Ginseng polysaccharides prevent mastitis through <i>Lactobacillus murinus</i> ‐derived deoxycholic acid and TGR5 signaling

Abstract Mastitis, a common inflammatory disease of breast tissue, has been linked to gut microbiota dysbiosis; however, evidence establishing a causal relationship and the potential for microbiome‐based therapies remains limited. This study investigated the gut‐mammary gland axis and how the prebiotic candidate ginseng polysaccharide (GP) prevents mastitis. Using Lipopolysaccharide (LPS)‐induced mouse models, we demonstrate that mastitis involves gut dysbiosis contributing to pathogenesis. GP prevented mastitis in a microbiota‐dependent manner. Mechanistically, GP selectively enriches Lactobacillus ( L .) murinus , boosting its metabolite deoxycholic acid (DCA) level in the bloodstream and mammary tissue. DCA suppressed inflammation by binding TGR5 (Takeda G‐protein‐coupled receptor 5), activating the cAMP‐PKA (cyclic adenosine monophosphate‐protein kinase A) pathway, and inhibiting NF‐κB/NLRP3 inflammasome. Additionally, combining GP with L. murinus enhanced protection, suggesting potential as a synbiotic. Overall, these findings reveal a novel gut‐mammary gland axis where GP acts by enhancing L. murinus ‐derived DCA and TGR5 signaling, highlighting the therapeutic potential of targeting this axis for mastitis prevention and management.