Inhibition of Interleukin-10 Signaling Induces Microbiota-dependent Chronic Colitis in Apolipoprotein E Deficient Mice.
Inhibition of Interleukin-10 Signaling Induces Microbiota-dependent Chronic Colitis in Apolipoprotein E Deficient Mice.
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DOI：
10.1097/mib.0000000000000699
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发表时间：
2016-04
影响因子：
4.9
通讯作者：
Vijay-Kumar M
中科院分区：
文献类型：
--
作者：
Singh V;Kumar M;San Yeoh B;Xiao X;Saha P;Kennett MJ;Vijay-Kumar M
载脂蛋白E（ApoE）除了在调节胆固醇转运和代谢中的作用之外，还介导有效的抗炎和免疫调节特性。然而，它在肠道中的作用，特别是在炎症期间，在很大程度上是未知的。对小鼠[C57 BL/6或ApoE缺陷型（ApoE-KO）小鼠]单次或四次注射（每周一次）抗白细胞介素（IL）-10受体单克隆抗体（1.0 mg/小鼠;腹膜内），并在最后一次注射后一周实施安乐死。在粪便样品中进行16 S rRNA测序以分析肠道细菌负荷及其组成。通过在饮用水中施用广谱抗生素来消除微生物群。将IL-10 KO小鼠与ApoE-KO小鼠或其WT同窝小鼠共饲养，以监测ApoE-KO小鼠中肠道微生物群的大肠杆菌生成潜力。ApoE-KO小鼠在中和IL-10信号传导后发生重度结肠炎，如通过分析的每个参数所评估的。16 S rRNA测序显示，ApoE-KO小鼠显示出肠道微生物群的升高和改变，伴随着肠道抗菌肽的产生受损。有趣的是，微生物群消融改善了ApoE-KO小鼠中的结肠炎发展。当与ApoE-KO小鼠共饲养时，在IL-10 KO小鼠中观察到急性和加速结肠炎。我们的研究强调了ApoE和IL-10在维持肠道稳态方面的新型相互作用，这种相互作用可能在炎症性肠病（IBD）发病机制中起关键作用。肠道灭菌和共饲养实验表明，微生物群在缺乏ApoE的小鼠IBD的发展中起关键作用。
Apolipoprotein E (ApoE) mediates potent anti-inflammatory and immunomodulatory properties in addition to its roles in regulating cholesterol transport and metabolism. However, its role in the intestine, specifically during inflammation is largely unknown. Mice [C57BL/6 or ApoE deficient (ApoE-KO) mice] were administered either single or four injections (weekly) of anti-interleukin (IL)-10 receptor monoclonal antibody (1.0 mg/mouse; intraperitoneally) and euthanized one week after the last injection. 16S rRNA sequencing was performed in fecal samples to analyze the gut bacterial load and its composition. Microbiota was ablated by administration of broad-spectrum antibiotics in drinking water. IL-10KO mice were cohoused with ApoE-KO mice or their WT littermates to monitor the colitogenic potential of gut microbiota harbored in ApoE-KO mice. ApoE-KO mice developed severe colitis upon neutralization of IL-10 signaling as assessed by every parameter analyzed. 16S rRNA sequencing revealed that the ApoE-KO mice display elevated and altered gut microbiota that were accompanied with impaired production of intestinal antimicrobial peptides. Interestingly, microbiota ablation ameliorates the colitis development in ApoE-KO mice. Exacerbated and accelerated colitis was observed in IL-10KO mice when cohoused with ApoE-KO mice. Our study highlights a novel interplay between ApoE and IL-10 in maintaining gut homeostasis and that such cross-talk may play a critical role in inflammatory bowel disease (IBD) pathogenesis. Gut sterilization and cohousing experiment suggests that microbiota play pivotal role in the development of IBD in mice lacking ApoE.