Abstract
Clostridium difficile is an anaerobic bacterium that has re-emerged as a facultative pathogen and can cause nosocomial diarrhea, colitis or even death. Peroxisome proliferator-activated receptor (PPAR) γ has been implicated in the prevention of inflammation in autoimmune and infectious diseases; however, its role in the immunoregulatory mechanisms modulating host responses to C. difficile and its toxins remains largely unknown. To characterize the role of PPARγ in C. difficile-associated disease (CDAD), immunity and gut pathology, we used a mouse model of C. difficile infection in wild-type and T cell-specific PPARγ null mice. The loss of PPARγ in T cells increased disease activity and colonic inflammatory lesions following C. difficile infection. Colonic expression of IL-17 was upregulated and IL-10 downregulated in colons of T cell-specific PPARγ null mice. Also, both the loss of PPARγ in T cells and C. difficile infection favored Th17 responses in spleen and colonic lamina propria of mice with CDAD. MicroRNA (miRNA)-sequencing analysis and RT-PCR validation indicated that miR-146b was significantly overexpressed and nuclear receptor co-activator 4 (NCOA4) suppressed in colons of C. difficile-infected mice. We next developed a computational model that predicts the upregulation of miR-146b, downregulation of the PPARγ co-activator NCOA4, and PPARγ, leading to upregulation of IL-17. Oral treatment of C. difficile-infected mice with the PPARγ agonist pioglitazone ameliorated colitis and suppressed pro-inflammatory gene expression. In conclusion, our data indicates that miRNA-146b and PPARγ activation may be implicated in the regulation of Th17 responses and colitis in C. difficile-infected mice.
Highlights
Clostridium difficile typically is a harmless environmental sporulated gram-positive anaerobic bacterium [1,2], but it has recently re-emerged as a significant enteric pathogen implicated in nosocomial diarrhea, colitis and even death, after antibiotic treatment
In line with the suppression of nuclear receptor co-activator 4 (NCOA4) expression we found that Peroxisome proliferator-activated receptor (PPAR) c target genes CD36 and GLUT4 were significantly downregulated in colons of C. difficileinfected mice (Figure 3), indicating that colonic Peroxisome proliferator-activated receptor c (PPARc) activity is suppressed in mice infected with C. difficile
Clostridium difficile is the most common cause of nosocomial infectious diarrhea in the U.S An increase in the severity and incidence of C. difficile infections has been reported in the last few years [47]
Summary
Clostridium difficile typically is a harmless environmental sporulated gram-positive anaerobic bacterium [1,2], but it has recently re-emerged as a significant enteric pathogen implicated in nosocomial diarrhea, colitis and even death, after antibiotic treatment. C. difficile grows in the intestine of individuals with altered commensal microflora [3,4] due to treatment with antimicrobials, immunosuppressants, cytostatic agents or proton pump inhibitors [5] An increase in both incidence and severity of C. difficile-associated disease (CDAD) has been reported over the last years [6,7,8]. Persistent or severe CDAD is currently being treated with discontinuation of the antibiotic therapy that led to the disease, and vancomycin therapy [15] These therapeutic approaches do not restore the normal microflora and are not effective in clostridial clearance, but further prolong C. difficile shedding and destroy beneficial gut anaerobic bacteria [15,16]. In contrast to targeting the bacterium and its toxins directly, the better understanding of the cellular and molecular basis underlying the host response will enable the rational development of host-targeted therapeutics for CDAD
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