Indole-3-carboxaldehyde from <i>Limosilactobacillus reuteri</i> targets the DUSP1/ERK/NOX2/ROS axis to enhance the bactericidal activity of macrophages and protects against sepsis.

The gut microbiota plays a critical regulatory role in the pathogenesis of sepsis, yet the immunomodulatory mechanisms of Limosilactobacillus reuteri (L. reuteri) and its metabolites in sepsis remain to be fully elucidated. This study found that the abundance of intestinal L. reuteri was significantly reduced in patients with bacterial sepsis and showed a negative correlation with disease severity. In a mouse model of sepsis induced by cecal ligation and puncture, fecal microbiota transplantation and live bacterial supplementation further confirmed that live L. reuteri effectively attenuated sepsis progression. Integrated metabolomic and network pharmacological analysis identified indole-3-carboxaldehyde (IAld), a metabolite derived from L. reuteri, which enhances macrophage bactericidal function and alleviates sepsis-associated organ damage. Mechanistically, IAld directly targets DUSP1 in macrophages, inhibits its phosphatase activity, thereby promoting ERK phosphorylation, upregulating NOX2 expression, stimulating reactive oxygen species production, and ultimately enhancing bacterial clearance. Notably, circulating IAld levels in septic patients were significantly inversely correlated with SOFA score, APACHE II score, and arterial lactate levels, and IAld safely enhanced the bactericidal function of human macrophages in vitro. This study is the first to systematically demonstrate that L. reuteri and its metabolite IAld exert a protective effect against sepsis through the DUSP1/ERK/NOX2/ROS axis, providing novel mechanistic insights and potential therapeutic targets for immunometabolic intervention in sepsis.