幽門螺旋桿菌 (H.pylori) 為一存在於胃腸道黏膜上的彎曲桿狀革蘭氏陰性微需氧菌，目前許多文獻已說明感染幽門螺桿菌與消化性潰瘍、淋巴瘤、胃癌等消化道疾病的發病機制有關，目前對於幽門螺旋桿菌的治療以服用克拉黴素 (Clarithromycin)、阿莫西林 (Amoxicillin)、甲硝唑 (Metronidazole) 等口服抗生素輔以質子幫浦阻斷劑多重療法為主要治療方法。本實驗室近年來已成功開發出胃部動態模擬系統，用以了解益生菌對H.pylori的抑制情況，及在動態模擬系統下添加Amoxicillin與益生菌共同抑制幽門螺旋桿菌，觀察其抑制情形效果。然而，由於胃的排空效應，這些益生菌與抗生素也會影響到腸道系統，然而目前尚缺少這樣的評估系統。本研究所開發的模擬腸道系統中，主要利用人類結腸癌細胞 (Caco-2) 作為研究對象，由於此細胞在體外長時間培養後會自發分化，分化後的微絨毛結構、細胞表面刷狀邊界、細胞間緊密連接、分泌水解酶等型態與正常腸細胞具有相似特徵，因此時常被用以體外模擬腸道上皮細胞的模型。因此本研究目的在利用3D列印技術開發出一簡化腸道動態模擬系統，以藉此了解在經過模擬胃部排空後，幽門螺旋桿菌、益生菌、抗生素等物質對於腸道細胞Caco-2的影響。
研究結果顯示在動態胃模擬系統中，投入1000 mg/L的抗生素Amoxicillin Sodium對於幽門螺旋桿菌的抑制有最佳的結果，抑制率為93.16%。而再進一步添加益生菌羅伊氏乳桿菌 (L.reuteri) 共同抑制幽門螺旋桿菌的實驗中，以組別1000 mg/L Amoxicillin Sodium+7ml OD1.0 L.reuteri達到最佳的抑制效果，抑制率達到99.85%，顯示在1000 mg/L Amoxicillin Sodium 的幫助下，隨著益生菌的添加，抑制率會隨之上升。Caco-2已成功培養出分化完整的細胞單層，其單層膜的跨膜上皮電阻 (Transepithelial electrical resistance, TEER) 值、Phenol red滲透性數值(Papp)、分化特性酶活力 (ALP activity、SUC activity) 皆達一定數值。而後投入靜態腸模擬系統，觀察各處理組對腸道上皮屏障功能之效果，發現抗生素Amoxicillin sodium與幽門螺旋桿菌會使腸道細胞存活率分別下降了5.2%和7.7%，顯示兩者在流入腸道環境中，可能會對細胞造成一些損傷;另外也觀察到益生菌羅伊氏乳桿菌在模擬系統當中不會對細胞有損害，在動態腸道模擬系統方面，已成功將細胞單層培養於動態腸道模擬反應槽中，細胞存活率可達79.5%。

Helicobacter pylori is a curved rod-shaped gram-negative microaerophilic bacteria that exists on the gastrointestinal mucosa. Currently, many literatures indicated that infection with Helicobacter pylori is related to the pathogenesis of peptic ulcer, lymphoma, gastric cancer and other digestive tract diseases. Nowadays, the main treatment for H.pylori is taking different therapy that is antibiotics such as Clarithromycin, Amoxicillin, Metronidazole used with proton pump inhibitor.
In recent years, our laboratory has successfully developed a gastric dynamic simulation system to understand the inhibitory effect of probiotics on H.pylori, and added Amoxicillin and probiotics to jointly inhibit H.pylori under the dynamic simulation system to observe the inhibitory effect. However, these probiotics and antibiotics still affect the intestinal system due to the gastric emptying effect and an assessment system is currently lacking. Among them, Caco-2 is a human colon cancer cell. Since this cell will spontaneously differentiate after a long-term culture in vitro, the differentiated microvilli structure, cell surface brush-like border, intercellular tight junction, secreted hydrolase and other types are closely related to intestinal cells. For this reasons, Caco-2 cell lines are usually used as a model to simulate intestinal epithelial cells in vitro. Therefore, the purpose of this study was to develop a simplified intestinal dynamic simulation system using 3D printing technology to understand the effects of H.pylori, probiotics, antibiotics and other substances on intestinal cells Caco-2 after simulated gastric emptying impact.
The research results showed that in the dynamic gastric simulation system, 500 mg of antibiotic Amoxicillin Sodium had the best effect on the inhibition of H.pylori, with an inhibition rate of 93.16%. In the experiment of further adding probiotics L.ruteri to inhibit H.pylori, the group 500 mg Amoxicillin Sodium+7ml OD1.0 L.reuteri achieved the best inhibitory effect, and the inhibition rate reached 99.85%, which showed that in 500mg Amoxicillin Sodium With the help of probiotics, the inhibition rate will increase. Caco-2 has successfully cultured a fully differentiated cell monolayer. The transepithelial electrical resistance (TEER) value, Phenol red permeability value (Papp), differentiation characteristic enzyme activity (ALP activity, SUC activity) of the monolayer membrane have been successfully cultured all reach a certain value. Then put it into the static intestinal simulation system to observe the effect of each treatment group on the intestinal epithelial barrier function. It was found that the antibiotics Amoxicillin sodium can decrease 5.2% survival rate of intestinal cells and H. pylori can decrease 7.7% survival rate of intestinal cells. It showed that both Amoxicillin sodium and H.pylori are flowing into the gut environment, possibly causing some damage to the cells. Successfully, in the dynamic intestinal simulation system, the cell survival rate can reach 83.4% by culturing the cell monolayer in the dynamic intestinal simulation reaction tank.

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