Dysbiotic gut microbiota causes transmissible Crohn's disease-like ileitis independent of failure in antimicrobial defence.
Dysbiotic gut microbiota causes transmissible Crohn's disease-like ileitis independent of failure in antimicrobial defence.
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DOI：
10.1136/gutjnl-2015-309333
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发表时间：
2016-02
期刊：
影响因子：
24.5
通讯作者：
Haller D
中科院分区：
文献类型：
--
作者：
Schaubeck M;Clavel T;Calasan J;Lagkouvardos I;Haange SB;Jehmlich N;Basic M;Dupont A;Hornef M;von Bergen M;Bleich A;Haller D
肠道微生物群的生态失调与克罗恩病（CD）有关。细菌在慢性小肠炎症发展中的因果作用缺乏功能证据。与人类病理学相似，TNFdeltaARE小鼠发生肿瘤坏死因子（TNF）驱动的CD样透壁炎症，主要累及回肠。将杂合TNFdeltaARE小鼠和野生型（WT）同窝仔圈养在常规（CONV）、无特定病原体（SPF）和无菌（GF）条件下。通过高通量16 S核糖体RNA基因测序分析微生物群落。使用LC-MS测量元蛋白质组。在抗生素治疗和将微生物群落转移到GF小鼠中后，跟踪疾病发展的时间和空间分辨率。通过免疫荧光和基因表达分析评估粒细胞浸润和潘氏细胞功能。GF-TNFdeltaARE小鼠在肠道中没有炎症，并且CONV-TNFdeltaARE小鼠的抗生素治疗减轻了回肠炎而不是结肠炎，表明疾病的严重程度和位置是微生物群依赖性的。SPF-TNFdeltaARE小鼠发展出与逐渐丧失抗微生物防御相关的独特回肠炎表型。16 S分析和元蛋白质组学揭示了发炎小鼠中细菌群落的特定组成和功能改变。疾病相关但不健康的微生物群的移植将CD样回肠炎传播给GF-TNFdeltaARE受体，并引发溶菌酶和cryptdin-2表达的丧失。GF-TNFdeltaARE小鼠与人CD相关的大肠杆菌LF 82的单联合不会诱导回肠炎。我们提供了明确的实验证据，肠道细菌生态失调的因果关系的作用，在发展中的慢性回肠炎症，随后失败的潘氏细胞功能。
Dysbiosis of the intestinal microbiota is associated with Crohn's disease (CD). Functional evidence for a causal role of bacteria in the development of chronic small intestinal inflammation is lacking. Similar to human pathology, TNFdeltaARE mice develop a tumour necrosis factor (TNF)-driven CD-like transmural inflammation with predominant ileal involvement. Heterozygous TNFdeltaARE mice and wildtype (WT) littermates were housed under conventional (CONV), specific pathogen-free (SPF) and germ-free (GF) conditions. Microbial communities were analysed by high-throughput 16S ribosomal RNA gene sequencing. Metaproteomes were measured using LC-MS. Temporal and spatial resolution of disease development was followed after antibiotic treatment and transfer of microbial communities into GF mice. Granulocyte infiltration and Paneth cell function was assessed by immunofluorescence and gene expression analysis. GF-TNFdeltaARE mice were free of inflammation in the gut and antibiotic treatment of CONV-TNFdeltaARE mice attenuated ileitis but not colitis, demonstrating that disease severity and location are microbiota-dependent. SPF-TNFdeltaARE mice developed distinct ileitis-phenotypes associated with gradual loss of antimicrobial defence. 16S analysis and metaproteomics revealed specific compositional and functional alterations of bacterial communities in inflamed mice. Transplantation of disease-associated but not healthy microbiota transmitted CD-like ileitis to GF-TNFdeltaARE recipients and triggered loss of lysozyme and cryptdin-2 expression. Monoassociation of GF-TNFdeltaARE mice with the human CD-related Escherichia coli LF82 did not induce ileitis. We provide clear experimental evidence for the causal role of gut bacterial dysbiosis in the development of chronic ileal inflammation with subsequent failure of Paneth cell function.