Crohn’s & Colitis Congress™

Sessions Speakers Exhibitors Floor Plan Buzz

P097 - REGULATION OF PANETH CELL LINEAGES FOR REGIONAL IMMUNE SPECIALIZATION TO CONTROL COMORBIDITY OF C. DIFFICILE INFECTION WITH IBD (Room Poster Hall)

Background: Hormone-like cytokines control C. difficile infection and counteract IBD. Apart from secreting bactericidal products, Paneth or Paneth-like cells act as a guardian that constitutes the niche for intestinal stem cells (ISC) to repair inflammation. However, little is explored about what subtypes of Paneth cells are regulated to sense microbial insults and sustain ISCs to specialize crypt immunity. We aim to determine a hormone cytokine gradient that can restrict ISC towards Paneth cells and facilitate the resolution of C. difficile inflammation. Methods: To determine the intestinal hormone-like cytokine signaling sustaining Paneth cells, we created transgenic mice and human induced pluripotent stem cells (iPSC) with inducible constitutively active Stat5 (icS5), which is a central node of cytokine signaling. The transgenic mice were treated with the murine (C. rodentium) or human pathogen (C. difficile) to test the effects of hormone-like cytokine (Leptin) upon Paneth cell differentiation and response to gut inflammation. ISC- or iPSC-derived organoids were differentiated to test the effects of hormone-like cytokines, inflammatory cytokines, and C. difficile toxins upon Paneth cell maturation and immune function. RNA sequencing and microarray analysis were used to test the gene signatures of Paneth cell lineages and cytokines. Results: Stat5 deficiency led to aberrant Paneth cells, gut dysbiosis and impaired induction of secretory lineages by pathogens, inflammatory cytokines or toxins, which exaggerated colitis. Constitutively or Leptin-active STAT5 gradient promoted niche differentiation and improved intestinal healing to counteract pathogen- or bacterial toxin-induced gut inflammation. Conclusion: Intestinal regional hormone cytokine-STAT5 gradient controls Paneth-like cell differentiation and location of ISC niche. Loss function of hormone cytokine-STAT5 gradient leads to the recurrence of C. difficile infection and comorbidity with IBD.