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

项目摘要/摘要 益生菌(罗氏乳杆菌17938)对2种实验性自身免疫性疾病小鼠的口服作用 可以对肠道微生物进行重新编程，显著降低疾病的严重性。一个鼠标模型本质上是相同的 作为一种称为IPEX综合征的人类疾病(免疫缺陷和多内分泌疾病，与x连锁 继承)。LR 17938降低了小鼠皮肤损伤的严重程度，改善了呼吸和肺部 炎症，并将小鼠的寿命从不到1个月延长到4个月。我们的研究发现 一种新的机制，其中腺苷，一种从ATP释放的快速作用的抗炎分子，通过 与白细胞(T细胞)上的其受体相互作用是益生菌LR 17938改善的原因 动物的健康。我们最近还发现，LR 17938改善了多发性硬化症小鼠模型的健康 硬化症。 由ATP产生的腺苷被两种肠道酶CD39和CD73分解，称为 胞外核苷酸酶。CD39和CD73存在于白细胞和肠道细胞上，但某些益生菌 也可以将三磷酸腺苷转化为腺苷。腺苷通过核苷转运体(NTS)转运到肠粘膜。 在吸收后，腺苷及其活性产物肌苷与T细胞上的受体(A2a)相互作用以抑制 体内的炎症。 益生菌生物学中的一个主要差距是我们缺乏对LR 17938如何影响腺苷途径的了解 在Treg缺乏症期间。我们发现，益生菌LR 17938含有5NTE(CD73)基因，而LR 17938含有CD73基因 在实验室厌氧培养时，能够从AMP中产生腺苷。然而，一株LR 17938菌株 5NTE突变(LR 179385NTE)不能从AMP产生腺苷。 目的1是比较LR 17938和LR 179385NTE对临床结局和腺苷的影响 在SF小鼠中的途径。目的2确定益生菌5NTE(CD73)在自身免疫保护中的关键作用。 在SF小鼠体内耗尽宿主CD73。本研究为进一步研究腺苷的作用机制奠定了基础。 产生与宿主免疫系统相互作用的益生菌菌株，以及对微生物的调控 Treg缺乏症的相关代谢物和转录组学。这些研究的长期目标是确定 如何选择最好的益生菌来缓解人类的原发性自身免疫性疾病。这些条件包括 由Foxp3基因突变/缺失引起的Ipex综合征，以及由其他单基因缺陷引起的IPEX样综合征。

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.