Persistent Gut Barrier Dysfunction and Mucosal Inflammation after Eradication of Giardia lamblia Infection: Implications for the Pathogenesis of Post-Infectious Irritable Bowel Syndrome

• Main Authors: Tzu-Ling Chen, 陳姿伶
• Other Authors: Linda C.H. Yu
• Format: Others
• Language: zh-TW
• Published: 2010
• Online Access: http://ndltd.ncl.edu.tw/handle/11174899024110726388

碩士 === 國立臺灣大學 === 生理學研究所 === 98 === Irritable bowel syndrome (IBS) is a functional gastrointestinal disorder characterized by abdominal pain and changes in bowel habits, for which neither apparent structural lesion nor presence of pathogen could be found. Recent data indicated that low grade intestinal inflammation, impaired mucosal barrier function, and enteric bacterial overgrowth were identified in IBS patients. Consistent evidence showed that IBS may be the adverse outcome of an acute episode of infectious gastroenteritis, termed post-infectious (PI) IBS. Giardia lamblia is the most frequently identified etiologic agent of waterborne disease worldwide. Recent epidemiological data from Norway indicated that more than 80 % of patients from an outbreak of giardiasis showed IBS symptoms after 12-30 months post-onset of Giardia infection and at least 6 months after the clearance of parasites. Despite that IBS represents a substantial clinical problem, its mechanism and pathogenesis remain poorly understood mainly due to the lack of animal models. The aim of the current study is to establish a PI-IBS model using Giardia-infected mice and to evaluate gut barrier dysfunction and mucosal inflammation during infection and after eradication of parasites. Balb/c mice were inoculated with 10e7 trophozoites of Giardia lamblia strain GS/M or pair-fed with phosphate-buffered saline (PBS). The trophozoites in the small intestines were enumerated weekly from PI day 0 to 49 to determine the time course of parasitic infection. Giardia colonization peaked at PI day 4-7 and this period was termed the ''infection phase''; the parasites were cleared by PI day 14, and therefore, day 21-49 was denoted the ''post-clearance phase''. Intestinal epithelial barrier dysfunction was evidenced by increased bacterial colony forming units (CFU) in the gut mucosa. The medium of mucosal endocytosed bacterial counts in the small and large intestines on PI day 7 (164.2 and 253.4 CFU/g) and on PI day 35（118.4 and 98.1 CFU/g）were respectively higher than the values on PI day 0（0.0 and 0.3 CFU/g）. In mouse pair-fed with PBS, the mucosal bacterial counts in small and large intestines on day 35 were comparable with day 0. Total bacterial counts in small and large intestines on PI day 7 in mouse infected with G. lamblia was 4 to 10 times higher than those pair-fed with PBS, suggesting bacterial overgrowth during giardiasis; whereas no difference was seen between the two groups on PI day 35. The numbers of superficial bacteria in small intestines of Giardia-infected mice increased on day 7 and day 35 compared to those pair-fed with PBS, suggesting bacterial adherence during infection and after clearance of Giardia. Increased tight junctional occludin cleavage was noticed in small intestinal mucosa during infection. Heightened intestinal myeloperoxidase activity was found on day 7 and 35. Increased percentage of neutrophils in white blood cells was seen on PI day 7, and augmented neutrophil infiltration into the crypt area in small intestinal tissues was observed on PI day 7 and 35. Elevated intestinal TNFα, IL-1βand MIP-1α levels were associated with increased epithelial iNOS expression on PI day 35. In conclusion, Giardia-infected mice showed persistent enteric bacterial influx accompanied by mucosal inflammation and neutrophil activation after parasite clearance. The post-giardiasis animals may be suitable models for investigating gut barrier dysfunction underlying the mechanism of PI-IBS.