Early-life fingolimod treatment improves intestinal homeostasis and pancreatic immune tolerance in non-obese diabetic mice
Early-life fingolimod treatment improves intestinal homeostasis and pancreatic immune tolerance in non-obese diabetic mice
复制标题
生命早期芬戈莫德治疗可改善非肥胖糖尿病小鼠的肠道稳态和胰腺免疫耐受
DOI：
10.1038/s41401-020-00590-4
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发表时间：
2021-01-20
影响因子：
8.2
通讯作者：
Pan，Li-long
中科院分区：
文献类型：
--
作者：
Jia，Ling-ling;Zhang，Ming;Pan，Li-long
芬戈莫德对多种疾病具有有益作用，包括 1 型糖尿病 (T1D) 和多种结肠炎临床前模型。肠道菌群失调和肠道免疫功能障碍导致 T1D 的发病机制。因此，芬戈莫德对T1D的有益作用可能在一定程度上通过维持肠道稳态来实现。在此，我们研究了芬戈莫德在非肥胖糖尿病（NOD）小鼠肠道功能障碍中的作用及其可能的机制。 NOD小鼠从断奶（3周龄）到31周龄期间接受芬戈莫德（例如，每天1 mg · kg−1）治疗。我们发现，芬戈莫德给药显着增强了肠道屏障（通过增强紧密连接蛋白的表达和降低肠道通透性来证明），减轻肠道微生物失调（通过减少肠道致病性变形菌群来证明）以及肠道免疫功能障碍（通过抑制CD4+细胞活化、减少1型辅助性T细胞和巨噬细胞以及调节性T细胞的扩增来证明）。我们进一步发现，芬戈莫德给药抑制CD4+细胞的活化和1型辅助T细胞的分化，促进胰腺中调节性T细胞的扩增，这可能有助于维持胰腺免疫耐受和降低T1D发病率。这种保护作用可能是由于芬戈莫德抑制结肠中 Toll 样受体 2/4/核因子-κB/NOD 样受体蛋白 3 炎症小体通路。总的来说，生命早期的芬戈莫德治疗可以减轻 T1D 患者肠道微生物失调和肠道免疫功能障碍，这可能有助于其抗糖尿病作用。
Fingolimod has beneficial effects on multiple diseases, including type 1 diabetes (T1D) and numerous preclinical models of colitis. Intestinal dysbiosis and intestinal immune dysfunction contribute to disease pathogenesis of T1D. Thus, the beneficial effect of fingolimod on T1D may occur via the maintenance of intestinal homeostasis to some extent. Herein, we investigated the role of fingolimod in intestinal dysfunction in non-obese diabetic (NOD) mice and possible mechanisms. NOD mice were treated with fingolimod (1 mg · kg−1per day, i.g.) from weaning (3-week-old) to 31 weeks of age. We found that fingolimod administration significantly enhanced the gut barrier (evidenced by enhanced expression of tight junction proteins and reduced intestinal permeability), attenuated intestinal microbial dysbiosis (evidenced by the reduction of enteric pathogenic Proteobacteria clusters), as well as intestinal immune dysfunction (evidenced by inhibition of CD4+cells activation, reduction of T helper type 1 cells and macrophages, and the expansion of regulatory T cells). We further revealed that fingolimod administration suppressed the activation of CD4+cells and the differentiation of T helper type 1 cells, promoted the expansion of regulatory T cells in the pancreas, which might contribute to the maintenance of pancreatic immune tolerance and the reduction of T1D incidence. The protection might be due to fingolimod inhibiting the toll-like receptor 2/4/nuclear factor-κB/NOD-like receptor protein 3 inflammasome pathway in the colon. Collectively, early-life fingolimod treatment attenuates intestinal microbial dysbiosis and intestinal immune dysfunction in the T1D setting, which might contribute to its anti-diabetic effect.