Elevated Human β-Defensin-2 Levels Indicate an Activation of the Innate Immune System in Patients With Irritable Bowel Syndrome
Elevated Human β-Defensin-2 Levels Indicate an Activation of the Innate Immune System in Patients With Irritable Bowel Syndrome
复制标题
DOI：
10.1038/ajg.2008.86
复制
发表时间：
2009-02-01
影响因子：
9.8
通讯作者：
Dobos, Gustav J.
中科院分区：
文献类型：
--
作者：
Langhorst, Jost;Junge, Angela;Dobos, Gustav J.
肠易激综合征（IBS）是一种高度流行的功能性疾病。根据罗马标准，肉眼和组织学炎症是IBS的关键排除标准。人类防御素似乎是胃肠道先天免疫系统的一部分。人β-防御素-2（HBD-2）是第一个发现的可诱导的人类抗菌蛋白。该表达由益生菌微生物和促炎细胞因子诱导。最近的研究结果表明，HBD-2表达在活动性肠道炎症，特别是在溃疡性结肠炎（UC）。我们的目的是评估粪便HBD-2的测量活动性UC和IBS患者，并在健康对照（HCs.METHODS）：粪便标本收集共100名参与者（30个活动性UC，46 IBS，和24 HC）。排除标准是目前使用益生菌和抗生素。此外，排除了C反应蛋白或白细胞升高、过去6个月内有细菌过度生长或感染性胃肠道疾病史的IBS患者。根据病史和当前症状，讨论所有参与受试者的疾病状态。此外，每例IBS和UC患者均接受回结肠镜检查和组织病理学检查。通过酶联免疫吸附测定（ELISA）测量粪便炎症标志物乳铁蛋白（Lf）和钙卫蛋白（Cal），并报告为μ g/g。通过ELISA测量粪便HBD-2，并报告为ng/g粪便。此外，对粪便HBD-2进行免疫印迹。结果：Lf和Cal在活动性UC中升高（平均值：152.1 +/- s.d.，P < 0.05），而在活动性UC中升高（平均值：152.1 +/- s.d.，P < 0.05）。374.7 μ g/g; 103.5 +/- 87.1 μ g/g），与IBS（8.3 +/- 19.4 μ g/g; 18.6 +/- 23.3 μ g/g）和HC（0.4 +/- 0.5 μ g/g; 7.1 +/- 7.9 μ g/g）相比。Scheffe事后检验显示活动性UC与IBS和HC之间存在显著差异（P = 0.006; P < 0.001）。相比之下，HBD-2水平在活动性UC中最高（平均值：106.9 +/- s.d. 91.5肠易激综合征患者中的含量几乎同样高（pts 76.0 +/- 67.9 ng/g），而HC的含量最低（29.9 +/- 16.1 ng/g）。Scheffe事后检验显示，患者组（UC和IBS）与HC之间存在显着差异（P < 0.001）。免疫组化结果与粪便分泌物结果一致，表明UC患者结肠上皮细胞中存在β-防御素2肽，IBS患者粪便HBD-2水平升高。结论：IBS患者HBD-2水平显著高于HC患者，与活动期UC患者相似。结果支持在没有炎症的宏观体征的情况下，IBS患者中粘膜先天防御系统朝向促炎反应的激活。
OBJECTIVES: Irritable bowel syndrome (IBS) is a highly prevalent functional disorder. According to the Rome criteria, macroscopic and histological inflammation is a crucial exclusion criterion for IBS. Human defensins appear to be part of the innate immune system in the gastrointestinal tract. Human beta-defensin-2 (HBD-2) was the first inducible human antimicrobial protein discovered. The expression is induced by probiotic microorganisms and proinflammatory cytokines. Recent results imply that HBD-2 is expressed in active intestinal inflammation, especially in ulcerative colitis (UC). Our aim was to evaluate fecal measurements of HBD-2 in patients with active UC and IBS, and in healthy controls (HCs).METHODS: Fecal specimens were collected from a total of 100 participants (30 with active UC, 46 IBS, and 24 HCs). Exclusion criteria were the current use of probiotics and antibiotics. Furthermore, IBS patients with elevated C-reactive protein or leukocytes, a history of bacterial overgrowth or infectious gastrointestinal disease over the last 6 month were excluded. Disease status was addressed in all participating subjects by medical history and current symptoms. In addition, each IBS and UC patient underwent ileocolonoscopy with histopathology. Fecal inflammation markers lactoferrin (Lf) and calprotectin (Cal) were measured by enzyme-linked immunosorbent assay (ELISA) and reported as mu g/g. Fecal HBD-2 was measured by ELISA and reported as ng/g feces. In addition, immunoblots were performed for fecal HBD-2. Paraffin-embedded tissue from colonic biopsies was tested for HBD-2 peptides by immunohistochemistry.RESULTS: Lf as well as Cal was elevated in active UC (mean: 152.1 +/- s.d. 374.7 mu g/g; 103.5 +/- 87.1 mu g/g), compared with IBS (8.3 +/- 19.4 mu g/g; 18.6 +/- 23.3 mu g/g), and HCs (0.4 +/- 0.5 mu g/g; 7.1 +/- 7.9 mu g/g). Scheffe post hoc tests revealed significant differences (P = 0.006; P < 0.001) between active UC vs. IBS and HC. In contrast, HBD-2 levels were highest in active UC (mean: 106.9 +/- s.d. 91.5 ng/g), almost as high in IBS (pts 76.0 +/- 67.9 ng/g), and lowest for HCs (29.9 +/- 16.1 ng/g). Scheffe post hoc tests revealed significant differences (P < 0.001) between the groups of patients (UC and IBS) vs. HCs. Immunohistochemical investigation was consistent with fecal secretion data and demonstrated the presence of beta-defensin 2 peptides in colonic epithelial enterocytes in UC as well as IBS patients with elevated fecal HBD-2.CONCLUSIONS: The results indicate significantly elevated levels of HBD-2 in patients with IBS compared with HCs and similar to those with active UC. The results support an activation of the mucosal innate defense system toward a proinflammatory response in IBS patients in the absence of macroscopic signs of inflammation.