title: The microbiota protects against ischemia/reperfusion-induced intestinal injury through nucleotide-binding oligomerization domain-containing protein 2 (NOD2) signaling.
abstract: Nucleotide-binding oligomerization domain-containing protein 2 (NOD2), an intracellular pattern recognition receptor, induces autophagy on detection of muramyl dipeptide (MDP), a component of microbial cell walls. The role of bacteria and NOD2 signaling toward ischemia/reperfusion (I/R)-induced intestinal injury response is unknown. Herein, we report that I/R-induced intestinal injury in germ-free (GF) C57BL/6 wild-type (WT) mice is worse than in conventionally derived mice. More important, microbiota-mediated protection against I/R-induced intestinal injury is abrogated in conventionally derived Nod2(-/-) mice and GF Nod2(-/-) mice. Also, WT mice raised in specific pathogen-free (SPF) conditions fared better against I/R-induced injury than SPF Nod2(-/-) mice. Moreover, SPF WT mice i.p. administered 10 mg/kg MDP were protected against injury compared with mice administered the inactive enantiomer, l-MDP, an effect lost in Nod2(-/-) mice. However, MDP administration failed to protect GF mice from I/R-induced intestinal injury compared with control, a phenomenon correlating with undetectable Nod2 mRNA level in the epithelium of GF mice. More important, the autophagy-inducer rapamycin protected Nod2(-/-) mice against I/R-induced injury and increased the levels of LC3(+) puncta in injured tissue of Nod2(-/-) mice. These findings demonstrate that NOD2 protects against I/R and promotes wound healing, likely through the induction of the autophagy response.
authors.affiliation: Department of Medicine, University of Florida, Gainesville, Florida; Department of Infectious Diseases & Pathology, University of Florida, Gainesville, Florida.
authors.forename: Ernesto
authors.initials: E
authors.lastname: Perez-Chanona
authors.affiliation: Departments of Medicine, Microbiology and Immunology, and Pharmacology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina.
authors.forename: Marcus
authors.initials: M
authors.lastname: Mühlbauer
authors.affiliation: Department of Medicine, University of Florida, Gainesville, Florida; Department of Infectious Diseases & Pathology, University of Florida, Gainesville, Florida; Departments of Medicine, Microbiology and Immunology, and Pharmacology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina. Electronic address: christian.jobin@medicine.ufl.edu.
authors.forename: Christian
authors.initials: C
authors.lastname: Jobin
mesh_terms: D000818:Animals; D001343:Autophagy / Q000235:genetics; D007413:Intestinal Mucosa / Q000378:metabolism; D007422:Intestines / Q000098:blood supply / Q000382:microbiology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D064307:Microbiota / Q000502:physiology*; D053473:Nod2 Signaling Adaptor Protein / Q000235:genetics / Q000378:metabolism*; D015427:Reperfusion Injury / Q000378:metabolism / Q000382:microbiology / Q000517:prevention & control*; D015398:Signal Transduction / Q000502:physiology*
chemical_list: D053473:Nod2 Signaling Adaptor Protein; C495945:Nod2 protein, mouse