Saikosaponin A protects chickens against pullorum disease via modulation of cholesterol

The worsening problem of antibiotic resistance prompts the need for alternative strategies that do not directly target bacteria. Virulent Salmonella pullorum strains can invade macrophages and lead to a systemic infection. Saikosaponin A (SSa), a bioactive saponin isolated from Radix bupleuri, has been demonstrated to exhibit anti-inflammatory, hepatoprotective, and cholesterol regulatory activity. The aim of this study was to investigate the effects of SSa on Salmonella-induced pullorum disease in chickens and clarify the possible mechanism. A S. pullorum-induced pullorum disease chicken model was used to confirm the protective effect of SSa in vivo. The model of HD11 cells infected with S. pullorum was used to investigate the molecular mechanism of SSa in vitro. In vivo, SSa prolonged the survival time and decreased the liver bacterial burdens in the pullorum disease model. In vitro, SSa dose-dependently suppressed the invasion of HD11 cells by S. pullorum. SSa depleted cholesterol in the lipid rafts, disrupted the formation of lipid rafts, and promoted the transcription of LXRα, ABCA1, and ABCG1. Moreover, the addition of water-soluble cholesterol and inhibition of LXRα with the LXRα antagonist geranylgeranyl pyrophosphate reversed the inhibitory effects of SSa on the invasion of HD11 cells by S. pullorum. In conclusion, the protective effect of SSa against S. pullorum infection is associated with the upregulation of the LXRα-ABCG1/ABCA1 pathway, which results in a decrease in cholesterol in the lipid rafts of HD11 cells, thereby suppressing the invasion of HD11 cells by S. pullorum. These results validate SSa as a host-target drug for the prevention of bacterial diseases, including those caused by S. pullorum.