摘要:「腸躁症」是腸胃科常見的的症候群, 其特徵是腹部的疼痛或絞痛合並有腸道功能的改變包括漲氣、腹瀉和便秘。其原因不明, 且無生物標的, 利用內視鏡也觀察不到腸道病變。「腸躁症」發病率相當地高, 約占腸胃科門診人數的10-40%。現有藥物對症狀改善效果不佳, 多半病人會尋求輔助性療法或非核准之藥物。 「腸躁症」病人對精神壓力的抗性較低, 較易出現恐慌和憂鬱症狀。最近文獻發現病人腸道有低程度發炎, 共生菌增生和上皮屏障失常的現象。目前「腸躁症」無動物模式可供研究, 致使消化醫學界對其病理機制了解甚少, 導致藥物開發受阻。「腸躁症」症狀的發生常見於精神壓力過大或腸道感染之後, 特稱為「後感染性腸躁症」。最新流行病學資料發現「腸躁症」和梨形蟲感染有關連。據估計在台北市, 導致急性腸胃炎的病原約16.4%為梨形蟲。 我們實驗室過去發現梨形蟲感染會引發上皮細胞凋亡和通透性增加 (Int J Parasitol (2008) 38: 923; Infect Immun. (2004) 72: 3536)。因此本計劃的假設為感染排除後會導致腸道屏障失常和共生菌轉移引起黏膜發炎和痛覺敏感等類似「腸躁症」的症狀。並將利用梨形蟲感染小鼠建立「後感染性腸躁症」動物模式來篩選和測試新開發藥物如草本純化萃取物之效用。本計劃的目的為探討梨形蟲感染後排除期的腸道屏障失常和神經痛覺敏感之機制, 以建立「後感染性腸躁症」的動物模式作治療用藥之研究。實驗方法是將梨形蟲感染後排除期之小鼠施以精神壓力, 再觀察腸道屏障失能, 蠕動異常和腹痛現象的發生。計劃將利用新建立的「後感染性腸躁症」小鼠模式來篩選和測試新開發純化的草本萃取物 (如清熱性草藥,大黃,芙苓菌等)來減緩腸道症狀, 以及辨認疾病生物標的和分子機制(如膽囊收縮素和氧化氮合成酶)。長期目標為開發可供「腸躁症」治療之商業化藥物。
Abstract: Irritable bowel syndrome (IBS) is characterized by abdominal discomfort or pain, and changes in bowel habit in the absence of identifiable etiology, biomarkers or macroscopic lesions. IBS represents a substantial clinical problem that accounts for 10-40 % of gastroenterology outpatients in Asia and Western countries. Despite its high prevalence, the exact cause of IBS remains poorly understood and none of the currently available drugs (e.g. antispasmodics, antidiarrheals, osmoticis, sedatives, antidepressants etc.) are globally effectively in treating IBS symptoms. More than half of the patients seek complementary and alternative medicine without any safety guidelines.Early reports documented that IBS patients display higher scores for anxiety and depression than normal subjects when perceiving psychological stress, and show symptoms of abdominal pain associated with either diarrhea or constipation. Recent findings revealed that low grade inflammation, small intestinal bacterial overgrowth and impaired intestinal barrier function were also present in IBS patients. The pathogenesis of IBS remains elusive and the development of targeted drugs is hindered due to the lack of appropriate animal models.IBS symptoms may begin after a stressful life event or after a bout of infectious gastroenteritis, termed post-infectious IBS (PI-IBS). A strong epidemiological connection was recently found between giardiasis and PI-IBS. It has been reported that 16.4% of gastroenteritis in Taipei emergency departments is due to infection with Giardia lamblia. Giarda is a strictly lumen-dwelling pathogen with exclusive access to the apical side of the enterocytes, where a vast amount of commensal bacteria normally resides. Our previous studies have shown that exposure to G. lamblia products induce enterocytic apoptosis and results in an increase of monolayer permeability (Int J Parasitol (2008) 38: 923; Infect Immun. (2004) 72: 3536). Therefore, we hypothesize that G. lamblia infection may trigger increased gut permeability and bacterial influx in animal models, leading to mucosal inflammation and nerve hypersensitivity that resembles PI-IBS.We plan to develop a post-giardiasis IBS mouse model to allow the identification of novel biomarkers and facilitate the testing of new drugs which would provide important information before proceeding to clinical trials for IBS patients. Several Chinese herbal extracts have been previously isolated and purified from our collaborated laboratories and affiliated pharmaceutical companies, and are ready for testing. The efficacy of these herbal extracts will be investigated in vivo in our PI-IBS mouse model and the molecular mechanism will be assessed in vitro using intestinal epithelial cells and neural cells.Our aim is to investigate the mechanism of intestinal barrier dysfunction and nerve hypersensitivity following Giardia infection and to establish a model of PI-IBS for future therapeutic development. Post-infected mice will be subjected to psychological stress to examine the increase in bowel motility and sensitivity in abdominal pain perception. We will then use this PI-IBS model to explore the pharmacological effect of novel herbal extracts (e.g. iridoids from heat-clearing herbs, Rheum tanguticum, and Poria cocos) on symptom alleviation, and to examine the involvement of new targets such as cholecystokinin and inducible nitric oxide synthase in the pathogenesis. The long term goal is to identify and commercialize novel pharmacological agents for clinical managements of IBS.