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Microbiota regulates neonatal disease tolerance to virus-evoked necrotizing enterocolitis by shaping the STAT1-NLRC5 axis in the intestinal epithelium.
Subramanian, Saravanan; Geng, Hua; Wu, Longtao; Du, Chao; Peiper, Amy M; Bu, Heng-Fu; Chou, Pauline M; Wang, Xiao; Tan, Stephanie C; Iyer, Neha R; Khan, Nazeer Hussain; Zechner, Ellen L; Fox, James G; Breinbauer, Rolf; Qi, Chao; Yamini, Bakhtiar; Ting, Jenny P; De Plaen, Isabelle G; Karst, Stephanie M; Tan, Xiao-Di.
Affiliation
  • Subramanian S; Pediatric Mucosal Inflammation and Regeneration Research Program, Center for Pediatric Translational Research and Education, Department of Pediatrics, College of Medicine, University of Illinois at Chicago, Chicago, IL 60612, USA.
  • Geng H; Pediatric Mucosal Inflammation and Regeneration Research Program, Center for Pediatric Translational Research and Education, Department of Pediatrics, College of Medicine, University of Illinois at Chicago, Chicago, IL 60612, USA.
  • Wu L; Department of Surgery, Section of Neurosurgery, The University of Chicago, Chicago, IL 60637, USA.
  • Du C; Department of Pediatrics, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA.
  • Peiper AM; Department of Molecular Genetics & Microbiology, University of Florida College of Medicine, Gainesville, FL 32610, USA.
  • Bu HF; Pediatric Mucosal Inflammation and Regeneration Research Program, Center for Pediatric Translational Research and Education, Department of Pediatrics, College of Medicine, University of Illinois at Chicago, Chicago, IL 60612, USA.
  • Chou PM; Department of Pathology, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA.
  • Wang X; Pediatric Mucosal Inflammation and Regeneration Research Program, Center for Pediatric Translational Research and Education, Department of Pediatrics, College of Medicine, University of Illinois at Chicago, Chicago, IL 60612, USA.
  • Tan SC; Department of Medical Education, Loyola University Chicago Stritch School of Medicine, Maywood, IL 60153, USA.
  • Iyer NR; Department of Molecular Genetics & Microbiology, University of Florida College of Medicine, Gainesville, FL 32610, USA.
  • Khan NH; Pediatric Mucosal Inflammation and Regeneration Research Program, Center for Pediatric Translational Research and Education, Department of Pediatrics, College of Medicine, University of Illinois at Chicago, Chicago, IL 60612, USA.
  • Zechner EL; Institute of Molecular Biosciences, University of Graz, 8010 Graz, Austria; BioTechMed-Graz, 8010 Graz, Austria.
  • Fox JG; Division of Comparative Medicine, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
  • Breinbauer R; Institute of Organic Chemistry, Graz University of Technology, 8010 Graz, Austria.
  • Qi C; Department of Pathology, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA.
  • Yamini B; Department of Surgery, Section of Neurosurgery, The University of Chicago, Chicago, IL 60637, USA.
  • Ting JP; Department of Genetics, Department of Microbiology-Immunology and the Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
  • De Plaen IG; Department of Pediatrics, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA.
  • Karst SM; Department of Molecular Genetics & Microbiology, University of Florida College of Medicine, Gainesville, FL 32610, USA.
  • Tan XD; Pediatric Mucosal Inflammation and Regeneration Research Program, Center for Pediatric Translational Research and Education, Department of Pediatrics, College of Medicine, University of Illinois at Chicago, Chicago, IL 60612, USA; Department of Research & Development, Jesse Brown Veterans Affair
Cell Host Microbe ; 2024 Sep 13.
Article in En | MEDLINE | ID: mdl-39293437
ABSTRACT
Microbiota and feeding modes influence the susceptibility of premature newborns to necrotizing enterocolitis (NEC) through mechanisms that remain unknown. Here, we show that microbiota colonization facilitated by breastmilk feeding promotes NOD-like receptor family CARD domain containing 5 (Nlrc5) gene expression in mouse intestinal epithelial cells (IECs). Notably, inducible knockout of the Nlrc5 gene in IECs predisposes neonatal mice to NEC-like injury in the small intestine upon viral inflammation in an NK1.1+ cell-dependent manner. By contrast, formula feeding enhances neonatal gut colonization with environment-derived tilivalline-producing Klebsiella spp. Remarkably, tilivalline disrupts microbiota-activated STAT1 signaling that controls Nlrc5 gene expression in IECs through a PPAR-γ-mediated mechanism. Consequently, this dysregulation hinders the resistance of neonatal intestinal epithelium to self-NK1.1+ cell cytotoxicity upon virus infection/colonization, promoting NEC development. Together, we discover the underappreciated role of intestinal microbiota colonization in shaping a disease tolerance program to viral inflammation and elucidate the mechanisms impacting NEC development in neonates.
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Full text: 1 Collection: 01-internacional Database: MEDLINE Language: En Journal: Cell Host Microbe Journal subject: MICROBIOLOGIA Year: 2024 Type: Article Affiliation country: United States
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Full text: 1 Collection: 01-internacional Database: MEDLINE Language: En Journal: Cell Host Microbe Journal subject: MICROBIOLOGIA Year: 2024 Type: Article Affiliation country: United States