Early-life fingolimod treatment improves intestinal homeostasis and pancreatic immune tolerance in non-obese diabetic mice  

作　　者：Ling-ling Jia Ming Zhang He Liu Jia Sun Li-long Pan 

机构地区：[1]Wuxi School of Medicine,Jiangnan University,Wuxi 214122,China [2]State Key Laboratory of Food Science and Technology,Jiangnan University,Wuxi 214122,China [3]School of Food Science and Technology,Jiangnan University,Wuxi 214122,China

出　　处：《Acta Pharmacologica Sinica》2021年第10期1620-1629,共10页中国药理学报（英文版）

基　　金：This work was supported by funds from the National Natural Science Foundation of China(Grant Nos.80270666,81870439,81901670,81973322,and National Youth 1000 Talents Plan);the Natural Science Foundation for Distinguished Young Scholars of Jiangsu Province(Grants No.:BK20200026);the Recruitment Plan for High-level,Innovative and Entrepreneurial Talents(innovative Research Team)of Jiangsu Province,the Jiangsu Province Qing Lan Project,Jiangsu Province"Six Summit Talents"program(Grant No.2019-YY-038);the collaborative innovation center of food safety and quality control in Jiangsu Province,National First-Class Discipline Program of Food Science and Technology(Grant No.JUFSTR20180103);Wuxi Social Development Funds for International Science&Technology Cooperation(Grant No.WX0303B010518180007PB);the Fundamental Research Funds for the Central Universities(Grant Nos.:81870439 and JUSRP22007);Chinese Postdoctoral Science Foundation(Grant No.2018M642169);Jiangsu Postdoctoral Research Foundation(Grant No.2018K237C);Wuxi Taihu Talent Project.

摘　　要：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^(−1) per 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.

关 键 词：FINGOLIMOD type 1 diabetes gut barrier enteric pathogens TLR2-NF-κB-NLRP3 

分 类 号：R96[医药卫生—药理学] R5[医药卫生—药学]