Host and microbiota interactions are critical for development of murine Crohn's-like ileitis.
Host and microbiota interactions are critical for development of murine Crohn's-like ileitis.
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作者：
肠道中宿主-微生物区系相互作用的放松是克罗恩病的一个关键特征。然而，目前尚不清楚与人类病理相关的共生和/或非生物微生物区系是否与克罗恩的发病机制有关。在这里，我们证明了肿瘤坏死因子Δ阳性小鼠的克罗恩样回肠炎是微生物群依赖的。无菌的肿瘤坏死因子ΔAre/+小鼠是无病的，微生物区系及其通过MyD88的先天识别对于肿瘤坏死因子的过度表达和疾病的发生是必不可少的。病变小鼠上皮在粘液屏障和细胞旁通透性方面无明显缺陷。然而，肿瘤坏死因子Δ是/+回肠炎与表达溶菌酶的潘氏细胞减少有关，这是由适应性免疫效应介导的。此外，我们发现，在肿瘤坏死因子ΔAre/+小鼠中，已建立的但不是早期的回肠炎涉及抗菌素的缺陷表达和微生物失调，其特征是Firmicuts扩张，包括附着上皮的节段性丝状细菌，以及类杆菌的丰度降低。在疾病的早期阶段通过抗生素调节微生物区系可以挽救回肠炎。我们的结果表明，在遗传易感的肿瘤坏死因子Δ是/+宿主中，本土微生物群足以驱动肿瘤坏死因子的过度表达和克罗恩回肠炎，而这种模型中的生物失调是疾病相关的改变，包括表达溶菌酶的潘氏细胞的丢失。
Deregulation of host-microbiota interactions in the gut is a pivotal characteristic of Crohn's disease. It remains unclear, however, whether commensals and/or the dysbiotic microbiota associated with pathology in humans are causally involved in Crohn's pathogenesis. Here we show that Crohn's-like ileitis in TnfΔARE+ mice is microbiota-dependent. Germ-free TnfΔARE/+ mice are disease-free and the microbiota and its innate recognition through Myd88 is indispensable for TNF overexpression and disease initiation in this model. The epithelium of diseased mice shows no major defects in mucus barrier and paracellular permeability. However, TnfΔARE/+ ileitis associates with reduction of lysozyme-expressing Paneth cells, mediated by adaptive immune effectors. Furthermore, we show that established but not early ileitis in TnfΔARE/+ mice involves defective expression of antimicrobials and dysbiosis, characterized by Firmicutes expansion, including epithelial-attaching Segmented Filamentous Bacteria, and decreased abundance of Bacteroidetes. Microbiota modulation by antibiotics treatment at an early disease stage rescues ileitis. Our results suggest that the indigenous microbiota is sufficient to drive TNF overexpression and Crohn's ileitis in the genetically susceptible TnfΔARE/+ hosts, whereas dysbiosis in this model results from disease-associated alterations including loss of lysozyme-expressing Paneth cells.
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影响因子：
32.4
作者：
Kontoyiannis, D;Pasparakis, M;Kollias, G
通讯作者：
Kollias, G
DOI：
10.1038/ismej.2012.8
发表时间：
2012-08
期刊：
The ISME journal
影响因子：
--
作者：
通讯作者：
--
DOI：
10.1084/jem.20020281
发表时间：
2002-12-16
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
Kontoyiannis D;Boulougouris G;Manoloukos M;Armaka M;Apostolaki M;Pizarro T;Kotlyarov A;Forster I;Flavell R;Gaestel M;Tsichlis P;Cominelli F;Kollias G
通讯作者：
Kollias G
影响因子：
29.4
作者：
Apostolaki, Maria;Manoloukos, Menelaos;Kollias, George
通讯作者：
Kollias, George
影响因子：
30.3
作者：
Gevers D;Kugathasan S;Denson LA;Vázquez-Baeza Y;Van Treuren W;Ren B;Schwager E;Knights D;Song SJ;Yassour M;Morgan XC;Kostic AD;Luo C;González A;McDonald D;Haberman Y;Walters T;Baker S;Rosh J;Stephens M;Heyman M;Markowitz J;Baldassano R;Griffiths A;Sylvester F;Mack D;Kim S;Crandall W;Hyams J;Huttenhower C;Knight R;Xavier RJ
通讯作者：
Xavier RJ