臺灣博碩士論文加值系統

結直腸癌為全球發生率第三高之癌症，其中又以腸炎相關結腸癌（colitis-associated colon cancer, CAC）治療難度大且死亡率高。現今發現攝食較高全穀類與低結腸發炎和癌症風險有關，故調整飲食型態可能可降低罹患腸炎相關結腸癌風險。台灣藜（Chenopodium formosanum, Djulis）為含有全面營養價值的無麩質作物，含多種機能性成分，目前多以脫殼的形式攝取。本研究室先前發現，台灣藜萃取物以脫殼形式具有較佳抑制人類結腸癌細胞存活率之效果。本研究欲模擬民眾日常食用之方式，探討烹煮過的脫殼台灣藜（cooked dehusk djulis, DD）對於腸炎相關結腸癌病變之預防效果。實驗將Fischer 344大鼠分為六組，分別為：N組及C組（標準飲食）、NH組及HD組（10% DD取代之標準飲食）、LD組（2.5% DD取代之標準飲食）及MD組（5% DD取代之標準飲食）。除N組及NH組外，其餘組別於實驗期第二週，以腹腔注射3劑40 mg/kg body weight 之1,2-dimethylhydrazine（DMH），並於實驗第三週給予連續一週含有1% dextran sulphate sodium（DSS）之飲用水，在實驗至第十週結束時犧牲大鼠。研究結果發現，相較於C組，不同劑量DD介入皆可有效改善DSS誘導之發炎症狀，於HD組更有效地抑制結直腸癌癌前病變指標。腸道黏膜蛋白結果也顯示HD組具有最佳抑制增生蛋白proliferating cell nuclear antigen（PCNA）及β-catenin、發炎蛋白phosphor-nuclear factor kappa-light-chain-enhancer of activated B cells（p-NFκB）/NFκB之效果，並提高抗氧化蛋白nuclear factor erythroid 2-related factor 2（Nrf2）表現，及結腸抗氧化酵素superoxide dismutase及catalase活性。此外，透過腸道菌相及糞便代謝物分析，顯示HD組具調節腸道菌群失衡及改善代謝異常的功效，對於維持腸道健康具有正面影響。以上結果皆顯示，DD可透過抗發炎、抗氧化、抗增生以及調節腸道菌相平衡和代謝紊亂等作用以抑制癌前病變，達到預防腸炎相關結腸癌之效果。

The incidence of colorectal cancer ranks third in the world, with colitis-associated colon cancer (CAC) being the most difficult to treat and having a high mortality rate. It has been found that a higher intake of whole grains is associated with a lower risk of inflammation and cancer in the colon, so dietary modification may reduce the risk of CAC. Djulis (Chenopodium formosanum) is a gluten-free crop with nutritional value and functional components, which is currently consumed in the dehusk form. Our laboratory has previously demonstrated that djulis extract, in its dehusk form, has a better inhibitory effect on the cell viability of human colon cancer cells. Therefore, this study was conducted to investigate the effect of cooked dehusk djulis (DD) on the prevention of CAC, simulating the daily consumption of the population. Fischer 344 rats were divided into six groups including N and C (standard diet), NH and HD (standard diet with 10% DD), LD (standard diet with 2.5% DD) and MD (standard diet with 5% DD). Except for the N and NH groups, the remaining groups were given three doses of 1,2-dimethylhydrazine (DMH) at 40 mg/kg body weight by intraperitoneal injection in the second week and 1% dextran sulphate sodium (DSS) in drinking water for one week in the third week. The results showed that compared with C group, all doses of DD intervention could effectively improve the inflammatory symptoms induced by DSS and HD group could effectively inhibit the indicators of colorectal cancer precancerous lesions. The results of colon mucosal proteins also showed that the HD group had the best effect on inhibiting proliferating cell nuclear antigen (PCNA) and β-catenin and phospho-nuclear factor kappa-light-chain-enhancer of activated B cells (p-NFκB)/NFκB and improved the expression of antioxidant proteins nuclear factor erythroid 2-related factor 2 (Nrf2) as well as the antioxidant enzymes superoxide dismutase and catalase activity in the colon. In addition, through the analysis of gut microbiota and fecal metabolites, it was shown that the HD group had the effect on regulating the imbalance of intestinal flora and improving metabolic abnormalities, which may have a positive impact on maintaining intestinal health. All these results showed that DD could inhibit precancerous lesions and prevent CAC through anti-inflammatory, antioxidative, anti-proliferative and regulating the balance of intestinal flora and metabolites.

目錄
摘要 i
Abstract ii
致謝 iii
目錄 iv
圖目次 vii
表目次 ix
縮寫表 x
第一章 前言 1
第二章 文獻回顧 2
第一節 腸炎相關結腸癌 2
（一） 結直腸癌流行病學之研究 2
（二） 結直腸癌致病機轉 5
（三） 異常腺窩病灶-微腺瘤-腺瘤 7
第二節 腸炎相關結腸癌之動物模式 9
（一） 化學誘發模式 9
（二） 動物模式 12
第三節 結直腸癌相關分子路徑 13
（一） 氧化壓力 13
（二） 發炎反應 15
（三） Nuclear factor erythroid 2-related factor 2（Nrf2） 17
（四） 細胞增生 19
第四節 結直腸癌與腸道菌相 20
第五節 腸道菌相及糞便代謝物 22
第六節 台灣藜 25
第三章 研究目的 29
第四章 材料與方法 30
第一節 實驗材料 30
（一） 實驗動物 30
（二） 脫殼台灣藜 30
（三） 實驗飼料組成 30
（四） 實驗藥品 31
（五） 儀器 33
第二節 實驗方法 35
（一） 實驗飼養與分組 35
（二） 脫殼台灣藜製備方法 35
（三） 脫殼臺灣藜烹煮前後一般成分及γ-胺基丁酸分析 35
（四） 實驗流程及架構 36
第三節 分析項目 40
（一） 脫殼台灣藜對動物生長情形 40
（二） 疾病活動指數 40
（三） 動物血清收集 41
（四） 動物肝腎功能評估 41
（五） 肝臟及腎臟秤重分析 41
（六） 盲腸組織處理 41
（七） 結腸組織癌前病變分析 41
（八） 抗氧化指標分析 42
（九） 結直腸癌相關分子途徑蛋白分析 42
（十） 腸道菌相 44
（十一） 糞便非標靶代謝體 45
第四節 統計分析 47
第五章 結果 48
第一節 脫殼台灣藜烹煮前後之成分變化 48
第二節 F344大鼠體重、攝食量及攝食效益 50
第三節 F344大鼠肝臟、腎臟重量及相關血清生化數值 52
第四節 F344大鼠盲腸及結腸之影響 55
第五節 F344大鼠疾病活動指數 58
第六節 F344大鼠結腸上皮組織病理及癌前指標評估 60
第七節 F344大鼠結腸抗氧化酵素活性 63
第八節 F344大鼠腸道黏膜蛋白表現量 65
第九節 F344大鼠腸道菌相組成 69
第十節 F344大鼠糞便代謝物 78
第六章 討論 95
第一節 脫殼台灣藜烹煮前後之成分組成差異 95
第二節 烹煮脫殼台灣藜對F344大鼠體重、攝食量及攝食效益之影響 97
第三節 烹煮脫殼台灣藜對F344大鼠肝臟、腎臟重量及相關血清生化數值之影響 98
第四節 烹煮脫殼台灣藜對F344大鼠疾病活動指數之影響 100
第五節 烹煮脫殼台灣藜對F344大鼠腸道組織及癌前病變之影響 102
第六節 烹煮脫殼台灣藜對F344大鼠結腸抗氧化相關蛋白及酵素活性之影響 105
第七節 烹煮脫殼台灣藜對F344大鼠腸黏膜發炎及增生蛋白表現之影響 107
第八節 烹煮脫殼台灣藜對F344大鼠腸道菌相組成之影響 110
第九節 烹煮脫殼台灣藜對F344大鼠糞便代謝物之影響 118
第十節 綜合討論 126
第七章 結論 133
參考文獻 134
圖目次
圖一、2020年全球不分性別及年齡之癌症發生率與死亡率 3
圖二、臺灣2022年兩性十大癌症死因死亡率 4
圖三、臺灣十大癌症死因死亡率-2012年與2022年比較 4
圖四、散發性結直腸癌及腸炎相關結腸癌的發展 6
圖五、AOM/DSS誘導小鼠早期結直腸腫瘤之組織病理學 8
圖六、DMH的代謝途徑 11
圖七、DSS誘導的結腸炎之病理機制 11
圖八、抗氧化酵素系統 14
圖九、NFκB調節之路徑 16
圖十、ROS對Nrf2路徑的活化機制 18
圖十一、Nrf2/HO-1和NFκB在發炎中的相互作用 18
圖十二、腸道菌群在結直腸癌發展中的作用 21
圖十三、代謝體相關資料庫 24
圖十四、台灣藜外觀及其構造 28
圖十五、實驗流程 39
圖十六、實驗架構 39
圖十七、烹煮脫殼台灣藜對雄性F344大鼠結腸長度及重量之影響 57
圖十八、烹煮脫殼台灣藜對雄性F344大鼠疾病活動指數之影響 59
圖十九、烹煮脫殼台灣藜對雄性F344大鼠結腸上皮H&E染色組織病理評估 61
圖二十、烹煮脫殼台灣藜對DMH/DSS誘導雄性F344大鼠結腸抗氧化酵素活性之影響 64
圖二十一、烹煮脫殼台灣藜對DMH/DSS誘導雄性F344大鼠結腸黏膜Nrf2蛋白表現量之影響 66
圖二十二、烹煮脫殼台灣藜對DMH/DSS誘導雄性F344大鼠結腸黏膜p-NFκB/NFκB、p-IκBα/IκBα及COX-2蛋白表現量之影響 67
圖二十三、烹煮脫殼台灣藜對DMH/DSS誘導雄性F344大鼠結腸黏膜PCNA及β-catenin蛋白表現量之影響 68
圖二十四、雄性F344大鼠的腸道菌相概況 72
圖二十五、烹煮脫殼台灣藜對DMH/DSS誘導雄性F344大鼠腸道菌相α多樣性之影響 73
圖二十六、烹煮脫殼台灣藜對DMH/DSS誘導雄性F344大鼠腸道菌相β多樣性之影響 74
圖二十七、烹煮脫殼台灣藜對DMH/DSS誘導雄性F344大鼠腸道菌相菌門相對豐度之影響 75
圖二十八、烹煮脫殼台灣藜對DMH/DSS誘導雄性F344大鼠腸道菌相組成之影響 76
圖二十九、烹煮脫殼台灣藜對DMH/DSS誘導雄性F344大鼠腸道菌相組成之影響（分支圖） 77
圖三十、烹煮脫殼台灣藜對DMH/DSS誘導雄性F344大鼠糞便樣品PLS-DA得分散佈圖之影響。 82
圖三十一、DMH/DSS誘導對雄性F344大鼠糞便樣樣品PLS-DA得分散佈圖之影響 83
圖三十二、高劑量烹煮脫殼台灣藜對DMH/DSS誘導雄性F344大鼠糞便樣品PLS-DA得分散佈圖之影響。 84
圖三十三、以PLS-DA分析判別DMH/DSS誘導對雄性F344大鼠糞便差異代謝物（VIP>1）的熱圖 85
圖三十四、以PLS-DA分析判別烹煮脫殼台灣藜對DMH/DSS誘導雄性F344大鼠糞便差異代謝物（VIP>1）的熱圖 87
圖三十五、以Metaboanalyst分析DMH/DSS誘導對雄性F344大鼠糞便差異代謝物路徑之摘要 89
圖三十六、以Metaboanalyst分析烹煮脫殼台灣藜對DMH/DSS誘導雄性F344大鼠糞便差異代謝物路徑之摘要 90
圖三十七、DMH/DSS誘導對雄性F344大鼠糞便代謝物影響之疾病指標 93
圖三十八、烹煮脫殼台灣藜對DMH/DSS誘導雄性F344大鼠糞便代謝物影響之疾病指標 94
圖三十九、C組指標菌屬和其差異代謝物（N組vs. C組vs. HD組）之相關性分析（熱圖） 131
圖四十、HD組指標菌屬和其差異代謝物（N組vs. C組vs. HD組）之相關性分析（熱圖） 132
表目次
表一、台灣藜與其他食品營養成分之比較 26
表二、脫殼台灣藜及烹煮脫殼台灣藜成分分析方法 36
表三、實驗分組 37
表四、實驗飼料組成 38
表五、疾病活動指數 40
表六、脫殼台灣藜及烹煮脫殼台灣藜之成分分析 49
表七、烹煮脫殼台灣藜對雄性F344大鼠體重、攝食量及攝食效益之影響 51
表八、烹煮脫殼台灣藜對雄性F344大鼠肝臟及腎臟重量之影響 53
表九、烹煮脫殼台灣藜對雄性F344大鼠血清尿素氮及肌酸酐濃度與天冬胺酸轉胺酶及丙胺酸轉胺酶活性之影響 54
表十、烹煮脫殼台灣藜對雄性F344大鼠盲腸總重量、相對盲腸重及盲腸內容物重量之影響 56
表十一、烹煮脫殼台灣藜對雄性F344大鼠以DMH/DSS誘導異常腺窩病灶、微腺瘤及腺瘤之影響 62
表十二、N組和C組之間差異性之糞便代謝物及其參與途徑 91
表十三、N組、C組和HD組之間差異性之糞便代謝物及其參與途徑 92
表十四、總整理：烹煮脫殼台灣藜對DMH/DSS誘導F344大鼠之影響 129

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