The Role of Bacterial Choline Metabolism in Host Stress Responses
细菌胆碱代谢在宿主应激反应中的作用
基本信息
- 批准号:10379873
- 负责人:
- 金额:$ 39.17万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2019
- 资助国家:美国
- 起止时间:2019-06-01 至 2024-03-31
- 项目状态:已结题
- 来源:
- 关键词:AddressAgonistAnimal ModelAnimalsAnti-Inflammatory AgentsAntiinflammatory EffectAtherosclerosisAutomobile DrivingBile AcidsCardiometabolic DiseaseCholineChronicClinical TrialsCommunitiesDataDevelopmentDiabetes MellitusDietDietary SupplementationDiseaseDrug TargetingEnvironmental ExposureEnvironmental Risk FactorEnzymesFMO3Fatty LiverFatty acid glycerol estersFecesFoodFutureGene ExpressionGenetic TranscriptionGenomeGerm-FreeGlucocorticoid ReceptorGlucocorticoidsGlucoseHealthcareHepaticHigh Fat DietHomeostasisHomo sapiensHormonesHumanHuman bodyImmunosuppressionInflammationIngestionInsulinInsulin ResistanceIntestinesLecithinLevocarnitineLinkLipidsLiverLyaseMediator of activation proteinMetabolicMetabolic DiseasesMetabolic PathwayMetabolic stressMetabolic syndromeMetabolismMicrobeMicronutrientsMolecularMultienzyme ComplexesMusMuscular AtrophyNon-Insulin-Dependent Diabetes MellitusNutrientNutritional StudyPathogenesisPathway interactionsPharmacologyPredispositionProductionReceptor ActivationResistance developmentRoleSignal TransductionSourceStressTestingTherapeuticTranscriptional RegulationTransplantationUnited StatesVolatile Fatty Acidsbasebiological adaptation to stresscardiometabolismcardiovascular disorder riskcare burdendietarydrug discoveryexperiencefollow-upglucocorticoid receptor alphagut microbeshost microbiotahuman modelinsightintegrated circuitknowledge basemicrobialmultiple omicsnovelnutrition related geneticsnutritional genomicsprogramsscreeningsmall molecule inhibitorsymbionttargeted treatmenttreatment strategytrimethylaminetrimethyloxamine
项目摘要
Insulin resistance represents a rapidly expanding health care burden in the United States, contributing to the pathogenesis of a number of cardiometabolic disorders. Recent evidence has emerged that microbes resident in the human intestine represent a key transmissible environmental factor contributing to insulin resistance and associated cardiometabolic disease. However, mechanisms by which gut microbial-derived factors signal to the host to promote insulin resistance are largely unknown. We have recently discovered a meta-organismal pathway where nutrients present in high fat foods (phosphatidylcholine, choline, and L-carnitine) can be metabolized by the gut microbial enzymes to generate trimethylamine (TMA), which is then further metabolized by the host enzyme flavin-containing monooxygenase 3 (FMO3) to produce trimethylamine-N- oxide (TMAO). Preliminary studies here demonstrate that the TMAO pathway is linked to insulin resistance and the development of type 2 diabetes in humans and animal models. Moreover, we show that pharmacologic inhibition of TMAO production confers striking protection against insulin resistance in mice. Mechanistically, we have found that host metabolic reprogramming driven by the glucocorticoid receptor (GR) requires direct transcriptional regulation of FMO3. Collectively, our preliminary data have led us to propose the following central hypothesis: The gut microbial metabolite TMAO is a GR-sensitive mediator of host stress responses that promote insulin resistance. The specific aims are: Aim 1. Testing the hypothesis that the gut microbial TMAO pathway directly impacts susceptibility for high fat diet-driven insulin resistance; and Aim 2. To determine whether transcriptional regulation of the host TMAO-producing enzyme FMO3 is necessary for GR-driven immunosuppression and metabolic reprogramming. We anticipate our studies to reveal new molecular mechanisms linking gut microbe-derived factors to insulin resistance and associated cardiometabolic disorder, which will ultimately be leveraged into to the first ever gut microbe-targeted therapeutics for the treatment of type 2 diabetes.
胰岛素抵抗代表了美国迅速扩大的医疗保健负担,导致许多心脏代谢疾病的发病机制。最近的证据表明,人类肠道中的微生物是导致胰岛素抵抗和相关心脏代谢疾病的关键传播环境因素。然而,肠道微生物源性因子向宿主发出信号以促进胰岛素抵抗的机制在很大程度上是未知的。我们最近发现了一种元生物途径,其中存在于高脂肪食物中的营养物质(磷脂酰胆碱,胆碱和L-肉毒碱)可以通过肠道微生物酶代谢产生三甲胺(TMA),然后通过宿主酶含黄素单加氧酶3(FMO 3)进一步代谢产生三甲胺-N-氧化物(TMAO)。这里的初步研究表明,TMAO途径与胰岛素抵抗和人类和动物模型中2型糖尿病的发展有关。此外,我们表明,药理学抑制TMAO生产赋予对小鼠胰岛素抵抗的显着保护。从机制上讲,我们发现糖皮质激素受体(GR)驱动的宿主代谢重编程需要FMO 3的直接转录调控。总的来说,我们的初步数据使我们提出了以下中心假设:肠道微生物代谢物TMAO是促进胰岛素抵抗的宿主应激反应的GR敏感介质。具体目标是:目标1。测试肠道微生物TMAO途径直接影响高脂肪饮食驱动的胰岛素抵抗的易感性的假设;和目标2。确定宿主TMAO生成酶FMO 3的转录调节是否是GR驱动的免疫抑制和代谢重编程所必需的。我们预计我们的研究将揭示将肠道微生物衍生因子与胰岛素抵抗和相关心脏代谢紊乱联系起来的新分子机制,这最终将被用于治疗2型糖尿病的首个肠道微生物靶向疗法。
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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Florian Rieder
Jonathan Mark Brown的其他文献
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{{ truncateString('Jonathan Mark Brown', 18)}}的其他基金
Dark GPCR signaling underlying the Microbiome-Gut-Brain Axis for Alzheimer's Disease and Related Dementia
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- 批准号:
10719150 - 财政年份:2023
- 资助金额:
$ 39.17万 - 项目类别:
Metaorganismal Endocrinology in Cardiometabolic Disease
心血管代谢疾病的代谢内分泌学
- 批准号:
10468993 - 财政年份:2021
- 资助金额:
$ 39.17万 - 项目类别:
Metaorganismal Endocrinology in Cardiometabolic Disease
心血管代谢疾病的代谢内分泌学
- 批准号:
10311272 - 财政年份:2021
- 资助金额:
$ 39.17万 - 项目类别:
Metaorganismal Endocrinology in Cardiometabolic Disease
心血管代谢疾病的代谢内分泌学
- 批准号:
10623318 - 财政年份:2021
- 资助金额:
$ 39.17万 - 项目类别:
Project 2: Gut microbial choline metabolites in cardiometabolic disease
项目2:心脏代谢疾病中的肠道微生物胆碱代谢物
- 批准号:
10653052 - 财政年份:2019
- 资助金额:
$ 39.17万 - 项目类别:
Project 2: Gut microbial choline metabolites in cardiometabolic disease
项目2:心脏代谢疾病中的肠道微生物胆碱代谢物
- 批准号:
10206255 - 财政年份:2019
- 资助金额:
$ 39.17万 - 项目类别:
Project 2: Gut microbial choline metabolites in cardiometabolic disease
项目2:心脏代谢疾病中的肠道微生物胆碱代谢物
- 批准号:
10447070 - 财政年份:2019
- 资助金额:
$ 39.17万 - 项目类别:
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