Lentinan enhances microbiota-derived isoursodeoxycholic acid levels to alleviate hepatic ischemia-reperfusion injury in mice.

Hepatic ischemia-reperfusion injury (HIRI) is an essential clinical concern caused by liver transplantation, resection, trauma, and shock that must be addressed immediately. Although the mechanisms underlying HIRI are well-documented, effective prevention and treatment strategies are still lacking. Inflammation is a central mechanism of HIRI, with macrophages playing a crucial role in initiating and amplifying the inflammatory response. Numerous plant polysaccharides exhibit substantial anti-inflammatory and hepatoprotective properties. However, the function of Lentinan (LNT) in HIRI has not been fully explored. Thus, this study aims to investigate the preventive potential of LNT in HIRI. Here, we reveal that oral administration of LNT considerably reduces hepatic inflammation and improves liver pathology in mice with HIRI by modulating gut microbiota. Specifically, LNT considerably increased microbiota-derived isoursodeoxycholic acid (IsoUDCA). Further experiments showed that IsoUDCA alleviates hepatic injury by suppressing macrophage inflammation. Mechanistically, IsoUDCA directly binds to and activates the neuron-derived clone 77 (Nur77) transcription factor, inhibiting the NF-κB signaling pathway in macrophages. Our findings shed light on the significant role of the LNT-microbiota-IsoUDCA-Nur77 axis in attenuating macrophage inflammation during HIRI, offering novel insights into potential therapeutic targets and avenues for preventing HIRI.