Dexi disruption depletes gut microbial metabolites and accelerates autoimmune diabetes
Dexi disruption depletes gut microbial metabolites and accelerates autoimmune diabetes
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Dexi 破坏会消耗肠道微生物代谢物并加速自身免疫性糖尿病
DOI：
10.1101/393421
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发表时间：
2018
期刊：
影响因子：
--
通讯作者：
Davison L
中科院分区：
文献类型：
--
作者：
Davison L
人类染色体16p13.13上CLEC16A基因的非编码遗传变异与自身免疫性疾病的风险有关，包括1型糖尿病和多发性硬化症。在这个区域，我们以前发现了DEXI，一个功能未知的候选致病基因，它改变了1型糖尿病的风险，其中T1D易感等位基因与DEXI低表达相关。在这里，我们通过CRISPR活体突变和深度表型分析证明，在非肥胖糖尿病(NOD)小鼠中，干扰Dexi表达的Dexi表达会加速糖尿病，这是一种自发的自身免疫性胰岛β细胞破坏模型。与野生型NOD小鼠相比，突变小鼠的血清IgM和IgA浓度增加，肠道微生物群和与微生物代谢相关的分子代谢物也发生了变化。这些发现表明，DEXI改变糖尿病风险的机制涉及微生物组的组成和功能及其对宿主代谢物的影响。这类代谢物，包括短链脂肪酸，如丁酸盐，已被证明改变了参与β细胞破坏的免疫细胞的活性和β细胞对自身免疫攻击的敏感性。一句摘要：Dexigene的破坏导致非肥胖糖尿病(NOD)小鼠糖尿病加速，并伴随着血清免疫球蛋白、肠道微生物群和微生物代谢产物的变化。
Non-coding genetic variants in the CLEC16A gene on human chromosome 16p13.13 are associated with risk of autoimmune diseases, including type 1 diabetes and multiple sclerosis. In this region, we previously identifiedDEXI, a candidate causal gene of unknown function, which alters the risk of type 1 diabetes, where the T1D predisposing allele is associated with lowerDEXIexpression. Here, we demonstrate by CRISPR mutagenesisin vivoand deep phenotyping that disruptedDexiexpression accelerates diabetes in the non-obese diabetic (NOD) mouse, a spontaneous model of autoimmune pancreatic beta-cell destruction. Mutant mice have increased serum IgM and IgA concentrations compared to wild-type NOD mice, as well as changes in both the gut microbiome and molecular metabolites associated with microbial metabolism. These findings suggest that the mechanism by whichDEXIalters diabetes risk involves the composition and function of the microbiome and its impact on host metabolites. Such metabolites, including short chain fatty acids such as butyrate, have been shown to alter the activity of the immune cells involved in beta-cell destruction and susceptibility of the beta cells to autoimmune attack.One Sentence Summary:Disruption of theDexigene leads to accelerated diabetes in the non-obese diabetic (NOD) mouse, accompanied by changes in serum immunoglobulins, gut microbiome and microbial metabolites.
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影响因子：
14.2
作者：
Ferreira, Manuel A. R.;Matheson, Melanie C.;Tang, Clara S.;Granell, Raquel;Ang, Wei;Hui, Jennie;Kiefer, Amy K.;Duffy, David L.;Baltic, Svetlana;Danoy, Patrick;Bui, Minh;Price, Loren;Sly, Peter D.;Eriksson, Nicholas;Madden, Pamela A.;Abramson, Michael J.;Holt, Patrick G.;Heath, Andrew C.;Hunter, Michael;Musk, Bill;Robertson, Colin F.;Le Souef, Peter;Montgomery, Grant W.;Henderson, A. John;Tung, Joyce Y.;Dharmage, Shyamali C.;Brown, Matthew A.;James, Alan;Thompson, Philip J.;Pennell, Craig;Martin, Nicholas G.;Evans, David M.;Hinds, David A.;Hopper, John L.
通讯作者：
Hopper, John L.
长寿的浆细胞能否维持肠道内健康的微生物群？
影响因子：
16.8
作者：
F. Jahnsen;E. Bækkevold;J. Hov;O. J. Landsverk
通讯作者：
O. J. Landsverk
日本代谢综合征患者遗传变异与缺血性中风的关联
DOI：
--
发表时间：
2009
期刊：
影响因子：
--
作者：
Yoshiyuki Kataoka;Mitsutoshi Oguri;Mizuho Hiramatsu;Hiroshi Matsuo;Takanori Nagahiro;Yumiko Yamamura;Manabu Miura;Yoshihisa Shibata;Yoshihiro Hanaki;Haruo Kamiya;Miyoshi Ohno;Kimihiko Kato;Tetsuo Fujimaki;Kazuhiro Yajima;Kiyoshi Yokoi;Sachi
通讯作者：
Sachi
影响因子：
32.4
作者：
Yurkovetskiy L;Burrows M;Khan AA;Graham L;Volchkov P;Becker L;Antonopoulos D;Umesaki Y;Chervonsky AV
通讯作者：
Chervonsky AV
探究染色体 16p13.13 在多发性硬化症易感性中的复杂作用：CIITA-CLEC16A-SOCS1 基因复合体中的独立遗传信号。
影响因子：
3.5
作者：
Zuvich,RebeccaL;Bush,WilliamS;McCauley,JacobL;Beecham,AshleyH;DeJager,PhilipL;InternationalMultipleSclerosisGeneticsConsortium;Ivinson,AdrianJ;Compston,Alastair;Hafler,DavidA;Hauser,StephenL;Sawcer,StephenJ;Pericak-Vance
通讯作者：
Pericak-Vance