Ginseng polysaccharides promote gut microbiota mediated deoxycholic acid to alleviate LPS-induced mastitis by regulating TGR5-cAMP-PKA-NF-κB/NLRP3 pathway

Abstract

Background Mastitis is one of the most serious diseases that troubles humans and animals, especially in the dairy industry. More and more evidence suggest that the gut microbiota is closely related to the pathogenesis of mastitis. Ginseng polysaccharide (GP), a main component of ginseng, can improve gut metabolism and regulate gut microbiota, but its underlying mechanism in mastitis is unclear. Results The present study found that GP alleviated lipopolysaccharide (LPS) induced mammary gland inflammation in mice and enriched beneficial bacteria such as Lactobacillus, while LPS stimulated mice enriched with harmful bacteria such as Proteus. Untargeted metabolomics results showed that compared with LPS challenge, the deoxycholic acid (DCA) level increased primarily and the bile secretion pathway was active in GP treatment. Transplanting the fecal microbiota of LPS-induced mice mastitis (FMT.LPS) into recipient mice led to mastitis, exacerbated mammary gland inflammation, and disrupted the blood-milk barrier. Interestingly, the result of 16S rRNA displayed that donor and recipient mice had similar gut microbiota structures, indicating a close correlation between microbial dysbiosis and the progression of mastitis. In vitro and in vivo experiments showed that DCA relieved LPS-induced mastitis, and its mechanism was that DCA-mediated TGR5 activation inhibited the NF-κB/NLRP3 pathways and mastitis caused by LPS via activating cAMP and PKA. Conclusion Our results suggested that GP alleviated LPS-induced mastitis by regulating secondary bile acid mediated by gut microbiota, providing a potential strategy to intervene in distal infections by regulating metabolites mediated by gut microbiota.