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.

Sjögren综合征（SS）是一种常见的自身免疫性疾病，影响美国数百万患者 这是针对口腔和眼粘膜及其秘书腺体的。 SS导致最严重的 水缺乏干眼症，通常导致眼睛刺激和恐惧症。 有越来越多的证据表明，微生物组，居住的微生物社区 身体具有潜在的免疫调节功能。在此提案中，我们试图阐明 SS与肠道微生物群之间的关系与最终确定目标 眼睛和/或菌群中的治疗靶标的治疗靶标。有证据表明 肠道营养不良（微生物失衡）有助于SS的发病机理。我们 假设肠道菌群支持维持体内稳态粘膜免疫 环境并抑制眼表面的测定引起的感染。 正常的共生微生物群的重建将促进眼粘膜的恢复 稳态。为了检验我们的假设，我们提出了三个具体目标：特定目标1将测试 假设在出现眼睛刺激的患者中，患有SS的患者具有共识 粪便障碍症导致抗炎短链脂肪酸（SCFA）的水平降低 与其他类型的泪液功能障碍和正常对照的患者相比 主题。在特定目标2中，我们将检验肠道营养不良调节的假设 急性炎症部位的炎症反应，特别是眼部炎症 和SS的慢性鼠模型。特定的目标3将检验Consensal肠道的假设 Microbiota保持连接的杯状细胞密度并防止欲望引起的杯状损失 通过产生treg并产生SCFA丁酸酯。   该提案的结果将有可能证明一种新的新范式 维持整个体内粘膜组织中体内稳态，包括眼表 由Cencensal Intestinal Microbiota及其 丁酸酯等代谢产物。此外，他们将为新的治疗提供理由 使用共生粪便微生物群来增强天然免疫调节 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