Colonization of larval zebrafish (Danio rerio) with adherent-invasive Escherichia coli prevents recovery of the intestinal mucosa from drug-induced enterocolitis.
Colonization of larval zebrafish (Danio rerio) with adherent-invasive Escherichia coli prevents recovery of the intestinal mucosa from drug-induced enterocolitis.
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炎症性肠病（IBD）是一系列慢性肠道疾病的广义术语，包括克罗恩病和溃疡性结肠炎。IBD的全球患病率正在上升，仅在美国就有超过100万患者受到影响。粘附侵袭性大肠杆菌（AIEC）是IBD活检中常见的致病菌。AIEC粘附并侵入上皮细胞，在体外可在吞噬细胞内存活。然而，AIEC如何在体内促进IBD仍不清楚。在这里，我们建立了一个幼斑马鱼（Danio rerio）模型，研究预先存在的肠道炎症和肠道AIEC定植之间的相互作用。我们使用促炎药物葡聚糖硫酸钠（DSS）诱导肠道炎症。其次是食源性感染的幼虫与AIEC使用原生动物草履虫尾，一种天然的猎物，作为一种媒介。我们发现，AIEC更强大的定殖斑马鱼肠道和清除慢于非致病性大肠杆菌。杆菌此外，DSS诱导的小肠结肠炎会增加幼虫肠道中的细菌负荷并降低细菌清除率。我们基准我们的模型对现有的啮齿动物模型使用两个突变体缺乏已知的AIEC毒力因子FimH和IbeA，这在啮齿动物和斑马鱼幼虫模型的毒力缺陷。最后，我们发现AIEC定植加剧DSS诱导的小肠结肠炎，并阻止炎症诱导的损伤恢复。总之，我们建立了一个高通量，遗传上易于处理的模型，以研究在预先存在的炎症背景下AIEC-宿主相互作用。虽然炎症性肠病的发病率正在上升，但影响IBD风险和严重程度的因素以及潜在机制仍有待充分了解。尽管宿主遗传学、微生物组和环境因素都已被证明与IBD的发展相关，但在这种情况下，因果关系很难解开。例如，AIEC是在IBD患者中发现的已知致病菌，但仍不清楚IBD期间的肠道炎症是否促进AIEC的定殖，或者AIEC定殖是否使宿主对促炎刺激更敏感。为了开发成功的治疗方法，了解易感宿主中导致AIEC感染的机制至关重要。在这里，我们表明，斑马鱼幼虫模型概括了其他动物模型中AIEC感染的关键特征，并可用于解决这些知识空白。
Inflammatory bowel disease (IBD) is a broad term for a range of chronic intestinal disorders, including Crohn’s disease and ulcerative colitis. The global prevalence of IBD is rising, with over one million patients affected in the United States alone. Adherent-invasive Escherichia coli (AIEC) is a pathobiont frequently found in IBD biopsies. AIEC adhere to and invade epithelial cells, and can survive inside phagocytes in vitro. However, how AIEC contribute to IBD in vivo remains unclear. Here, we established a larval zebrafish (Danio rerio) model to study the interplay between pre-existing intestinal inflammation and AIEC colonization of the gut. We used the pro-inflammatory drug dextran sulfate sodium (DSS) to induce intestinal inflammation. This was followed by food-borne infection of larvae with AIEC using the protozoan Paramecium caudatum, a natural prey, as a vehicle. We show that AIEC more robustly colonize the zebrafish gut and are cleared slower than non-pathogenic E. coli. In addition, DSS-induced enterocolitis increases bacterial burden and decreases bacterial clearance in the larval gut. We benchmark our model against existing rodent models using two mutants deficient in the known AIEC virulence factors FimH and IbeA, which have virulence defects in both rodent and the larval zebrafish model. Finally, we show that AIEC colonization exacerbates DSS-induced enterocolitis and prevents recovery from inflammation-induced damage. In conclusion, we established a high-throughput, genetically tractable model to study AIEC-host interactions in the context of pre-existing inflammation. Although inflammatory bowel diseases are on the rise, what factors influence IBD risk and severity, and the underlying mechanisms remain to be fully understood. Although host genetics, microbiome, and environmental factors have all been shown to correlate with the development of IBD, cause and effect are difficult to disentangle in this context. For example, AIEC is a known pathobiont found in IBD patients, but it remains unclear if gut inflammation during IBD facilitates colonization with AIEC, or if AIEC colonization makes the host more susceptible to pro-inflammatory stimuli. It is critical to understand the mechanisms that contribute to AIEC infections in a susceptible host in order to develop successful therapeutics. Here, we show that the larval zebrafish model recapitulates key features of AIEC infections in other animal models and can be utilized to address these gaps in knowledge.
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影响因子：
4.6
作者：
Bretin A;Lucas C;Larabi A;Dalmasso G;Billard E;Barnich N;Bonnet R;Nguyen HTT
通讯作者：
Nguyen HTT
影响因子：
6.7
作者：
Dreux N;Denizot J;Martinez-Medina M;Mellmann A;Billig M;Kisiela D;Chattopadhyay S;Sokurenko E;Neut C;Gower-Rousseau C;Colombel JF;Bonnet R;Darfeuille-Michaud A;Barnich N
通讯作者：
Barnich N
影响因子：
4.4
作者：
Crepin, Sebastien;Harel, Jos;Dozois, Charles M.
通讯作者：
Dozois, Charles M.
影响因子：
29.4
作者：
Darfeuille-Michaud, A;Neut, C;Colombel, JF
通讯作者：
Colombel, JF
影响因子：
3.1
作者：
Barnich, N;Bringer, MA;Darfeuille-Michaud, A
通讯作者：
Darfeuille-Michaud, A