The impact of TLR1 on dysbiosis and intestinal inflammation

描述（由申请人提供）：炎症性肠病（IBD）是由宿主遗传学、环境损伤（如饮食或感染）和肠道微生物群的复杂相互作用引起的。虽然肠道微生物群参与IBD的病因学是公认的，但尚不清楚微生物群的变化（称为微生态失调）是如何发生的，也不清楚微生态失调对粘膜免疫的影响。我们的初步数据表明，在儿童IBD患者中选择了人类TLR1的多态性，其废除了信号传导。使用小鼠模型，我们发现感染耶尔森氏菌的TLR1缺陷小鼠无法增加体重，表现出抗肿瘤免疫反应，并在感染后10周改变了微生物群。具体来说，我们看到硫酸盐还原菌的增加，这也在IBD患者中发现，同时益生菌乳酸菌的减少。在此，我提出了一个扩展的研究项目（K01 DK8275），将检查由肠道病原体，小肠结肠炎耶尔森氏菌感染后，在TLR1信号的情况下，生态失调的原因。该项目将着眼于确定宿主因素、致病策略以及导致生态失调的肠道细菌的作用。此外，我们将研究改变的微生物群如何影响炎症和粘膜免疫。这些数据将为遗传学如何影响粘膜免疫提供重要的见解，并提出一套新的策略，为具有特定遗传背景的患者提供定制治疗。

DESCRIPTION (provided by applicant): Inflammatory bowel disease (IBD) is caused by the complex interaction of host genetics, environmental insults such as diet or infection, and the gut microbiota. While it is well accepted that commensal microbiota are involved in the etiology of IBD, it is not well understood how changes in the microbiota, termed dysbiosis, occur nor is it understood the impact that dysbiosis has on mucosal immunity. Our preliminary data demonstrate that a polymorphism in human TLR1, which abrogates signaling, is selected in pediatric IBD patients. Using a mouse model, we have found that TLR1-deficient mice infected with Yersinia have a failure to gain weight, demonstrate anti-commensal immune responses and have an altered microbiota ten weeks after infection. Specifically, we see an increase in sulfate-reducing bacteria, which has also been identified in patients with IBD, and a concomitant decrease in probiotic Lactobacillus. Herein, I propose an extension of research project (K01 DK8275) that will examine the cause of dysbiosis in the absence of TLR1-signaling after infection by the enteropathogen, Yersinia enterocolitica. The project will look to identify host factors, pathogenic strategies and the contribution of commensal bacteria that contribute to dysbiosis. Further, we will examine how an altered microbiota may impact inflammation and mucosal immunity. These data will provide important insights into how genetics can influence mucosal immunity as well as suggest a new set of strategies to tailor treatments to patients with particular genetic backgrounds.