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

项目总结/摘要 对患有2种实验性自身免疫性疾病的小鼠口服益生菌（罗伊氏乳杆菌DSM 17938） 可以重新编程肠道微生物并显著降低疾病的严重程度。一个小鼠模型本质上是相同的 在人类中称为IPEX综合征（免疫缺陷和多内分泌病，伴有X染色体连锁 继承）。LR 17938降低了小鼠皮肤病变的严重程度，改善了呼吸和肺功能。 炎症，并将小鼠的寿命从不到1个月延长至> 4个月。我们的研究发现 一种新的机制，其中腺苷，一种从ATP释放的速效抗炎分子， 与白色血细胞（T细胞）上的受体相互作用是益生菌LR 17938改善 动物的健康。我们最近还发现，LR 17938改善了小鼠模型的健康状况， 硬化症 由ATP产生的腺苷被两种肠道酶CD 39和CD 73分解，称为 外核苷酸酶CD 39和CD 73存在于白色血细胞和肠细胞上，但某些益生菌 也可以将ATP转化为腺苷。腺苷通过核苷转运蛋白（NTs）转运到肠粘膜。 吸收后，腺苷及其活性产物肌苷与T细胞上的受体（A2 A）相互作用，抑制T细胞增殖。 体内的炎症。 益生菌生物学的一个主要空白是我们对LR 17938如何影响腺苷途径缺乏了解 在Treg缺乏症我们发现益生菌LR 17938含有5 NTE（CD 73）基因， 在实验室厌氧培养时，能够从AMP中产生腺苷。然而，LR 17938菌株 具有5 NTE突变（LR 17938 Δ 5 NTE）的人不能从AMP产生腺苷。 目的1是评估LR 17938与LR 17938 β 5 NTE对临床结局和腺苷 SF小鼠中的通路。目的2是确定益生菌5 NTE（CD 73）在自身免疫保护中的关键作用， 消耗SF小鼠中的宿主CD 73。这项研究将导致进一步研究腺苷的机制- 产生与宿主免疫系统相互作用的益生菌菌株，以及调节微生物 相关代谢物和转录组学在Treg缺陷中的作用。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原发性自身免疫性疾病。这些条件包括 IPEX综合征由于Foxp 3基因突变/缺失，和IPEX样综合征由于其他单基因缺陷。

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.