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.
项目总结/文摘:
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)
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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