to uncover the biological mechanisms behind psychiatric disorders and their treatment. The journal emphasizes studies that bridge pre-clinical and clinical research, covering cellular, molecular, integrative, clinical, imaging, and psychopharmacology levels.
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