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

• 批准号: 9751067
• 负责人: Katti Robin Crakes
• 金额: $ 3.77万
• 依托单位: UNIVERSITY OF CALIFORNIA AT DAVIS
• 依托单位国家: 美国
• 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/9751067
• 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

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

项目总结 人类免疫缺陷病毒(HIV)感染的特点是CD4+T细胞耗尽并持续 由于上皮屏障的破坏和微生物产物的系统性移位而引起的免疫激活。 HIV的免疫靶点如CD4+T细胞、巨噬细胞、树突状细胞等一直是研究的重点 多年来一直是研究的焦点，但这些细胞类型的修饰并不能解释艾滋病毒诱导的上皮损伤。 出于这个原因，更好地了解上皮细胞代谢和与肠道微生物区系的相互作用 是HIV肠道屏障功能的一个重要方面。研究表明，使用益生菌治疗 微生物区系可以积极地影响粘膜免疫反应，支持肠道上皮屏障的更新，以及 抑制炎症。我们使用益生菌植物乳杆菌注射在慢性阻塞性肺疾病回肠环模型中。 研究SIV感染恒河猴上皮损伤和修复的机制。通过一个 代谢组学的方法，我发现上皮细胞的损伤可能与丙二酸的蓄积、激活有关 转录因子核因子-kB与下游上皮损伤。用植物乳杆菌处理降低了细胞内的 肠道中的丙二酸，修复了上皮细胞的完整性。我们想要研究丙二酸代谢在 有勇气回答有关微生物区系在调节肠道屏障中的作用和 免疫系统中的艾滋病毒和其他炎症性疾病。首先，我们将测试丙二酸盐的来源 用细胞培养模型和蛋白质组学分析艾滋病毒感染中的过量生产。然后，我们将评估 丙二酸蓄积激活核因子-kB的分子机制及是否抑制该途径 从基因上可以防止上皮完整性的表型变化。最后，我们将对L. 植物通过丙二酸还原减少上皮损伤。这项研究的结果将解决 HIV感染中肠道微生物区系与宿主细胞功能之间的免疫代谢联系。识别 慢性肠道炎症和损伤的调节因素将是对 以胃肠道为靶点的自身免疫性或传染性疾病。 假设1：人类免疫缺陷病毒引起的上皮屏障损伤是由于丙二酸的产生增加 感染。此外，我们假设，植物乳杆菌可以通过减少 丙二酸积聚。 目的1：证明上皮细胞对HIV感染的反应产生过量的丙二酸 目的2：确定丙二酸是否通过翻译后丙二酸化诱导核因子-kB的活化 目的3：研究植物乳杆菌通过丙二酸还原修复上皮损伤的能力