Use of tryptophan-synthesizing bacteria to enhance intestinal motility
利用色氨酸合成菌增强肠道蠕动
基本信息
- 批准号:10453687
- 负责人:
- 金额:$ 19.12万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2021
- 资助国家:美国
- 起止时间:2021-07-19 至 2024-06-30
- 项目状态:已结题
- 来源:
- 关键词:AgonistApplications GrantsAromatic-L-Amino-Acid DecarboxylasesBacillus subtilisBacteriaBehaviorBiochemicalBlood specimenBrainCell DegranulationCellsChemicalsClostridium difficileConstipationDiarrheaDietDigestionDigestive System DisordersDiseaseDrug TargetingElementsEndocrine GlandsEnteralEnterobacteriaceaeEnterochromaffin CellsEpithelialEpithelial CellsEssential Amino AcidsFormulationFutureGastric EmptyingGastrointestinal DiseasesGastrointestinal MotilityGastrointestinal tract structureGenesGoalsGoblet CellsHealthHumanHydroxyindoleacetic AcidIndolesInfectionInflammatoryInflammatory Bowel DiseasesIntestinal MotilityIntestinal SecretionsIntestinesInvestigationKnowledgeKynurenineLarge IntestineLinkLocationMeasuresMediatingMotorMucous MembraneMusNausea and VomitingNeuronsOutcome MeasurePatientsPatternPharmacologyPhysiological ProcessesPopulationProbioticsProductionPropertyProteinsRecurrenceReflex actionReporterResearch DesignRoleSerotoninSerotonin Receptors 5-HT4Signal TransductionSignaling MoleculeSmall IntestinesSocietiesSourceSymptomsTestingTissuesTransgenic OrganismsTryptaminesTryptophanTryptophan 5-monooxygenaseTryptophan SynthaseWaste ProductsWaterbasecell motilitydesigndietaryeffective therapyfecal transplantationgut bacteriagut microbiomegut microbiotaimprovedinnovationintestinal epitheliummicrobiomemicrobiotamicroorganismneurochemistrynovelnovel strategiesoptogeneticsprobiotic therapyreceptorresponseserotonin receptorspatiotemporalsuccesssymptom treatmenttargeted treatmenttranslational approachtreatment strategyvirtual
项目摘要
Project Summary/Abstract
Functional and inflammatory disorders of the gastrointestinal tract represent a significant burden to patients
and to society. These disorders are difficult to treat, and recurrence of symptoms is common. As a result,
there are ongoing efforts to develop more effective treatment options. The gut microbiome is now recognized
as a dynamic entity that can influence a wide variety of physiological processes, ranging from the integrity of
the intestinal epithelial barrier to brain neurochemistry and behavior. The clear success of fecal microbiome
transplants in the treatment of C. difficile infections has highlighted the potential of utilizing the microbiome as a
means of improving health. The studies that are included in this grant application are designed to exploit
specific biochemical properties of certain bacterial strains to test novel treatment strategies for functional bowel
disorders. We will test the hypothesis that tryptophan-synthesizing bacteria increase active tryptophan
metabolites that enhance colonic motility through the activation of 5-HT4 receptors.
Tryptophan is an essential amino acid that is typically acquired from the diet, but can also be produced by
enteric bacteria. In addition to being incorporated into proteins, it serves as a precursor molecule for serotonin
(5-HT), or it can be enzymatically converted to form kynurenine and its derivatives.
In the epithelium of the intestine, enterochromaffin cells convert tryptophan to 5-HT. When 5-HT is
released from these cells it triggers enteric reflexes that increase propulsive motility and epithelial secretion.
Changes in 5-HT signaling have been identified in functional and inflammatory conditions of the gut, and drugs
targeting 5-HT receptors have been developed for the treatment of constipation and diarrhea. In Specific Aim
1 of this proposal, we will test the hypothesis that treatment of mice with a bacterial strain that is known to
produce tryptophan, and which has been used safely in probiotic formulations, results in increased mucosal 5-
HT levels and enhanced intestinal motility.
Specific Aim 2 of this proposal is aimed at determining the mechanisms by which tryptophan producing
bacteria promote motility. The 5-HT receptor that is most directly linked to propulsive motility is the 5-HT4
receptor. We will test whether this receptor is involved and determine what tissues express the receptor that
mediate this effect. We will also examine what changes in motility patterns and neuronal activity are
associated with enhanced propulsive motility, and we will test whether increasing the tryptophan metabolite,
tryptamine, can enhance the motility augmenting effect of tryptophan-producing bacteria.
The results of these studies could provide a predictive translational strategy for the use of probiotic
bacteria, with known biochemical features, for the treatment of constipation.
项目总结/摘要
胃肠道的功能性和炎症性疾病对患者来说是一个重大负担
和社会。这些疾病很难治疗,症状复发很常见。因此,在本发明中,
目前正在努力开发更有效的治疗方案。肠道微生物组现已得到认可
作为一个动态的实体,可以影响各种各样的生理过程,从完整的
肠上皮屏障对脑神经化学和行为的影响。粪便微生物组的明显成功
移植治疗C.艰难梭菌感染突出了利用微生物组作为
改善健康的手段。在这个补助金申请中包含的研究旨在利用
某些细菌菌株的特定生化特性,以测试功能性肠的新治疗策略
紊乱我们将检验合成色氨酸的细菌增加活性色氨酸的假设
通过激活5-HT 4受体增强结肠运动的代谢物。
色氨酸是一种必需氨基酸,通常从饮食中获得,但也可以通过
肠道细菌除了被整合到蛋白质中,它还作为血清素的前体分子
(5-HT),或者其可以酶促转化以形成犬尿氨酸及其衍生物。
在肠上皮中,肠嗜铬细胞将色氨酸转化为5-HT。当5-HT
从这些细胞释放,它触发肠反射,增加推进运动和上皮分泌。
5-HT信号的变化已经在肠道的功能和炎症条件下被确定,并且药物
已经开发出靶向5-HT受体的药物用于治疗便秘和腹泻。具体目标
1,我们将测试用已知的细菌菌株治疗小鼠的假设,
产生色氨酸,并已安全地用于益生菌制剂,导致粘膜5-
HT水平和增强肠蠕动。
该提案的具体目标2旨在确定色氨酸产生的机制。
细菌促进运动。与推进运动最直接相关的5-HT受体是5-HT 4
受体的我们将测试这种受体是否参与其中,并确定哪些组织表达这种受体,
介导这种效应。我们还将研究运动模式和神经元活动的变化
与增强的推进运动有关,我们将测试是否增加色氨酸代谢物,
色胺可增强产葡聚糖细菌的运动增强作用。
这些研究的结果可以为益生菌的使用提供预测性的翻译策略
细菌,具有已知的生物化学特征,用于治疗便秘。
项目成果
期刊论文数量(6)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
Interplay of Broccoli/Broccoli Sprout Bioactives with Gut Microbiota in Reducing Inflammation in Inflammatory Bowel Diseases.
- DOI:10.1016/j.jnutbio.2022.109238
- 发表时间:2022-11
- 期刊:
- 影响因子:0
- 作者:Johanna M. Holman;Molly Hurd;P. Moses;G. Mawe;Zhang Tao;S. Ishaq;Yanyan Li
- 通讯作者:Johanna M. Holman;Molly Hurd;P. Moses;G. Mawe;Zhang Tao;S. Ishaq;Yanyan Li
Monitoring Gut Epithelium Serotonin and Melatonin Overflow Provides Spatial Mapping of Inflammation.
- DOI:10.1002/cbic.202200334
- 发表时间:2023-01-17
- 期刊:
- 影响因子:0
- 作者:
- 通讯作者:
Direct and indirect mechanisms by which the gut microbiota influence host serotonin systems.
- DOI:10.1111/nmo.14346
- 发表时间:2022-10
- 期刊:
- 影响因子:3.5
- 作者:Legan, Theresa B.;Lavoie, Brigitte;Mawe, Gary M.
- 通讯作者:Mawe, Gary M.
Tryptophan-synthesizing bacteria enhance colonic motility.
色氨酸合成细菌增强结肠蠕动。
- DOI:10.1111/nmo.14629
- 发表时间:2023
- 期刊:
- 影响因子:3.5
- 作者:Legan,TheresaB;Lavoie,Brigitte;Norberg,Emilia;Ley,IsabellaC;Tack,Stephanie;Tompkins,ThomasA;Wargo,MatthewJ;Mawe,GaryM
- 通讯作者:Mawe,GaryM
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Brigitte Lavoie其他文献
Brigitte Lavoie的其他文献
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{{ truncateString('Brigitte Lavoie', 18)}}的其他基金
Mechanisms of gallbladder smooth muscle dysfunction
胆囊平滑肌功能障碍的机制
- 批准号:
10667646 - 财政年份:2022
- 资助金额:
$ 19.12万 - 项目类别:














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