Identification and characterization of competition-factors of commensal E. coli and their role in inhibition of enteropathogens in the inflamed intestine

据世界卫生组织称，胃肠道感染是一个主要的全球健康问题，每年夺去180万人的生命。共生菌群在肠道中大量繁殖，有助于防止这些感染。由肠道病原体引起的炎症通过迄今为止尚不清楚的机制使正常的微生物群不稳定，并导致病原体过度生长。到目前为止，人们一直认为只有病原体（如沙门氏菌）才能从肠道炎症中受益。然而，我们最近观察到，在小鼠结肠炎模型中，某些大肠杆菌菌株（即共生小鼠分离大肠杆菌8178）比其他菌株（即大肠杆菌尼塞尔）更能与鼠伤寒沙门氏菌竞争。在本项目中，我们计划研究炎症肠道中竞争性大肠杆菌过度生长和病原体抑制的分子机制。我们的目标是通过使用两种独立的遗传筛选方法，确定有助于大肠杆菌8178竞争表型的性状（=“竞争基因”），但在大肠杆菌尼塞尔中不存在。我们将分析大肠杆菌泛基因组中“竞争基因”的分布，并解决它们在体内刺激下的调节问题。这一结果将进一步加深我们对竞争性大肠杆菌在肠道病原菌感染中的作用的认识，并为今后益生菌的改良提供依据。

Gastrointestinal infections are a major global health problem claiming 1.8 million lives per year according to the WHO. The commensal microflora, populating the intestine to high levels, con-tributes to protection against these infections. Inflammation, induced by enteric pathogens des-tabilizes the normal microbiota by so far poorly understood mechanisms and leads to pathogen overgrowth. So far, it has been assumed that only pathogens (i.e. Salmonella enterica spp.I serovar Typhimurium) can benefit from intestinal inflammation. However, we have recently ob-served that certain E. coli strains (i.e. commensal mouse isolate E. coli 8178) in contrast to oth-ers (i.e. E. coli Nissle) can out-compete Salmonella Typhimurium in a mouse colitis model. In the proposed project we plan to investigate the molecular mechanisms of competitive E. coli overgrowth and pathogen suppression in the inflamed gut. We aim at identifying traits that con-tribute to the competitive phenotype of E. coli 8178 (= 'competition-genes') but are absent in E. coli Nissle by using two independent genetic screening approaches. We will analyze the distri-bution of 'competition-genes' within the E. coli pangenome and address their regulation in re-sponse to in vivo stimuli. The results will enhance our understanding of the role of competitive E. coli in enteropathogen infection and may be exploited for the improvement of probiotics in the future.