Commensal microbiota modulates ocular surface mucosal inflammation

共生微生物群调节眼表粘膜炎症

• 批准号: 10076324
• 负责人: CINTIA S. DE PAIVA
• 金额: $ 3.28万
• 依托单位: BAYLOR COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-09-01 至 2022-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10076324
• 关键词: Acute; Affect; Anti-Inflammatory Agents; Antibiotics; Autoimmune Diseases; Autoimmune Process; Butyrates; C57BL/6 Mouse; Cell Density; Chronic; Clinical; Communities; Cornea; Desiccation; Development; Disease; Distant; Dry Eye Syndromes; Economic Burden; Environment; Environmental Risk Factor; Epithelial; Epithelium; Exocrine Glands; Eye; Eye diseases; FDA approved; Feces; Female; Functional disorder; Genes; Germ-Free; Gland; Goals; Goblet Cells; Health; Homeostasis; House mice; IL2RA gene; Immune; Immune response; Individual; Inflammation; Inflammatory; Inflammatory Response; Interferons; Interleukin 2 Receptor; Interleukin-17; Intestines; Knockout Mice; Lacrimal gland structure; Maintenance; Mediator of activation protein; Microbe; Modeling; Mucositis; Mucous Membrane; Mus; Oral; Pathogenesis; Patients; Pharmaceutical Preparations; Photophobia; Productivity; Reaction; Regulatory T-Lymphocyte; Risk Factors; Severities; Sjogren' s Syndrome; Stains; Stress; Supplementation; Susceptibility Gene; Systemic disease; Testing; Therapeutic Uses; Time; Volatile Fatty Acids; aqueous; bacterial community; cohort; commensal microbes; cost; cytokine; dysbiosis; experimental study; eye dryness; fecal microbiota; fecal transplantation; germ free condition; gut microbiome; gut microbiota; immunoregulation; improved; irritation; microbiome; microbiota; microorganism; mouse model; mucosal site; novel; ocular surface; patient subsets; prevent; reconstitution; response; restoration; sex; therapeutic target

Sjögren syndrome (SS) is a common autoimmune disease affecting millions of patients in the US that targets oral and ocular mucosa and their secretory glands. SS causes the most severe aqueous deficient dry eye disease that often results in disabling eye irritation and photophobia. There is mounting evidence that the microbiome, the community of microorganisms that inhabit the body, has a potent immunoregulatory functions. In this proposal we seek to elucidate the relationship between SS and the intestinal microbiota with the eventual goal of identifying therapeutic targets within the eye and/or the microbiota with which to treat SS. Evidence suggests that intestinal dysbiosis (microbial imbalance) contributes to the pathogenesis of SS. We hypothesize that intestinal microbiota support maintenance of the homeostatic mucosal immune environment and suppress desiccation-induced inflammation on the ocular surface. Reconstitution of normal commensal microbiota would promote restoration of ocular mucosal homeostasis. To test our hypothesis, we propose three Specific Aims: Specific Aim 1 will test the hypothesis that among patients presenting with eye irritation, those with SS have commensal fecal dysbiosis resulting in decreased levels of the anti-inflammatory short chain fatty acid (SCFA) butyrate in the stool compared to patients with other types of tear dysfunction and normal control subjects. In Specific Aim 2 we will test hypothesis that intestinal dysbiosis modulates the inflammatory response to stress at distant mucosal sites, specifically ocular inflammation, in acute and chronic murine models of SS. Specific Aim 3 will test the hypothesis that commensal intestinal microbiota maintains conjunctival goblet cell density and prevents desiccation-induced goblet loss by generating Tregs and producing SCFA butyrate. Results of this proposal will have potential to demonstrate a novel new paradigm for maintenance of homeostasis in mucosal tissues throughout the body, including the ocular surface that has a very low abundance microbiota, by commensal intestinal microbiota and their metabolites such as butyrate. Furthermore, they will provide rationale for a novel treatment approach utilizing commensal fecal microbiota to enhance natural immunoregulatory mechanisms to suppress development of mucosal autoimmune disease.

干燥综合征 (SS) 是一种常见的自身免疫性疾病，影响着美国数百万患者 针对口腔和眼粘膜及其分泌腺。 SS 造成最严重的 水缺乏性干眼病，通常会导致眼睛发炎和畏光。 越来越多的证据表明，微生物组，即栖息的微生物群落 机体，具有强效的免疫调节功能。在本提案中，我们试图阐明 SS 和肠道微生物群之间的关系，最终目标是确定 用于治疗 SS 的眼睛和/或微生物群内的治疗靶点。有证据表明 肠道菌群失调（微生物失衡）是 SS 的发病机制之一。我们 假设肠道微生物群支持维持粘膜免疫稳态 环境并抑制眼表干燥引起的炎症。 正常共生微生物群的重建将促进眼粘膜的恢复 体内平衡。为了检验我们的假设，我们提出了三个具体目标：具体目标 1 将检验 假设在出现眼部刺激的患者中，患有 SS 的患者具有共生性 粪便生态失调导致抗炎短链脂肪酸 (SCFA) 水平下降 与其他类型泪液功能障碍且控制正常的患者相比，粪便中丁酸盐的含量 科目。在具体目标 2 中，我们将检验肠道菌群失调调节肠道菌群的假设。 急性炎症时，远处粘膜部位对应激的炎症反应，特别是眼部炎症 和慢性SS小鼠模型。具体目标 3 将检验以下假设：共生肠道 微生物群维持结膜杯状细胞密度并防止干燥引起的杯状细胞损失 通过生成 Tregs 并产生 SCFA 丁酸盐。 该提案的结果将有可能展示一种新颖的新范式 维持全身粘膜组织的稳态，包括眼表 通过共生肠道微生物群及其微生物群，其微生物群丰度非常低 代谢物，例如丁酸盐。此外，他们将为一种新的治疗方法提供理论依据 利用共生粪便微生物群增强自然免疫调节的方法 抑制粘膜自身免疫性疾病发展的机制。