The microbiota plays a critical role in systemic innate immunity by priming the immune system through recognition of peptidoglycan by the pattern recognition receptor Nod1. This study shows that the microbiota is a source of peptidoglycan that enhances the function of bone marrow-derived neutrophils, which are essential for killing pathogens such as Streptococcus pneumoniae and Staphylococcus aureus. This effect requires Nod1 signaling, which recognizes mesoDAP-containing peptidoglycan found in Gram-negative bacteria, but not Nod2 or Tlr4. The study demonstrates that peptidoglycan translocates from the gut to the bloodstream and that its levels in the serum correlate with neutrophil function. In vivo administration of Nod1 ligands restores neutrophil function after microbiota depletion, and Nod1-deficient mice show increased susceptibility to pneumococcal sepsis, highlighting the role of Nod1 in priming innate defenses. The microbiota constantly modulates the innate immune system, enhancing its ability to respond rapidly to pathogens. Disruption of the microbiota, such as by broad-spectrum antibiotics, may impair innate immune defenses, increasing susceptibility to infections. The study provides a direct example of how microbial products benefit the host by enhancing systemic innate immune function. The findings challenge the traditional view of innate immunity as quiescent in the absence of infection and activated only upon pathogen recognition. Instead, they suggest that the microbiota continuously primes the immune system, facilitating a rapid response to pathogens.The microbiota plays a critical role in systemic innate immunity by priming the immune system through recognition of peptidoglycan by the pattern recognition receptor Nod1. This study shows that the microbiota is a source of peptidoglycan that enhances the function of bone marrow-derived neutrophils, which are essential for killing pathogens such as Streptococcus pneumoniae and Staphylococcus aureus. This effect requires Nod1 signaling, which recognizes mesoDAP-containing peptidoglycan found in Gram-negative bacteria, but not Nod2 or Tlr4. The study demonstrates that peptidoglycan translocates from the gut to the bloodstream and that its levels in the serum correlate with neutrophil function. In vivo administration of Nod1 ligands restores neutrophil function after microbiota depletion, and Nod1-deficient mice show increased susceptibility to pneumococcal sepsis, highlighting the role of Nod1 in priming innate defenses. The microbiota constantly modulates the innate immune system, enhancing its ability to respond rapidly to pathogens. Disruption of the microbiota, such as by broad-spectrum antibiotics, may impair innate immune defenses, increasing susceptibility to infections. The study provides a direct example of how microbial products benefit the host by enhancing systemic innate immune function. The findings challenge the traditional view of innate immunity as quiescent in the absence of infection and activated only upon pathogen recognition. Instead, they suggest that the microbiota continuously primes the immune system, facilitating a rapid response to pathogens.