Xenobiotic Receptor Regulation of <i>Clostridium difficile</i> ‐Associated Tissue Damage and Inflammation
Notice bibliographique
Résumé
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
Récupéré en direct depuis OpenAlex et désinversé. Les résumés ne sont pas conservés dans cette base de données : les index inversés représentent 8,6 Go des 9,3 Go de texte de la base, et le serveur dispose de 13 Go libres.
Comment cette classification a été obtenuedéplier
Prédiction machine sur la base complète
Imitation des enseignantsNi prévalence calibrée, ni vérité terrain. Validation humaine à venir. Le volet Gemma est une étiquette directe du modèle pour chaque travail de la base, lue sur la notice réduite au titre. Le volet Codex est un classifieur appris des 10 348 étiquettes directes de Codex et calibré sur les taux pondérés de l'échantillon; les champs sans appui suffisant ne portent aucun appel Codex. Le mode candidate est l'union des deux volets; le consensus est leur intersection. Ces sorties portent le statut machine_predicted_unvalidated et ne sont pas des étiquettes humaines.
Scores du classifieur distillé par catégorie (deux têtes)
| Catégorie | Codex | Gemma |
|---|---|---|
| Métarecherche | 0,000 | 0,000 |
| Méta-épidémiologie (sens strict) | 0,000 | 0,000 |
| Méta-épidémiologie (sens large) | 0,000 | 0,000 |
| Bibliométrie | 0,000 | 0,000 |
| Études des sciences et des technologies | 0,000 | 0,000 |
| Communication savante | 0,000 | 0,000 |
| Science ouverte | 0,000 | 0,000 |
| Intégrité de la recherche | 0,000 | 0,000 |
| Charge utile insuffisante (le modèle a refusé de juger) | 0,002 | 0,001 |
Scores machine (provisoires)
Les deux têtes enseignantes du modèle étudiant, lues sur ce travail. Un score ordonne la base pour la relecture; il n'affirme jamais une catégorie, et le statut de validation accompagne chaque rangée tel quel.
Scores de référence d'un modèle non mature (critères de maturité non atteints, 7 itérations). Un score ordonne; il n'affirme jamais une catégorie.
score_only:v0-immature-baseline · tel quel depuis la passe de notation : score_only signifie que le nombre peut ordonner les travaux, et qu'aucune étiquette de catégorie n'en découleClassification
machine, non validéePrédiction automatique; un appel candidat d’une seule source (Gemma direct ou Codex distillé), pas un consensus.
Le détail, modèle par modèle et score par score, se trouve en fin de page sous « Comment cette classification a été obtenue ».