Gut dysbiosis and tryptophan metabolism in lupus
狼疮中的肠道菌群失调和色氨酸代谢
基本信息
- 批准号:10675349
- 负责人:
- 金额:$ 28.64万
- 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:2019-01-11 至 2023-12-31
- 项目状态:已结题
- 来源:
- 关键词:AnabolismAntibiotic TherapyAutoimmuneAutoimmune DiseasesAutoimmunityBackBacteriaBiologicalBiological AssayCatabolismCellsClinicalCommunitiesComplexData SetDevelopmentDietDiseaseDisease ProgressionEssential Amino AcidsEtiologyFRAP1 geneFecesFeedsGene ExpressionGene LibraryGenerationsGenesGenetic Predisposition to DiseaseGenomeGnotobioticGoalsHumanImmuneImmune responseImmune systemIndividualInflammationInflammatoryInterferonsInvestigationKynurenineLabelLibrariesLigandsLupusMetabolismModelingModificationMusNeuropsychiatric Systemic Lupus ErythematosusNutritionalParticipantPathogenesisPathogenicityPathway interactionsPatientsPeripheral Blood Mononuclear CellPhylogenetic AnalysisPilot ProjectsPopulationProductionPropertyPublishingRibosomal DNASLEB1 geneSLEB3 geneSamplingSerotoninSerumSeverity of illnessSurveysSusceptibility GeneSystemic Lupus ErythematosusTestingTherapeuticTracerTryptophanTryptophan Metabolism PathwayVariantVolatile Fatty Acidsaryl hydrocarbon receptor ligandautoimmune pathogenesisbacterial communitybasecohortcongenicdietarydysbiosisfecal microbiotagut bacteriagut dysbiosisgut microbiomegut microbiotaimmune activationimmunoregulationin vitro Assayinterdisciplinary approachlupus prone micemicrobialmicrobiomemicrobiotamicrobiota transplantationmouse modeloxidationpathobiontpreventprogrammed cell death protein 1reconstructionsystemic autoimmunity
项目摘要
Project Summary/Abstract
Tryptophan (Trp) is an essential amino acid that is used for the biosynthesis of key compounds such as serotonin
(5HT), NAD, kynurenine (Kyn), and AhR ligands. The gut microbiome is a critical participant in Trp metabolism
through which it modulates immune activation. High Kyn and low 5HT levels have been found in lupus patients,
which has been proposed to be the consequence of increased oxidation or interferon levels associated with this
disease. Imbalance of gut microbial populations has been associated with lupus in patients and mouse models.
Based on published studies as well as our unpublished results presented here, the premise of this proposal is
that gut dysbiosis is an essential player in Trp metabolite imbalance in lupus, and that the interplay between the
gut microbiota, Trp metabolism, and genetic susceptibility modulates systemic autoimmunity.
Using a congenic model in which lupus-prone mice (B6.Sle1.Sle2.Sle3, or TC for short) share over 95% of their
genome with control B6 mice, we showed that transfers of TC fecal microbiota induce a transient autoimmunity
in gnotobiotic (GF) B6 mice. As in lupus patients, the serum and feces of TC mice present high Kyn and low 5HT
levels, and this metabolite imbalance was eliminated by a broad-spectrum antibiotic treatment. Furthermore, a
low Trp diet prevented autoimmunity while a high Trp diet accelerated disease progression. In a NYU cohort of
well-characterized lupus patients, disease severity was positively correlated with a reduction of fecal bacterial
diversity and negatively correlated with Trp serum levels. A preliminary analysis predicted that SLE patients had
a greater abundance of bacteria with an enhanced catabolism of Trp into Kyn. We postulate that clinical lupus
disease activity is in part driven by specific gut dysbiosis resulting in greater Trp catabolism and/or increased
Trp catabolic products that enhance genetically driven pro-inflammatory pathways. To test this hypothesis, we
propose three specific aims: 1. To elucidate the effect of Trp on the immunoregulatory properties of the fecal
microbiota of lupus mice. 2. To evaluate the mitigation of gut dysbiosis by dietary Trp in lupus-prone mice. 3. To
determine whether altered Trp metabolism in SLE patients is associated with an enrichment for Trp-catabolizing
fecal microbiota.
With a multidisciplinary approach, we propose to dissect the mechanisms by which genetically-prone (mouse or
human) individuals develop autoimmune activation that leads to gut dysbiosis, which feeds back to autoimmune
activation. A consequence of this gut dysbiosis is a disruption of Trp metabolism with the generation of
metabolites that activate pro-inflammatory pathways such as mTOR and AhR. Lupus genetic susceptibility may
also alter the expression of genes in the endogenous Trp pathway. Establishing causal relationships between
these variables and the identification of gut taxa responsible for Trp degradation would represent a significant
shift in our understanding of a mechanism by which the microbiome could contribute to lupus pathogenesis.
项目总结/摘要
色氨酸(Trp)是一种必需氨基酸,用于生物合成关键化合物,如血清素
(5HT)NAD、犬尿氨酸(Kyn)和AhR配体。肠道微生物组是Trp代谢的关键参与者
从而调节免疫激活。在狼疮患者中发现了高Kyn和低5 HT水平,
这被认为是氧化或干扰素水平增加的结果
疾病肠道微生物种群的不平衡与患者和小鼠模型中的狼疮有关。
根据已发表的研究以及我们在此提出的未发表的结果,该建议的前提是
肠道生态失调是狼疮Trp代谢失衡的重要因素,
肠道微生物群、Trp代谢和遗传易感性调节全身性自身免疫。
使用一种同类模型,在该模型中,狼疮易感小鼠(B6.Sle1.Sle2.Sle3,或简称TC)共享超过95%的
我们用对照B6小鼠的基因组,我们发现TC粪便微生物群的转移诱导了短暂的自身免疫,
在gnotobiotic(GF)B6小鼠中。与狼疮患者一样,TC小鼠的血清和粪便呈现高Kyn和低5 HT
水平,这种代谢物的不平衡被消除了广谱抗生素治疗。而且有
低Trp饮食防止自身免疫,而高Trp饮食加速疾病进展。在纽约大学的一群
在特征明确的狼疮患者中,疾病严重程度与粪便细菌减少呈正相关,
多样性与血清Trp水平呈负相关。初步分析预测SLE患者有
大量的细菌增加了Trp进入Kyn的催化活性。我们假设临床狼疮
疾病活动部分由特定的肠道生态失调驱动,导致更大的Trp催化和/或增加的
色氨酸分解代谢产物,增强基因驱动的促炎途径。为了验证这个假设,我们
提出三个具体目标:1.为了阐明色氨酸对粪便免疫调节特性的影响,
狼疮小鼠的微生物群。2.评价饮食色氨酸对狼疮易感小鼠肠道生态失调的缓解作用。3.到
确定SLE患者中色氨酸代谢的改变是否与色氨酸分解代谢的富集有关
粪便微生物群
通过多学科的方法,我们建议剖析遗传倾向性(小鼠或
人类)个体发展自身免疫激活,导致肠道生态失调,其反馈给自身免疫
activation.这种肠道生态失调的结果是Trp代谢的破坏,
代谢物,激活促炎途径,如mTOR和AhR。狼疮遗传易感性可能
还改变内源性Trp途径中基因的表达。建立因果关系
这些变量和负责Trp降解的肠道分类群的鉴定将代表一个重要的
我们对微生物群可能导致狼疮发病机制的理解发生了转变。
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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Laurence Morel其他文献
Laurence Morel的其他文献
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{{ truncateString('Laurence Morel', 18)}}的其他基金
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10638468 - 财政年份:2023
- 资助金额:
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Determinants of follicular helper T cell expansion in lupus
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10644534 - 财政年份:2022
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Determinants of follicular helper T cell expansion in lupus
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10679012 - 财政年份:2022
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Determinants of follicular helper T cell expansion in lupus
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- 批准号:
10065726 - 财政年份:2020
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Determinants of follicular helper T cell expansion in lupus
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10212953 - 财政年份:2020
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Gut dysbiosis and tryptophan metabolism in lupus
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- 资助金额:
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Gut dysbiosis and tryptophan metabolism in lupus
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10543063 - 财政年份:2019
- 资助金额:
$ 28.64万 - 项目类别:
Gut dysbiosis and tryptophan metabolism in lupus
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10667605 - 财政年份:2016
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