Antibiotics promote inflammation through the translocation of native commensal colonic bacteria

Gut. 2016 Jul;65(7):1100-9. doi: 10.1136/gutjnl-2014-309059. Epub 2015 Jun 4.

Abstract

Objective: Antibiotic use is associated with an increased risk of developing multiple inflammatory disorders, which in turn are linked to alterations in the intestinal microbiota. How these alterations in the intestinal microbiota translate into an increased risk for inflammatory responses is largely unknown. Here we investigated whether and how antibiotics promote inflammation via the translocation of live native gut commensal bacteria.

Design: Oral antibiotics were given to wildtype and induced mutant mouse strains, and the effects on bacterial translocation, inflammatory responses and the susceptibility to colitis were evaluated. The sources of the bacteria and the pathways required for bacterial translocation were evaluated using induced mutant mouse strains, 16s rRNA sequencing to characterise the microbial communities, and in vivo and ex vivo imaging techniques.

Results: Oral antibiotics induced the translocation of live native commensal bacteria across the colonic epithelium, promoting inflammatory responses, and predisposing to increased disease in response to coincident injury. Bacterial translocation resulted from decreased microbial signals delivered to colonic goblet cells (GCs), was associated with the formation of colonic GC-associated antigen passages, was abolished when GCs were depleted and required CX3CR1(+) dendritic cells. Bacterial translocation occurred following a single dose of most antibiotics tested, and the predisposition for increased inflammation was only associated with antibiotics inducing bacterial translocation.

Conclusions: These findings reveal an unexpected outcome of antibiotic therapy and suggest that bacterial translocation as a result of alterations in the intestinal microflora may provide a link between increasing antibiotic use and the increased incidence of inflammatory disorders.

Keywords: ANTIBIOTICS; BACTERIAL TRANSLOCATION; GUT IMMUNOLOGY; INFLAMMATION.

MeSH terms

  • Animals
  • Anti-Bacterial Agents / pharmacology*
  • Bacterial Translocation / drug effects*
  • Bacterial Translocation / immunology
  • CX3C Chemokine Receptor 1
  • Colitis / microbiology
  • Colon / microbiology*
  • Cytokines / metabolism
  • Dendritic Cells / chemistry
  • Disease Susceptibility
  • Enterococcus faecalis / isolation & purification
  • Escherichia coli / isolation & purification
  • Goblet Cells / immunology
  • Goblet Cells / metabolism*
  • Goblet Cells / microbiology*
  • Inflammation / microbiology*
  • Intestine, Small / microbiology
  • Lymph Nodes / microbiology*
  • Mesentery
  • Mice
  • Mice, Inbred C57BL
  • Myeloid Differentiation Factor 88
  • Receptors, Chemokine / analysis

Substances

  • Anti-Bacterial Agents
  • CX3C Chemokine Receptor 1
  • Cx3cr1 protein, mouse
  • Cytokines
  • Myd88 protein, mouse
  • Myeloid Differentiation Factor 88
  • Receptors, Chemokine