RT Journal Article SR Electronic T1 Constitutive STAT5 activation regulates Paneth and Paneth-like cells to control Clostridium difficile colitis JF Life Science Alliance JO Life Sci. Alliance FD Life Science Alliance LLC SP e201900296 DO 10.26508/lsa.201900296 VO 2 IS 2 A1 Ruixue Liu A1 Richard Moriggl A1 Dongsheng Zhang A1 Haifeng Li A1 Rebekah Karns A1 Hai-Bin Ruan A1 Haitao Niu A1 Christopher Mayhew A1 Carey Watson A1 Hansraj Bangar A1 Sang-wook Cha A1 David Haslam A1 Tongli Zhang A1 Shila Gilbert A1 Na Li A1 Michael Helmrath A1 James Wells A1 Lee Denson A1 Xiaonan Han YR 2019 UL https://www.life-science-alliance.org/content/2/2/e201900296.abstract AB 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.