背景:代谢和酒精相关肝病(MetALD)在肝病患者中的患病率很高,但目前尚无MetALD的有效治疗方法。作为一种典型的食用中草药,抗炎,抗氧化剂,菊花水提取物的保肝性能。(WECM)已经证明。然而,其对MetALD的治疗效果及相关机制尚不清楚.
目的:研究WECM抗MetALD的潜在机制。
方法:我们在高脂肪和高蔗糖加酒精饮食(HFHSAD)后构建了MetALD大鼠模型。MetALD大鼠用WECM以2.1、4.2和8.4g/kg/d治疗6周。确定疗效,并通过血清和肝脏生化标志物测定预测WECM对MetALD的相关通路,组织病理学切片分析,肠道微生物群的16SrDNA测序和非靶向血清代谢组学分析。通过RT-PCR和Western印迹检测过氧化物酶体增殖物激活受体α(PPARα)和γ(PPARγ)信号通路中基因和蛋白质的变化。
结果:WECM治疗可显着减轻肝脏脂肪变性,MetALD大鼠高脂血症和肝损伤标志物。此外,WECM改善血管内皮功能,高血压,和系统的氧化应激。机械上,WECM治疗改变了肠道微生物群的整体结构,通过维持厚壁菌/拟杆菌比例和减少有害细菌丰度,如梭菌,Faecalibaculum,和Herminiimonas.值得注意的是,WECM促进15-脱氧-△12,14-前列腺素J2(15d-PGJ2)的释放,进一步激活PPARγ以降低血清TNF-α,IL-1β,和IL-6水平。此外,WECM上调PPARα并下调CD36和FABP4的水平以改善脂质代谢。
结论:我们的发现提供了第一个证据,证明WECM治疗显著改善了肝脏脂肪变性,MetALD大鼠通过调节肠道菌群并激活15d-PGJ2/PPARγ和PPARα信号通路,实现氧化应激和炎症反应。
BACKGROUND: Metabolic and alcohol-associated liver disease (MetALD) shows a high prevalence rate in liver patients, but there is currently no effective treatment for MetALD. As a typical edible traditional Chinese medicinal herb, the anti-inflammatory, antioxidant, and hepatoprotective properties of water extract of Chrysanthemum morifolium Ramat. (WECM) has been demonstrated. However, its therapeutic effect on MetALD and the associated mechanisms remain unclear.
OBJECTIVE: To investigate the underlying mechanisms of WECM against MetALD.
METHODS: We constructed a MetALD rat model following a high-fat & high-sucrose plus alcohol diet (HFHSAD). MetALD rats were treated with WECM at 2.1, 4.2, and 8.4 g/kg/d for six weeks. Efficacy was determined, and pathways associated with WECM against MetALD were predicted through serum and hepatic biochemical marker measurement, histopathological section analysis, 16S rDNA sequencing of the gut microbiota and untargeted serum metabolomics analyses. Changes in genes and proteins in the peroxisome proliferator-activated receptor alpha (PPARα) and gamma (PPARγ) signaling pathways were detected by RT‒PCR and Western blotting.
RESULTS: WECM treatment significantly attenuated hepatic steatosis, hyperlipidemia and markers of liver injury in MetALD rats. Moreover, WECM improved vascular endothelial function, hypertension, and systematic oxidative stress. Mechanistically, WECM treatment altered the overall structure of the gut microbiota through maintaining Firmicutes/Bacteroidota ratio and reducing harmful bacterial abundances such as Clostridium, Faecalibaculum, and Herminiimonas. Notably, WECM promoted 15-deoxy-△12, 14-prostaglandin J2 (15d-PGJ2) release and further activated the PPARγ to reduce serum TNF-α, IL-1β, and IL-6 levels. Additionally, WECM upregulated PPARα and downregulated the levels of CD36 and FABP4 to improve lipid metabolism.
CONCLUSIONS: Our findings provide the first evidence that WECM treatment significantly improved hepatic steatosis, oxidative stress and inflammation in MetALD rats by regulating the gut microbiota and activating the 15d-PGJ2/PPARγ and PPARα signaling pathway.