• Rhamnose, a gut microbiota-derived metabolite, alleviates LPS-induced systemic inflammation and organ damage in mice without affecting basal cytokine homeostasis.
• Mechanistically, rhamnose binds to CEACAM1 at specific sites (V39, D40, T101), promoting CEACAM1-LGALS9 interaction and upregulating DUSP1, which inhibits p38 phosphorylation and reduces proinflammatory cytokine expression.
• The study identifies the CEACAM1/LGALS9-p38 axis as a novel regulatory pathway in endotoxemia, offering a potential therapeutic target for sepsis and infection-induced organ damage.
• Rhamnose emerges as a promising candidate anti-inflammatory agent, with implications for developing microbiota-based or dietary interventions to control excessive inflammation.