減重手術對代謝性發炎疾患的影響：著重在第二型糖尿病及代謝性內毒素血症

Abstract

肥胖及第二型糖尿病都被認為是慢性低程度的發炎狀態，目前有許多的生物因子可能與肥胖及糖尿病有關，但詳細的關聯及機轉目前仍不清楚。減重手術不只減輕體重，還可以改善及預防包含第二型糖尿病在內的代謝疾病。不同的減重手術會導致不同的生理病理變化，因此，減重手術對於肥胖、糖尿病及其可能相關因子的研究，提供了一個很好的平台。 胎球蛋白-A (fetuin-A) 及基質金屬蛋白脢-7 (matrix metalloproteinase-7)都是第二型糖尿病的相關因子，我們研究的第一部分是研究有或無糖尿病的肥胖病人，在接受減重手術前後血中胎球蛋白-A及基質金屬蛋白脢-7的變化。我們招募了130位接受減重手術的肥胖病人（包含41位Y型胃繞道、67位迷你胃繞道和22位胃袖狀切除），其中43位病人在手術前患有第二型糖尿病，手術一年後只有5位仍保有糖尿病。患有第二型糖尿病的肥胖病人在手術前血中的胎球蛋白-A和基質金屬蛋白脢-7濃度明顯比沒有糖尿病的肥胖病人高，在接受三種減重手術一年後，血中的胎球蛋白-A濃度都明顯降低，而基質金屬蛋白脢-7的濃度則沒有改變。經多因子變項分析後，術前的胎球蛋白-A與舒張壓及醣化血色素有關，而術後的胎球蛋白-A則與腰臀圍比和醣化血色素相關；另一方面，手術前的基質金屬蛋白脢-7與年紀、舒張壓、天冬氨酸轉氨酶(aspartate transaminase)、丙氨酸轉氨酶(alanine transaminase)及丙麩氨轉肽酶(gamma-glutamyl transferase)有關，而術後的基質金屬蛋白脢-7則與年紀和丙麩氨轉肽酶相關。 近年研究發現血中脂多醣結合蛋白(lipopolysaccharide binding protein)與肥胖及肥胖相關代謝疾病有關，在研究的第二部分，我們主要針對減重手術前後血中脂多醣結合蛋白和其他相關臨床因子的變化來做分析。我們招募了178位接受四種不同減重手術的肥胖病人和38位正常體重的受試者，在手術前肥胖病人血中的脂多醣結合蛋白濃度明顯比正常體重的人高，在接受減重手術一年後，肥胖者血中的脂多醣結合蛋白明顯降低。這些接受減重手術的肥胖病人，經多因子變項分析後，術前血中脂多醣結合蛋白濃度只與高敏感度C-反應蛋白(hs-CRP)有關，而手術前後脂多醣結合蛋白的改變程度也與高敏感度C-反應蛋白的改變程度相關，但手術一年後，血中脂多醣結合蛋白和高敏感度C-反應蛋白的關聯性則消失不見。 第二部分的結果發現胃腸繞道手術會降低與全身性菌血症相關的脂多醣結合蛋白濃度，近年的研究也證實胃腸繞道手術會改變腸道菌種，而腸道屏障的完整性對於限制腸內菌在腸胃道管腔內，避免腸內菌引起全身性菌血症扮演了關鍵的角色。因此，在第三部分，我們利用接受十二指腸空腸繞道手術和假手術的大鼠模型，來探討胃腸繞道手術對於腸道通透性及腸道屏障的影響。研究結果發現在接受十二指腸空腸繞道手術後，食物段及混合段的小腸腸內菌數目明顯增加，而在食物段、混合段及大腸的腸道通透性則降低，而且食物段和混合段小腸內的絨毛高度、腸道腺窩的深度和腸黏膜上的緊密連接蛋白(occludin)及增殖細胞核抗原(proliferating cell nuclear antigen)的表現量都明顯增加。因此，我們的動物實驗證實十二指腸空腸繞道手術會改變腸內菌，並藉由增加小腸上皮細胞增生和增加細胞間隙緊密結合蛋白的表現來降低腸道通透性，研究結果顯示胃腸繞道手術可以增加腸道屏障功能，這或許可以解釋減重手術為何可以降低肥胖病人血中的菌血症。

Obesity and type 2 diabetes (T2DM) are both characterized as a state of chronic low-grade inflammation. There are several possible biomarkers for obesity and T2DM, but the relationships and detailed mechanisms were not well discovered. Bariatric surgery not only reduces body weight, but also improves and prevents obesity related disorders, including T2DM. Different procedures lead to different pathophysiological changes. Therefore, bariatric surgery provides a good tool to study the detail mechanisms of obesity, T2DM, and the associated biomarkers. Fetuin-A and matrix metalloproteinase-7 (MMP-7) are both T2DM-associated markers. The first part of my study aimed to investigate the changes of fetuin-A and MMP-7 in obese subjects with and without T2DM after bariatric surgery. We enrolled 130 obese subjects that received bariatric surgery, including 41 Roux-en-Y gastric bypass (RYGB), 67 mini-gastric bypass (MGB), and 22 sleeve gastrectomy (SG) patients. Forty-three patients suffered from T2DM prior to surgery, and only five remained diabetic one year after surgery. The fetuin-A and MMP-7 levels are both higher in obese T2DM than non-T2DM subjects. The level of fetuin-A is reduced one year after RYGB, MGB, and SG, but the level of MMP-7 remains unchanged. In multi-variate analyses, the preoperative fetuin-A was significantly related to the diastolic blood pressure (DBP) and glycosylated hemoglobin (HbA1c), while the postoperative fetuin-A was independently related to the waist-to-hip ratio and HbA1c. Moreover, the preoperative MMP-7 level was significantly related to age, DBP, aspartate transaminase, alanine transaminase, and gamma-glutamyl transferase (rGT), while the postoperative MMP-7 level was independently related to age and rGT. Recent studies have shown serum lipopolysaccharide binding protein (LBP) is associated with obesity and related metabolic disorder. In the second part, we investigated LBP concentration and its associations with clinical variables after bariatric surgery. One hundred and seventy eight obese subjects receiving different bariatric surgeries and 38 normal weight individuals were enrolled. Serum LBP levels were higher in the obese participants than in the normal weight participants at baseline, and significantly decreased one year after bariatric surgery in the obese group. In the bariatric participants, after multivariate analyses, preoperative LBP and the change of LBP with surgery were independently associated only with hs-CRP and the change of hs-CRP respectively, while none of the postoperative variables was independently associated with LBP. The relationship between LBP and hs-CRP disappeared after bariatric surgery. Gastrointestinal bypass changes the gut microbiota and decreases systemic endotoxemia in obese subjects. Epithelial barrier integrity is crucial for confining enteric bacteria in the lumen and preventing gut-derived endotoxemia. Therefore, the third part of our study aimed to evaluate the changes in intestinal permeability and gut barrier between rats receiving Roux-en-Y duodenojejunal bypass (DJB) or sham operation (SO). Enteric bacterial numbers were increased in the alimentary and common limbs after DJB. Reduced dextran permeability was found in the alimentary limb, common limb, and colon after DJB. Moreover, increased villus height and crypt depth were found to be associated with higher mucosal levels of occludin and proliferating cell nuclear antigen levels in the alimentary and common limbs after DJB. In summary, DJB in rats altered gut microbiota, and reduced intestinal permeability due to increased epithelial proliferation and tight junctional protein expression. Our results show that bypass surgery led to fortification of the intestinal barrier functions, which may provide an explanation for the decreased risk of systemic endotoxemia in postoperative patients.