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（取自研究者的摘要）特发性炎症性肠病（IBD），克罗恩病和溃疡性结肠炎，折磨约0.1％的人口西方世界，是由IBD之间的多因素互动产生的敏感性基因和环境药物。这个工作模型提案解决了硫酸盐还原细菌（SRB）在 IBD的启动和进展。硫酸细菌是正常的肠道菌群，其特征是它们的使用能力硫酸盐作为末端电子受体，最终生产有毒气体硫化物（H2S）。研究人员假设外源性硫酸盐可以增强H2S的产生，从而引发结肠炎症。他们进一步提出IBD可能反映了易感性的遗传背景这会导致对SRB生成的H2S的异常敏感性。结肠的损害 H2S的上皮将促进细菌和食物抗原的易位，导致对正常良性抗原的炎症反应，结果与许多间接数据和组织病理学特征一致 IBD。实验方法使用一种新型的分子生态策略来检查小鼠肠中SRB种群的发展并定义饮用水硫酸盐对其多样性和代谢的影响活动。然后，使用IBD的鼠标模型来检验以下假设。饮用水硫酸盐可以通过细菌H2S引发结肠炎症生产。确认细菌生成的硫化物的作用实验性结肠炎将代表第一个结论性证据正常肠道细菌的环境调节，导致遗传学编码的炎症障碍。这一发现将加剧获得的努力来自人类受试者的佐证数据，将为 IBD的预防或治疗治疗。