Modulation of colonic immunometabolic responses during Clostridioides difficile infection ameliorates disease severity and inflammation.
Sci Rep
; 13(1): 14708, 2023 09 07.
Article
em En
| MEDLINE
| ID: mdl-37679643
ABSTRACT
Clostridioides difficile infection (CDI) is the leading cause of antibiotic-associated diarrhea, and its clinical symptoms can span from asymptomatic colonization to pseudomembranous colitis and even death. The current standard of care for CDI is antibiotic treatment to achieve bacterial clearance; however, 15 to 35% of patients experience recurrence after initial response to antibiotics. We have conducted a comprehensive, global colonic transcriptomics analysis of a 10-day study in mice to provide new insights on the local host response during CDI and identify novel host metabolic mechanisms with therapeutic potential. The analysis indicates major alterations of colonic gene expression kinetics at the acute infection stage, that are restored during the recovery phase. At the metabolic level, we observe a biphasic response pattern characterized by upregulated glycolytic metabolism during the peak of inflammation, while mitochondrial metabolism predominates during the recovery/healing stage. Inhibition of glycolysis via 2-Deoxy-D-glucose (2-DG) administration during CDI decreases disease severity, protects from mortality, and ameliorates colitis in vivo. Additionally, 2-DG also protects intestinal epithelial cells from C. difficile toxin damage, preventing loss of barrier integrity and secretion of proinflammatory mediators. These data postulate the pharmacological targeting of host immunometabolic pathways as novel treatment modalities for CDI.
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Clostridioides difficile
/
Infecções por Clostridium
Aspecto:
Patient_preference
Limite:
Animals
Idioma:
En
Revista:
Sci Rep
Ano de publicação:
2023
Tipo de documento:
Article
País de afiliação:
Estados Unidos