Development of an XBP1 agonist,HLJ2,as a potential therapeutic agent for ulcerative colitis

Xiao-nan TANG,Hai-jing ZHANG,Guang-ming SONG,Hua-chen SONG,Wen-jie WANG,Lian-qiu WU

(State Key Laboratory of Bioactive Substances and Functions of Natural Medicines,Institute of Materia Medica,Chinese Academy of Medical Sciences and Peking Union Medical College,Beijing 100050,China）

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Development of an XBP1 agonist,HLJ2,as a potential therapeutic agent for ulcerative colitis

Xiao-nan TANG,Hai-jing ZHANG,Guang-ming SONG,Hua-chen SONG,Wen-jie WANG,Lian-qiu WU

(State Key Laboratory of Bioactive Substances and Functions of Natural Medicines,Institute of Materia Medica,Chinese Academy of Medical Sciences and Peking Union Medical College,Beijing 100050,China）

OBJECTIVETo identify the valid targets and new drugs of ulcerative colitis(UC),a recurrent and intractable inflammatory bowel disease.METHODSandRESULTSIn an in vivo mouse model of DSS-induced colitis,HLJ2 decreased weight loss,colon contracture,disease activity index(DAI),colon mucosa damage index(CMDI)and histopathological index(HI).HLJ2 also decreased myelo?peroxidase(MPO)activity and reduced production of the inflammatory cytokines TNF-α,IL-1β,and IL-6.HLJ2 improved intestinal mucosa damage induced by dextran sodium sulfate(DSS)and increased the expression of ZO-1 and claudin-1.Fecal 16s rRNA high-throughput sequencing demon?strated a significant improvement in UC intestinal dysbacteriosis in mice treated with HLJ2,including increased abundance of probiotics such as Lachnospiraceae,Prevotellaceae,and Lactobacillaceae.At the same time there was a reduction in the abundance of pathogenic or conditional pathogenic microor?ganisms such as Bacteroidaceae,Porphyromonadaceae,Deferribacteraceae,and Pseudomonadaceae in HLJ2-treated mice compared with untreated mice.CONCLUSIONOur results demonstrated that the XBP1 agonist HLJ2 inhibits inflammation,regulates the intestinal flora,and protects the intestinal mucosa.It is thus a potential therapeutic agent for ulcerative colitis.

ulcerative colitis;XBP1;intestinal flora;intestinal mucosa;cytokines

Lian-qiu WU,Tel:(010)63031589,E-mail：wlq@imm.ac.cn