Ginseng polysaccharides prevent mastitis through Lactobacillus murinus-derived deoxycholic acid and TGR5 signaling

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.