Gut microbiota-driven IL-17A production by hepatic γδ T cells enhances neutrophil defense against systemic 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 protective effect against systemic S. aureus infection. Specifically, commensal microbiota-derived signals prime hepatic γδ 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 γδ T cell IL-17A production, reduced neutrophil mobilization, and compromised host resistance to infection. Notably, we found that colonization with the commensal Limosilactobacillus reuteri (L. reureri) activates this hepatic γδT17-neutrophil axis, enhancing host defense against S. aureus. 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 S. aureus infections.金黄色葡萄球菌（Staphylococcus aureus, S. aureus）血流感染是一类严重的临床威胁，且随着抗生素耐药性不断攀升、死亡率居高不下，其危害进一步加剧。尽管肠道菌群（gut microbiota）被认为是全身免疫的关键调控因子，但其介导抗侵袭性细菌感染保护作用的具体机制仍未完全阐明。本研究通过动物模型，探究了肠道菌群在早期金黄色葡萄球菌血流感染过程中对肝脏免疫应答的调控作用。研究结果显示，肠道菌群可对全身性金黄色葡萄球菌感染发挥保护作用。具体而言，共生菌群来源的信号可预致敏肝脏γδ T细胞，使其在遭遇细菌感染时能够快速产生IL-17A。这种依赖于肠道菌群的IL-17A应答随后可促进中性粒细胞向肝脏募集，进而促进细菌清除并限制病原体全身播散。破坏肠道菌群则会损害肝脏γδ T细胞的IL-17A产生能力，降低中性粒细胞动员水平，并削弱宿主的抗感染抵抗力。值得注意的是，本研究发现定植共生罗伊氏乳杆菌（Limosilactobacillus reuteri，原文缩写为L. reureri）可激活该肝脏γδT17细胞-中性粒细胞轴，增强宿主对抗金黄色葡萄球菌的防御能力。本研究揭示了一条全新的肠-肝轴：肠道菌群通过调控肝脏γδ T细胞功能，构建起抵御侵袭性细菌病原体的早期免疫屏障，为提升宿主对抗致命性金黄色葡萄球菌感染的防御能力提供了潜在治疗策略。