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Background and Purpose Short-chain fatty acids are fermentation end products produced by gut bacteria, which have been shown to ameliorate inflammatory bowel diseases and allergic asthma. However, the mechanism involved remains largely unknown. Here, we investigate the protective effects and mechanisms of sodium butyrate (SB) on LPS-induced mastitis model. Experimental Approach Effects of increasing doses of SB on blood-milk barrier function and inflammation are studied in BALB/c mice with LPS-induced mastitis. The underlying mechanisms of anti-inflammatory effects of SB were further investigated in LPS-stimulated mouse mammary epithelial cells (mMECs). Key Results The results show that SB decreased LPS-induced disruption in mammary tissues, infiltration of inflammatory cells and the levels of TNF-α, IL-6 and IL-1β. SB up-regulated the tight junction proteins occludin and claudin-3 and reduced blood-milk barrier permeability in LPS-induced mastitis. Studies in vitro revealed that SB inhibited LPS-induced inflammatory response by inhibition of the NF-κB signalling pathway and histone deacetylases in LPS-stimulated mMECs. Conclusions and Implications In our model, SB protected against LPS-induced mastitis by preserving blood-milk barrier function and depressing pro-inflammatory responses, suggesting the potential use of SB as a prophylactic agent to protect blood-milk barrier function in mastitis.

Glycyrrhizin, a triterpene glycoside isolated from licorice root, is known to have anti-inflammatory activities. However, the effect of glycyrrhizin on mastitis has not been reported. The purpose of this study was to investigate the anti-inflammatory effect and mechanism of action of glycyrrhizin on lipopolysaccharide (LPS)-induced mastitis in mouse. An LPS-induced mouse mastitis model was used to confirm the anti-inflammatory activity of glycyrrhizin in vivo. Primary mouse mammary epithelial cells were used to investigate the molecular mechanism and targets of glycyrrhizin. In vivo, glycyrrhizin significantly attenuated the mammary gland histopathological changes, myeloperoxidase activity and infiltration of neutrophilic granulocytes and downregulated the expression of tumor necrosis factor-α, interleukin (IL)-1β and IL-6 caused by LPS. In vitro, glycyrrhizin dose-dependently inhibited the LPS-induced expression of tumor necrosis factor-α, IL-6, and RANTES. Western blot analysis showed that glycyrrhizin suppressed LPS-induced nuclear factor-κB and interferon regulatory factor 3 activation. However, glycyrrhizin did not inhibit nuclear factor-κB and interferon regulatory factor 3 activation induced by MyD88-dependent (MyD88, IKKβ) or TRIF-dependent (TRIF, TBK1) downstream signaling components. Moreover, glycyrrhizin did not act though affecting the function of CD14 or expression of Toll-like receptor 4. Finally, we showed that glycyrrhizin decreased the levels of cholesterol of lipid rafts and inhibited the translocation of Toll-like receptor 4 to lipid rafts. Moreover, glycyrrhizin activated ATP-binding cassette transporter A1, which could induce cholesterol efflux from lipid rafts. In conclusion, we find that the anti-inflammatory effects of glycyrrhizin may be attributable to its ability to activate ATP-binding cassette transporter A1. Glycyrrhizin might be a useful therapeutic reagent for the treatment of mastitis and other inflammatory diseases.