Unraveling the contribution of gut microbiome in trichloroethene-mediated autoimmunity

揭示肠道微生物组在三氯乙烯介导的自身免疫中的作用

基本信息

批准号：
10927562
负责人：
M. FIROZE KHAN
金额：
$ 15.82万
依托单位：
UNIVERSITY OF TEXAS MED BR GALVESTON
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-09-22 至 2024-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10927562
关键词：
16S ribosomal RNA sequencing Acceleration Adoptive Transfer Affect Antibiotics Antioxidants Autoimmune Diseases Autoimmune Responses Autoimmunity CD4 Positive T Lymphocytes Cecum Cells Chemicals Circulation Colon Data Development Disease Disease Marker Disease Outcome Disease Progression Endotoxins Environment Environmental Pollutants Environmental Risk Factor Epithelium Equilibrium Etiology Exposure to FOXP3 gene Feces Female Functional disorder Genes Genetic Germ-Free Goals Histology Hormonal Human IL17 gene Immune Immune system Impairment Industrialization Inflammasome Inflammatory Inflammatory Response Interleukin-1 beta Interleukin-10 Interleukin-6 Intestinal permeability Intestines Kidney Knowledge Lactobacillus Lead Leucocytic infiltrate Life Link Measures Mediating Metabolic Metabolism Metals Morphology Mucosal Immunity Mucous Membrane Mus Occupational Organic solvent product Oxidative Stress Pathogenesis Pathogenicity Pathologic Permeability Phenotype Play Population Predisposition Probiotics Process Proteins Regulatory T-Lymphocyte Ribosomal RNA Role Sampling Serum Signal Transduction Source Supplementation Systemic Lupus Erythematosus T-Lymphocyte TNF gene Testing Therapeutic Tight Junctions Time Trichloroethylene Volatile Fatty Acids chronic autoimmune disease cytokine design dysbiosis fatty acid supplementation fecal transplantation feeding gut dysbiosis gut homeostasis gut microbiome gut microbiota host microbiome in vivo innovation insight intestinal homeostasis lupus-like metagenomic sequencing microbial microbiome microbiome alteration microbiome composition microbiota novel novel therapeutics pathogenic microbe prevent probiotic therapy systemic inflammatory response transmission process whole genome

项目摘要

ABSTRACT Trichloroethene (trichloroethylene, TCE), an environmental and occupational agent, is known to cause autoimmune diseases (ADs), including SLE-like disease in humans. The etiology of SLE is likely multifactorial, which includes genetic, hormonal and environmental triggers. There is increasing evidence that environmental factors, including changes in microbiota contribute to ADs. Using female MRL+/+ mice, we have established that TCE causes early induction of the disease. Our preliminary studies in these mice also show that TCE exposure leads to gut microbiome dysbiosis along with decreases in several important bacterial short-chain fatty acids (SCFAs). However, the contribution and mechanisms by which gut microbiota lead to TCE-mediated early induction of SLE are not known, and are the major focus of this proposal. We will test the central hypothesis that TCE exposure in genetically susceptible populations causes gut microbiome dysbiosis and impaired intestinal integrity together with mucosal immune dysregulation, which contribute to systemic autoimmune responses and eventually lead to SLE. To achieve our overarching goal of understanding the role of gut microbiome in TCE-mediated SLE, the following specific aims will be pursued. Aim 1 will establish that TCE exposure causes its SLE-producing effects via dysbiosis of gut microbiota, and gut microbiota from TCE- treated MRL+/+ mice can transmit SLE phenotypes to control mice. Using fecal samples, 16S rRNA and metagenomic sequencing (WGS) will be performed to assess differential composition of the gut microbiome, and differences in the functional genes. Furthermore, using feces from TCE-treated mice, fecal microbiome transplant (FMT) studies will be performed in germ-free mice, which will firmly establish that altered microbiome plays a causative role in TCE-mediated autoimmunity. Aim 2 will determine if TCE-microbiome- host interactions contribute to disease outcome by affecting intestinal integrity and mucosal immunity. We will measure gut permeability in vivo, tight junction proteins and endotoxin levels in the circulation. Contribution of oxidative stress to epithelial permeability will also be assessed. We will also determine if TCE treatment skews the Treg-Th17 balance towards a Th17 phenotype, along with intestinal inflammasome activation and inflammatory cytokines. Adoptive transfer of Tregs will then be done to restore gut homeostasis. Aim 3 will determine if imbalances in bacterial SCFAs contribute to SLE pathogenesis by affecting mucosal immunity and barrier functions, and probiotic therapy can ameliorate TCE-mediated autoimmunity by restoring SCFAs. We will examine profiles of SCFAs and mucosal Tregs during initiation and progression of the disease, and conduct supplementation studies with SCFAs and probiotics to further establish the mechanisms by which microbiota contributes to TCE-mediated SLE. Successful completion of these aims will establish the causal role of gut microbiome dysbiosis in TCE-mediated SLE, delineate novel mechanisms contributing to disease pathogenesis, and help in designing novel therapeutic microbial targets for autoimmunity/SLE.

抽象的三氯乙烯（trichloroethene，TCE）是一种环境和职业物质，已知会导致自身免疫性疾病 (AD)，包括人类的 SLE 样疾病。 SLE 的病因可能是多因素的，其中包括遗传、荷尔蒙和环境触发因素。越来越多的证据表明环境因素，包括微生物群的变化，会导致AD。使用雌性 MRL+/+ 小鼠，我们建立了 TCE 会导致疾病的早期诱发。我们对这些小鼠的初步研究还表明，TCE 暴露会导致肠道微生物群失调，以及几种重要细菌短链的减少脂肪酸（SCFA）。然而，肠道微生物群导致 TCE 介导的贡献和机制 SLE 的早期诱导尚不清楚，但这是本提案的主要焦点。我们将测试中央假设遗传易感人群接触三氯乙烯会导致肠道微生物群失调，肠道完整性受损以及粘膜免疫失调，导致全身性自身免疫反应并最终导致系统性红斑狼疮。实现我们理解角色的总体目标为了研究 TCE 介导的 SLE 中肠道微生物组的变化，将追求以下具体目标。目标 1 将确定 TCE 暴露通过肠道菌群失调而导致 SLE 产生，而肠道菌群则来自 TCE- 接受治疗的 MRL+/+ 小鼠可以将 SLE 表型传递给对照小鼠。使用粪便样本、16S rRNA 和将进行宏基因组测序（WGS）来评估肠道微生物组的差异组成，以及功能基因的差异。此外，使用 TCE 处理小鼠的粪便，粪便微生物组移植（FMT）研究将在无菌小鼠中进行，这将坚定地证实改变的微生物组在 TCE 介导的自身免疫中发挥着致病作用。目标 2 将确定 TCE-微生物组- 宿主相互作用通过影响肠道完整性和粘膜免疫来促进疾病结果。我们将测量体内肠道通透性、循环中的紧密连接蛋白和内毒素水平。贡献还将评估氧化应激对上皮通透性的影响。我们还将确定 TCE 治疗是否存在偏差 Treg-Th17 向 Th17 表型平衡，以及肠道炎症体激活和炎症细胞因子。然后将进行 Tregs 的过继转移以恢复肠道稳态。目标3将确定细菌 SCFA 失衡是否通过影响粘膜免疫而导致 SLE 发病机制，以及屏障功能和益生菌治疗可以通过恢复 SCFA 来改善 TCE 介导的自身免疫。我们将检查疾病发生和进展期间 SCFA 和粘膜 Tregs 的概况，以及进行短链脂肪酸和益生菌的补充研究，以进一步建立其机制微生物群有助于 TCE 介导的 SLE。成功完成这些目标将建立因果关系肠道微生物群失调在 TCE 介导的 SLE 中的作用，描绘了导致疾病的新机制发病机制，并有助于设计针对自身免疫/系统性红斑狼疮的新型治疗微生物靶点。