The intestinal microbiota are necessary for stressor-induced enhancement of splenic macrophage microbicidal activity

Brain Behav Immun. 2012 Mar;26(3):371-82. doi: 10.1016/j.bbi.2011.11.002. Epub 2011 Nov 12.


The indigenous microbiota impact mucosal, as well as systemic, immune responses, but whether the microbiota are involved in stressor-induced immunomodulation has not been thoroughly tested. A well characterized murine stressor, called social disruption (SDR), was used to study whether the microbiota are involved in stressor-induced enhancement of macrophage reactivity. Exposure to the SDR Stressor enhanced the ability of splenic macrophages to produce microbicidal mediators (e.g., inducible nitric oxide synthase (iNOS), superoxide anion, and peroxynitrite) and to kill target Escherichia coli. Exposure to the SDR Stressor also increased cytokine production by LPS-stimulated splenic macrophages. These effects, however, were impacted by the microbiota. Microbicidal activity and cytokine mRNA in splenic macrophages from Swiss Webster germfree mice that lack any commensal microbiota were not enhanced by exposure to the SDR Stressor. However, when germfree mice were conventionalized by colonizing them with microbiota from CD1 conventional donor mice, exposure to the SDR Stressor again increased microbicidal activity and cytokine mRNA. In follow-up experiments, immunocompetent conventional CD1 mice were treated with a cocktail of antibiotics to disrupt the intestinal microbiota. While exposure to the SDR Stressor-enhanced splenic macrophage microbicidal activity and cytokine production in vehicle-treated mice, treatment with antibiotics attenuated the SDR Stressor-induced increases in splenic macrophage reactivity. Treatment with antibiotics also prevented the stressor-induced increase in circulating levels of bacterial peptidoglycan, suggesting that translocation of microbiota-derived peptidoglycan into the body primes the innate immune system for enhanced activity. This study demonstrates that the microbiota play a crucial role in stressor-induced immunoenhancement.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cytokines / immunology*
  • Escherichia coli
  • Immunity, Mucosal
  • Immunomodulation
  • Intestines / immunology*
  • Intestines / microbiology*
  • Macrophage Activation / immunology*
  • Macrophages / immunology*
  • Metagenome / immunology*
  • Mice
  • Nitric Oxide Synthase Type II / immunology
  • Peroxynitrous Acid / immunology
  • Spleen / immunology
  • Stress, Psychological / immunology*
  • Superoxides / immunology


  • Cytokines
  • Superoxides
  • Peroxynitrous Acid
  • Nitric Oxide Synthase Type II