Human
pregnane X receptor (PXR) has been implicated in the pathogenesis of
inflammatory bowel disease (IBD).
Rifaximin, a human PXR activator, is in clinical trials for treatment of IBD and has demonstrated efficacy in
Crohn's disease and active
ulcerative colitis. In the current study, the protective and therapeutic role of
rifaximin in IBD and its respective mechanism were investigated. PXR-humanized (hPXR), wild-type, and Pxr-null mice were treated with
rifaximin in the
dextran sulfate sodium (DSS)-induced and trinitrobenzene
sulfonic acid (TNBS)-induced IBD models to determine the protective function of human PXR activation in IBD. The therapeutic role of
rifaximin was further evaluated in DSS-treated hPXR and Pxr-null mice. Results demonstrated that preadministration of
rifaximin ameliorated the clinical hallmarks of
colitis in DSS- and TNBS-treated hPXR mice as determined by
body weight loss and assessment of
diarrhea, rectal
bleeding, colon length, and histology. In addition, higher survival rates and recovery from
colitis symptoms were observed in hPXR mice, but not in Pxr-null mice, when
rifaximin was administered after the onset of symptoms. Nuclear factor κB (NF-κB) target genes were markedly down-regulated in hPXR mice by
rifaximin treatment. In vitro NF-κB reporter assays demonstrated inhibition of NF-κB activity after
rifaximin treatment in colon-derived cell lines expressing hPXR. These findings demonstrated the preventive and therapeutic role of
rifaximin on IBD through human PXR-mediated inhibition of the NF-κB signaling cascade, thus suggesting that human PXR may be an effective target for the treatment of IBD.