Lycium Barbarum Polysaccharide Attenuates Staphylococcus aureus -Induced Mastitis via the Gut Microbiota-Derived Indole-3-Propionic Acid/AhR–IL-22–STAT3 Axis

Mastitis caused by Staphylococcus aureus (S. aureus) is marked by inflammation and disruption of the blood–milk barrier (BMB), posing health risks to humans and animals. We investigated the therapeutic effects of Lycium barbarum polysaccharide (LBP) in lactating mice with S. aureus-induced mastitis. Oral LBP reduced bacterial colonization, inflammatory cytokines, oxidative stress, and BMB damage. 16S rRNA sequencing and fecal microbiota transplantation (FMT) confirmed that protective effects depended on gut microbiota modulation. Metabolomic analysis revealed that LBP promoted microbial tryptophan metabolism, elevating indole-3-propionic acid (IPA). Mechanistically, IPA activated the aryl hydrocarbon receptor (AhR) and upregulated IL-22–STAT3 signaling, thereby enhancing the epithelial integrity and suppressing inflammation. Pharmacological inhibition of AhR or STAT3 abolished these benefits. Collectively, our results demonstrate that LBP mitigates S. aureus-induced mastitis through a microbiota-dependent IPA–AhR–IL-22–STAT3 axis, providing new insights into microbiota-targeted strategies for infection-associated inflammation.