title: Retinoic Acid Improves Incidence and Severity of Necrotizing Enterocolitis by Lymphocyte Balance Restitution and Repopulation of LGR5+ Intestinal Stem Cells.
abstract: Necrotizing enterocolitis (NEC) is the most devastating gastrointestinal disease of the premature infant. We have recently shown that NEC development occurs after an increase in proinflammatory CD4Th17 (Th17) cells and reduced anti-inflammatory forkhead box P3 regulatory T cells (Tregs) to the premature small intestine of mice and humans, which can be experimentally reversed in mice by administration of all-trans retinoic acid (ATRA). We have also shown that NEC is characterized by apoptosis of Lgr5-positive intestinal stem cells (ISCs-Lgr5 cells) within the crypts of Lieberkühn, which are subsequently essential for intestinal homeostasis. We now hypothesize that the normal lymphocyte balance within the lamina propria of the intestine can be achieved via administration of ATRA which restores mucosal integrity by preventing the loss of ISCs. Using both in vivo and in vitro strategies, we now demonstrate that Th17 recruitment and Treg depletion lead to increased apoptosis within ISC niches, significantly impairing proliferative capacity and mucosal healing. ATRA exerted its protective effects by preventing T cell imbalance, ultimately leading to the protection of the ISC pool preventing the development of NEC in mice. These findings raise the exciting possibility that dietary manipulations could prevent and treat NEC by modulating lymphocyte balance and the ISC pool within the newborn small intestine.
authors.affiliation: *Division of General Pediatric Surgery, Johns Hopkins University and Bloomberg Children's Center, Johns Hopkins Hospital, Baltimore, Maryland†Division of Newborn Medicine, Children's Hospital of Pittsburgh of UPMC, Pittsburgh, Pennsylvania‡Division of Pediatric Pathology, Children's Hospital of Pittsburgh of UPMC, Pittsburgh, Pennsylvania§Department of Surgery, University of Pittsburgh, Pittsburgh, Pennsylvania¶Department of Surgery, Johns Hopkins University School of Medicine, Baltimore, Maryland.
authors.forename: Diego F
authors.initials: DF
authors.lastname: Niño
authors.forename: Chhinder P
authors.initials: CP
authors.lastname: Sodhi
authors.forename: Charlotte E
authors.initials: CE
authors.lastname: Egan
authors.forename: Qinjie
authors.initials: Q
authors.lastname: Zhou
authors.forename: Joyce
authors.initials: J
authors.lastname: Lin
authors.forename: Peng
authors.initials: P
authors.lastname: Lu
authors.forename: Yukihiro
authors.initials: Y
authors.lastname: Yamaguchi
authors.forename: Hongpeng
authors.initials: H
authors.lastname: Jia
authors.forename: Laura Y
authors.initials: LY
authors.lastname: Martin
authors.forename: Misty
authors.initials: M
authors.lastname: Good
authors.forename: William B
authors.initials: WB
authors.lastname: Fulton
authors.forename: Thomas
authors.initials: T
authors.lastname: Prindle
authors.forename: John A
authors.initials: JA
authors.lastname: Ozolek
authors.forename: David J
authors.initials: DJ
authors.lastname: Hackam
mesh_terms: D000818:Animals; D002470:Cell Survival / Q000187:drug effects / Q000235:genetics; D002478:Cells, Cultured; D020345:Enterocolitis, Necrotizing / Q000188:drug therapy* / Q000517:prevention & control*; D005434:Flow Cytometry; D007150:Immunohistochemistry; D007422:Intestines / Q000166:cytology*; D008214:Lymphocytes / Q000166:cytology* / Q000187:drug effects*; D008810:Mice, Inbred C57BL; D060888:Real-Time Polymerase Chain Reaction; D043562:Receptors, G-Protein-Coupled / Q000378:metabolism*; D013234:Stem Cells / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism*; D014212:Tretinoin / Q000627:therapeutic use*
chemical_list: D043562:Receptors, G-Protein-Coupled; D014212:Tretinoin