Integrated analysis of behavioral, epigenetic, and gut microbiome analyses in App(NL-G-F), App(NL-F), and wild type mice.
Integrated analysis of behavioral, epigenetic, and gut microbiome analyses in App(NL-G-F), App(NL-F), and wild type mice.
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DOI：
10.1038/s41598-021-83851-4
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发表时间：
2021-02-25
影响因子：
4.6
通讯作者：
Raber J
中科院分区：
文献类型：
--
作者：
Kundu P;Torres ERS;Stagaman K;Kasschau K;Okhovat M;Holden S;Ward S;Nevonen KA;Davis BA;Saito T;Saido TC;Carbone L;Sharpton TJ;Raber J
大脑中发生的表观遗传机制以及肠道微生物组组成的改变可能会导致阿尔茨海默病 (AD)。人类淀粉样前体蛋白敲入 (KI) 小鼠含有瑞典和伊比利亚突变 (AppNL-F) 或这两种突变以及北极突变 (AppNL-G-F)。在这项研究中，我们评估了 6 个月大的 AppNL-F、AppNL-G-F 和 C57BL/6J 野生型 (WT) 小鼠的行为和认知表现是否与肠道微生物组相关，以及基因型是否调节这种关联。在行为测试中观察到的基因型效应是测试依赖性的。肠道微生物组的生物多样性和组成与小鼠行为和认知表现的各个方面相关，但基因型的差异调节了这些关系。这些基因型依赖性关联包括 Lachnospiraceae 和 Ruminococcaceae 家族的成员。在一组雌性小鼠中，我们评估了海马体中的 DNA 甲基化，并研究了海马体 DNA 甲基化的改变是否与肠道微生物组相关。在其他差异甲基化区域中，我们鉴定了一个与 Tomm40 基因 3'UTR 和 Apoe 基因启动子区域重叠的 1 Kb 区域，该区域在 AppNL-G-F 小鼠的海马中甲基化程度显着高于 WT 小鼠。整合的肠道微生物组海马 DNA 甲基化分析揭示了 Lachnospiraceae 家族内的扩增子序列变异 (ASV) 与 Apoe 基因甲基化之间的正相关关系。因此，这些微生物可能通过神经组织中AD易感基因的表观遗传变化对AD相关的行为和认知表现产生影响，或者表观基因组的这种变化可以引起肠道生理学的改变，从而影响肠道微生物组中这些类群的生长。
Epigenetic mechanisms occurring in the brain as well as alterations in the gut microbiome composition might contribute to Alzheimer’s disease (AD). Human amyloid precursor protein knock-in (KI) mice contain the Swedish and Iberian mutations (AppNL-F) or those two and also the Arctic mutation (AppNL-G-F). In this study, we assessed whether behavioral and cognitive performance in 6-month-old AppNL-F, AppNL-G-F, and C57BL/6J wild-type (WT) mice was associated with the gut microbiome, and whether the genotype modulates this association. The genotype effects observed in behavioral tests were test-dependent. The biodiversity and composition of the gut microbiome linked to various aspects of mouse behavioral and cognitive performance but differences in genotype modulated these relationships. These genotype-dependent associations include members of the Lachnospiraceae and Ruminococcaceae families. In a subset of female mice, we assessed DNA methylation in the hippocampus and investigated whether alterations in hippocampal DNA methylation were associated with the gut microbiome. Among other differentially methylated regions, we identified a 1 Kb region that overlapped ing 3′UTR of the Tomm40 gene and the promoter region of the Apoe gene that and was significantly more methylated in the hippocampus of AppNL-G-F than WT mice. The integrated gut microbiome hippocampal DNA methylation analysis revealed a positive relationship between amplicon sequence variants (ASVs) within the Lachnospiraceae family and methylation at the Apoe gene. Hence, these microbes may elicit an impact on AD-relevant behavioral and cognitive performance via epigenetic changes in AD-susceptibility genes in neural tissue or that such changes in the epigenome can elicit alterations in intestinal physiology that affect the growth of these taxa in the gut microbiome.
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影响因子：
48
作者：
Callahan BJ;McMurdie PJ;Rosen MJ;Han AW;Johnson AJ;Holmes SP
通讯作者：
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影响因子：
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Buniello, Annalisa;MacArthur, Jacqueline A. L.;Parkinson, Helen
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影响因子：
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通讯作者：
Schuebeler, Dirk
影响因子：
4
作者：
Cadena-del-Castilloa, Carla;Valdes-Quezada, Christian;Recillas-Targa, Felix
通讯作者：
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