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

## TL;DR

The gut microbiota helps protect against deadly Staphylococcus aureus infections by boosting liver immune responses through γδ T cells and neutrophils.

## Contribution

A novel gut-liver immune axis involving γδ T cells and IL-17A is identified as a defense mechanism against S. aureus.

## Key findings

- Gut microbiota primes hepatic γδ T cells to produce IL-17A, aiding in neutrophil recruitment and bacterial clearance.
- Disrupting the gut microbiota weakens host resistance to S. aureus by impairing IL-17A and neutrophil responses.
- Limosilactobacillus reuteri enhances host defense via indole metabolites that activate the γδT17-neutrophil axis.

## Abstract

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 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 Limosilactobacillus reuteri (L. reuteri) activates this hepatic γδT17-neutrophil axis, enhancing host defense against S. aureus 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 S. aureus infections.