ABSTRACT

Activation of the NOX4/NLRP3 inflammasome pathway has been associated with fibrosis in other organs. An imbalance in intestinal bacteria is an important driving factor of liver fibrosis through the liver-gut axis. This study aimed to explore whether the effect of ursolic acid (UA) on liver fibrosis was associated with the NOX4/NLRP3 inflammasome pathways and intestinal bacteria. Wild-type (WT), NLRP3^−/-, and NOX4^−/- mice and AP-treated mice were injected with CCI4 and treated with or without UA. The intestinal contents of the mice were collected and analyzed by 16S rRNA sequencing. UA alleviated liver fibrosis, which manifested as decreases in collagen deposition, liver injury, and the expression of fibrosis-related factors, and the expression of NOX4 and NLRP3 was significantly inhibited by UA treatment. Even after CCI4 injection, liver damage and fibrosis-related factors were significantly decreased in NLRP3^−/-, NOX4^−/-, and AP-treated mice. Importantly, the expression of NLRP3 was obviously inhibited in NOX4^−/- and AP-treated mice. In addition, the diversity of intestinal bacteria and the abundance of probiotics in NLRP3^−/- and NOX4^−/- mice was significantly higher than those in WT mice, while the abundance of harmful bacteria in NLRP3^−/- and NOX4^−/- mice was significantly lower than that in WT mice. The NOX4/NLRP3 inflammasome pathway plays a crucial role in liver fibrosis and is closely associated with the beneficial effect of UA. The mechanism by which the NOX4/NLRP3 inflammasome pathway is involved in liver fibrosis may be associated with disordered intestinal bacteria.

 抽象的

NOX4/NLRP3 炎性体途径的激活与其他器官的纤维化有关。肠道细菌失衡是肝肠轴肝纤维化的重要驱动因素。本研究旨在探讨熊果酸（UA）对肝纤维化的影响是否与NOX4/NLRP3炎症小体通路和肠道细菌有关。野生型 (WT)、 NLRP3 ^-/-和NOX4 ^-/-小鼠以及 AP 处理的小鼠注射 CCI4，并用或不用 UA 治疗。收集小鼠肠道内容物并通过16S rRNA测序进行分析。 UA减轻肝纤维化，表现为胶原沉积、肝损伤和纤维化相关因子表达减少，且UA治疗显着抑制NOX4和NLRP3的表达。即使注射 CCI4 后， NLRP3 ^−/- 、NOX4 ^−/-和 AP 治疗的小鼠的肝损伤和纤维化相关因子也显着减少。重要的是，NLRP3 的表达在NOX4 ^-/-和 AP 处理的小鼠中明显受到抑制。此外， NLRP3 ^−/-和NOX4 ^−/-小鼠肠道细菌多样性和益生菌丰度显着高于WT小鼠，而NLRP3 ^−/-和NOX4 ^−/-小鼠体内有害菌丰度显着高于WT小鼠。明显低于WT小鼠。 NOX4/NLRP3炎症小体通路在肝纤维化中发挥着至关重要的作用，并与UA的有益作用密切相关。 NOX4/NLRP3炎症小体通路参与肝纤维化的机制可能与肠道细菌紊乱有关。