Dogan Belgin, Suzuki Haruo, Herlekar Deepali, Sartor R Balfour, Campbell Barry J, Roberts Carol L, Stewart Katrina, Scherl Ellen J, Araz Yasemin, Bitar Paulina P, Lefébure Tristan, Chandler Brendan, Schukken Ynte H, Stanhope Michael J, Simpson Kenneth W
Departments of *Clinical Sciences, and †Population Medicine and Diagnostic Sciences, College of Veterinary Medicine, Cornell University, Ithaca, New York; ‡Department of Environmental Science and Engineering, Graduate School of Science and Engineering, Yamaguchi University, Yamaguchi, Japan; §Departments of Medicine, and ‖Microbiology and Immunology, University of North Carolina at Chapel Hill School of Medicine, Chapel Hill, North Carolina; ¶Department of Gastroenterology, Institute of Translational Medicine, University of Liverpool, Liverpool, United Kingdom; and **Department of Medicine, Jill Roberts Center for Inflammatory Bowel Disease, Weill Medical College of Cornell University, New York, New York. Dr. T. Lefébure is now with the Université de Lyon and Université Lyon 1, Centre National de la Recherche Scientifique, Ecologie des Hydrosystèmes Naturels et Anthropisés, Villeurbanne, France.
Inflamm Bowel Dis. 2014 Nov;20(11):1919-32. doi: 10.1097/MIB.0000000000000183.
Perturbations of the intestinal microbiome, termed dysbiosis, are linked to intestinal inflammation. Isolation of adherent-invasive Escherichia coli (AIEC) from intestines of patients with Crohn's disease (CD), dogs with granulomatous colitis, and mice with acute ileitis suggests these bacteria share pathoadaptive virulence factors that promote inflammation.
To identify genes associated with AIEC, we sequenced the genomes of phylogenetically diverse AIEC strains isolated from people with CD (4), dogs with granulomatous colitis (2), and mice with ileitis (2) and 1 non-AIEC strain from CD ileum and compared them with 38 genome sequences of E. coli and Shigella. We then determined the prevalence of AIEC-associated genes in 49 E. coli strains from patients with CD and controls and correlated genotype with invasion of intestinal epithelial cells, persistence within macrophages, AIEC pathotype, and growth in standardized conditions.
Genes encoding propanediol utilization (pdu operon) and iron acquisition (yersiniabactin, chu operon) were overrepresented in AIEC relative to nonpathogenic E. coli. PduC (propanediol dehydratase) was enriched in CD-derived AIEC, correlated with increased cellular invasion, and persistence in vitro and was increasingly expressed in fucose-containing media. Growth of AIEC required iron, and the presence of chuA (heme acquisition) correlated with persistence in macrophages. CD-associated AIEC with lpfA 154 (long polar fimbriae) demonstrated increased invasion of epithelial cells and translocation across M cells.
Our findings provide novel insights into the genetic basis of the AIEC pathotype, supporting the concept that AIEC are equipped to exploit and promote intestinal inflammation and reveal potential targets for intervention against AIEC and inflammation-associated dysbiosis.
肠道微生物群的紊乱，即生态失调，与肠道炎症有关。从克罗恩病（CD）患者的肠道、肉芽肿性结肠炎犬以及急性回肠炎小鼠中分离出黏附侵袭性大肠杆菌（AIEC），这表明这些细菌具有共同的促炎致病适应性毒力因子。
为了鉴定与AIEC相关的基因，我们对从CD患者（4株）、肉芽肿性结肠炎犬（2株）、回肠炎小鼠（2株）中分离出的系统发育多样的AIEC菌株以及1株来自CD回肠的非AIEC菌株进行了基因组测序，并将它们与38株大肠杆菌和志贺氏菌的基因组序列进行比较。然后，我们测定了49株来自CD患者和对照的大肠杆菌菌株中AIEC相关基因的流行情况，并将基因型与肠道上皮细胞侵袭、巨噬细胞内存活、AIEC致病型以及标准化条件下的生长情况相关联。
相对于非致病性大肠杆菌，编码丙二醇利用（pdu操纵子）和铁摄取（耶尔森菌素、chu操纵子）的基因在AIEC中过度表达。PduC（丙二醇脱水酶）在CD来源的AIEC中富集，与细胞侵袭增加和体外存活相关，并且在含岩藻糖的培养基中表达增加。AIEC的生长需要铁，chuA（血红素摄取）的存在与巨噬细胞内存活相关。带有lpfA 154（长极毛）的CD相关AIEC表现出上皮细胞侵袭增加和跨M细胞转运。
我们的研究结果为AIEC致病型的遗传基础提供了新的见解，支持了AIEC能够利用并促进肠道炎症的概念，并揭示了针对AIEC和炎症相关生态失调的潜在干预靶点。
