Proanthocyanidin metabolites produced by commensal gut microbes may promote metabolic resilience
共生肠道微生物产生的原花青素代谢物可能会促进代谢弹性
基本信息
- 批准号:9791158
- 负责人:
- 金额:$ 38.53万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2018
- 资助国家:美国
- 起止时间:2018-09-24 至 2022-08-31
- 项目状态:已结题
- 来源:
- 关键词:AddressAdipocytesBacteriaBacterial GenomeBerryBile AcidsBiologicalBiological AssayBiological AvailabilityBloodBody WeightCell Culture TechniquesCellsChronic DiseaseColonCommunitiesCoupledDataDietary PolyphenolEnterobacter cloacaeEvaluationFat-Restricted DietFemaleFluorescent in Situ HybridizationFruitGene ExpressionGene ProteinsGerm-FreeGnotobioticGrapesGrowthHealthHepatocyteHigh Fat DietHistologicHumanHuman MicrobiomeImmunofluorescence ImmunologicIn VitroIncubatedInflammationInstitutional Review BoardsIntestinesKnowledgeLactic acidLinkLipopolysaccharidesLiquid ChromatographyLongitudinal StudiesMammalian CellMass Spectrum AnalysisMetabolicMetabolic DiseasesMetabolic syndromeMetforminMethodsMicrobiologyModelingMolecular TargetMonitorMucolyticsMucous body substanceMusMuscle CellsNon-Insulin-Dependent Diabetes MellitusObesityOutcomePhenotypePre-Clinical ModelProanthocyanidinsProbioticsProductionProteinsResearch DesignResolutionSamplingSerumShotgunsSpicesSupplementationTestingThickTight JunctionsTimeTissuesUncertaintyUrineValidationVirusWeight Gainabsorptionbacterial communitybariatric surgerybasecommensal bacteriaefficacy testingglucose metabolismglucose productionglucose uptakegut bacteriagut microbesgut microbiotahost microbiomeimmunoregulationimprovedinflammatory markerinfluenzavirusintestinal epitheliummalemetabolomemetagenomic sequencingmicrobialmicrobiomemouse modelmultidisciplinarynovelnutritionoccludinoral glucose tolerancepolyphenolprebioticsresilience
项目摘要
Project Summary: This multidisciplinary proposal aims to define how proanthocyanidins (PACs), a major class
of grape polyphenols (GPs), alter the intestinal milieu to promote a biological signature associated with resilience
to metabolic syndrome (MetS) and type-2 diabetes (T2D). Using urine, blood, and gut microbiota samples from
PAC-supplemented mice and GP-supplemented humans, microbiome-wide association studies will be
performed to correlate changes in bacterial strains/species to increases/decreases in microbial metabolites
(MMs). PAC treatment of bacteria in vitro and of germfree mice inoculated with bacterial isolates or defined
consortia will establish relationships between specific commensal bacteria and PAC-derived MMs, which will
then be tested for bioactivity in mammalian cell culture assays and a high-fat diet (HFD)-induced mono-
associated germfree (GF) model of MetS/T2D. PACs are associated with metabolic resilience; however,
mechanism(s) of systemic protection have remained elusive due to generally poor absorption and uncertainty
about molecular targets. PACs reach the colon where they are biotransformed to MM with greater bioavailability;
however, the specific bacteria responsible for these transformations, the molecular targets of resulting MM, and
validation of their efficacy in preclinical models of MetS/T2D remain to be investigated. We observed that GP
supplementation can induce a bloom in the mucolytic gut bacterium Akkermansia muciniphila in association with
reduced serum lipopolysaccharide, less intestinal and systemic inflammation, increased expression of tight
junction protein occludin, improved glucose metabolism, and less adiposity and weight gain in HFD-fed mice.
Increased abundance of A. muciniphila has been observed after gastric bypass surgery and metformin treatment,
underlining its importance in positive metabolic outcomes. GP-supplemented mice also showed: 1) decreased
bacterial community richness; 2) alterations in genera consistent with improved gut barrier integrity and lactic
acid-production; 3) decreased serum levels of bacterial-derived secondary bile acids; 4) decreased thickness of
the mucus layer adjacent to the intestinal epithelium with redistribution of mucus in the colon; and 5) increased
serum levels of desaminotyrosine (DAT), a PAC-derived MM associated with immune modulation and resilience
against virus-induced inflammation. Finally, we showed that PACs, are sufficient to increase intestinal
abundance of A. muciniphila. Our data suggest PAC-induced alterations of the intestinal milieu promote
metabolic resilience. To establish cause-effect relationships we propose to: 1) correlate urine/blood metabolites
with gut bacterial strains/species using samples collected in longitudinal studies of GP-supplemented humans
and PAC-treated mice with concomitant monitoring of metabolic and histological phenotypes in HFD- and low-
fat diet (LFD)-fed murine hosts; 2) perform in vitro and germfree mouse studies to confirm relationship of specific
bacteria isolate/consortia to specific MM; 3) investigate bioactivities of PAC-derived MM in cell-based assays
related to glucose metabolism and the B29-monoassociated GF mouse model of HFD-induced MetS/T2D.
项目摘要:这个多学科提案旨在定义原花青素 (PAC) 这一主要类别如何
葡萄多酚 (GP),改变肠道环境,促进与恢复力相关的生物特征
代谢综合征 (MetS) 和 2 型糖尿病 (T2D)。使用来自以下来源的尿液、血液和肠道微生物样本
补充 PAC 的小鼠和补充 GP 的人类,微生物组范围内的关联研究将
将细菌菌株/物种的变化与微生物代谢物的增加/减少相关联
(MM们)。 PAC 处理体外细菌和接种细菌分离株或定义的无菌小鼠
联盟将在特定共生细菌和 PAC 衍生的 MM 之间建立关系,这将
然后在哺乳动物细胞培养测定和高脂饮食(HFD)诱导的单-
MetS/T2D 相关无菌 (GF) 模型。 PAC 与代谢弹性相关;然而,
由于普遍吸收不良和不确定性,系统性保护机制仍然难以捉摸
关于分子靶标。 PAC 到达结肠,在那里它们被生物转化为具有更高生物利用度的 MM;
然而,负责这些转化的特定细菌、产生 MM 的分子靶标以及
其在 MetS/T2D 临床前模型中的功效验证仍有待研究。我们观察到全科医生
补充剂可以诱导粘液溶解肠道细菌 Akkermansia muciniphila 的繁殖,并与以下因素相关:
降低血清脂多糖,减少肠道和全身炎症,增加紧密表达
连接蛋白 occludin,改善了 HFD 喂养小鼠的葡萄糖代谢,减少了肥胖和体重增加。
在胃绕道手术和二甲双胍治疗后观察到 A. muciniphila 丰度增加,
强调其对积极代谢结果的重要性。补充 GP 的小鼠还表现出:1)
细菌群落丰富度; 2) 属的改变与肠道屏障完整性和乳酸的改善一致
产酸; 3)降低细菌衍生的次级胆汁酸的血清水平; 4) 厚度减少
与肠上皮相邻的粘液层,粘液在结肠中重新分布; 5) 增加
血清脱氨酪氨酸 (DAT) 水平,这是一种 PAC 衍生的 MM,与免疫调节和恢复力相关
对抗病毒引起的炎症。最后,我们证明 PAC 足以增加肠道
大量的 A. muciniphila。我们的数据表明 PAC 诱导的肠道环境改变促进
代谢弹性。为了建立因果关系,我们建议:1)关联尿液/血液代谢物
使用在补充 GP 的人类纵向研究中收集的样本对肠道细菌菌株/物种进行研究
和 PAC 处理的小鼠,同时监测 HFD 和低饮食中的代谢和组织学表型
脂肪饮食(LFD)喂养的鼠宿主; 2) 进行体外和无菌小鼠研究以确认特定的关系
特定 MM 的细菌分离物/菌群; 3) 在基于细胞的测定中研究 PAC 衍生的 MM 的生物活性
与葡萄糖代谢和 HFD 诱导的 MetS/T2D 的 B29 单相关 GF 小鼠模型有关。
项目成果
期刊论文数量(0)
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Diana Elizabeth Roopchand其他文献
Diana Elizabeth Roopchand的其他文献
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{{ truncateString('Diana Elizabeth Roopchand', 18)}}的其他基金
Interactions of dietary polyphenols, gut microbiota and intestinal epithelium
膳食多酚、肠道微生物群和肠上皮的相互作用
- 批准号:
9108579 - 财政年份:2016
- 资助金额:
$ 38.53万 - 项目类别:
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