Song Ting-Yu, Yang Xiu-Fang, Wang Jun-Yi, Yin Lian-Hong, Zhao Xue-Rong, Wang Ning, Xu You-Wei, Qi Yan, Xiong Cun-Quan, Xu Li-Na
College of Pharmacy, Dalian Medical University, Western 9 Lvshunnan Road, Dalian 116044, China.
School of Jiangsu Medical College, Jiefang South Road, Yancheng 224005, China.
Phytomedicine. 2025 Nov;147:157235. doi: 10.1016/j.phymed.2025.157235. Epub 2025 Sep 5.
The pathogenesis of metabolic dysfunction-associated fatty liver disease (MAFLD) involves gut microbiota dysbiosis. This study investigated pseudolaric acid B (PAB), a diterpenoid from Pseudolarix kaempferi, for its potential to ameliorate MAFLD via microbiota-metabolite-host signaling pathways.
We evaluated the effects of PAB on MAFLD in high-fat diet (HFD)-fed mice. 16S rRNA sequencing and metabolomics analyzed the regulations of PAB on gut microbiota and metabolites. The fecal microbiota transplantation (FMT) experiment was conducted to validate the causal role of the gut microbiota in the efficacy of PAB. Mechanistic studies employed molecular docking, microscale thermal migration (MST), western blot, immunofluorescence, and PCR to elucidate how PAB alleviates hepatic lipid metabolism dysregulation in MAFLD via microbial metabolites. In vivo intervention with candidate metabolites assessed improvement of disease phenotypes.
PAB effectively alleviatd the symptoms of HFD-induced MAFLD in mice, and repaired dysbiosis of intestinal microbiota, especially g_Faecalibaculum, g_Allobaculum, g_Ileibacterium, and g_Dubosiella, which were markedly down-regulated by PAB and showed a positive correlation with liver injury. FMT confirmed the relevance of PAB efficacy to the microbial community structure. Moreover, PAB intervention led to a dramatically enrichment of the tryptophan metabolism pathway, with cinnabarinic acid (CA), a microbial tryptophan metabolite, exhibiting a significat negative correlation with the abundance of the down-regulated bacteria. CA supplementation alleviated HFD-induced MAFLD in mice, indicating the hepatoprotective effect of CA. Molecular docking and MST revealed CA binds stablly to aryl hydrocarbon receptor (AhR) with higher affinity/stability, indicating a direct interaction between them. Mechanistically, PAB increased CA level and then activited AhR, downregulated hepatic lipogenesis genes by AhR-mediated IL-22/JAK1/STAT3 pathway.
PAB exerts a protective effect against MAFLD via restructuring the gut microbiota ecosystem, and activating CA/AhR/IL-22 signaling axis to reduce lipogenesis. These findings reveal a novel microbiota-metabolite-host mechanism and highlight PAB as a promising prebiotic-based therapeutic candidate for MAFLD.
代谢功能障碍相关脂肪性肝病（MAFLD）的发病机制涉及肠道微生物群失调。本研究调查了来自金钱松的二萜类化合物土槿酸B（PAB）通过微生物群-代谢物-宿主信号通路改善MAFLD的潜力。
我们评估了PAB对高脂饮食（HFD）喂养小鼠MAFLD的影响。16S rRNA测序和代谢组学分析了PAB对肠道微生物群和代谢物的调控。进行了粪便微生物群移植（FMT）实验，以验证肠道微生物群在PAB疗效中的因果作用。机制研究采用分子对接、微量热泳动（MST）、蛋白质免疫印迹、免疫荧光和聚合酶链反应，以阐明PAB如何通过微生物代谢物减轻MAFLD中肝脏脂质代谢失调。用候选代谢物进行体内干预评估疾病表型的改善情况。
PAB有效减轻了HFD诱导的小鼠MAFLD症状，并修复了肠道微生物群失调，特别是g_Faecalibaculum、g_Allobaculum、g_Ileibacterium和g_Dubosiella，它们被PAB显著下调，并与肝损伤呈正相关。FMT证实了PAB疗效与微生物群落结构的相关性。此外，PAB干预导致色氨酸代谢途径显著富集，微生物色氨酸代谢物朱红酸（CA）与下调细菌的丰度呈显著负相关。补充CA减轻了HFD诱导的小鼠MAFLD，表明CA具有肝脏保护作用。分子对接和MST显示CA以更高的亲和力/稳定性与芳烃受体（AhR）稳定结合，表明它们之间存在直接相互作用。机制上，PAB增加CA水平，然后激活AhR，通过AhR介导的IL-22/JAK1/STAT3途径下调肝脏脂肪生成基因。
PAB通过重组肠道微生物群生态系统和激活CA/AhR/IL-22信号轴以减少脂肪生成，对MAFLD发挥保护作用。这些发现揭示了一种新的微生物群-代谢物-宿主机制，并突出了PAB作为一种有前景的基于益生元的MAFLD治疗候选物。
