Xenobiotic Receptor Regulation of <i>Clostridium difficile</i> ‐Associated Tissue Damage and Inflammation
Bibliographic record
Abstract
Background The current treatments available for C. difficile infections (CDI) target the bacteria, however they do nothing to treat the damaging inflammation triggered by the virulence factors, TcdA and TcdB. Indeed, enhanced chemokine/cytokine expression during CDI is associated with poor clinical outcomes. Interestingly, a number of rifamycin antibiotics have been shown to have potent activity against C. difficile , while also exhibiting anti‐inflammatory effects through their ability to activate the pregnane X receptor (PXR) – a nuclear receptor, and inhibit NFκB signaling. In the current study, we sought to test the hypothesis that targeting the PXR could prove to be an effective strategy to reduce C. difficile toxin‐induced inflammation and tissue damage. Aims Assess the ability of the PXR to attenuate TcdB‐induced cytokine/chemokine production in vitro To test whether PXR activation can attenuate TcdA/B‐induced damage and inflammation in an in vivo model of C. difficile toxin exposure Determine the mechanism by which activation of the PXR attenuates TcdA/B‐induced damage and inflammation Methods We first assessed the ability of the PXR to modulate the production of the neutrophil chemokines CXCL8/IL‐8 and CXCL2/MIP‐2 from human colonic intestinal epithelial cells (IECs; Caco‐2). Caco‐2 IECs were treated for 16 hours with purified C. difficile TcdB (2.5μg/mL) in the presence of PXR agonists at various concentrations (rifampicin or SR12813). Cell lysates were harvested to evaluate cell death and toxin function by immunoblot for caspase‐3 and glucosylated RAC1, respectively. We then assessed whether PXR activation could attenuate toxin‐induced inflammation and tissue damage in vivo. Wild‐type and PXR−/− mice were administered TcdA/B (25μg; intrarectal administration) with/without PCN (25mg/kg), a rodent specific PXR agonist. After 4 hours of TcdA/B exposure, colonic tissues were harvested and pro‐inflammatory gene expression was assessed by q‐PCR and neutrophil infiltration assessed by flow cytometry. Results Activation of the PXR attenuated C. difficile TcdB‐induced CXCL8/IL‐8 and CXCL2/MIP‐2 release in Caco‐2 IECs. This effect was not due to PXR agonists altering IEC survival, as assessed by caspase‐3 cleavage, nor due to a direct inhibition of TcdB function as assessed by the glucosylation status of RAC1. In our in vivo studies, we found that PXR activation attenuated TcdA/B induced gene expression of the pro‐inflammatory cytokines/chemokines IL‐17A, CXCL1, CXCL2 and CXCL10. PXR activation also significantly decreased toxin‐induced neutrophil infiltration to the colon when compared to control (TcdA/B) animals. Furthermore, PXR−/− mice challenged with TcdA/B displayed a hyper‐susceptible phenotype and significantly increased pro‐inflammatory gene expression when compared to wild‐type TcdA/B‐treated mice. Conclusions Although there are many emerging treatments for CDI, drug tolerability, disease recurrence, resistance and dosing remain problematic. Taken together, these data will help us expand our knowledge of the PXR's role in host‐pathogen interactions, and its potential to be modulated for the treatment of inflammation and tissue damage in CDI. Support or Funding Information Crohn's & Colitis Canada, Dr. Keith Sharkey's CCFC Chair in IBD Research, The Dr. Lloyd Sutherland Investigator in IBD/GI Research, Canadian Foundation for Innovation, Canada Research Chairs Program
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.000 |
| Insufficient payload (model declined to judge) | 0.002 | 0.001 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".