Berberine Hydrochloride Reduces the Intracellular Survival of Salmonella Typhimurium by Enhancing Host Autophagic Flux Through the Inhibition of the Type III Secretion System

<i>Salmonella</i> Typhimurium, a significant intracellular foodborne pathogen, regulates host cell autophagy to achieve its own survival by injecting effector proteins into host cells via its type III secretion system (T3SS). Berberine hydrochloride (BH), an isoquinoline alkaloid derived from medicinal plants such as <i>Coptis chinensis</i>, has demonstrated potential antibacterial and immunomodulatory properties. However, the mechanisms by which BH combats <i>S.</i> Typhimurium by enhancing host autophagic flux through the inhibition of the type III secretion system remain to be fully elucidated. Here, we found that BH disrupts biofilm formation of <i>S.</i> Typhimurium, significantly inhibits the expression of genes associated with T3SS, and robustly enhances autophagy activity in macrophages infected with the pathogen. In a mouse model (C57BL/6 female 20 ± 1 g/mouse), BH significantly improved survival rates, reduced bacterial loads in tissues, and alleviated pathological damage. Molecular docking studies revealed that BH binds to key T3SS proteins, including SipB, SseA, and SsrB. These findings indicate that BH holds promise as a potentially effective therapeutic strategy for combating <i>S.</i> Typhimurium infections.