Pregnane X receptor activation ameliorates DSS-induced inflammatory bowel disease via inhibition of NF-κB target gene expression
Abstract
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.
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Synthetic NR1I2 agonists exert protective effects in mouse models of colitis.
“administration of synthetic NR1I2 agonists exerts protective effects in mouse models of colitis (Dou et al., 2013; Garg et al., 2016; Shah et al., 2007; Terc et al., 2014; Venkatesh et al., 2014).”
From Understanding the Holobiont: How Microbial Metabolites Affect Human Health and Shape the Immune System (2017) · cites this paper as Shah et al., 2007
LCA and related secondary bile acids can reduce pro-inflammatory cytokine production and NFkB target expression via vitamin D receptor and pregnane X receptor binding.
“secondary bile acids such as LCA have also been shown to suppress pro-inflammatory cytokine production and NFkB target expression through binding to both the vitamin D receptor (Bakke and Sun, 2018; Makishima et al., 2002) and pregnane X receptor (Shah et al., 2007; Staudinger et al., 2001).”
From Antibiotics-Driven Gut Microbiome Perturbation Alters Immunity to Vaccines in Humans (2019) · cites this paper as Shah et al., 2007
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“Nr1i2 / mice exhibit impaired epithelial barrier function, and administration of synthetic NR1I2 agonists exerts protective effects in mouse models of colitis (Dou et al., 2013; Garg et al., 2016; Shah et al., 2007; Terc et al., 2014; Venkatesh et al., 2014).”
BackgroundAntibiotics-Driven Gut Microbiome Perturbation Alters Immunity to Vaccines in Humans
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- Authors
- Shah, Y. M., Ma, X., Morimura, K., Kim, I., & Gonzalez, F. J.
- Affiliations
- National Institutes of Health (US)
- Venue
- American Journal of Physiology-Gastrointestinal and Liver Physiology
- Publisher
- American Physiological Society
- Published
- 2007-04
- Volume
- 292
- Issue
- 4
- Pages
- G1114-G1122
- ISSN
- 0193-1857 (ISSN-L)
- 1522-1547
- OpenAlex
- W2102490761
- Cited by
- 231
- References
- 41
- Citations by year
- 2026: 3 · 2025: 8 · 2024: 13 · 2023: 11 · 2022: 18 · 2021: 18 · 2020: 9 · 2019: 18 · 2018: 10 · 2017: 16 · 2016: 8 · 2015: 17 · 2014: 14 · 2013: 14 · 2012: 2
- FWCI
- 4.92
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- American Journal of Physiology-Gastrointestinal and Liver Physiology (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Inflammatory Bowel Disease
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Peroxisome Proliferator-Activated Receptors
- Life Sciences › Immunology and Microbiology › Immunology › Psoriasis: Treatment and Pathogenesis
- Keywords
- pregnane X receptor, inflammatory bowel disease, DSS-induced colitis, NF-κB target genes, pregnenolone-16α-carbonitrile, PXR agonists, intestinal permeability, epithelial barrier function, inflammatory cytokines, colonic inflammation
- MeSH terms
- Pregnane X Receptor, Animals, Colitis, Colon, Disease Models, Animal, Gastrointestinal Agents, Glutathione Transferase, Humans, Mice, Inbred C57BL, Pregnenolone Carbonitrile, Receptors, Steroid, Repressor Proteins, RNA, Messenger, Severity of Illness Index, Time Factors, Transfection, Inflammatory Bowel Diseases, Gene Expression, Cytokines, Dextran Sulfate, NF-kappa B, Mice, Knockout, ATP-Binding Cassette Transporters, Cytoprotection, HCT116 Cells, Mice
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