The study by Clarke et al. (2014) investigates the role of the microbiota in modulating systemic innate immunity. The authors demonstrate that the microbiota translocates peptidoglycan from the gut to bone marrow-derived neutrophils, enhancing their function against pathogens such as *Streptococcus pneumoniae* and *Staphylococcus aureus*. This effect is mediated through the recognition of peptidoglycan by the pattern recognition receptor Nod1, which activates the NF-κB signaling pathway. The absence of Nod1 results in reduced neutrophil function and increased susceptibility to early pneumococcal sepsis. The study also shows that Nod1 ligands can restore neutrophil function after microbiota depletion, highlighting the systemic immunomodulatory role of the microbiota. These findings challenge the traditional view of innate immunity as quiescent and suggest that the microbiota constantly modulates the immune system to facilitate a rapid response to infections.The study by Clarke et al. (2014) investigates the role of the microbiota in modulating systemic innate immunity. The authors demonstrate that the microbiota translocates peptidoglycan from the gut to bone marrow-derived neutrophils, enhancing their function against pathogens such as *Streptococcus pneumoniae* and *Staphylococcus aureus*. This effect is mediated through the recognition of peptidoglycan by the pattern recognition receptor Nod1, which activates the NF-κB signaling pathway. The absence of Nod1 results in reduced neutrophil function and increased susceptibility to early pneumococcal sepsis. The study also shows that Nod1 ligands can restore neutrophil function after microbiota depletion, highlighting the systemic immunomodulatory role of the microbiota. These findings challenge the traditional view of innate immunity as quiescent and suggest that the microbiota constantly modulates the immune system to facilitate a rapid response to infections.