Gut dysbiosis and tryptophan metabolism in lupus

狼疮中的肠道菌群失调和色氨酸代谢

• 批准号: 10079461
• 负责人: Laurence Morel
• 金额: $ 44.12万
• 依托单位: UNIVERSITY OF FLORIDA
• 依托单位国家: 美国
• 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: https://reporter.nih.gov/project-details/10079461
• 关键词: Anabolism; Antibiotic Therapy; Autoimmune; Autoimmune Diseases; Autoimmunity; Back; Bacteria; Biological; Biological Assay; Catabolism; Cells; Clinical; Communities; Complex; Data Set; Development; Diet; Disease; Disease Progression; Essential Amino Acids; Etiology; FRAP1 gene; Feces; Feeds; Gene Expression; Gene Library; Generations; Genes; Genetic Predisposition to Disease; Genome; Gnotobiotic; Goals; Human; Immune; Immune response; Immune system; Individual; Inflammation; Inflammatory; Interferons; Investigation; Kynurenine; Label; Libraries; Ligands; Lupus; Metabolism; Modeling; Modification; Mus; Neuropsychiatric Systemic Lupus Erythematosus; Nutritional; Participant; Pathogenesis; Pathogenicity; Pathway interactions; Patients; Peripheral Blood Mononuclear Cell; Phylogenetic Analysis; Pilot Projects; Population; Production; Property; Publishing; Recombinant DNA; SLEB1 gene; SLEB3 gene; Sampling; Serotonin; Serum; Severity of illness; Surveys; Susceptibility Gene; Systemic Lupus Erythematosus; Testing; Therapeutic; Tracer; Tryptophan; Tryptophan Metabolism Pathway; Variant; Volatile Fatty Acids; aryl hydrocarbon receptor ligand; autoimmune pathogenesis; bacterial community; base; cohort; congenic; dietary; dysbiosis; fecal microbiota; gut bacteria; gut dysbiosis; gut microbiome; gut microbiota; immune activation; immunoregulation; in vitro Assay; interdisciplinary approach; lupus prone mice; microbial; microbiome; microbiota; microbiota transplantation; mouse model; oxidation; pathobiont; prevent; programmed cell death protein 1; reconstruction; systemic autoimmunity

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.

项目摘要/摘要 色氨酸（TRP）是一种必需的氨基酸，用于关键化合物（例如5-羟色胺）的生物合成 （5HT），NAD，Kynurenine（Kyn）和AHR配体。肠道微生物组是TRP代谢的关键参与者 通过它调节免疫激活。在狼疮患者中发现了较高的Kyn和低5HT水平， 已提出是与此相关的氧化或干扰素水平升高的结果 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，该提议的前提是 肠道营养不良是狼疮中TRP代谢物失衡的重要参与者，并且是 肠道菌群，TRP代谢和遗传敏感性调节系统性自身免疫性。 使用富含狼疮的小鼠（b6.sle1.sle22.sle3或TC）的同类模型，共享超过95％ 带有对照B6小鼠的基因组，我们表明TC粪便菌群的转移会诱导瞬时自身免疫性 在Gnotobiotic（GF）B6小鼠中。与狼疮患者一样，TC小鼠的血清和粪便呈高和低5HT 水平，这种代谢物失衡通过广谱抗生素治疗消除。此外， 低TRP饮食可防止自身免疫性，而高TRP饮食加速疾病进展。在纽约大学队列中 特征良好的狼疮患者，疾病的严重程度与粪便细菌的减少呈正相关 多样性和否定性与TRP血清水平相关。初步分析预测SLE患者有 细菌的丰度更大，TRP的分解代谢增强为Kyn。我们假设临床狼疮 疾病活动部分是由特异性肠道营养不良的驱动，导致TRP分解代谢更大和/或增加 TRP分解代谢产物增强了基因驱动的促炎途径。为了检验这一假设，我们 提出三个特定目的：1。阐明TRP对粪便免疫调节特性的影响 狼疮小鼠的微生物群。 2。评估狼trp饮食中腹部饮食中的肠道营养不良的缓解症中的小鼠。 3 确定SLE患者中TRP代谢的改变是否与TRP促成的富集有关 粪便菌群。 通过一种多学科的方法，我们建议剖析基因易发的机制（小鼠或 人）个体发展自身免疫性激活，导致肠道营养不良，从而反馈自身免疫性 激活。这种肠道营养不良的结果是TRP代谢的破坏 激活促炎途径（例如MTOR和AHR）的代谢产物。狼疮遗传易感性可能 还改变了内源性TRP途径中基因的表达。建立因果关系 这些变量以及负责TRP降解的肠分类单元的识别将代表重要的 我们对微生物组可能有助于狼疮发病机理的机制的理解的转移。