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

• 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
• 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' 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

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.

项目摘要 心理危险因素反复被认为是炎症性肠病不可或缺的方面 （IBD）。尤其是压力已反复显示为爆发的强有力预测指标。虽然有几项研究 试图在应力和微生物组桥轴之间建立机械关系 （MGBA），尚未达到令人满意的解释。部分原因是对化学诱导的依赖 IBD的模型，尤其是葡聚糖硫酸钠（DSS）结肠炎。很少有文献研究的效果 对克罗恩病和回肠炎的心理压力。在这里，我们提出了一系列研究以研究压力 以及我们的CD样回肠炎的小鼠模型SAMP1/YITFC（SAMP1）中的MGBA。 为了诱发心理压力，我们使用约束压力（RS）。我们小组的初步数据已证明 除升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树突状细胞水平升高并改变 回肠固有层中的细胞因子表达。根据以前的文献和我们的初步数据，我们假设 这种心理压力引起了肠道微生物组的变化，而肠道微生物组又促进了促炎症 回复。 为了解决我们的假设，我们提出以下三个目标。我们的第一个目标将验证压力的能力 在我们的CD样肠炎的小鼠模型中，肠炎恶化。为了实现这一目标，我们将对我们的 小鼠急性和慢性应激，并观察到导致的炎症变化。此外，我们将衡量 压力通过诱导缓解并随后将SAMP1小鼠带到压力而引起救济的能力。 我们的第二个目标将表征后压力免疫反应及其改变微生物组的能力。我们 将利用我们的SAMP1ΔCD1-DTR小鼠（一种有选择性诱导的树突状细胞敲除模型）来表征 树突状细胞对应激的反应。随后，我们将使用收获的 压力和无数小鼠的骨髓。在我们的第三个目标中，我们将确定是否改变了压力 微生物组是必要的和/或足以诱导免疫反应。无菌（GF）和特定病原体 自由（SPF）小鼠将通过压力或 未育的捐助者。随后，将评估受体小鼠的炎症反应，并 将确定微生物组的代谢组。 尽管压力可能是每个CD患者一生中不可避免的方面，但我们认为我们的工作可能会导致 减轻压力的有害影响的疗法。具体而言，使用我们独特的小鼠CD样回肠炎模型， 我们希望发现新颖的治疗策略，例如培养基或益生元，以防止炎症作用 压力。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模型将其移植到无菌（GF）小鼠中。