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: 10321633
• 负责人: Laurence Morel
• 金额: $ 15.17万
• 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 2022-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10321633
• 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; Ribosomal 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.

项目概要/摘要 色氨酸 (Trp) 是一种必需氨基酸，用于生物合成血清素等关键化合物 (5HT)、NAD、犬尿氨酸 (Kyn) 和 AhR 配体。肠道微生物组是色氨酸代谢的关键参与者 它通过它调节免疫激活。在狼疮患者中发现高 Kyn 和低 5HT 水平， 这被认为是与此相关的氧化或干扰素水平增加的结果 疾病。肠道微生物群的失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未发表的结果，该提案的前提是 肠道菌群失调是狼疮色氨酸代谢失衡的一个重要因素，并且肠道菌群之间的相互作用 肠道微生物群、色氨酸代谢和遗传易感性调节系统性自身免疫。 使用同类模型，其中易患狼疮的小鼠（B6.Sle1.Sle2.Sle3，简称 TC）共享超过 95% 的 通过与对照 B6 小鼠的基因组比较，我们发现 TC 粪便微生物群的转移会诱导短暂的自身免疫 在限生 (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 5HT 水平，并且这种代谢失衡可以通过广谱抗生素治疗消除。此外，一个 低色氨酸饮食可预防自身免疫，而高色氨酸饮食则加速疾病进展。在纽约大学的一个队列中 特征明确的狼疮患者，疾病严重程度与粪便细菌减少呈正相关 多样性且与血清色氨酸水平呈负相关。初步分析预测 SLE 患者患有 细菌丰度增加，色氨酸分解代谢为 Kyn 的能力增强。我们假设临床狼疮 疾病活动部分是由特定的肠道菌群失调引起的，导致色氨酸分解代谢增加和/或增加 Trp 分解代谢产物可增强基因驱动的促炎途径。为了检验这个假设，我们 提出三个具体目标： 1. 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. 评估膳食色氨酸对狼疮易感小鼠肠道菌群失调的缓解作用。 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相关 粪便微生物群。 通过多学科的方法，我们建议剖析遗传倾向（小鼠或 人类）个体发展自身免疫激活，导致肠道菌群失调，进而反馈给自身免疫 激活。这种肠道菌群失调的后果是色氨酸代谢被破坏，并产生 激活促炎途径的代谢物，例如 mTOR 和 AhR。狼疮的遗传易感性可能 还改变内源色氨酸途径中基因的表达。建立因果关系 这些变量以及负责色氨酸降解的肠道分类群的鉴定将代表着重要的意义。 我们对微生物组导致狼疮发病机制的理解发生了转变。