Gut microbiota drives IL-17A production by hepatic gamma delta T cells to enhance neutrophil recruitment and host resistance against Staphylococcus aureus infection

Staphylococcus aureus (S. aureus) 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 S. aureus bloodstream infection using animal models. Our findings demonstrate that the gut microbiota exerts a proactive protective effect against systemic S. aureus infection. Specifically, commensal microbiota-derived signals prime hepatic gamma delta T cells for rapid 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 gamma delta T cell IL-17A production, reduced neutrophil mobilization, and compromised host resistance to infection. Notably, we found that colonization with the commensal Lactobacillus reuteri (L. reureri) activates this hepatic gamma deltaT17-neutrophil axis, enhancing host defense against S. aureus. This study reveals a novel gut-liver axis whereby intestinal microbiota orchestrates hepatic gamma delta T cell function to establish an early immunological barrier against invasive bacterial pathogens, offering potential therapeutic avenues for enhancing host defense against life-threatening S. aureus infections.