Commensal microbiota modulates ocular surface mucosal inflammation
Commensal microbiota modulates ocular surface mucosal inflammation
批准号:
9752628
负责人:
CINTIA S. DE PAIVA
金额:
$55.9万
依托单位国家:
美国
项目类别:
财政年份:
2017
资助国家:
美国
项目状态:
已结题
起止时间:
2017-09-01 至 2022-08-31
关键词:
AcuteAffectAnti-inflammatoryAntibioticsAutoimmune DiseasesAutoimmune ProcessButyratesC57BL/6 MouseCell DensityChronicClinicalCommunitiesCorneaDesiccationDevelopmentDiseaseDistantDry Eye SyndromesEconomic BurdenEnvironmentEnvironmental Risk FactorEpithelialExocrine GlandsEyeEye diseasesFDA approvedFecesFemaleFunctional disorderGenesGerm-FreeGlandGoalsGoblet CellsHealthHomeostasisHouse miceIL2RA geneImmuneImmune responseIndividualInflammationInflammatoryInflammatory ResponseInterferonsInterleukin 2 ReceptorInterleukin-17IntestinesKnockout MiceLacrimal gland structureMaintenanceMediator of activation proteinMicrobeModelingMucositisMucous MembraneMusOralPathogenesisPatientsPharmaceutical PreparationsPhotophobiaProductivityReactionRegulatory T-LymphocyteRisk FactorsSeveritiesSjogren&aposs SyndromeStainsStressSupplementationSusceptibility GeneSystemic diseaseTestingTherapeutic UsesTimeVolatile Fatty Acidsaqueousbacterial communitycohortcommensal microbescostcytokinedysbiosisexperimental studyeye drynessfecal microbiotafecal transplantationgerm free conditiongut microbiomegut microbiotaimmunoregulationimprovedirritationmicrobiomemicrobiotamicroorganismmouse modelmucosal sitenovelocular surfacepatient subsetspreventreconstitutionresponserestorationsextherapeutic target
中文摘要
Sjögren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
目标是口腔和眼睛粘膜及其分泌腺。SS导致了最严重的
缺水的干眼症,通常导致眼睛不适和畏光。
越来越多的证据表明,微生物群落,即栖息于
对人体而言,具有强大的免疫调节功能。在这项建议中,我们试图澄清
SS与肠道微生物区系的关系及最终鉴定目标
眼内和/或用于治疗SS的微生物区系内的治疗靶点。有证据表明
肠道微生物失衡是SS的发病机制之一。我们
假设肠道微生物区系支持维持动态平衡的粘膜免疫
保护环境,抑制干燥引起的眼表炎症。
正常共生微生物区系的重建将促进眼粘膜的恢复
动态平衡。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将测试
假设在表现为眼睛刺激的患者中,患有SS的患者具有共生性
粪便生物失调导致抗炎短链脂肪酸(SCFA)水平下降
大便中丁酸盐与其他类型泪液功能障碍患者和正常对照组的比较
研究对象。在特定的目标2中,我们将检验假设,即肠道生物失调调节
急性期远端粘膜部位的炎症反应,特别是眼部炎症
和慢性SS小鼠模型。特定目标3将检验共生肠道的假设
微生物区系维持结膜杯状细胞密度并防止干燥引起的杯状细胞丢失
通过产生Tregs和生产SCFA丁酸酯。
这一提议的结果将有可能展示一种新的
维持全身粘膜组织的动态平衡,包括眼表
具有非常低丰度的微生物群,由共生的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理论基础。
利用共生体粪便微生物区系加强天然免疫调节的探讨
抑制粘膜自身免疫性疾病发展的机制。
英文摘要
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.
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会议论文
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海外基金