Microbiota regulates neonatal disease tolerance to virus-evoked necrotizing enterocolitis by shaping the STAT1-NLRC5 axis in the intestinal epithelium

Saravanan Subramanian; Hua Geng; Longtao Wu; Chao Du; Amy M Peiper; Heng-Fu Bu; Pauline M Chou; Xiao Wang; Stephanie C Tan; Neha R Iyer; Nazeer Hussain Khan; Ellen L Zechner; James G Fox; Rolf Breinbauer; Chao Qi; Bakhtiar Yamini; Jenny P Ting; Isabelle G De Plaen; Stephanie M Karst; Xiao-Di Tan

doi:10.1016/j.chom.2024.08.013

Microbiota regulates neonatal disease tolerance to virus-evoked necrotizing enterocolitis by shaping the STAT1-NLRC5 axis in the intestinal epithelium

Cell Host Microbe. 2024 Sep 13:S1931-3128(24)00320-2. doi: 10.1016/j.chom.2024.08.013. Online ahead of print.

Authors

Saravanan Subramanian¹, Hua Geng¹, Longtao Wu², Chao Du³, Amy M Peiper⁴, Heng-Fu Bu¹, Pauline M Chou⁵, Xiao Wang¹, Stephanie C Tan⁶, Neha R Iyer⁴, Nazeer Hussain Khan¹, Ellen L Zechner⁷, James G Fox⁸, Rolf Breinbauer⁹, Chao Qi⁵, Bakhtiar Yamini², Jenny P Ting¹⁰, Isabelle G De Plaen³, Stephanie M Karst⁴, Xiao-Di Tan¹¹

Affiliations

¹ 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.
² Department of Surgery, Section of Neurosurgery, The University of Chicago, Chicago, IL 60637, USA.
³ Department of Pediatrics, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA.
⁴ Department of Molecular Genetics & Microbiology, University of Florida College of Medicine, Gainesville, FL 32610, USA.
⁵ Department of Pathology, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA.
⁶ Department of Medical Education, Loyola University Chicago Stritch School of Medicine, Maywood, IL 60153, USA.
⁷ Institute of Molecular Biosciences, University of Graz, 8010 Graz, Austria; BioTechMed-Graz, 8010 Graz, Austria.
⁸ Division of Comparative Medicine, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
⁹ Institute of Organic Chemistry, Graz University of Technology, 8010 Graz, Austria.
¹⁰ 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.
¹¹ 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 Affairs Medical Center, Chicago, IL 60612, USA. Electronic address: xtan25@uic.edu.

PMID: 39293437
DOI: 10.1016/j.chom.2024.08.013

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.

Keywords: Early life microbiota colonization; NLRC5; PPAR-γ; STAT1; autoimmunity; breastmilk feeding and formula feeding; intestinal epithelial cells; necrotizing enterocolitis; tilivalline-producing Klebsiella spp.; viral inflammation and NK cell cytotoxicity.