Therapeutic role of rifaximin in inflammatory bowel disease: clinical implication of human pregnane X receptor activation.

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.

Cheng J ，Shah YM ，Ma X ，Pang X ，Tanaka T ，Kodama T ，Krausz KW ，Gonzalez FJ ... -  《-》

Pregnane X receptor activation ameliorates DSS-induced inflammatory bowel disease via inhibition of NF-kappaB target gene expression.

Pregnane X receptor (PXR) expression was shown to be protective in inflammatory bowel disease (IBD). However, the mechanism by which PXR provides protection remains unclear. Wild-type and Pxr-null mice were treated with the PXR agonist pregnenolone-16alpha-carbonitrile or vehicle and administered 2.5% dextran sulfate sodium (DSS) in drinking water to induce IBD. Typical clinical symptoms were evaluated on a daily basis. In vivo intestinal permeability assays and proinflammatory cytokine analysis were performed. PXR agonist-treated mice were protected from DSS-induced colitis compared with vehicle-treated mice, as defined by body weight loss, diarrhea, rectal bleeding, colon length, and histology. Pregnenolone-16alpha-carbonitrile did not decrease the severity of IBD in Pxr-null mice. PXR agonist treatment did not increase epithelial barrier function but did decrease mRNA expression of several NF-kappaB target genes in a PXR-dependent manner. The present study clearly demonstrates a protective role for PXR agonist in DSS-induced IBD. The data suggest that PXR-mediated repression of NF-kappaB target genes in the colon is a critical mechanism by which PXR activation decreases the susceptibility of mice to DSS-induced IBD.

Shah YM ，Ma X ，Morimura K ，Kim I ，Gonzalez FJ ... -  《AMERICAN JOURNAL OF PHYSIOLOGY-GASTROINTESTINAL AND LIVER PHYSIOLOGY》

Pregnane X receptor as a target for treatment of inflammatory bowel disorders.

Pregnane X receptor (PXR; NR1I2), a member of the nuclear receptor superfamily, has a major role in the induction of genes involved in drug transport and metabolism. Recent studies in mice have provided insight into a novel function for PXR in inflammatory bowel disease (IBD). The mechanism of the protective effect of PXR activation on IBD is not fully established, but is due in part to the attenuation of nuclear factor (NF)-κB signaling that results in lower expression of proinflammatory cytokines. Recent clinical trials with the antibiotic rifaximin, a PXR agonist in the gastrointestinal system, have revealed its potential therapeutic value in the treatment of intestinal inflammation in humans. Thus, PXR may be a novel target for IBD therapy.

Cheng J ，Shah YM ，Gonzalez FJ 《-》

Activation of intestinal human pregnane X receptor protects against azoxymethane/dextran sulfate sodium-induced colon cancer.

The role of intestinal human pregnane X receptor (PXR) in colon cancer was determined through investigation of the chemopreventive role of rifaximin, a specific agonist of intestinal human PXR, toward azoxymethane (AOM)/dextran sulfate sodium (DSS)-induced colon cancer. Rifaximin treatment significantly decreased the number of colon tumors induced by AOM/DSS treatment in PXR-humanized mice, but not wild-type or Pxr-null mice. Additionally, rifaximin treatment markedly increased the survival rate of PXR-humanized mice, but not wild-type or Pxr-null mice. These data indicated a human PXR-dependent therapeutic chemoprevention of rifaximin toward AOM/DSS-induced colon cancer. Nuclear factor κ-light-chain-enhancer of activated B cells-mediated inflammatory signaling was upregulated in AOM/DSS-treated mice, and inhibited by rifaximin in PXR-humanized mice. Cell proliferation and apoptosis were also modulated by rifaximin treatment in the AOM/DSS model. In vitro cell-based assays further revealed that rifaximin regulated cell apoptosis and cell cycle in a human PXR-dependent manner. These results suggested that specific activation of intestinal human PXR exhibited a chemopreventive role toward AOM/DSS-induced colon cancer by mediating anti-inflammation, antiproliferation, and proapoptotic events.

Cheng J ，Fang ZZ ，Nagaoka K ，Okamoto M ，Qu A ，Tanaka N ，Kimura S ，Gonzalez FJ ... -  《-》

EFFECT OF PREGNANE XENOBIOTIC RECEPTOR ACTIVATION ON INFLAMMATORY BOWEL DISEASE TREATED WITH RIFAXIMIN.

Wan YC ，Li T ，Han YD ，Zhang HY ，Lin H ，Zhang B ... -  《JOURNAL OF BIOLOGICAL REGULATORS AND HOMEOSTATIC AGENTS》