Stress Induced Inflammation and Dysbiosis in a Mouse Model of Crohn's Disease

克罗恩病小鼠模型中应激诱导的炎症和生态失调

基本信息

批准号：
10213020
负责人：
Adrian S Gomez-Nguyen
金额：
$ 5.1万
依托单位：
CASE WESTERN RESERVE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-08-01 至 2023-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10213020
关键词：
16S ribosomal RNA sequencing Acute Address Adrenal hormone preparation Age Anti-Inflammatory Agents Anxiety Bacteria Behavioral Bone Marrow Chemicals Chimera organism Chronic Chronic stress Colitis Corticosterone Crohn&apos s disease Data Dendritic Cells Development Dexamethasone Disease Disease remission Epithelial Etiology Exposure to Failure Feces Flare Frequencies Future Genetic Germ-Free Goals Gut associated lymphoid tissue Harvest Histologic Human Human Microbiome Ileitis Immune response Immune system Immunology Immunology procedure Inflammation Inflammatory Inflammatory Bowel Diseases Inflammatory Response Innate Immune Response Intestines Knock-out Laboratories Lamina Propria Lead Life Literature Marrow Measures Mental Depression Modeling Monitor Mucous Membrane Mus Oral Patients Phenotype Population Probiotics Psychological Stress Recurrent disease Relapse Risk Factors Series Serum Shapes Sodium Dextran Sulfate Steroids Stress Sulfonic Acids Tissues Transplantation Work acute stress base comorbidity cytokine depressive symptoms diphtheria toxin receptor dysbiosis experience fecal transplantation germ free condition gut microbiome gut-brain axis inflammatory disease of the intestine mesenteric lymph node metabolome microbiome microbiome alteration microbiome research mouse model novel therapeutic intervention perceived stress prebiotics prevent psychologic response restraint stress stool sample therapy development transplant model

项目摘要

PROJECT SUMMARY Psychological risk factors have repeatedly been recognized as integral facets of inflammatory bowel disease (IBD). Stress, in particular, has been repeatedly shown as a strong predictor of flare-ups. Though several studies have attempted to establish a mechanistic relationship between stress and the microbiome-gut-brain axis (MGBA), a satisfying explanation has not been reached. In part, this is due to the reliance on chemically induced models of IBD, particularly Dextran Sodium Sulfate (DSS) colitis. Very little literature exists studying the effect of psychological stress on Crohn’s disease and ileitis. Here, we propose a series of studies to investigate stress and the MGBA in our mouse model of CD-like ileitis, the SAMP1/YitFc (SAMP1). To induce psychological stress, we use restraint stress (RS). Preliminary data from our group has demonstrated that RS is capable of inducing a depressive-like phenotype in addition to raising serum corticosterone levels. Exposure to acute RS resulted in elevated levels of dendritic cells in the mesenteric lymph node and altered cytokine expression in ileal lamina propria. Based on previous literature and our preliminary data, we hypothesize that psychological stress induces a change in the gut microbiome which, in turn, promotes a pro-inflammatory response. To address our hypothesis, we propose the following three aims. Our first aim will validate the ability of stress to worsen intestinal inflammation in our mouse model of CD-like ileitis. To accomplish this aim, we will subject our mice to acute and chronic stress and observe resultant inflammatory changes. Furthermore, we will measure the ability of stress to provoke relapse by inducing remission and subsequently exposing SAMP1 mice to stress. Our second aim will characterize the post-stress immune response and its ability to alter the microbiome. We will make use of our SAMP1ΔCD1-DTR mouse, a selectively inducible dendritic cell knock-out model, to characterize the dendritic cell response to stress. Subsequently, we will generate a bone marrow chimera using harvested marrow from stressed and unstressed mice. In our third aim, we will determine whether the stress-altered microbiome is necessary and/or sufficient to induce an immune response. Germ-free (GF) and specific pathogen free (SPF) mice will receive a fecal microbiome transplantation (FMT) via oral gavage from stressed or unstressed donors. Subsequently, the inflammatory response of the recipient mice will be assessed and the metabolome of the microbiome will be determined. Though stress may be an unavoidable aspect of every CD patient’s life, we believe that our work can lead to therapies that mitigate the harmful effects of stress. Specifically, using our unique mouse model of CD-like ileitis, we hope to discover novel therapeutic strategies, such as pro- or prebiotics, to prevent the inflammatory effects of stress. Future goals of this project include studying the microbiomes of human patients with perceived stress and transplanting into germ-free (GF) mice using our validated human FMT model.

项目概要心理危险因素一再被认为是炎症性肠病不可分割的一部分 (IBD)，多项研究已多次证明压力是疾病发作的有力预测因素。试图建立压力与微生物组-肠-脑轴之间的机械关系（MGBA），尚未达成令人满意的解释，部分原因是对化学诱导的依赖。 IBD 模型，特别是右旋糖酐硫酸钠 (DSS) 结肠炎模型，研究其影响的文献很少。心理压力对克罗恩病和回肠炎的影响在这里，我们提出了一系列研究来调查压力。以及我们的 CD 样回肠炎小鼠模型中的 MGBA，SAMP1/YitFc (SAMP1)。我们小组的初步数据表明，为了诱发心理压力，我们使用了约束压力（RS）。除了提高血清皮质酮水平外，RS 还能够诱导抑郁样表型。暴露于急性 RS 会导致肠系膜淋巴结中的树突状细胞水平升高，根据之前的文献和我们的初步数据，我们勇敢地观察回肠固有层中的细胞因子表达。心理压力会引起肠道微生物群的变化，进而促进促炎症反应回复。为了解决我们的假设，我们提出以下三个目标，我们的第一个目标是验证压力的能力。为了实现这一目标，我们将研究 CD 样回肠炎小鼠模型中肠道炎症的恶化。小鼠急性和慢性应激并观察由此产生的炎症变化。压力通过诱导缓解并随后将 SAMP1 小鼠暴露于压力而引发复发的能力。我们的第二个目标是表征应激后免疫反应及其改变微生物组的能力。将利用我们的 SAMP1ΔCD1-DTR 小鼠（一种选择性诱导的树突状细胞敲除模型）来表征随后，我们将使用收获的骨髓嵌合体。在我们的第三个目标中，我们将确定压力是否会改变小鼠的骨髓。微生物组对于诱导免疫反应是必要的和/或充分的。自由（SPF）小鼠将通过口服强饲法接受粪便微生物移植（FMT）随后，将评估受体小鼠的炎症反应，并评估无压力的供体。将确定微生物组的代谢组。尽管压力可能是每个 CD 患者生活中不可避免的一个方面，但我们相信我们的工作可以带来具体来说，使用我们独特的 CD 样回肠炎小鼠模型来减轻压力的有害影响。我们希望发现新的治疗策略，例如益生元或益生元，以预防炎症效应该项目的未来目标包括研究有压力的人类患者的微生物组。并使用我们经过验证的人类 FMT 模型移植到无菌 (GF) 小鼠中。