Nod2 influences microbial resilience and susceptibility to colitis following antibiotic exposure

Mucosal Immunol. 2019 May;12(3):720-732. doi: 10.1038/s41385-018-0128-y. Epub 2019 Jan 16.

Abstract

Inflammatory bowel disease (IBD) etiology involves genetic susceptibility, environmental triggers, and the gut microbiome. Antibiotic exposure is associated with IBD, both in early life and adulthood. Here, we investigated whether Nod2-deficiency influenced response of the gut microbiota to antibiotics and subsequent colitis susceptibility. Wild-type and Nod2-/- littermate mice were treated with amoxicillin as adults or neonates, and fecal samples were collected for 16S rRNA sequencing. Five weeks after antibiotic exposure, dextran sulfate sodium (DSS) colitis was induced. Antibiotic treatment altered the microbiota of adult WT and Nod2-/- mice, but recovery was delayed in Nod2-/- mice. Neonatal antibiotic treatment significantly changed the microbiota at weaning in WT and Nod2-/- littermates; however, Nod2-/- mice maintained reduced microbial diversity 14 days after cessation of antibiotics. Although treatment of adult mice did not influence susceptibility to colitis, neonatally treated Nod2-/- mice developed a more severe colitis. Moreover, the colitis phenotype was transferable through fecal transplantation into germ-free Nod2-/- recipients, and was associated with changes in intestinal T cells and the cytokine milieu following inflammation. These data demonstrate that neonatal antibiotic exposure has long-lasting influence on the microbiota and mucosal immunity, and may explain how NOD2 contributes to the risk of intestinal inflammation.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amoxicillin / administration & dosage
  • Amoxicillin / adverse effects*
  • Animals
  • Animals, Newborn
  • Anti-Bacterial Agents / administration & dosage
  • Anti-Bacterial Agents / adverse effects*
  • Colitis / genetics
  • Colitis / metabolism*
  • Disease Models, Animal
  • Disease Susceptibility
  • Fecal Microbiota Transplantation
  • Gastrointestinal Microbiome / drug effects*
  • Gastrointestinal Microbiome / physiology
  • Gene-Environment Interaction
  • Humans
  • Inflammatory Bowel Diseases / genetics
  • Inflammatory Bowel Diseases / metabolism*
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Nod2 Signaling Adaptor Protein / genetics
  • Nod2 Signaling Adaptor Protein / metabolism*
  • Risk

Substances

  • Anti-Bacterial Agents
  • Nod2 Signaling Adaptor Protein
  • Nod2 protein, mouse
  • Amoxicillin