Gut microbiota-driven IL-17A production by hepatic γδ T cells enhances neutrophil defense against systemic <i>Staphylococcus aureus</i> infection

<i>Staphylococcus aureus</i> (<i>S. aureus</i>) bloodstream infections pose a significant clinical threat, exacerbated by increasing antibiotic resistance and high mortality. While the gut microbiota is recognized as a key modulator of systemic immunity, the mechanisms underlying its protective role against invasive bacterial infections remain incompletely understood. Here, we investigated how gut microbiota influences hepatic immune responses during early <i>S. aureus</i> bloodstream infection using animal models. Our findings demonstrate that the gut microbiota exerts a protective effect against systemic <i>S. aureus</i> infection. Specifically, commensal microbiota-derived signals prime hepatic γδ T cells for rapid interleukin-17A (IL-17A) production upon bacterial challenge. This microbiota-dependent IL-17A response subsequently promotes neutrophil recruitment to the liver, facilitating bacterial clearance and limiting systemic dissemination. Disruption of the gut microbiota impaired hepatic γδ T cell IL-17A production, reduced neutrophil mobilization, and compromised host resistance to infection. Notably, we found that colonization with the commensal <i>Limosilactobacillus reuteri</i> (<i>L. reuteri)</i> activates this hepatic γδT17-neutrophil axis, enhancing host defense against <i>S. aureus</i> as a mechanism involving indole metabolites. This study reveals a novel gut-liver axis whereby intestinal microbiota orchestrates hepatic γδ T cell function to establish an early immunological barrier against invasive bacterial pathogens, offering potential therapeutic avenues for enhancing host defense against life-threatening <i>S. aureus</i> infections.