Commensal microbiota modulates ocular surface mucosal inflammation

共生微生物群调节眼表粘膜炎症

• 批准号: 10244985
• 负责人: CINTIA S. DE PAIVA
• 金额: $ 47.57万
• 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 2023-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10244985
• 关键词: Acute; Affect; Anti-Inflammatory Agents; Antibiotics; Autoimmune; Autoimmune Diseases; Butyrates; C57BL/6 Mouse; Cell Density; Chronic; Clinical; Communities; Cornea; Desiccation; Development; Disease; Distant; Dry Eye Syndromes; Economic Burden; Environment; Environmental Risk Factor; Epithelial; Exocrine Glands; Eye; 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; autoimmune inflammation; 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，在美国影响数百万患者 靶向口腔和眼粘膜及其分泌腺。SS导致最严重的 常导致眼刺激和眼恐惧症的水缺乏性干眼病。 越来越多的证据表明，微生物组，即栖息在 对机体，具有强大的免疫调节功能。在本建议中，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 眼内的治疗靶点和/或用于治疗SS的微生物群。证据表明 肠道生态失调（微生物失衡）有助于SS的发病机制。我们 假设肠道微生物群支持维持稳态粘膜免疫 环境和抑制眼表干燥诱导的炎症。 重建正常的眼内微生物群将促进眼粘膜的恢复 体内平衡为了验证我们的假设，我们提出了三个具体目标：具体目标1将测试 假设在出现眼刺激的患者中，SS患者有眼刺激， 粪便生态失调导致抗炎性短链脂肪酸（SCFA）水平降低 与其他类型泪液功能障碍患者和正常对照组相比， 科目在具体目标2中，我们将检验肠道生态失调调节 急性炎症反应中，远端粘膜部位对应激的炎症反应，特别是眼部炎症， 和SS的慢性鼠模型。具体目标3将检验以下假设： 微生物群维持结膜杯状细胞密度并防止干燥诱导的杯状细胞损失 通过产生调节性T细胞和产生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（包括眼表）的稳态 它有一个非常低丰度的微生物群，通过肠道微生物群和它们的 代谢物如丁酸盐。此外，它们将为一种新的治疗方法提供依据。 利用粪便微生物群增强天然免疫调节的方法 抑制粘膜自身免疫性疾病发展的机制。

项目成果

IL-17 Producing Lymphocytes Cause Dry Eye and Corneal Disease With Aging in RXRα Mutant Mouse.

• DOI: 10.3389/fmed.2022.849990
• 发表时间: 2022
• 期刊: Frontiers in medicine
• 影响因子: 3.9
• 作者: Alam J;Yazdanpanah G;Ratnapriya R;Borcherding N;de Paiva CS;Li D;Guimaraes de Souza R;Yu Z;Pflugfelder SC
• 通讯作者: Pflugfelder SC