Gut host-microbiome-pathogen interaction: understanding the pathophysiology of bacterial infections

肠道是一个独特的器官系统。除了消化和吸收营养的关键功能外，它还拥有丰富多样的微生物群。在猪肉生产中，肠道感染是最佳动物性能和行业经济竞争力的主要障碍。在肠道中发生的宿主-微生物组-病原体相互作用在健康和疾病状态中都起作用。猪痢疾（SD）是一种以粘液样腹泻和血性腹泻为特征的疾病，是当前养猪业面临的一个挑战。没有可用的疫苗，使抗生素成为治疗和控制疾病的唯一方法。它是由螺旋体Brachyspira hyocytteriae引起的，在爆发期间，高达100%的畜群可能受到影响。尽管自SD首次被描述以来已有近100年的时间，但我们仍然不了解病变如何发展。在这里，我们建议定义导致SD的机制，并为感染控制和预防策略提供依据。 我们以前已经表明，短螺旋体感染导致结肠中高水平的一氧化氮（NO）副产物。NO刺激肠中的血管舒张、粘液和氯化物分泌，所有这些都有助于SD的标志性临床体征：血性腹泻。目的1探讨NO在结肠炎和血性腹泻发生发展过程中的作用及来源。我们将采用我们的体外结肠培养模型，结合空间基因表达和组织学技术，以了解NO如何有助于SD。接下来，我们将探索如何应用NO抑制剂来预防临床症状。 目的2研究一种新型短螺旋菌细菌素对结肠菌群的选择能力。其他研究表明，没有微生物群的猪不会出现SD的临床症状。我们将使用体外和动物试验，分子成像和高通量测序的组合，以阐明病原体如何积极调节结肠微生物组的优势，最终导致严重的疾病。 目的3探讨短螺旋体为逃避宿主防御而采取的免疫抑制策略。使用从结肠分离的免疫细胞，我们将通过分析这些细胞的转录组来探索病原体如何抑制初始免疫反应。这一目标将揭示为什么以前的疫苗开发工作失败，并有助于未来的改进。在当前的后抗生素时代，面对多重耐药细菌，需要新的替代品来控制肠道细菌感染。这里提出的工作将阐明宿主-微生物组-病原体三合会相互作用的机制，以及我们如何利用这些知识来开发减轻疾病的新策略，同时不会导致抗菌药物耐药性。

The intestinal tract is a unique organ system. Beyond its key functions of digestion and absorption of nutrients, it harbours a rich and diverse microbiota. In pork production, intestinal infections are a major barrier to optimal animal performance and to the industry economic competitiveness. The host-microbiome-pathogen interactions that takes place in the intestines play a role in both healthy and diseased states. Swine dysentery (SD), characterized by mucoid and bloody diarrhea, is a current challenge in the swine industry. There are no vaccines available, leaving antibiotics as the only way to treat and control the disease. It is caused by the spirochete Brachyspira hyodysenteriae, and during outbreaks up to 100% of a herd can be affected. Despite almost 100 years since SD was first described, we do still not understand how lesions develop. Here we propose to define the mechanisms that lead to SD, and to provide the basis for infection control and prevention strategies. We have previously shown that Brachyspira infection leads to high levels of nitric oxide (NO) by-products in the colon. NO stimulates vasodilation, mucus and chloride secretion in the intestine, all of which contribute to the hallmark clinical sign of SD: bloody diarrhea. Objective 1 will characterize the role and source of NO during the development of colitis and bloody diarrhea. We will employ our in vitro colon culture model, in combination with spatial gene expression and histology techniques, to understand how NO contributes to SD. Next, we will explore how an NO-inhibitor can be applied to prevent clinical signs. Objective 2 will investigate the ability of a novel Brachyspira bacteriocin to select the microbiota in the colon. Others have shown that pigs without a microbiota do not develop the clinical signs of SD. We will use a combination of in vitro and animal trials, molecular imaging and high-throughput sequencing, to clarify how the pathogen actively modulates the colon microbiome in its advantage, culminating in severe disease. Objective 3 will profile the immunosuppressive strategies employed by Brachyspira to avoid the host defences. Using immune cells isolated from the colon, we will explore how the pathogen supresses the initial immune response by profiling the transcriptome of these cells. This objective will shed a light on why previous vaccine development efforts have failed, and help future improvements. In the current post-antibiotic era, in face of multi-drug resistant bacteria, novel alternatives to control intestinal bacterial infections are needed. The work proposed here will clarify the mechanisms through which the host-microbiome-pathogen triad interact, and how we can leverage this knowledge to develop new strategies that mitigate disease, while not contributing to antimicrobial resistance.