The xenobiotic sensing pregnane X receptor regulates tissue damage and inflammation triggered by C difficile toxins

Sarah L. Erickson, Laurie Alston, Kristoff Nieves, Thomas K.H. Chang, Sridhar Mani, Kyle L. Flannigan, Simon A. Hirota

Research output: Contribution to journalArticle

Abstract

Clostridioides difficile (formerly Clostridium difficile; C difficile), the leading cause of nosocomial antibiotic-associated colitis and diarrhea in the industrialized world, triggers colonic disease through the release two toxins, toxin A (TcdA) and toxin B (TcdB), glucosyltransferases that modulate monomeric G-protein function and alter cytoskeletal function. The initial degree of the host immune response to C difficile and its pathogenic toxins is a common indicator of disease severity and infection recurrence. Thus, targeting the intestinal inflammatory response during infection could significantly decrease disease morbidity and mortality. In the current study, we sought to interrogate the influence of the pregnane X receptor (PXR), a modulator of xenobiotic and detoxification responses, which can sense and respond to microbial metabolites and modulates inflammatory activity, during exposure to TcdA and TcdB. Following intrarectal exposure to TcdA/B, PXR-deficient mice (Nr1i2−/−) exhibited reduced survival, an effect that was associated with increased levels of innate immune cell influx. This exacerbated response was associated with a twofold increase in the expression of Tlr4. Furthermore, while broad-spectrum antibiotic treatment (to deplete the intestinal microbiota) did not alter the responses in Nr1i2−/− mice, blocking TLR4 signaling significantly reduced TcdA/B-induced disease severity and immune responses in these mice. Lastly, to assess the therapeutic potential of targeting the PXR, we activated the PXR with pregnenolone 16α-carbonitrile (PCN) in wild-type mice, which greatly reduced the severity of TcdA/B-induced damage and intestinal inflammation. Taken together, these data suggest that the PXR plays a role in the host's response to TcdA/B and may provide a novel target to dampen the inflammatory tissue damage in C difficile infections.

Original languageEnglish (US)
Pages (from-to)2198-2212
Number of pages15
JournalFASEB Journal
Volume34
Issue number2
DOIs
StatePublished - Feb 1 2020

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Keywords

  • Clostridioides difficile
  • Nr1i2
  • eosinophils
  • neutrophils
  • pregnane X receptor
  • toxin

ASJC Scopus subject areas

  • Biotechnology
  • Biochemistry
  • Molecular Biology
  • Genetics

Cite this

Erickson, S. L., Alston, L., Nieves, K., Chang, T. K. H., Mani, S., Flannigan, K. L., & Hirota, S. A. (2020). The xenobiotic sensing pregnane X receptor regulates tissue damage and inflammation triggered by C difficile toxins. FASEB Journal, 34(2), 2198-2212. https://doi.org/10.1096/fj.201902083RR