Given the clinical low efficient treatment based on mono-brain-target design in Alzheimer’s disease (AD) and an increasing emphasis on microbiome-gut-brain axis which was considered as a crucial pathway to affect the progress of AD along with metabolic changes, integrative metabolomic signatures and microbiotic community profilings were applied on the early age (2-month) and mature age (6-month) of presenilin1/2 conditional double knockout (PS cDKO) mice which exhibit a series of AD-like phenotypes, comparing with gender and age-matched C57BL/6 wild-type (WT) mice to clarify the relationship between microbiota and metabolomic changes during the disease progression of AD. Urinary and fecal samples from PS cDKO mice and gender-matched C57BL/6 wild-type (WT) mice both at age of 2 and 6 months were collected. Urinary metabolomic signatures were measured by the gas chromatography-time-of-flight mass spectrometer, as well as 16S rRNA sequence analysis was performed to analyse the microbiota composition at both ages. Furthermore, combining microbiotic functional prediction and Spearman’s correlation coefficient analysis to explore the relationship between differential urinary metabolites and gut microbiota. In addition to memory impairment, PS cDKO mice displayed metabolic and microbiotic changes at both of early and mature ages. By longitudinal study, xylitol and glycine were reduced at both ages. The disturbed metabolic pathways were involved in glycine, serine and threonine metabolism, glyoxylate and dicarboxylate metabolism, pentose and glucuronate interconversions, starch and sucrose metabolism, and citrate cycle, which were consistent with functional metabolic pathway predicted by the gut microbiome, including energy metabolism, lipid metabolism, glycan biosynthesis and metabolism. Besides reduced richness and evenness in gut microbiome, PS cDKO mice displayed increases in Lactobacillus, while decreases in norank_f_Muribaculaceae, Lachnospiraceae_NK4A136_group, Mucispirillum, and Odoribacter. Those altered microbiota were exceedingly associated with the levels of differential metabolites. The urinary metabolomics of AD may be partially mediated by the gut microbiota. The integrated analysis between gut microbes and host metabolism may provide a reference for the pathogenesis of AD.

中文翻译：

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presenilin1/2 条件性双基因敲除小鼠的尿液代谢组学变化和微生物改变

鉴于阿尔茨海默病 (AD) 中基于单脑靶点设计的临床低效治疗以及越来越强调微生物组 - 肠 - 脑轴被认为是影响 AD 进展以及代谢变化的关键途径，综合治疗代谢组学特征和微生物群落分析应用于早老素1 / 2条件双敲除（PS cDKO）小鼠的早期（2个月）和成熟年龄（6个月），与性别相比，这些小鼠表现出一系列AD样表型和年龄匹配的 C57BL/6 野生型 (WT) 小鼠，以阐明 AD 疾病进展过程中微生物群与代谢组学变化之间的关系。收集了 2 个月和 6 个月大的 PS cDKO 小鼠和性别匹配的 C57BL/6 野生型 (WT) 小鼠的尿液和粪便样本。通过气相色谱-飞行时间质谱仪测量尿液代谢组学特征，并进行 16S rRNA 序列分析以分析两个年龄段的微生物群组成。此外，结合微生物功能预测和 Spearman 相关系数分析，探讨不同尿液代谢物与肠道微生物群之间的关系。除了记忆障碍外，PS cDKO 小鼠在早期和成熟时期都表现出代谢和微生物变化。通过纵向研究，木糖醇和甘氨酸在两个年龄段都减少了。受干扰的代谢途径涉及甘氨酸、丝氨酸和苏氨酸代谢、乙醛酸和二羧酸代谢、戊糖和葡萄糖醛酸相互转化、淀粉和蔗糖代谢以及柠檬酸循环，这与肠道微生物组预测的功能代谢途径一致，包括能量代谢、脂质代谢、聚糖生物合成和代谢。除了肠道微生物组的丰富度和均匀度降低外，PS cDKO 小鼠的乳酸杆菌增加，而 norank_f_Muribaculaceae、Lachnospiraceae_NK4A136_group、Mucispirillum 和 Odoribacter 减少。那些改变的微生物群与差异代谢物的水平密切相关。AD 的尿液代谢组学可能部分由肠道微生物群介导。肠道微生物与宿主代谢的综合分析可为AD的发病机制提供参考。除了肠道微生物组的丰富度和均匀度降低外，PS cDKO 小鼠的乳酸杆菌增加，而 norank_f_Muribaculaceae、Lachnospiraceae_NK4A136_group、Mucispirillum 和 Odoribacter 减少。那些改变的微生物群与差异代谢物的水平密切相关。AD 的尿液代谢组学可能部分由肠道微生物群介导。肠道微生物与宿主代谢的综合分析可为AD的发病机制提供参考。除了肠道微生物组的丰富度和均匀度降低外，PS cDKO 小鼠的乳酸杆菌增加，而 norank_f_Muribaculaceae、Lachnospiraceae_NK4A136_group、Mucispirillum 和 Odoribacter 减少。那些改变的微生物群与差异代谢物的水平密切相关。AD 的尿液代谢组学可能部分由肠道微生物群介导。肠道微生物与宿主代谢的综合分析可为AD的发病机制提供参考。