Indoleacrylic Acid Attenuates Inflammatory Progression In PGISp Mice Via Modulates Intestinal Microbiota And AhR Activation

Background&objectives.Recently,accumulating evidence has suggested that gut microbiota may be involved in the occurrence and development of ankylosing spondylitis(AS).It has been recognized that the healthy intestinal microbiota produces sufficient aryl hydrocarbon receptor(AhR)agonists to maintain intestinal homeostasis and immune balance.Administration of AhR ligands has been proven effective for improving pathological progressions in various autoimmune and inflammatory disesases.Indoleacrylic Acid(IA),an recognized AhR ligand produced by some probiotic bacteria,has been shown anti-inflammatory effects in vitro.However,the effectiveness and underlying mechanism of IA treatment to AS or SpA is unknown,and thus elucidating these became the purpose of our study.Methods.In this study,proteoglycan-induced spondyloarthritis(PGISp)mice were established and administrated with IA orally for 4 consecutive weeks.The disease severity was measured with the clinical and histological evaluations of arthritis,spondylitis and intestinal inflammation.Pro-inflammatory cytokine levels and the intestinal barrier function were also assessed.Then,16S rDNA sequencing was performed to analyze the alterations in the gut microbiota.In order to explore the possible molecular mechanism,the protein expression and activation of AhR,MIF,and NF-?B signal pathway was explored by western blot.Results.We found that IA administration significantly attenuates arthritis and decreases the serum levels of several pro-inflammatory such as TNF-?,IL-17,IL-23 and IL-6.Meanwhile,IA can improve the histological alterations of spine,peripheral joints and ileum.Besides,IA also altered the intestinal microbial composition with increased Lachnospiraceae NK4A136 and Odoribacter,and decreased pathogen such as Rodentibacter.Also,bacterial phenotypic prediction revealed that relative abundances of Gram's positive bacteria and anaerobic bacteria were elevated in IA-treated mice,while biofilm froming and stress tolerant abilities were decreased.The intestinal barrier function is recovered with less intestinal permeability and higher expressions of ZO-1 and occludin due to IA treatment.Furthermore,IA inhibited production of MIF in PGISp mice,which is a proinflammatory factor inducing inflammation and predicting spinal progression in AS.Inhibition of NF-?B/MIF signaling pathway via AhR activation may be the underlying mechanism.Conclusion.IA treatment exhibited a protective role in attenuating spondyloarthritis severity in PGISp mice model for ankylosing spondylitis.The underlying mechanism of IA anti-inflammatory effect is probably modulating the intestinal microbiota and inhibiting NF-?B/MIF signaling pathway via AhR activation in PGISp mice.Our results indicated the notable therapeutic potential and application prospect of IA adminstration in AS.