Division of Rheumatology, Department of Internal Medicine, CHA Bundang Medical Center, CHA University, 59 Yatap-ro, Bundang-gu, Seongnam, 13496, South Korea.
Department of Precision Medicine, Sungkyunkwan University School of Medicine, 2066 Seobu-ro, Jangan-gu, Suwon, 16416, South Korea.
J Autoimmun. 2023 May;137:102997. doi: 10.1016/j.jaut.2023.102997. Epub 2023 Feb 1.
Escherichia coli (E.coli) infection has been proposed to play an important role as an initial trigger in the development of autoimmunity via molecular mimicry. However, there has been no preliminary cohort study to establish the association of E.coli infection with autoimmune diseases. Therefore, we conducted a large scale, population-matched cohort study to determine the risk of autoimmune disease among patients with exposure to E.coli.
Utilizing the National Health Insurance Service database, we retrospectively analyzed a total of 259,875 Korean children that consisted of 23,625 exposed and 236,250 unexposed persons from January 1, 2002 to December 31, 2017. The exposed cohort was defined as patients diagnosed with E.coli infection. Unexposed controls were matched by birth year and sex at a 1:10 ratio for each exposed patient, using incidence density sampling. The primary outcome was autoimmune disease development. We used the Cox model to estimate the risks of autoimmune diseases among patients diagnosed with E.coli infection.
Over a mean follow-up of 10 years, there were 1455 autoimmune disease cases among exposed patients (incidence rate, 63.6 per 10,000 person-years) and 11,646 autoimmune disease cases among unexposed persons (incidence rate, 50.4 per 10,000 person-years), with an adjusted hazard ratio (HR) of 1.254 (95% CI 1.187-1.325). E.coli infection was associated with increased risks of autoimmune diseases; Reactive arthritis, HR 1.487, 95% CI 1.131-1.956; Henoch Schönlein purpura, HR 1.265, 95% CI 1.050-1.524; Systemic lupus erythematosus, HR 1.838, 95% CI 1.165-2.898; Sjögren's syndrome, HR 2.002, 95% CI 1.342-2.987; IgA nephropathy, HR 1.613, 95% CI 1.388-1.874. Kaplan-Meier cumulative incidence curves also showed a significant association between E.coli infection and incident autoimmune disease (p < 0.0001). This relationship was not only independent of demographic variables, but also remained consistent across various sensitivity analyses. On the other hand, patients with longer hospital stay for E.coli infection were at a higher risk of autoimmune disease (p = 0.0003), and the risk of autoimmune disease also tended to increase, as the frequency of E.coli infection was higher. Moreover, the relative risk of autoimmune disease seemed to be attenuated by use of antibiotics and a history of intestinal infectious disease, but elevated by coexistence of other autoimmune diseases.
Our cohort study indicates that E.coli infection was significantly associated with increased susceptibility to autoimmune diseases, even after adjusting for different factors. Thus, among environmental factors, a previous history of E.coli infection could be a predisposing risk factor in the development of autoimmune diseases.
大肠杆菌（E.coli）感染被认为通过分子模拟在自身免疫疾病的发展中起着重要的初始触发作用。然而，目前还没有初步的队列研究来确定大肠杆菌感染与自身免疫性疾病之间的关联。因此，我们进行了一项大规模的、人群匹配的队列研究，以确定大肠杆菌感染患者患自身免疫性疾病的风险。
利用国家健康保险服务数据库，我们回顾性分析了 2002 年 1 月 1 日至 2017 年 12 月 31 日期间的 259875 名韩国儿童，其中包括 23625 名暴露组和 236250 名未暴露组。暴露组定义为诊断为大肠杆菌感染的患者。未暴露对照组通过发病率密度抽样，按出生年份和性别与每个暴露患者 1:10 的比例匹配。主要结局是自身免疫性疾病的发生。我们使用 Cox 模型来估计大肠杆菌感染患者患自身免疫性疾病的风险。
在平均 10 年的随访期间，暴露组中有 1455 例自身免疫性疾病（发病率为 63.6/10000 人年），未暴露组中有 11646 例自身免疫性疾病（发病率为 50.4/10000 人年），调整后的风险比（HR）为 1.254（95%CI 1.187-1.325）。大肠杆菌感染与自身免疫性疾病的发生风险增加相关；反应性关节炎，HR 1.487，95%CI 1.131-1.956；过敏性紫癜，HR 1.265，95%CI 1.050-1.524；系统性红斑狼疮，HR 1.838，95%CI 1.165-2.898；干燥综合征，HR 2.002，95%CI 1.342-2.987；IgA 肾病，HR 1.613，95%CI 1.388-1.874。Kaplan-Meier 累积发病率曲线也显示大肠杆菌感染与自身免疫性疾病的发生之间存在显著相关性（p<0.0001）。这种关系不仅独立于人口统计学变量，而且在各种敏感性分析中仍然一致。另一方面，大肠杆菌感染住院时间较长的患者发生自身免疫性疾病的风险更高（p=0.0003），并且随着大肠杆菌感染频率的增加，自身免疫性疾病的风险也趋于增加。此外，自身免疫性疾病的相对风险似乎因使用抗生素和肠道传染病史而降低，但因同时存在其他自身免疫性疾病而升高。
我们的队列研究表明，大肠杆菌感染与自身免疫性疾病的易感性增加显著相关，即使在调整了不同因素后也是如此。因此，在环境因素中，大肠杆菌感染的既往史可能是自身免疫性疾病发生的一个易感风险因素。
