APOE genetics influence murine gut microbiome.
APOE genetics influence murine gut microbiome.
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DOI：
10.1038/s41598-022-05763-1
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发表时间：
2022-02-03
影响因子：
4.6
通讯作者：
Estus S
中科院分区：
文献类型：
--
作者：
Zajac DJ;Green SJ;Johnson LA;Estus S
载脂蛋白E（APOE）等位基因影响多种人类疾病的发病机制和风险，使其成为疾病治疗和预防的主要目标。以前，我们和其他人报道了APOE等位基因与肠道微生物组之间的关联。在这里，我们评估了APOE杂合性的影响，并测试了这些总体结果是否扩展到维持在理想条件下进行微生物组分析的小鼠。为了模拟人类APOE等位基因，本研究使用了C57 B1/6背景的APOE靶向置换（TR）小鼠。为了尽量减少遗传漂变，在研究前将纯合APOE 3小鼠与纯合APOE 2或纯合APOE 4小鼠杂交，并将所得杂合后代进一步杂交以产生研究小鼠。为了最大限度地提高环境均匀性，将具有混合基因型的小鼠圈养在一起，并将笼中使用过的垫料混合并作为新垫料的一部分添加回去。从3月龄、5月龄和7月龄的小鼠获得粪便样品，并通过16 S核糖体RNA基因扩增子测序分析微生物群。效应大小的线性判别分析（LefSe）确定了与APOE状态相关的分类群，描述为分支图，以显示系统发育相关性。测试了APOE状态对α多样性（Shannon H指数）和β多样性（主坐标分析和PERMANOVA）的影响。通过经典的单变量分析确定与APOE状态相关的个体分类群。通过使用已发表的微生物组全基因组关联数据来评估APOE小鼠中的发现是否在人类中复制。进化枝图显示雄性小鼠中APOE的显著差异和雌性小鼠中的有限差异。粪便微生物组的丰富度和均匀度（α多样性）以及微生物群落组成（β多样性）与雄性小鼠的APOE状态密切相关，但与雌性小鼠无关。经典的单变量分析显示，个体分类群与APOE显著增加或减少，说明了与杂合子动物相关的逐步APOE 2-APOE 3-APOE 4模式，在逐步模式中呈中间趋势。来自梭菌纲、梭菌目、瘤胃球菌科和相关属的细菌的相对丰度随着APOE 2状态而增加。丹毒鞭毛虫的相对丰度随着APOE 4状态的增加而增加，这一发现延伸到人类。在这项研究中，小鼠以理想的方式进行微生物组研究，肠道微生物组谱与雄性APOE-TR小鼠的APOE状态密切相关。在小鼠和人类中，丹毒鞭毛虫随着APOE 4而增加。APOE等位基因效应在杂合子动物中一般表现为中等。在人类中进一步评估这些发现，以及评估APOE相关微生物群对疾病相关表型的影响的研究，对于确定肠道微生物组的改变是否代表APOE等位基因影响疾病的新机制是必要的。
Apolipoprotein E (APOE) alleles impact pathogenesis and risk for multiple human diseases, making them primary targets for disease treatment and prevention. Previously, we and others reported an association between APOE alleles and the gut microbiome. Here, we evaluated effects of APOE heterozygosity and tested whether these overall results extended to mice maintained under ideal conditions for microbiome analyses. To model human APOE alleles, this study used APOE targeted replacement (TR) mice on a C57Bl/6 background. To minimize genetic drift, homozygous APOE3 mice were crossed to homozygous APOE2 or homozygous APOE4 mice prior to the study, and the resulting heterozygous progeny crossed further to generate the study mice. To maximize environmental homogeneity, mice with mixed genotypes were housed together and used bedding from the cages was mixed and added back as a portion of new bedding. Fecal samples were obtained from mice at 3-, 5- and 7-months of age, and microbiota analyzed by 16S ribosomal RNA gene amplicon sequencing. Linear discriminant analysis of effect size (LefSe) identified taxa associated with APOE status, depicted as cladograms to show phylogenetic relatedness. The influence of APOE status was tested on alpha-diversity (Shannon H index) and beta-diversity (principal coordinate analyses and PERMANOVA). Individual taxa associated with APOE status were identified by classical univariate analysis. Whether findings in the APOE mice were replicated in humans was evaluated by using published microbiome genome wide association data. Cladograms revealed robust differences with APOE in male mice and limited differences in female mice. The richness and evenness (alpha-diversity) and microbial community composition (beta-diversity) of the fecal microbiome was robustly associated with APOE status in male but not female mice. Classical univariate analysis revealed individual taxa that were significantly increased or decreased with APOE, illustrating a stepwise APOE2-APOE3–APOE4 pattern of association with heterozygous animals trending as intermediate in the stepwise pattern. The relative abundance of bacteria from the class Clostridia, order Clostridiales, family Ruminococacceae and related genera increased with APOE2 status. The relative abundance of Erysipelotrichia increased with APOE4 status, a finding that extended to humans. In this study, wherein mice were maintained in an ideal fashion for microbiome studies, gut microbiome profiles were strongly and significantly associated with APOE status in male APOE-TR mice. Erysipelotrichia are increased with APOE4 in both mice and humans. APOE allelic effects appeared generally intermediate in heterozygous animals. Further evaluation of these findings in humans, as well as studies evaluating the impact of the APOE-associated microbiota on disease-relevant phenotypes, will be necessary to determine if alterations in the gut microbiome represent a novel mechanism whereby APOE alleles impact disease.
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DOI：
10.1056/nejmoa1211851
发表时间：
2013-01-10
期刊：
The New England journal of medicine
影响因子：
--
作者：
Guerreiro R;Wojtas A;Bras J;Carrasquillo M;Rogaeva E;Majounie E;Cruchaga C;Sassi C;Kauwe JS;Younkin S;Hazrati L;Collinge J;Pocock J;Lashley T;Williams J;Lambert JC;Amouyel P;Goate A;Rademakers R;Morgan K;Powell J;St George-Hyslop P;Singleton A;Hardy J;Alzheimer Genetic Analysis Group
通讯作者：
Alzheimer Genetic Analysis Group
影响因子：
4.6
作者：
Harach T;Marungruang N;Duthilleul N;Cheatham V;Mc Coy KD;Frisoni G;Neher JJ;Fåk F;Jucker M;Lasser T;Bolmont T
通讯作者：
Bolmont T
影响因子：
14.9
作者：
McCarthy DJ;Chen Y;Smyth GK
通讯作者：
Smyth GK
影响因子：
3.7
作者：
Azevedo, Orleancio G. R.;Bolick, David T.;Guerrant, Richard L.
通讯作者：
Guerrant, Richard L.
影响因子：
14.2
作者：
Gale, Stephen C.;Gao, Li;Mikacenic, Carmen;Coyle, Susette M.;Rafaels, Nicholas;Dudenkov, Tanda Murray;Madenspacher, Jennifer H.;Draper, David W.;Ge, William;Aloor, Jim J.;Azzam, Kathleen M.;Lai, Lihua;Blackshear, Perry J.;Calvano, Steven E.;Barnes, Kathleen C.;Lowry, Stephen F.;Corbett, Siobhan;Wurfel, Mark M.;Fessler, Michael B.
通讯作者：
Fessler, Michael B.