Mechanisms linking gut microbiota metabolomics and epithelial repair in HIV infection

HIV感染中肠道微生物代谢组学和上皮修复的联系机制

基本信息

批准号：
9623898
负责人：
Katti Robin Crakes
金额：
$ 3.7万
依托单位：
UNIVERSITY OF CALIFORNIA AT DAVIS
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-07-01 至 2022-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9623898
关键词：
Acetylation Address Affect Antibodies Autoimmune Diseases Biological Assay CD4 Positive T Lymphocytes Caco-2 Cells Carbon Catabolism Cell Communication Cell Culture Techniques Cell physiology Cells Cellular Metabolic Process Chronic Communicable Diseases Dendritic Cells Dicarboxylic Acids Disease Dose Epithelial Epithelial Cells Exhibits Exposure to Fermentation Gastrointestinal tract structure Gene Expression Regulation Goals Growth Gut associated lymphoid tissue HIV HIV Envelope Protein gp120 HIV Infections HIV Seropositivity Health Homeostasis Immune Immune Targeting Immune response Immune system In Vitro Individual Infection Inflammation Inflammatory Inflammatory Response Inflammatory disease of the intestine Injections Interleukin-1 beta Intestines Laboratories Lactobacillus plantarum Link Lymphocyte Macaca mulatta Malonates Mass Fragmentography Measurement Measures Metabolism Methylation Microbe Modality Modeling Modification Molecular Mucosal Immune Responses NF-kappa B Outcome Study Oxidative Stress Pathogenesis Pathway interactions Patients Phenotype Phosphorylation Play Post-Translational Protein Processing Probiotics Production Proteins Proteomics Recovery Regulatory Element Regulatory T-Lymphocyte Research Role SIV Site Source TNFRSF5 gene Testing Therapeutic Intervention Tight Junctions Time Viral Virus Diseases Western Blotting activating transcription factor antiretroviral therapy cell injury cell type cytokine effective therapy gut microbiota immune activation in vivo insight macrophage metabolomics microbial microbiota new therapeutic target novel therapeutics p65 prevent probiotic therapy repaired response time use

项目摘要

PROJECT SUMMARY Human immunodeficiency virus (HIV) infection is characterized by depletion in CD4+ T cells and persistent immune activation as a result of epithelial barrier disruption and systemic translocation of microbial products. Immune targets of HIV such as CD4+ T cells, macrophages, and dendritic cells have been the main research focus for many years, but modifications in these cell types have not explained HIV-induced epithelial damage. For this reason, better understanding of epithelial cell metabolism and interactions with gut microbiota has been an important aspect of intestinal barrier function in HIV. Studies have shown that treatment with probiotic microbiota can positively impact mucosal immune responses, support renewal of the gut epithelial barrier, and suppress inflammation. We utilized injections of probiotic L. plantarum in a ligated ileal loop model in chronic SIV-infected rhesus macaques to investigate mechanisms of epithelial damage and repair. Through a metabolomics approach, I found that epithelial cell damage may be linked to malonate accumulation, activating transcription factor NF-kB and downstream epithelial damage. Treatment with L. plantarum reduced levels of malonate in the gut and repaired epithelial integrity. We want to investigate the role of malonate metabolism in the gut to answer mechanistic questions regarding the role of microbiota in modulating gut barriers and the immune system in HIV and other inflammatory diseases. First, we will test the source of malonate overproduction in HIV infection using cell culture models and proteomic analysis. Then, we will assess the molecular mechanisms of NF-kB activation by malonate accumulation and determine if inhibiting this pathway genetically could prevent phenotypic changes in epithelial integrity. Finally, we will evaluate the ability of L. plantarum to reduce epithelial damage through malonate reduction. The outcomes from this study will address the immunometabolomic connection between gut microbiota and host cell function in HIV infection. Identifying regulatory elements of chronic gut inflammation and damage will be an essential contribution to research in autoimmune or infectious diseasees targeting the gastrointestinal tract. Hypothesis 1: Epithelial barrier damage is induced by increased malonate production in response to HIV infection. Furthermore, we hypothesize that L. plantarum can restore epithelial barrier integrity by reducing malonate accumulation. Aim 1: To demonstrate that epithelial cells produce excess malonate in response to HIV infection Aim 2: To determine if malonate induces NF-kB activation through post-translational malonylation Aim 3: To investigate the ability of L. plantarum to repair epithelial damage through malonate reduction

项目概要人类免疫缺陷病毒 (HIV) 感染的特点是 CD4+ T 细胞耗竭并持续存在由于上皮屏障破坏和微生物产物的全身易位而导致的免疫激活。 CD4+ T细胞、巨噬细胞、树突状细胞等HIV免疫靶点已成为主要研究对象多年来一直是人们关注的焦点，但这些细胞类型的改变并不能解释艾滋病毒引起的上皮损伤。因此，更好地了解上皮细胞代谢以及与肠道微生物群的相互作用已经成为可能。是艾滋病毒肠道屏障功能的一个重要方面。研究表明，益生菌治疗微生物群可以积极影响粘膜免疫反应，支持肠道上皮屏障的更新，抑制炎症。我们在慢性回肠结扎模型中注射了益生菌植物乳杆菌。感染 SIV 的恒河猴研究上皮损伤和修复机制。通过一个通过代谢组学方法，我发现上皮细胞损伤可能与丙二酸积累有关，激活转录因子 NF-kB 和下游上皮损伤。用植物乳杆菌治疗可降低肠道中的丙二酸并修复上皮完整性。我们想要研究丙二酸代谢在肠道回答有关微生物群在调节肠道屏障中的作用的机制问题 HIV 和其他炎症性疾病中的免疫系统。首先我们要测试一下丙二酸的来源使用细胞培养模型和蛋白质组分析来抑制 HIV 感染的过量生产。然后，我们将评估通过丙二酸积累激活 NF-kB 的分子机制并确定是否抑制该途径从遗传上讲，可以防止上皮完整性的表型变化。最后我们对L的能力进行评估。 plantarum 通过减少丙二酸来减少上皮损伤。这项研究的结果将解决 HIV感染中肠道微生物群与宿主细胞功能之间的免疫代谢组学联系。识别慢性肠道炎症和损伤的调节元件将对以下研究做出重要贡献针对胃肠道的自身免疫性疾病或传染病。假设 1：上皮屏障损伤是由 HIV 引起的丙二酸产量增加引起的感染。此外，我们假设植物乳杆菌可以通过减少上皮屏障的完整性来恢复丙二酸积累。目标 1：证明上皮细胞响应 HIV 感染产生过量的丙二酸目标 2：确定丙二酸是否通过翻译后丙二酰化诱导 NF-kB 激活目标 3：研究植物乳杆菌通过丙二酸还原修复上皮损伤的能力