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: 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
• 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

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