宿主消化道微生物相及代謝疾病對大腸腺瘤及頸動脈內皮斑塊形成之研究：著重於幽門桿菌感染與高血糖

The study of gut microbiota and host metabolic disease related colon adenomatous polyp and carotid artery plaque formation: Focus on Helicobacter pylori infection and Hyperglycemia

胡光濬(Kuang-Chun Hu)

指導教授 ： 吳明賢

共同指導教授 ： 劉俊人(Chun-Jen Liu)

國立臺灣大學/醫學院/臨床醫學研究所/博士(2018年)

https://doi.org/10.6342/NTU201802147

摘要

本研究分為三個部分，前兩個部分為回溯性研究，研究的目標是討論高血糖合併幽門螺旋桿菌感染對於大腸腺瘤性瘜肉及頸動脈斑塊生成的影響。研究對象收集自2006年1月至2015年6月至馬偕醫院健康檢查中心，同時接受全身健檢包含胃鏡大腸內視鏡檢查及頸動脈超音波檢查的受檢者資料。記錄研究對象的大腸鏡檢查結果，同時記錄受檢者的顱外頸動脈超音波的結果，分析頸動脈內皮是否有斑塊形成的現象。再由理學檢查及生化檢查數據，得到研究對象的BMI；血壓；血糖；糖化血色素(HbA1C)；膽固醇；幽門螺旋桿菌感染狀況等檢驗數值作分析。
第一部分的研究聚焦於高血糖與幽門桿菌感染之間的交互作用，對於大腸腺瘤性瘜肉形成的影響。結果顯示：男性、年紀、BMI、幽門螺旋桿菌感染及醣化血色素>6.5%是促進形成大腸腺瘤的獨立危險因子。不論有無幽門螺旋桿菌感染，大腸腺瘤的發生率都會隨著糖化血色素的上升而增加(HbA1c < 5.6%, 27.93% vs 22.06%; 5.7% ≤ HbA1c ≤ 6.4%, 29.82% vs 27.54%; HbA1c ≥ 6.5 %, 57.14% vs 32.47%)。而有感染的受檢者，上升的比例更高。對於有幽門螺旋桿菌感染的受檢者而言，當醣化血色素上升到7%，相對於正常醣化血色素且無幽門螺旋桿菌感染的受檢者而言，其產生大腸腺瘤性瘜肉的勝算比增加到4.79 (95% CI 2.92 –7.84, p < 0.0001)。第二部份的研究重點在於合併大腸腺瘤性瘜肉與頸動脈斑塊危險因子的評估，由多變項邏輯回歸分析發現，當受檢者年齡大於60歲，男性，BMI大於27，LDL＞130 mg/dL，醣化血色素大於6.5%，高敏感性C反應蛋白大於0.3 mg/L，幽門螺旋桿菌感染陽性，以及使用高血壓控制藥物等，都是造成合併大腸腺瘤性瘜肉及頸動脈斑塊形成的獨立危險因子。當醣化血色素介於5.7% – 6.4%，相較於醣化血色素正常者(HbA1c≦5.6%)，合併產生大腸腺瘤性瘜肉及頸動脈斑塊的勝算比為1.792; 95% CI, 1.161 – 2.767; p = 0.0085)；而當醣化血色素大於6.5%；勝算比上升到3.507; 95% CI, 1.969 – 6.245; p < 0.0001)。而對於幽門螺旋桿菌感染陽性者，相較於醣化血色素正常者，當醣化血色素介於5.7% – 6.4%，合併產生大腸腺瘤性瘜肉及頸動脈斑塊的風險為3.646; 95% CI, 2.323–5.732; p < 0.0001)，當醣化血色素大於6.5%，相對於未感染幽門螺旋桿菌且醣化血色素正常者，其合併產生大腸腺瘤性瘜肉及頸動脈斑塊的風險甚至上升到15倍以上(OR：15.870, 95% CI, 8.661–29.082; p < 0.0001)。
第三部分的研究則著重在幽門螺旋桿菌感染與大腸腺瘤性瘜肉因果關係的探討。我們將受檢者分成3組：Group 1: 於第一次檢查中未發現大腸腺瘤性瘜肉，且幽門螺旋桿菌檢查為陰性。Group 2: 於第一次檢查中未發現大腸腺瘤性瘜肉，幽門螺旋桿菌檢查為陽性，但是在第二次內視鏡檢查，幽門螺旋桿菌檢查為陰性。Group 3: 於第一次檢查中未發現大腸腺瘤性瘜肉，幽門螺旋桿菌檢查為陽性，而且在第二次內視鏡檢查，幽門螺旋桿菌檢查仍為陽性。結果發現每一千人-年發生管狀腺瘤的比例在Group 1為71.76，在Group 2則為51.60；Group 3則為160.52。三組之間皆有明顯的差異。在沒有幽門螺旋桿菌感染的受檢者中，當BMI > 27其產生大腸腺瘤性瘜肉的風險上升到2.32 (95% CI=1.394, 3.860, p =0.001)。將Group 2 及 Group 3 的受檢者合併，進行造成大腸腺瘤危險因子的單變項及多變項分析。可以發現持續有幽門螺旋桿菌感染的受檢者，大腸腺瘤產生的風險是已無幽門螺旋桿菌感染者的3.04倍 (HR: 3.04, 95% CI = 1.754, 5.280, p <0.0001)。實驗結束時間點(endpoint)的糖化血色素值，在單變項分析時；亦是造成大腸腺瘤的危險因子(HR: 1.30，95% CI = 1.02, 1.65, p = 0.034)，但是多變項分析時，未達到統計學上明顯的差異。
高血糖合併幽門螺旋桿菌的感染時，對於大腸腺瘤性瘜肉的形成有加乘作用。高血糖合併幽門螺旋桿菌感染是同時發生頸動脈斑塊及大腸腺瘤的核心危險因子。幽門螺旋桿菌的存在與大腸腺瘤的形成有因果關係。根除幽門螺旋桿菌不僅僅是降低了消化性潰瘍及胃部惡性疾病的形成，也減少了大腸腺瘤性瘜肉發生。

關鍵字

幽門螺旋桿菌 ； 高血糖 ； 大腸腺瘤 ； 頸動脈斑塊

並列摘要

This study comprises three separate parts. The first two parts were retrospective and aimed at evaluating the relationship between hyperglycemia and Helicobacter pylori (H. pylori) infection and their effects on colon adenomatous polyp and carotid artery plaque formations. We enrolled asymptomatic participants who accepted upper endoscopies with a H. pylori test, colonoscopy, and carotid artery sonography examinations on the same day at the MacKay Memorial Hospital Health Evaluation Center from January 2006 to June 2015. We collected data on all baseline characteristics and anthropometric measures, including age, body weight, and body mass index (BMI), and on biochemistry laboratory results including total cholesterol, triglycerides, blood glucose, and glycosylated hemoglobin (HbA1c) levels for further analysis. We focused on associations between hyperglycemia presence and H. pylori infection and formation of either colon adenomatous polyps or carotid artery plaques.
The first part of the study was designed to investigate the association between H. pylori and hyperglycemia status in patients at a risk of colon adenoma. Our results revealed male sex, age, BMI, H. pylori infection, and an HbA1c level ≥ 6.5% as independent risk factors for adenomas. The prevalence of adenoma was increased in patients with elevated HbA1c levels in both H. pylori-positive and -negative groups (HbA1c < 5.6%, 27.93% vs. 22.06%; 5.7% ≤ HbA1c ≤ 6.4%, 29.82% vs. 27.54%; HbA1c ≥ 6.5 %, 57.14% vs. 32.47%). The OR for adenoma was 1.44 (95% CI, 1.20–1.73) in H. pylori- positive patients or 1.68 (95% CI, 1.05–2.70) in H. pylori- negative patients with HbA1c ≥ 7.0%. If both conditions were present, the OR was 4.79 (95% CI, 2.92–7.84). In the second part of our study, we found that age ≥ 60 years, male sex, BMI > 27, LDL > 130 mg/dL, HbA1c ≥ 6.5%, hs-CRP > 0.3 mg/L, and H. pylori infection were independent risk factors for synchronous colorectal adenoma and carotid artery plaque formation. The OR for synchronous colon adenoma and carotid artery plaque was significantly higher in the participants with HbA1c levels of 5.7%–6.4% and HbA1c ≥ 6.5% than in those with normal HbA1c in the H. pylori- negative group. The OR was increased further in H. pylori- positive patients when the HbA1c level ≥6.5% was 15.87 (95% CI, 8.661–29.082; p <0.0001).
The third part of our study was a retrospective cohort study to evaluate the cause–effect of H. pylori infection and progression of colorectal adenoma. The incidence rates of colorectal adenoma progression in participants with persistent H. pylori infection (persistent group) and those after successful eradication of this bacterium (eradication group) were 160.52 and 51.60 per 1000 person-years, respectively (P = 0.0003). Compared with the eradication group, the persistent group had a higher risk of colorectal adenoma (hazards ratio, 3.04; 95% CT, 1.754–5.280; P <0.0001).
Hyperglycemia combined with H. pylori infection was an increased risk factor for synchronous colorectal adenoma and carotid artery plaque formation. H. pylori eradication not only decreased the incidence of gastric malignancy disease but also reduced the likelihood of colorectal adenoma development. Diabetes control may be warranted in higher prevalence areas.

並列關鍵字

Colon adenoma ； carotid artery plaque ； Helicobacter pylori ； hyperglycemia

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