Recognition of peptidoglycan from the microbiota by Nod1 enhances systemic innate immunity

Humans are colonized by a large and diverse bacterial flora
(the microbiota) essential for the development of the gut
immune system1–3. A broader role for the microbiota as a
major modulator of systemic immunity has been proposed4,5;
however, evidence and a mechanism for this role have
remained elusive. We show that the microbiota are a source
of peptidoglycan that systemically primes the innate immune
system, enhancing killing by bone marrow–derived neutrophils
of two major pathogens: Streptococcus pneumoniae and
Staphylococcus aureus. This requires signaling via the pattern
recognition receptor nucleotide-binding, oligomerization
domain–containing protein-1 ( Nod1, which recognizes
meso-diaminopimelic acid (mesoDAP)-containing
peptidoglycan found predominantly in Gram-negative
bacteria), but not Nod2 (which detects peptidoglycan found
in Gram-positive and Gram-negative bacteria) or Toll-like
receptor 4 ( Tlr4, which recognizes lipopolysaccharide)6,7.
We show translocation of peptidoglycan from the gut to
neutrophils in the bone marrow and show that peptidoglycan
concentrations in sera correlate with neutrophil function.
In vivo administration of Nod1 ligands is sufficient to
restore neutrophil function after microbiota depletion.
Nod1−/− mice are more susceptible than wild-type mice to
early pneumococcal sepsis, demonstrating a role for Nod1
in priming innate defenses facilitating a rapid response to
infection. These data establish a mechanism for systemic
immunomodulation by the microbiota and highlight potential
adverse consequences of microbiota disruption by broadspectrum
antibiotics on innate immune defense to infection.