Mechanistic studies to develop a polysaccharide degradation signature (PDS) and its application in improving host health
开发多糖降解特征(PDS)的机制研究及其在改善宿主健康中的应用
基本信息
- 批准号:10260593
- 负责人:
- 金额:$ 51.12万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2020
- 资助国家:美国
- 起止时间:2020-09-15 至 2024-05-31
- 项目状态:已结题
- 来源:
- 关键词:AdultAminoglycoside AntibioticsAnaerobic BacteriaAntioxidantsAvena sativaBacteriaBacteriodetesBacteroidesBacteroidetesBarleyBiochemicalBioinformaticsBiologicalBiological AssayBiological AvailabilityCellsChemopreventive AgentCisplatinColonCommunitiesComplexCytoprotectionDataDatabasesDepositionDevelopmentDietDietary ComponentDietary FiberDietary PolysaccharideDistalEnvironmentEnzymesFamilyFermentationFiberFirmicutesGene ClusterGene ExpressionGenesGenomeGenomicsGerm-FreeGnotobioticGoalsGrowthHairHair CellsHarvestHealthHealth BenefitHealth PromotionHumanHydrolysisIndividualLinkMediatingMetabolismMicrobeModelingMolecularMolecular ProfilingMucinsNoiseNutritionalOligosaccharidesPectinsPharmaceutical PreparationsPharmacologyPhenolsPhylogenetic AnalysisPhytochemicalPlantsPolysaccharidesPrevotellaProteinsProxyReportingRiceSensory HairStructureSystemTreesVolatile Fatty AcidsWheatX-Ray CrystallographyZebrafishbasecolon microbiomeferulic acidimprovedin vivomembermicrobialmicrobiomemicroorganismmultiple omicsnutritionpolypeptidepredictive signatureprotein complexresponsesearch enginesensorsugartranscriptomicsyeast two hybrid system
项目摘要
PROJECT SUMMARY/ABSTRACT
The human colon harbors a large number of microorganisms that collectively are referred to as the colonic
microbiome. The microbes in the colonic microbiome are dominated by bacteria of the phyla Bacteroidetes and
Firmicutes. Among the Bacteriodetes, Prevotella spp. and Bacteroides spp. abound in the colonic environment
and have evolved a complex protein machinery that allows them to harvest energy from both host undegradable
polysaccharides in the diet and host derived-glycans, such as mucin. Central to the mechanism underlying
polysaccharide degradation by the Bacteroidetes is the Polysaccharide Degradation Locus (PUL) or Loci (PULs)
present on their genomes. The PULs are composed of gene clusters that encode proteins that enable the
Bacteroidetes to sense, transport, and degrade diverse polysaccharides to their unit sugars for fermentation. A
large protein, known as the Hybrid Two Component System (HTCS), is conserved in the PULs of the
Bacteroidetes and functions by sensing either a polysaccharide or its oligosaccharides to turn on the expression
of the hydrolytic enzymes and their associated transporters. In this proposal, we demonstrate that indeed the
Bacteroidetes HTCS contain sensor modules that sense unique polysaccharides or their degradative products
in the colonic environment. Thus, we hypothesized that the diverse sensors in the HTCS polypeptides collectively
can serve as a proxy for polysaccharide sensing in the colon of an individual. We have designated this proxy as
the Polysaccharide Degradation Signature or PDS. By using more than 3000 HTCS sequences in the publicly
available databases, we constructed a phylogenetic tree that appeared to cluster the sensor modules into
different branches. Among host undegradable polysaccharides found in human diets, such as wheat, barley, rice
and oats, is arabinoxylan. We, therefore, used growth on arabinoxylan and transcriptomic analysis to determine
the PULs that target soluble arabinoxylan and insoluble arabinoxylan degradation, respectively, in three
members of the human colonic Bacteroidetes. Our data showed that clusters in our phylogenetic tree or PDS
can be matched to arabinoxylan sensing and metabolism. Interestingly, we also discovered that the Bacteroides
spp that metabolize complex arabinoxylan release the plant phenolic compound ferulic acid and that the
compound accumulates in the spent medium. Ferulic acid is known to have antioxidant effects and also to protect
against mechanosensory hair loss. We will, therefore, determine whether a synbiotic of complex arabinoxylan
and arabinoxylan-metabolizing Bacteroidetes has the capacity to confer protection against mechanosensory hair
loss in germ-free zebrafish. Confirmation of this observation will allow us, through transcriptomics analysis, to
determine the underlying molecular mechanisms for this protection. Furthermore, we will use biochemical and
structural analyses to completely characterize the mechanism of arabinoxylan degradation by the human colonic
Bacteroidetes. We also anticipate that our development of the PDS will allow rational manipulation of the
polysaccharides sensed by an individual’s microbiome for health and nutritional benefits.
项目总结/摘要
人类结肠含有大量的微生物,这些微生物统称为结肠微生物。
微生物组结肠微生物组中的微生物以拟杆菌门的细菌为主,
厚壁菌门在拟杆菌中,普雷沃氏菌属(Prevotella spp.)和拟杆菌属。大量存在于结肠环境中
并进化出了一种复杂的蛋白质机制,使它们能够从两种宿主体内获取能量,
饮食中的多糖和宿主衍生的聚糖,如粘蛋白。对基本机制至关重要
拟杆菌的多糖降解是多糖降解位点(PUL)或位点(普尔斯)
存在于它们的基因组中。普尔斯是由基因簇组成的,这些基因簇编码的蛋白质能够使
拟杆菌能够感知、运输和降解各种多糖,并将其转化为单位糖用于发酵。一
大蛋白,称为杂交双组分系统(HTCS),在大肠杆菌的普尔斯中是保守的。
拟杆菌通过感知多糖或其寡糖来启动表达
水解酶及其相关的转运蛋白。在这个提议中,我们证明了事实上
拟杆菌HTCS含有传感器模块,其感测独特的多糖或其降解产物
在结肠环境中。因此,我们假设HTCS多肽中的不同传感器共同
可以作为个体结肠中多糖传感的代表。我们已指定此代理为
多糖降解特征或PDS。通过使用公开的3000多个HTCS序列,
可用的数据库,我们构建了一个系统发育树,似乎聚类传感器模块到
不同的分支在人类饮食中发现的宿主不可降解多糖中,如小麦、大麦、大米
是阿拉伯木聚糖。因此,我们使用阿拉伯木聚糖生长和转录组学分析来确定
分别靶向可溶性阿拉伯木聚糖和不溶性阿拉伯木聚糖降解的普尔斯在三个
人类结肠拟杆菌的成员。我们的数据显示,在我们的系统发育树或PDS中,
可以与阿拉伯木聚糖传感和代谢相匹配。有趣的是,我们还发现类杆菌
代谢复合阿拉伯木聚糖的spp释放植物酚化合物阿魏酸,
化合物在用过的培养基中积累。已知阿魏酸具有抗氧化作用,
对抗机械感觉性脱发因此,我们将确定复合阿拉伯木聚糖的合生元
而代谢阿拉伯聚糖的拟杆菌有能力保护头发免受机械感觉的伤害
无菌斑马鱼的损失。这一观察结果的证实将使我们能够通过转录组学分析,
确定这种保护的潜在分子机制。此外,我们将使用生物化学和
结构分析,以完全表征人结肠癌细胞降解阿拉伯木聚糖的机制
拟杆菌我们还预计,我们的PDS的发展将允许合理的操纵,
这些多糖被个体的微生物组感知,以提供健康和营养益处。
项目成果
期刊论文数量(0)
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会议论文数量(0)
专利数量(0)
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{{ truncateString('ISAAC CANN', 18)}}的其他基金
Mechanistic studies to develop a polysaccharide degradation signature (PDS) and its application in improving host health
开发多糖降解特征(PDS)的机制研究及其在改善宿主健康中的应用
- 批准号:
10798637 - 财政年份:2020
- 资助金额:
$ 51.12万 - 项目类别:
Mechanistic studies to develop a polysaccharide degradation signature (PDS) and its application in improving host health
开发多糖降解特征(PDS)的机制研究及其在改善宿主健康中的应用
- 批准号:
10099985 - 财政年份:2020
- 资助金额:
$ 51.12万 - 项目类别:
Mechanistic studies to develop a polysaccharide degradation signature (PDS) and its application in improving host health
开发多糖降解特征(PDS)的机制研究及其在改善宿主健康中的应用
- 批准号:
10407070 - 财政年份:2020
- 资助金额:
$ 51.12万 - 项目类别:
Mechanistic studies to develop a polysaccharide degradation signature (PDS) and its application in improving host health
开发多糖降解特征(PDS)的机制研究及其在改善宿主健康中的应用
- 批准号:
10643928 - 财政年份:2020
- 资助金额:
$ 51.12万 - 项目类别:
DOMAIN ANALYSIS OF M ACEIVORANS REPLICATION PROTEIN A 1
M ACEIVORANS 复制蛋白 A 1 的结构域分析
- 批准号:
7357984 - 财政年份:2006
- 资助金额:
$ 51.12万 - 项目类别:
CHARACTERIZATION OF A NOVEL ZINC FINGER IN THE ARCHAEA
古细菌中新型锌指的表征
- 批准号:
7181227 - 财政年份:2005
- 资助金额:
$ 51.12万 - 项目类别:
DOMAIN ANALYSIS OF M ACEIVORANS REPLICATION PROTEIN A 1
M ACEIVORANS 复制蛋白 A 1 的结构域分析
- 批准号:
7181229 - 财政年份:2005
- 资助金额:
$ 51.12万 - 项目类别:
NOVEL CARBOHYDRATE BINDING MODULES FROM T POLYSACCHAROLYTICUM
来自 T 多糖的新型碳水化合物结合模块
- 批准号:
7181228 - 财政年份:2005
- 资助金额:
$ 51.12万 - 项目类别:
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