title: The cytosolic bacterial peptidoglycan sensor Nod2 affords stem cell protection and links microbes to gut epithelial regeneration.
abstract: The intestinal crypt is a site of potential interactions between microbiota products, stem cells, and other cell types found in this niche, including Paneth cells, and thus offers a potential for commensal microbes to influence the host epithelium. However, the complexity of this microenvironment has been a challenge to deciphering the underlying mechanisms. We used in vitro cultured organoids of intestinal crypts from mice, reinforced with in vivo experiments, to examine the crypt-microbiota interface. We find that within the intestinal crypt, Lgr5(+) stem cells constitutively express the cytosolic innate immune sensor Nod2 at levels much higher than in Paneth cells. Nod2 stimulation by its bona fide agonist, muramyl-dipeptide (MDP), a peptidoglycan motif common to all bacteria, triggers stem cell survival, which leads to a strong cytoprotection against oxidative stress-mediated cell death. Thus, gut epithelial restitution is Nod2 dependent and triggered by the presence of microbiota-derived molecules.
authors.affiliation: Institut Pasteur, Unité de Pathogénie Microbienne Moléculaire, 75015 Paris, France; INSERM U 786, Institut Pasteur, 75015 Paris, France.
authors.forename: Giulia
authors.initials: G
authors.lastname: Nigro
authors.affiliation: Institut Pasteur, Unité de Pathogénie Microbienne Moléculaire, 75015 Paris, France; Institut de Génomique Fonctionnelle, CNRS UMR 5203, Inserm U661, 34000 Montpellier, France.
authors.forename: Raffaella
authors.initials: R
authors.lastname: Rossi
authors.affiliation: Institut Pasteur, Imagopole, 75015 Paris, France.
authors.forename: Pierre-Henri
authors.initials: PH
authors.lastname: Commere
authors.affiliation: Institut de Génomique Fonctionnelle, CNRS UMR 5203, Inserm U661, 34000 Montpellier, France.
authors.forename: Philippe
authors.initials: P
authors.lastname: Jay
authors.affiliation: Institut Pasteur, Unité de Pathogénie Microbienne Moléculaire, 75015 Paris, France; INSERM U 786, Institut Pasteur, 75015 Paris, France; Chaire de Microbiologie et Maladies Infectieuses, Collège de France, 75005 Paris, France. Electronic address: philippe.sansonetti@pasteur.fr.
authors.forename: Philippe J
authors.initials: PJ
authors.lastname: Sansonetti
mesh_terms: D000119:Acetylmuramyl-Alanyl-Isoglutamine / Q000737:chemistry / Q000494:pharmacology*; D000818:Animals; D019610:Cytoprotection; D003600:Cytosol / Q000378:metabolism; D004848:Epithelium / Q000187:drug effects / Q000382:microbiology; D041981:Gastrointestinal Tract / Q000166:cytology / Q000187:drug effects / Q000382:microbiology*; D007422:Intestines / Q000166:cytology / Q000382:microbiology / Q000502:physiology; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D053473:Nod2 Signaling Adaptor Protein / Q000378:metabolism*; D009940:Organoids; D010457:Peptidoglycan / Q000737:chemistry; D043562:Receptors, G-Protein-Coupled / Q000235:genetics / Q000378:metabolism; D012038:Regeneration; D013234:Stem Cells / Q000187:drug effects
chemical_list: C493597:Lgr5 protein, mouse; D053473:Nod2 Signaling Adaptor Protein; C495945:Nod2 protein, mouse; D010457:Peptidoglycan; D043562:Receptors, G-Protein-Coupled; D000119:Acetylmuramyl-Alanyl-Isoglutamine