Inflammation drives dysbiosis and bacterial invasion in murine models of ileal Crohn's disease.
Inflammation drives dysbiosis and bacterial invasion in murine models of ileal Crohn's disease.
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DOI：
10.1371/journal.pone.0041594
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发表时间：
2012
期刊：
影响因子：
3.7
通讯作者：
Simpson KW
中科院分区：
文献类型：
--
作者：
Craven M;Egan CE;Dowd SE;McDonough SP;Dogan B;Denkers EY;Bowman D;Scherl EJ;Simpson KW
了解克罗恩病（CD）中遗传易感性、微生物组、环境和免疫系统之间的相互作用对于制定最佳治疗策略至关重要。我们试图在小鼠回肠炎模型中研究炎症、回肠微生物组和宿主遗传学之间关系的动力学。我们通过灌胃弓形虫、鼠贾第虫、低剂量吲哚美辛（LDI; 0.1 mg/mouse）或高剂量吲哚美辛（HDI; 1 mg/mouse）诱导C57 BL 6小鼠的回肠炎症。通过16S rDNA焦磷酸测序和荧光原位杂交评估粘膜微生物组的组成和空间分布。粘液。用定量PCR方法对大肠杆菌进行计数，并对大肠杆菌的菌群、基因型和致病型进行鉴定。中重度回肠炎。gondii（第8天）和HDI引起从> 95%的革兰氏+厚壁菌门到> 95%的革兰氏-变形菌门的一致转变。这伴随着微生物多样性的减少和粘附性和侵袭性大肠杆菌的粘膜侵袭。大肠杆菌，反映了回肠CD的生态失调。相反，在由贾第鞭毛虫诱导的轻度回肠炎小鼠中，没有出现微生态失调和细菌入侵。遗传易感性与T.弓形虫感染显示CD易感基因型NOD2 −/−的微生态失调和细菌入侵最严重，而回肠炎抗性CCR2 −/−小鼠的微生态失调减少。用CD治疗性抗TNF-α-mAb消除炎症，缓解生态失调和细菌入侵。急性回肠炎诱导粘膜侵袭性大肠杆菌的生态失调和增殖。大肠杆菌，无论触发和基因型。将CCR2鉴定为治疗性干预的靶标，以及发现宿主基因型和炎症的治疗性阻断影响回肠生态失调的阈值和程度与开发CD的有效疗法高度相关。
Understanding the interplay between genetic susceptibility, the microbiome, the environment and the immune system in Crohn’s Disease (CD) is essential for developing optimal therapeutic strategies. We sought to examine the dynamics of the relationship between inflammation, the ileal microbiome, and host genetics in murine models of ileitis. We induced ileal inflammation of graded severity in C57BL6 mice by gavage with Toxoplasma gondii, Giardia muris, low dose indomethacin (LDI;0.1 mg/mouse), or high dose indomethacin (HDI;1 mg/mouse). The composition and spatial distribution of the mucosal microbiome was evaluated by 16S rDNA pyrosequencing and fluorescence in situ hybridization. Mucosal E. coli were enumerated by quantitative PCR, and characterized by phylogroup, genotype and pathotype. Moderate to severe ileitis induced by T. gondii (day 8) and HDI caused a consistent shift from >95% Gram + Firmicutes to >95% Gram - Proteobacteria. This was accompanied by reduced microbial diversity and mucosal invasion by adherent and invasive E. coli, mirroring the dysbiosis of ileal CD. In contrast, dysbiosis and bacterial invasion did not develop in mice with mild ileitis induced by Giardia muris. Superimposition of genetic susceptibility and T. Gondii infection revealed greatest dysbiosis and bacterial invasion in the CD-susceptible genotype, NOD2−/−, and reduced dysbiosis in ileitis-resistant CCR2−/− mice. Abrogating inflammation with the CD therapeutic anti-TNF-α-mAb tempered dysbiosis and bacterial invasion. Acute ileitis induces dysbiosis and proliferation of mucosally invasive E. coli, irrespective of trigger and genotype. The identification of CCR2 as a target for therapeutic intervention, and discovery that host genotype and therapeutic blockade of inflammation impact the threshold and extent of ileal dysbiosis are of high relevance to developing effective therapies for CD.
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作者：
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