Modulation of immune responses to Clostridium difficile by peroxisome proliferator-activated receptor γ and miRNA-146b (164.14)

Clostridium difficile is typically a harmless anaerobic bacterium but has recently re-emerged as a pathogen that can cause nosocomial diarrhea, colitis and death. To investigate the role of peroxisome proliferator-activated receptor (PPAR) γ in modulating immune responses to C. difficile we have performed several studies using a mouse model of antibiotic-induced C. difficile-associated disease (CDAD). The loss of PPARγ in T cells increased disease activity, body weight loss, and colonic inflammatory lesions after infection. It also resulted in upregulated IL-17 and MCP-1, and downregulated IL-10 expression, suggesting that a Th17 phenotype predominates during CDAD in mice lacking T cell PPARγ. Treatment of C. difficile-infected mice with PPAR γ agonists ameliorates disease severity and colonic lesions. RNA-seq results in colonic specimens indicated that three miRNAs were significantly overexpressed in infected mice: mmu-miR-146b, mmu-miR-1940, and mmu-miR-1298 (FDR P < 0.05). Real-time PCR results validated that infection results in overexpression of miR-146b, a molecule involved in regulating immunity and inflammation. Furthermore, NCOA4, a co-activator of PPARγ and target of miR-146b, was down-regulated in colons of infected mice. We provide novel evidence supporting a role for PPARγ in regulating C. difficile-related inflammation and immunopathology and explore the potential role of miRNA in modulating host responses to C. difficile.