Abstract
Clostridium difficile impairs Paneth cells, driving intestinal inflammation that exaggerates colitis. Besides secreting bactericidal products to restrain C. difficile, Paneth cells act as guardians that constitute a niche for intestinal epithelial stem cell (IESC) regeneration. However, how IESCs are sustained to specify Paneth-like cells as their niche remains unclear. Cytokine-JAK-STATs are required for IESC regeneration. We investigated how constitutive STAT5 activation (Ca-pYSTAT5) restricts IESC differentiation towards niche cells to restrain C. difficile infection. We generated inducible transgenic mice and organoids to determine the effects of Ca-pYSTAT5-induced IESC lineages on C. difficile colitis. We found that STAT5 absence reduced Paneth cells and predisposed mice to C. difficile ileocolitis. In contrast, Ca-pYSTAT5 enhanced Paneth cell lineage tracing and restricted Lgr5 IESC differentiation towards pYSTAT5+Lgr5-CD24+Lyso+ or cKit+ niche cells, which imprinted Lgr5hiKi67+ IESCs. Mechanistically, pYSTAT5 activated Wnt/β-catenin signaling to determine Paneth cell fate. In conclusion, Ca-pYSTAT5 gradients control niche differentiation. Lack of pYSTAT5 reduces the niche cells to sustain IESC regeneration and induces C. difficile ileocolitis. STAT5 may be a transcription factor that regulates Paneth cells to maintain niche regeneration.
Highlights
The prevalence of Clostridium difficile infection has increased in patients with inflammatory bowel diseases (IBDs) and has become a major healthcare burden over the past decade (Kaplan, 2015; Rao& Higgins, 2016)
All results are expressed as mean ± SEM, and t tests and ANOVA were used to compare the significance of a difference
While it remains unknown whether C. difficile infection has a causal link with IBD (Monaghan et al, 2015), a recent multi-center study defined a baseline prevalence of 7.5% for C. difficile infection amongst pediatric IBD patients compared with only 0.8% for controls with celiac disease (Martinelli et al, 2014)
Summary
The prevalence of Clostridium difficile infection has increased in patients with inflammatory bowel diseases (IBDs) and has become a major healthcare burden over the past decade (Kaplan, 2015; Rao& Higgins, 2016). C. difficile infection is associated with increased disease severity and need for ileostomy or colectomy in patients with IBD (Chen et al, 2017); yet, preventive and therapeutic approaches are extremely limited by a lack of understanding of the essential cell types and key signaling proteins that are usurped in C. difficile infection to impair mucosal healing in IBD (Monaghan et al, 2015). The injured IESCs result in impaired intestinal epithelial (IEC) repair and reduced anti-microbial peptide production, which in turn drives persistent infection and mucosal inflammation progression to ileitis and/or colitis (Monaghan et al, 2015). STAT5-dependent JAK2 signaling is required for anti-inflammatory cytokine production and IEC repair, and mutations or single nucleotide polymorphisms in JAK2-STAT5 increase susceptibility to colitis and ileal Crohn’s disease (Gilbert et al, 2012a; Huang et al, 2015; Chuang et al, 2016). C. difficile toxin has been implicated in suppression of the Wnt and JAK2-STAT5 pathways to impair IECs (Nam et al, 2012; Chen et al, 2018), but mechanistic studies are lacking
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