摘要
Thalidomide(THA)is renowned for its potent anti-inflammatory properties.This study aimed to elucidate its underlying mechanisms in the context of Crohn's disease(CD)development.Mouse colitis models were established by dextran sulfate sodium(DSS)treatment.Fecal microbiota and metabolites were analyzed by metagenomic sequencing and mass spectrometry,respectively.Antibiotic-treated mice served as models for microbiota depletion and transplantation.The expression of forkhead box P3+(FOXP3+)regulatory T cells(Tregs)was measured by flow cytometry and immunohistochemical assay in colitis model and patient cohort.THA inhibited colitis in DSS-treated mice by altering the gut microbiota profile,with an increased abundance of probiotics Bacteroides fragilis,while pathogenic bacteria were depleted.In addition,THA increased beneficial metabolites bile acids and significantly restored gut barrier function.Transcriptomic profiling revealed that THA inhibited interleukin-17(IL-17),IL-1βand cell cycle signaling.Fecal microbiota transplantation from THA-treated mice to microbiota-depleted mice partly recapitulated the effects of THA.Specifically,increased level of gut commensal B.fragilis was observed,correlated with elevated levels of the microbial metabolite 3alpha-hydroxy-7-oxo-5beta-cholanic acid(7-ketolithocholic acid,7-KA)following THA treatment.This microbial metabolite may stable FOXP3 expression by targeting the receptor FMR1 autosomal homolog 1(FXR1)to inhibit autophagy.An interaction between FOXP3 and FXR1 was identified,with binding regions localized to the FOXP3 domain(aa238-335)and the FXR1 domain(aa82-222),respectively.Conclusively,THA modulates the gut microbiota and metabolite profiles towards a more beneficial composition,enhances gut barrier function,promotes the differentiation of FOXP3+Tregs and curbs pro-inflammatory pathways.
基金
supported by grants from the National Natural Science Foundation of China(Grant Nos.:82360112)
the project supported by Jiangxi Provincial Natural Science Foundation,China(Grant No.:20232BAB216021)
China Postdoctoral Science Foundation(Grant No.:2023M741522)
the Key Laboratory Project of Digestive Diseases in Jiangxi Province,China(Program No.:2024SSY06101)
Jiangxi Clinical Research Center for Gastroenterology,China(Program No.:20223BCG74011).
