Role of epithelial ROS signaling in mediating psychological stress-induced mucosal dysfunction and colitis predisposition
上皮ROS信号在介导心理应激引起的粘膜功能障碍和结肠炎易感性中的作用
基本信息
- 批准号:10521707
- 负责人:
- 金额:$ 68.55万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2022
- 资助国家:美国
- 起止时间:2022-07-31 至 2027-05-31
- 项目状态:未结题
- 来源:
- 关键词:AblationAdhesionsAnaerobic BacteriaAnimalsBacteriaBacteroidesBiological FactorsCatecholaminesCell LineCell physiologyCellular StressChronicCitrobacterCitrobacter rodentiumColitisColonCorticotropin-Releasing HormoneDataDiseaseDisease susceptibilityEnterobacteriaceaeEnvironmentEnzymesEpithelialEpithelial CellsEtiologyExhibitsExposure toFamilyFemaleFlagellinFunctional disorderGenerationsGenetic Predisposition to DiseaseGerm CellsGerm-FreeGlucocorticoidsGrowthGut MucosaHealthHormone ReceptorHormonesHumanHydrogen PeroxideImmuneImmune responseImmune systemIncidenceIndividualInfectionInfectious colitisInflammatoryInflammatory Bowel DiseasesInflammatory ResponseIntestinesLaboratoriesLinkMediatingMetagenomicsMicrobeMucinsMucolyticsMucous MembraneMucous body substanceMusNADPNeuraminidaseOrganismOutcomeOxidasesPathway interactionsPatientsPharmacologyPhysiologyPolysaccharidesPredispositionProductionPsychological StressPsychosocial StressReactive Oxygen SpeciesResistanceRiskRoleSeveritiesSialic AcidsSideSignal TransductionSignaling MoleculeStressStructureSympathetic Nervous SystemT-LymphocyteTestingThinnessUp-RegulationWorkantimicrobialbacterial resistancecatalasecohesioncolon microbiotadysbiosisenteric pathogenexperimental studygastrointestinal epitheliumgut microbesgut microbiotagut-brain axishost microbiotahost-microbe interactionshypothalamic-pituitary-adrenal axisintestinal epitheliummalemembermicrobialmicrobial communitymicrobiomemicrobiome analysismicrobiotamouse modelmucosal microbiotanovelpathobiontpathogenpathogenic microbepsychosocial stressorsresponserestraint stresssocial defeatsocial stressstressortargeted treatmentvillin
项目摘要
PROJECT SUMMARY/ABSTRACT:
Inflammatory bowel diseases (IBD) are becoming more prevalent in the US and represent a major societal health
concern. Exposure to psychosocial stressors increases the likelihood of developing IBD in genetically
predisposed individuals, implicating a brain-gut axis in the IBD etiological framework. An emerging line of work
has established that stress-induced disruptions to the gut microbiota (i.e. dysbiosis) may be the most proximate
cause of stress-induced IBD predisposition. This includes data from our laboratory where we showed that a
mouse adaptive pathogen (C. rodentium) was more effective at colonizing and inducing colitis in mice colonized
by a microbiota from mice exposed to a chronic social defeat stressor. Moreover, our new preliminary data
provides evidence stress exacerbates chronic, immune mediated (T-cell) colitis. However, how the gut
microbiota and mucosal layer becomes dysregulated in response to stressors and why those changes
predispose worsened colitis, is not yet understood. We recently demonstrated that stress induces large shifts in
intestinal epithelial cell (IEC) activity that tightly corresponded to changes in gut microbiota function and thinning
of the mucus layer. Of those changes observed in IECs, our preliminary data indicate that the reactive-oxygen
species (ROS)-generating capacity of IECs may be the most proximate causes of stress-induced dysbiosis and
mucosal disruption. Signs of stress in IECs were absent in germ-free (GF) mice at baseline, thus implicating the
microbiota in IEC responsiveness. Nevertheless, IECs were still primed to respond differentially to an ex vivo
bacterial challenge (evidenced by an increased expression in the ROS-generating enzyme dual oxidase
(DUOX2), suggesting that host stress signaling molecules and the gut microbiota are together involved in
regulating IEC activity. Intriguingly, the upregulation in DUOX2 and ROS activity in IECs corresponded to
expansion of ROS-resistant bacteria that are capable of mucus degradation. These data led us to build a
cohesive framework underlying this proposal, whereby stress hormones ‘prime’ IECs to respond to endogenous
microbiota signaling/adhesion through heightened ROS generation. This enhanced ROS activity at the mucosal
interface creates a unique niche for mucosal associated microbes that are resistant to ROS activity and survive
by degrading mucus glycans that normally provide a barrier against both endogenous microbes and pathogens.
We hypothesize that this IEC-directed expansion of ROS-resistant, mucus-degrading endogenous microbes is
what underlies IBD susceptibility in organisms exposed to chronic, unabated stress.
项目概要/摘要:
炎症性肠病(IBD)在美国变得越来越普遍,并代表了一个主要的社会健康问题
忧虑。暴露于社会心理压力源会增加遗传性 IBD 的可能性
易感个体,暗示 IBD 病因学框架中存在脑肠轴。新兴的工作领域
已经确定压力引起的肠道微生物群破坏(即菌群失调)可能是最直接的影响
压力诱发 IBD 易感性的原因。这包括我们实验室的数据,我们表明
小鼠适应性病原体(C. rodentium)在定植小鼠中更有效地定植并诱导结肠炎
是由暴露于慢性社交挫败压力源的小鼠体内的微生物群产生的。此外,我们的新初步数据
提供证据表明压力会加剧慢性免疫介导(T 细胞)结肠炎。然而,肠道如何
微生物群和粘膜层因应激源而变得失调以及这些变化的原因
诱发结肠炎恶化,目前尚不清楚。我们最近证明,压力会引起巨大的转变
肠上皮细胞(IEC)活性与肠道微生物群功能和变薄的变化密切相关
的粘液层。在 IEC 中观察到的这些变化中,我们的初步数据表明活性氧
IEC 的物种(ROS)生成能力可能是应激引起的生态失调的最直接原因
粘膜破坏。在基线时,无菌 (GF) 小鼠中 IEC 不存在应激迹象,因此暗示
IEC 反应性中的微生物群。尽管如此,IEC 仍准备好对离体反应做出不同的反应。
细菌挑战(ROS 生成酶双氧化酶表达增加证明
(DUOX2),表明宿主应激信号分子和肠道微生物群共同参与
规范 IEC 活动。有趣的是,IEC 中 DUOX2 和 ROS 活性的上调对应于
能够降解粘液的 ROS 抗性细菌的扩增。这些数据引导我们建立一个
该提案背后的凝聚力框架,其中应激激素“启动”IEC以应对内源性
通过增加 ROS 生成来增强微生物群信号传导/粘附。这增强了粘膜处的ROS活性
界面为粘膜相关微生物创造了一个独特的生态位,这些微生物能够抵抗 ROS 活性并存活下来
通过降解通常提供抵抗内源微生物和病原体屏障的粘液聚糖。
我们假设 IEC 指导的 ROS 抗性、粘液降解内源微生物的扩张是
暴露于长期、未减弱的压力的生物体易感 IBD 的原因是什么。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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Jacob Matthew Allen其他文献
Jacob Matthew Allen的其他文献
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{{ truncateString('Jacob Matthew Allen', 18)}}的其他基金
Role of epithelial ROS signaling in mediating psychological stress-induced mucosal dysfunction and colitis predisposition
上皮ROS信号在介导心理应激引起的粘膜功能障碍和结肠炎易感性中的作用
- 批准号:
10667614 - 财政年份:2022
- 资助金额:
$ 68.55万 - 项目类别:
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