Astragalus polysaccharide protects experimental colitis through an aryl hydrocarbon receptor‐dependent autophagy mechanism

Abstract

AbstractBackground and PurposeDisruption of intestinal barriers plays a vital role in the pathogenesis of colitis. The aryl hydrocarbon receptor (AhR) is a recognition sensor that mediates intestinal immune homeostasis and minimizes intestinal inflammation. Astragalus polysaccharide (APS) exerts pharmacological actions in colitis; however, the mechanism has not been elucidated. We investigated whether APS protects through AhR‐dependent autophagy.Experimental ApproachThe symptoms of dextran sulfate sodium (DSS)‐induced colitis in mice involving intestinal barrier function and inflammatory injury were evaluated after APS administration. Intestinal‐specific Becn1 conditional knockout (Becn1 cKO) mice were constructed and compared with wild‐type mice. Autophagy and the effects of APS were investigated after the deactivation of AhRs. The relationship between APS‐induced AhRs and autophagic Becn1 was investigated using a dual‐luciferase reporter system and chromatin immunoprecipitation (ChIP)‐quantitative polymerase chain reaction assay. Caco‐2 cells were used to investigate inflammatory responses and AhR‐dependent autophagy.Key ResultsAPS improved intestinal barrier function in inflammatory injury in colitis mice. APS triggered autophagic flow; however, knockout of Becn1 in the gut increased susceptibility to colitis, leading to diminished epithelial barrier function and severe intestinal inflammation, impairing the protective effects of APS. Mechanistically, APS‐triggered autophagy depends on AhR expression. Activated AhR binds to the promoter Becn1 to operate transcription of genes involved in anti‐inflammation and intestinal barrier repair, while deactivation of AhR correlated with intestinal inflammation and the therapeutic function of APS.Conclusions and ImplicationsAPS protects colitis mice by targeting autophagy, especially as the AhR stimulates the repair of damaged intestinal barrier functions.