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Impact of probiotic-mediated adenosine metabolism in regulating immune dysfunction.

益生菌介导的腺苷代谢对调节免疫功能障碍的影响。

基本信息

批准号：
10043458
负责人：
Yuying Liu
金额：
$ 7.78万
依托单位：
UNIVERSITY OF TEXAS HLTH SCI CTR HOUSTON
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-06-25 至 2022-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10043458
关键词：
5&apos -Nucleotidase Adenosine Affect Agonist Anaerobic Bacteria Animals Anti-Inflammatory Agents Autoimmune Diseases Autoimmune Process Autoimmunity Biology Blood Breathing Breeding CTLA4 gene Cells Clinical Common Variable Immunodeficiency Disease Eczema Engineered Probiotics Enzymes Eragrostis Evolution FOXP3 gene Female Gene Deletion Generations Genes Genetic Goals Gut Mucosa Health Hematopoietic Stem Cell Transplantation Homeostasis Human IL2RA gene Immune Immune System Diseases Immune Tolerance Immune system Immunologic Deficiency Syndromes Immunologics Inflammation Inflammatory Inosine Insulin-Dependent Diabetes Mellitus Intestines Knock-out Laboratories Lactobacillus reuteri Lead Leukocytes Life Life Expectancy Link Longevity Lung Inflammation Mediating Metabolism Multiple Sclerosis Mus Mutate Mutation Nucleoside Transporter Oral Oral Administration Outcome Pathway interactions Patients Phenotype Physiological Processes Preventive Probiotics Process Production Purinergic P1 Receptors Regulatory T-Lymphocyte Research Role STAT1 gene Severities Severity of illness Signal Transduction Single-Gene Defect Syndrome T-Cell Development T-Lymphocyte Therapeutic Effect Wiskott-Aldrich Syndrome absorption adenosine deaminase clinical phenotype congenital immunodeficiency dysbiosis effector T cell experimental study extracellular feeding gut microbes gut microbiota immunoregulation improved infancy innovation insight male microbial mouse model novel novel strategies receptor screening skin lesion transcriptomics

项目摘要

PROJECT SUMMARY/ABSTRACT Oral feeding of a probiotic (Lactobacillus reuteri DSM 17938) to mice with 2 experimental autoimmune diseases can reprogram the gut microbes and markedly reduce disease severity. One mouse model is essentially the same as a condition in humans called IPEX syndrome (immunodeficiency and polyendocrinopathy, with x-linked inheritance). LR 17938 reduced the severity of the mouse’s skin lesions, improved breathing and lung inflammation, and prolonged the mouse’s life span from less than 1 month to > 4 months. Our studies identified a novel mechanism in which an adenosine, a rapid-acting anti-inflammatory molecule released from ATP, by interacting with its receptor on white blood cells (T cells) was responsible for the probiotic LR 17938 to improve the animal’s health. We also recently found that LR 17938 improves health in a mouse model of multiple sclerosis. Adenosine generated from ATP is broken down by 2 intestinal enzymes, CD39 and CD73, called ectonucleotidases. CD 39 and CD 73 are present on white blood cells and intestinal cells, but certain probiotics can also convert ATP to adenosine. Adenosine is transported into gut mucosa by nucleoside transporters (NTs). After absorption, adenosine and its active product inosine interact with a receptor (A2A) on T cells to inhibit inflammation in the body. A major gap in probiotic biology is our lack of understanding of how LR 17938 affects the adenosine pathway during Treg deficiency. We found that probiotic LR 17938 contains 5NTE (CD73) gene and that LR 17938 would be able to generate adenosine from AMP when anaerobically cultured the laboratory. However, a LR 17938 strain with a 5NTE mutation (LR 179385NTE) could not generate adenosine from AMP. Aim 1 is to assess the effects of LR 17938 to compare with LR 179385NTE on clinical outcome and the adenosine pathway in SF mice. Aim 2 is to define the critical role of probiotic 5NTE (CD73) in autoimmune protection by depleting host CD73 in SF mice. This study will lead to further investigate the mechanism of adenosine- producing probiotic strain in interaction with host immune system, as well as in modulation of microbial associated metabolites and transcriptomics in Treg deficiency. The long-term goal of these studies is to determine how to choose the best probiotic to relieve primary autoimmune diseases in humans. These conditions include IPEX syndrome due to Foxp3 gene mutation/deletion, and IPEX-like syndrome due to other single gene defects.

项目总结/文摘