Gut dysbiosis and tryptophan metabolism in lupus

项目摘要/摘要 色氨酸(Trp)是生物合成5-羟色胺等关键化合物所必需的氨基酸。 (5HT)、NAD、犬尿氨酸(Kyn)和AhR配体。肠道微生物群是色氨酸代谢的重要参与者。 它通过它来调节免疫激活。在狼疮患者中发现了高Kyn和低5HT水平， 它被认为是与此相关的氧化或干扰素水平增加的结果 疾病。在患者和小鼠模型中，肠道微生物种群的失衡与狼疮有关。 基于已发表的研究以及我们在这里提供的未发表的结果，这项提议的前提是 肠道代谢失调是狼疮Trp代谢物失衡的重要因素，而 肠道微生物区系、色氨酸代谢和遗传易感性调节系统自身免疫。 使用一种同源模型，在该模型中，易患狼疮的小鼠(B6.Sle1.Sle2.Sle3，简称TC)共享超过95%的 与对照B6小鼠的基因组进行比较，我们发现TC粪便微生物区系的转移诱导了一过性自身免疫 在诺维菌素(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值。 水平，这种代谢物失衡被广谱抗生素治疗消除。此外，a 低Trp饮食可防止自身免疫，而高Trp饮食则加速疾病进展。在纽约大学的一群 狼疮患者特征良好，病情严重程度与粪便细菌减少呈正相关 多样性，并与血清色氨酸水平呈负相关。初步分析预测，SLE患者有 细菌数量增加，色氨酸分解代谢增强。我们假设临床上的狼疮 疾病活动的部分原因是特定的肠道生物失调导致更大的色氨酸分解代谢和/或增加 色氨酸分解代谢产品，增强基因驱动的促炎途径。为了检验这一假设，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 狼疮小鼠的微生物区系。2.评价膳食色氨酸对狼疮小鼠肠道代谢紊乱的缓解作用。3.至 确定SLE患者色氨酸代谢的改变是否与色氨酸分解代谢的丰富有关 粪便微生物区系。 通过一个多学科的方法，我们建议剖析遗传易感性(老鼠或 人类)个体产生自身免疫激活，导致肠道生物失调，后者反馈给自身免疫 激活。这种肠道生物失调的后果是色氨酸代谢的中断，伴随着 激活促炎途径的代谢物，如mTOR和AhR。狼疮遗传易感性可能 也改变内源性色氨酸途径中的基因表达。建立两国之间的因果关系 这些变量和对Trp降解负责的肠道分类群的鉴定将具有重要的意义 我们对微生物群参与狼疮发病机制的理解发生了转变。

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 Based on published studies as well as our unpublished results presented here, the premise of this proposal is that gut dysbiosis is an essential player in Trp metabolite imbalance in lupus, and that the interplay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.