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Research ArticleGASTROINTESTINAL, HEPATIC, PULMONARY, AND RENAL

Therapeutic Role of Rifaximin in Inflammatory Bowel Disease: Clinical Implication of Human Pregnane X Receptor Activation

Jie Cheng, Yatrik M. Shah, Xiaochao Ma, Xiaoyan Pang, Toshiya Tanaka, Tatsuhiko Kodama, Kristopher W. Krausz and Frank J. Gonzalez
Journal of Pharmacology and Experimental Therapeutics October 2010, 335 (1) 32-41; DOI: https://doi.org/10.1124/jpet.110.170225
Jie Cheng
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Yatrik M. Shah
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Xiaochao Ma
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Xiaoyan Pang
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Toshiya Tanaka
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Tatsuhiko Kodama
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Kristopher W. Krausz
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Frank J. Gonzalez
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Abstract

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.

Footnotes

  • This work was supported by the Intramural Research Program of the National Institutes of Health National Cancer Institute.

  • Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.

    doi:10.1124/jpet.110.170225.

  • ↵Embedded Image The online version of this article (available at http://jpet.aspetjournals.org) contains supplemental material.

  • ABBREVIATIONS:

    PXR
    pregnane X receptor
    Rifax
    rifaximin, 4-deoxy-4′-methylpyrido[1′,2′-1,2]imidazo[5,4-c]rifamycin SV
    RIF
    rifampicin, 3-(4-methylpiperazinyliminomethyl)rifamycin SV
    IBD
    inflammatory bowel disease
    DSS
    dextran sulfate sodium
    TNBS
    trinitrobenzene sulfonic acid
    NF-κB
    nuclear factor κB
    hPXR
    PXR-humanized
    WT
    wild type
    DSS/RIF
    coadministration of rifampicin and DSS
    DSS/Rifax
    coadministration of rifaximin and DSS
    TNBS/Rifax
    coadministration of rifaximin and TNBS
    iNOS
    inducible nitric-oxide synthase
    TNF
    tumor necrosis factor
    CCR2
    chemokine motif receptor 2
    IFN
    interferon
    ICAM-1
    intercellular adhesion molecule 1
    MCP-1
    monocyte chemoattractant protein 1
    IL
    interleukin
    qPCR
    quantitative real-time PCR
    HNF4α
    hepatocyte nuclear factor 4 α
    SCD-1
    stearoyl-CoA desaturase-1
    DMSO
    dimethyl sulfoxide
    RXR
    retinoid X receptor
    H&E
    hematoxylin and eosin.

  • Received May 12, 2010.
  • Accepted July 8, 2010.
  • Copyright © 2010 by The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 381 (3)
Journal of Pharmacology and Experimental Therapeutics
Vol. 381, Issue 3
1 Jun 2022
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Research ArticleGASTROINTESTINAL, HEPATIC, PULMONARY, AND RENAL

Therapeutic Role of Rifaximin in Inflammatory Bowel Disease: Clinical Implication of Human Pregnane X Receptor Activation

Jie Cheng, Yatrik M. Shah, Xiaochao Ma, Xiaoyan Pang, Toshiya Tanaka, Tatsuhiko Kodama, Kristopher W. Krausz and Frank J. Gonzalez
Journal of Pharmacology and Experimental Therapeutics October 1, 2010, 335 (1) 32-41; DOI: https://doi.org/10.1124/jpet.110.170225

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Research ArticleGASTROINTESTINAL, HEPATIC, PULMONARY, AND RENAL

Therapeutic Role of Rifaximin in Inflammatory Bowel Disease: Clinical Implication of Human Pregnane X Receptor Activation

Jie Cheng, Yatrik M. Shah, Xiaochao Ma, Xiaoyan Pang, Toshiya Tanaka, Tatsuhiko Kodama, Kristopher W. Krausz and Frank J. Gonzalez
Journal of Pharmacology and Experimental Therapeutics October 1, 2010, 335 (1) 32-41; DOI: https://doi.org/10.1124/jpet.110.170225
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