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ENVIRONMENTAL MODULATION OF INTESTINAL SULFIDOGENS AND I

肠道硫化物和 I 的环境调节

基本信息

批准号：
6178806
负责人：
Rex Gaskins
金额：
$ 12.2万
依托单位：
UNIVERSITY OF ILLINOIS AT URBANA-CHAMPAIGN
依托单位国家：
美国
项目类别：
财政年份：
1999
资助国家：
美国
起止时间：
1999-09-30 至 2002-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/6178806
关键词：
Desulfovibrio colon disease /disorder model gastrointestinal epithelium gene environment interaction genetic susceptibility hydrogen sulfide inflammation inflammatory bowel diseases laboratory mouse pathologic process

项目摘要

DESCRIPTION (Taken from the Investigator's Abstract) The idiopathic inflammatory bowel diseases (IBD), Crohn's disease and ulcerative colitis, afflict approximately 0.1% of the population of the western world and result from multifactorial interactions between IBD susceptibility genes and environmental agents. The working model of this proposal addresses the role of sulfate-reducing bacteria (SRB) in the initiation and progression of IBD. Sulfidogenic bacteria are members of the normal intestinal microbiota and are characterized by their ability to use sulfate as a terminal electron acceptor, culminating in the production of the toxic gas hydrogen sulfide (H2S). The investigator postulates that exogenous sulfate can enhance H2S production and thereby trigger colonic inflammation. They further propose that IBD may reflect a predisposing genetic background that causes abnormal sensitivity to SRB-generated H2S. Damage of the colonic epithelium by H2S would promote translocation of bacterial and food antigens, resulting in inflammatory responses to normally benign antigens, an outcome consistent with much circumstantial data and the histopathological features of IBD. The experimental approach uses a novel molecular ecology strategy to examine the development of SRB population in the mouse intestine and to define the effects of drinking water sulfate on their diversity and metabolic activities. A mouse model of IBD is then used to test the hypothesis that drinking water sulfate can trigger colonic inflammation through bacterial H2S production. Confirmation of a role for bacterial-generated sulfide in experimental colitis would represent the first conclusive evidence for environmental modulation of normal gut bacteria contributing to a genetically encoded inflammatory disorder. That finding would intensify efforts to obtain corroborative data from human subjects and would present a novel target for prophylactic or therapeutic treatments for IBD.

描述(摘自调查人员摘要) 特发性炎症性肠病(IBD)、克罗恩病和溃疡性结肠炎，困扰着大约0.1%的人口西方世界和IBD之间多因素相互作用的结果易感基因和环境因子。它的工作模式是提案涉及硫酸盐还原细菌(SRB)在 IBD的发生和发展。产硫细菌是正常的肠道微生物区系，以其使用能力为特征硫酸盐作为末端电子受体，最终产生有毒气体硫化氢(硫化氢)。研究人员假设外生性硫酸盐可以促进硫化氢的产生，从而引发结肠炎。他们进一步提出IBD可能反映了易感的遗传背景。这导致对SRB产生的硫化氢异常敏感。结肠损伤硫化氢作用下的上皮细胞会促进细菌和食物抗原的移位，导致对正常良性抗原的炎症反应，这是一种结果与许多环境数据和组织病理学特征相一致 IBD。实验方法使用了一种新的分子生态学策略来检测SRB菌群在小鼠肠道中的发育并确定饮用水中硫酸盐对细菌多样性和代谢的影响活动。然后，使用IBD的小鼠模型来检验这一假设饮用水硫酸盐可通过细菌硫化氢引发结肠炎制作。确认细菌生成的硫化物在实验性结肠炎将是第一个确凿的证据正常肠道细菌的环境调节在遗传上起作用编码的炎症性疾病。这一发现将加强努力，以获得来自人类受试者的确证数据，并将提供一个新的目标 IBD的预防性或治疗性治疗。