Influence of gut microbiota strain variation on mucosal T-cell phenotype
肠道微生物菌株变异对粘膜 T 细胞表型的影响
基本信息
- 批准号:10449983
- 负责人:
- 金额:$ 3.64万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2021
- 资助国家:美国
- 起止时间:2021-08-01 至 2023-01-31
- 项目状态:已结题
- 来源:
- 关键词:Anaerobic BacteriaAntigensBacteriaBiological AssayCellsClinicColitisCollectionCommunitiesComplexCoupledDataDiseaseExcisionExposure toFlow CytometryFrequenciesGenetic studyGerm-FreeGnotobioticGoalsHumanImmuneImmune responseImmune systemImmunityIndividualInflammatoryInflammatory Bowel DiseasesInterleukin-17InterventionIntestinesLinkMeasuresMethodsMicrobeMucosal Immune SystemMucous MembraneMusPathway interactionsPhenotypePredispositionT cell responseT-LymphocyteTaxonomyTestingTissuesVariantadaptive immune responsebacterial communitybasecell typechronic inflammatory diseaseenzyme linked immunospot assayexperimental studygut inflammationgut microbiotaimmunoregulationin vivomembermicrobialmicrobiomemicrobiotamurine colitispreventstem
项目摘要
PROJECT SUMMARY
Inflammatory bowel diseases (IBD) are chronic inflammatory conditions characterized by a dysregulated
immune response that results in intestinal inflammation and tissue damage. Over the past decade, an
increasing body of evidence has associated IBD with inappropriate interactions between the gut microbiota and
the mucosal immune system. Despite these associations, there have been few studies identifying causal links
between specific components of the human gut microbiota and intestinal inflammation. This proposal is
focused on discovering specific bacterial strains within the gut microbiota that induce inflammatory T cell
responses, with the goal of identifying key strains that contribute to colitis progression. To interrogate T cell
responses to individual strains, we will utilize gnotobiotic mice coupled with an ex vivo restimulation assay to
measure T cell responses by ELISPOT and flow cytometry. Aim 1 – In our preliminary findings, we provide two
examples where our approach successfully identified candidate Th17 stimulating strains from culture
collections derived from two IBD donors. Both these results were validated in vivo, demonstrating proof-of-
concept for rational modulation of immune tone by selective removal of candidate strains. To expand on these
findings, we will extend our method to further explore the influence of genus, species, and strain diversity
on Th17 stimulation within IBD-associated microbiotas. This data will indicate if there are particular
taxonomic groups that stimulate Th17 cells, or if diversity at the strain level drives variation in T cell responses.
Aim 2 – In our preliminary results, we find no difference in colitis progression between groups of microbes that
drive Th17 induction and groups of microbes that do not drive Th17 induction, suggesting the microbes that
determine Th17 frequency in a homeostatic setting may not be the same microbes that drive colitis in a
disease setting. To expand on these findings, we will assess how individual microbes within IBD-
associated microbiotas potentiate colitis. These approaches will determine if the colitogenic capacity of a
culture collection can be abrogated by the selective removal of particular strains.
项目摘要
炎症性肠病(IBD)是慢性炎症性病症,其特征在于,
导致肠道炎症和组织损伤的免疫反应。在过去的十年里,
越来越多的证据将IBD与肠道微生物群之间的不适当相互作用联系起来,
粘膜免疫系统尽管存在这些关联,但很少有研究确定因果关系
人类肠道微生物群的特定成分与肠道炎症之间的关系。这项建议是
专注于发现肠道微生物群中诱导炎性T细胞的特定细菌菌株,
反应,目的是确定有助于结肠炎进展的关键菌株。审问T细胞
响应于单个菌株,我们将利用与离体再刺激测定偶联的无菌小鼠,
通过ELISPOT和流式细胞术测量T细胞应答。目标1 -在我们的初步调查结果中,我们提供了两个
我们的方法成功地从培养物中鉴定出候选Th 17刺激菌株的实例
来自两个IBD供体的收集物。这两个结果都在体内得到了验证,证明了
通过选择性去除候选菌株来合理调节免疫强度的概念。为了扩展这些
研究结果,我们将扩展我们的方法,以进一步探讨属,种和菌株多样性的影响
对IBD相关微生物群内Th 17刺激的影响。这些数据将表明是否有特定的
刺激Th 17细胞的分类群,或者菌株水平的多样性是否驱动T细胞应答的变化。
目的2 -在我们的初步结果中,我们发现在结肠炎的进展中,
驱动Th 17诱导的微生物和不驱动Th 17诱导的微生物组,表明
在稳态环境中确定Th 17频率可能与在稳态环境中驱动结肠炎的微生物不同。
疾病设置。为了扩展这些发现,我们将评估IBD中的单个微生物-
相关的微生物增强结肠炎。这些方法将确定A的大肠杆菌能力是否
培养物收集可以通过选择性去除特定菌株来取消。
项目成果
期刊论文数量(0)
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科研奖励数量(0)
会议论文数量(0)
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