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：
10201464
负责人：
Yuying Liu
金额：
$ 7.8万
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 2022-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10201464
关键词：
5&apos -Nucleotidase Adenosine Affect Agonist Anaerobic Bacteria Animals Anti-Inflammatory Agents Autoimmune Autoimmune Diseases 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 systemic inflammatory response 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.

项目摘要/摘要用2种实验性自身免疫性疾病的益生菌（Reuteri DSM 17938）的口服喂养（Reuteri DSM 17938）可以重新编程肠道微生物并显着降低疾病的严重程度。一个鼠标模型本质上是相同的作为人类中的一种称为IPEX综合征的疾病（免疫缺陷和多内分泌病，X连锁遗产）。 LR 17938降低了鼠标皮肤病变的严重程度，呼吸改善和肺炎症，并将鼠标的寿命从不到1个月延长到4个月。我们的研究确定了一种新的机制，其中腺苷是一种从ATP释放的快速作用抗炎分子，与其在白细胞上的受体相互作用（T细胞）是益生菌LR 17938的原因，以改善动物的健康。我们最近还发现，LR 17938改善了多个鼠标模型的健康硬化。来自ATP产生的腺苷被2种肠酶CD39和CD73分解，称为核苷酸酶。 CD 39和CD 73存在于白细胞和肠细胞上，但某些益生菌还可以将ATP转换为腺苷。腺苷通过核苷转运蛋白（NTS）转运到肠粘膜中。遭受痛苦后，腺苷及其活性产物的肌苷与T细胞上的接收器（A2A）相互作用以抑制体内炎症。益生菌生物学的主要差距是我们对LR 17938如何影响腺苷途径的了解不足在Treg缺乏症中。我们发现益生菌LR 17938包含5NTE（CD73）基因，LR 17938将当厌氧培养实验室时，能够从AMP中产生腺苷。但是，LR 17938菌株具有5NTE突变（LR179385NTE）无法从AMP产生腺苷。 AIM 1是评估LR 17938与LR179385NTE对临床结果和腺苷的影响 SF小鼠的途径。 AIM 2是定义益生菌5NTE（CD73）在自身免疫保护中的关键作用在SF小鼠中耗尽宿主CD73。这项研究将导致进一步研究腺苷的机制与宿主免疫系统的相互作用以及微生物的调节中产生益生菌菌株 Treg缺乏症中的相关代谢物和转录组学。这些研究的长期目标是确定如何选择最佳的益生菌来挽救人类原发性自身免疫性疾病。这些条件包括由于FOXP3基因突变/缺失以及其他单一基因缺陷引起的IP3基因突变/缺失和IPEX样综合征。

项目成果

期刊论文数量（4）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Limosilactobacillus reuteri and Lacticaseibacillus rhamnosus GG differentially affect gut microbes and metabolites in mice with Treg deficiency.

罗伊氏柠檬酸乳杆菌和鼠李糖乳杆菌 GG 对 Treg 缺陷小鼠的肠道微生物和代谢物产生不同的影响。

DOI：
10.1152/ajpgi.00072.2021
发表时间：
2021
期刊：
American journal of physiology. Gastrointestinal and liver physiology
影响因子：
0
作者：
Liu,Yuying;Hoang,ThomasK;Taylor,ChristopherM;Park,EvelynS;Freeborn,Jasmin;Luo,Meng;Roos,Stefan;Rhoads,JMarc
通讯作者：
Rhoads,JMarc

Treg-associated monogenic autoimmune disorders and gut microbial dysbiosis.

DOI：
10.1038/s41390-021-01445-2
发表时间：
2022-01
期刊：
Pediatric research
影响因子：
3.6
作者：
Liu Y;Freeborn J;Armbrister SA;Tran DQ;Rhoads JM
通讯作者：
Rhoads JM

Probiotic-derived ecto-5'-nucleotidase produces anti-inflammatory adenosine metabolites in Treg-deficient scurfy mice.

益生菌衍生的 ecto-5-核苷酸酶在 Treg 缺陷的头屑小鼠中产生抗炎腺苷代谢物。

DOI：
10.21203/rs.3.rs-2781715/v1
发表时间：
2023
期刊：
Research square
影响因子：
0
作者：
Liu,Yuying;Armbrister,ShabbaA;Okeugo,Beanna;Mills,TingtingW;Daniel,RheaC;Oh,Jee-Hwan;Pijkeren,Jan-Peter;Park,EvelynS;Saleh,ZeinaM;Lahiri,Sharmistha;Roos,Stefan;Rhoads,JMarc
通讯作者：
Rhoads,JMarc

The Association of Gut Microbiota and Treg Dysfunction in Autoimmune Diseases.