Role of Commensal Microbiota in Stressor-Induced Immunomodulation

共生微生物群在应激源诱导的免疫调节中的作用

• 批准号: 8701731
• 负责人: MICHAEL T BAILEY
• 金额: $ 23.07万
• 依托单位: OHIO STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-02-01 至 2016-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8701731
• 关键词: Address; Affect; American; Animal Model; Anxiety; Autoimmune Diseases; Bacterial Translocation; Catecholamines; Chronic; Chronic Disease; Clinical; Communities; Data; Development; Disease; Experimental Autoimmune Encephalomyelitis; Experimental Models; Exposure to; Grant; Hormones; Human; Immune; Immune system; Inflammation; Inflammatory; Interleukin-1; Intestines; Knowledge; Lead; Leukocytes; Mediating; Medical; Microbe; Modeling; Multiple Sclerosis; Mus; Nervous system structure; Neuraxis; Neurosecretory Systems; Patients; Pattern recognition receptor; Physiological; Play; Population; Process; Production; Publishing; Receptor Signaling; Role; Signal Transduction; Societies; Spleen; Stress; Structure; Sympathetic Nervous System; Symptoms; Testing; biological adaptation to stress; commensal microbes; cytokine; design; economic impact; immunoregulation; macrophage; microbial; nervous system disorder; novel; pathogen; psychosocial; public health relevance; receptor; response; social; stressor; therapeutic target

DESCRIPTION (provided by applicant): Chronic inflammatory diseases affect millions of Americans each year, and have a significant medical, psychosocial, and economic impact on both the patient and on society. Multiple sclerosis is a chronic, degenerative neurological disorder involving immune-mediated inflammatory demyelinating processes, and is significantly exacerbated by comorbid conditions, such as stress and anxiety. Despite this knowledge, the mechanisms by which this occurs are not yet well understood. The studies in this proposal will test the highly novel and integrative hypothesis that the intestinal microbiota are involved in stressor-induced enhancement of systemic inflammation that leads to symptom exacerbation in an animal model of multiple sclerosis. We have made the exciting discovery that the intestinal microbiota are necessary for stressor-induced increases in splenic IL-1¿ to occur. This is important, because IL-1 plays a central role in the development of many chronic inflammatory diseases, including multiple sclerosis. How the microbiota lead to increased IL-1 during stressor exposure, as well as the effects on chronic inflammatory diseases, is not well understood. During repeated social defeat, commensal microbes can translocate from their primary niche to the interior of the body. Because there is accumulating evidence that neuroendocrine hormones, such as sympathetic nervous system-derived catecholamine hormones, can impact microbial populations, Aim 1 will test whether stressor-induced activation of the sympathetic nervous system leads to translocation of commensal microbiota. As further confirmation that microbial translocation is necessary for stressor-induced immunoenhancement to occur, Aim 2 will test the hypothesis that stressor-induced increases in splenic IL-1¿ are dependent upon both macrophage pattern recognition receptor signaling and inflammasome formation. Finally, to determine whether the microbiota contribute to stressor-induced exacerbation of a chronic disease, a widely used animal model of multiple sclerosis, namely experimental autoimmune encephalomyelitis (EAE) will be employed. The effects of repeated social defeat on EAE progression will be determined in germfree mice (i.e., mice that have never come into contact with commensal microbes) and conventional mice. By integrating the results of Aims 1, 2, and 3, we will identify novel mechanisms by which stressor exposure can exacerbate a chronic inflammatory disease. These findings would ultimately facilitate the rational design and use of microbiota-targeting therapeutics to treat chronic disease.

慢性炎症性疾病每年影响数百万美国人，并对患者和社会产生重大的医疗，心理和经济影响。多发性硬化症是一种慢性退行性神经系统疾病，涉及免疫介导的炎性脱髓鞘过程，并且会因共病状况（如压力和焦虑）而显著加重。尽管有这些知识，但这种情况发生的机制尚未得到很好的理解。该提案中的研究将测试高度新颖和综合的假设，即肠道微生物群参与应激源诱导的全身炎症增强，导致多发性硬化症动物模型中的症状加重。我们已经取得了令人兴奋的发现，肠道微生物群是必要的应激诱导增加脾IL-1的发生。这一点很重要，因为IL-1在许多慢性炎症性疾病（包括多发性硬化症）的发展中起着核心作用。微生物群如何在应激暴露期间导致IL-1增加，以及对慢性炎症性疾病的影响尚不清楚。在反复的社会失败中，肠道微生物可以从它们的主要生态位转移到身体内部。因为有越来越多的证据表明神经内分泌激素，如交感神经系统衍生的儿茶酚胺激素，可以影响微生物种群，目标1将测试压力诱导的交感神经系统激活是否会导致肠道微生物群的易位。作为进一步证实微生物易位是应激物诱导的免疫增强发生所必需的，目标2将测试应激物诱导的脾IL-1的增加依赖于巨噬细胞模式识别受体信号传导和炎性小体形成的假设。最后，为了确定微生物群是否有助于应激源诱导的慢性疾病恶化，将采用广泛使用的多发性硬化症动物模型，即实验性自身免疫性脑脊髓炎（EAE）。反复社交失败对EAE进展的影响将在无菌小鼠（即，从未接触过肠道微生物的小鼠）和常规小鼠。通过整合目标1、2和3的结果，我们将确定压力源暴露加剧慢性炎症性疾病的新机制。这些发现将最终促进合理设计和使用微生物靶向治疗慢性疾病的疗法。