Advertisement

The Pregnane X Receptor and Indole-3-Propionic Acid Shape the Intestinal Mesenchyme to Restrain Inflammation and Fibrosis

  • Kyle L. Flannigan
    Affiliations
    Department of Physiology & Pharmacology, University of Calgary, Calgary, AB, Canada

    Snyder Institute for Chronic Diseases, University of Calgary, Calgary, AB, Canada

    Alberta Children’s Hospital Research Institute, University of Calgary, Calgary, AB, Canada
    Search for articles by this author
  • Kristoff M. Nieves
    Affiliations
    Department of Physiology & Pharmacology, University of Calgary, Calgary, AB, Canada

    Snyder Institute for Chronic Diseases, University of Calgary, Calgary, AB, Canada

    Alberta Children’s Hospital Research Institute, University of Calgary, Calgary, AB, Canada
    Search for articles by this author
  • Holly E. Szczepanski
    Affiliations
    Department of Physiology & Pharmacology, University of Calgary, Calgary, AB, Canada

    Snyder Institute for Chronic Diseases, University of Calgary, Calgary, AB, Canada

    Alberta Children’s Hospital Research Institute, University of Calgary, Calgary, AB, Canada
    Search for articles by this author
  • Alex Serra
    Affiliations
    Department of Physiology & Pharmacology, University of Calgary, Calgary, AB, Canada

    Snyder Institute for Chronic Diseases, University of Calgary, Calgary, AB, Canada

    Alberta Children’s Hospital Research Institute, University of Calgary, Calgary, AB, Canada
    Search for articles by this author
  • Joshua W. Lee
    Affiliations
    Department of Physiology & Pharmacology, University of Calgary, Calgary, AB, Canada

    Snyder Institute for Chronic Diseases, University of Calgary, Calgary, AB, Canada

    Alberta Children’s Hospital Research Institute, University of Calgary, Calgary, AB, Canada
    Search for articles by this author
  • Laurie A. Alston
    Affiliations
    Department of Physiology & Pharmacology, University of Calgary, Calgary, AB, Canada

    Snyder Institute for Chronic Diseases, University of Calgary, Calgary, AB, Canada
    Search for articles by this author
  • Hena Ramay
    Affiliations
    International Microbiome Centre, University of Calgary, AB, Canada
    Search for articles by this author
  • Sridhar Mani
    Affiliations
    Department of Medicine, Albert Einstein College of Medicine, Bronx, NY, USA
    Search for articles by this author
  • Simon A. Hirota
    Correspondence
    Correspondence: SA Hirota, 3330 Hospital Dr. NW, HSC 1845, Calgary, Alberta, Canada, T2N 4N1.
    Affiliations
    Department of Physiology & Pharmacology, University of Calgary, Calgary, AB, Canada

    Department of Microbiology, Immunology and Infectious Diseases, University of Calgary, Calgary, AB, Canada

    Snyder Institute for Chronic Diseases, University of Calgary, Calgary, AB, Canada

    Alberta Children’s Hospital Research Institute, University of Calgary, Calgary, AB, Canada
    Search for articles by this author
Open AccessPublished:October 25, 2022DOI:https://doi.org/10.1016/j.jcmgh.2022.10.014
      This paper is only available as a PDF. To read, Please Download here.

      ABSTRACT

      Background & Aims

      Fibrosis is a common complication of the inflammatory bowel diseases(IBD). The pregnane X receptor(PXR; encoded by NR1I2) suppresses intestinal inflammation and has been shown to influence liver fibrosis. In the intestine, PXR-signaling is influenced by microbiota-derived indole-3-propionic acid(IPA). Here, we sought to assess the role of the PXR in regulating intestinal inflammation and fibrosis.

      Methods

      Intestinal inflammation was induced using dextran sulphate sodium(DSS). Fibrosis was assessed in wild-type(WT), Nr1i2-/-, epithelial-specific Nr1i2-/- and fibroblast-specific Nr1i2-/- mice. Immune cell influx was quantified by flow cytometry and cytokines by Luminex. Myofibroblasts isolated from WT and Nr1i2-/- mice were stimulated with cytomix or LPS and mediator production assessed by qPCR and Luminex.

      Results

      Following recovery from DSS-induced colitis, WT mice exhibited fibrosis, a response that was exacerbated in Nr1i2-/- mice. This was correlated with greater neutrophil infiltration and innate cytokine production. Deletion of the PXR in fibroblasts, but not the epithelium, recapitulated this phenotype. Inflammation and fibrosis were reduced by IPA administration, whereas depletion of the microbiota exaggerated intestinal fibrosis. Nr1i2-deficient myofibroblasts were hyperresponsive to stimulation, producing increased levels of inflammatory mediators compared to WT cells. In biopsies from patients with active Crohn’s disease(CD) and ulcerative colitis(UC), expression of NR1I2 was reduced, correlating with increased expression of fibrotic and innate immune genes. Finally, both CD and UC patients exhibited reduced levels of fecal IPA.

      Conclusions

      These data highlight a role for IPA and its interactions with the PXR in regulating the mesenchyme and the development of inflammation and fibrosis, suggesting microbiota metabolites may be a vital determinant in the progression of fibrotic complications in IBD.

      KEYWORDS

      Abbreviations:

      IPA (indole-3-propionic acid), IBD (inflammatory bowel diseases), PXR (pregnane X receptor), LPS (lipopolysaccharide), CD (Crohn’s disease), UC (ulcerative colitis), NR1I2 (nuclear receptor subfamily 1 group I member 2), Col1a1 (collagen, type I, alpha 1), Col1a2 (collagen, type I, alpha 2), Col3a1 (collagen, type 3, alpha 1), CFS2 (colony stimulating factor 2), CSF3 (colony stimulating factor 3), CXCL1 (C-X-C Motif chemokine ligand 1), CXCL2 (C-X-C Motif chemokine ligand 2), CXCL8 (C-X-C Motif chemokine ligand 8), CXCL9 (C-X-C Motif chemokine ligand 9), Cyp3a11 (cytochrome P450, family 3, subfamily a, polypeptide 11), G-CSF (granulocyte colony-stimulating factor), GM-CSF (granulocyte-macrophage colony-stimulating factor), LP (lamina propria), MHC (major histocompatibility complex), αSMA (alpha smooth muscle actin), MMP (matrix metalloproteinase), WT (wild-type), 4-OHT (4-hydroxytamoxifen), DSS (dextran sulphate sodium), GF (germ-free), PCN (pregnenolone 16α-carbonitrile), TNFα (tumor necrosis factor alpha), IFNγ (interferon gamma), IL-1β (interleukin 1 beta), IL-5 (interleukin 5), TGFβ (transforming growth factor beta), PCF (propyl chloroformate)