Shanghai Innovation Center of TCM Health Service, Shanghai University of Traditional Chinese Medicine, Shanghai, China.
Oxford Suzhou Centre for Advanced Research, Suzhou Industrial Park, Jiangsu, China.
Microbiol Spectr. 2024 Jun 4;12(6):e0197923. doi: 10.1128/spectrum.01979-23. Epub 2024 Apr 22.
Numerous studies have supported that nonalcoholic fatty liver disease (NAFLD) is highly associated with gut microbiota dysbiosis. Ling-Gui-Zhu-Gan decoction (LG) has been clinically used to treat NAFLD, but the underlying mechanism remains unknown. This study investigated the therapeutic effect and mechanisms of LG in mice with NAFLD induced by a high-fat diet (HD). An HD-induced NAFLD mice model was established to evaluate the efficacy of LG followed by biochemical and histopathological analysis. Metagenomics, metabolomics, and transcriptomics were used to explore the structure and metabolism of the gut microbiota. LG significantly improved hepatic function and decreased lipid droplet accumulation in HD-induced NAFLD mice. LG reversed the structure of the gut microbiota that is damaged by HD and improved intestinal barrier function. Meanwhile, the LG group showed a lower total blood bile acids (BAs) concentration, a shifted BAs composition, and a higher fecal short-chain fatty acids (SCFAs) concentration. Furthermore, LG could regulate the hepatic expression of genes associated with the primary BAs biosynthesis pathway and peroxisome proliferator-activated receptor (PPAR) signaling pathway. Our study suggested that LG could ameliorate NAFLD by altering the structure and metabolism of gut microbiota, while BAs and SCFAs are considered possible mediating substances.
Until now, there has still been no study on the gut microbiota and metabolomics of Ling-Gui-Zhu-Gan decoction (LG) in nonalcoholic fatty liver disease (NAFLD) mouse models. Our study is the first to report on the reshaping of the structure and metabolism of the gut microbiota by LG, as well as explore the potential mechanism underlying the improvement of NAFLD. Specifically, our study demonstrates the potential of gut microbial-derived short-chain fatty acids (SCFAs) and blood bile acids (BAs) as mediators of LG therapy for NAFLD in animal models. Based on the results of transcriptomics, we further verified that LG attenuates NAFLD by restoring the metabolic disorder of BAs via the up-regulation of Fgf15/FXR in the ileum and down-regulation of CYP7A1/FXR in the liver. LG also reduces lipogenesis in NAFLD mice by mediating the peroxisome proliferator-activated receptor (PPAR) signaling pathway, which then contributes to reducing hepatic inflammation and improving intestinal barrier function to treat NAFLD.
多项研究表明，非酒精性脂肪性肝病（NAFLD）与肠道微生物群落失调密切相关。苓桂术甘汤（LG）已被临床用于治疗 NAFLD，但具体机制尚不清楚。本研究通过高脂肪饮食（HD）诱导的 NAFLD 小鼠模型，探讨 LG 的治疗效果和作用机制。建立 HD 诱导的 NAFLD 小鼠模型，评估 LG 的疗效，进行生化和组织病理学分析。采用宏基因组学、代谢组学和转录组学技术，探讨肠道微生物群落的结构和代谢。LG 显著改善了 HD 诱导的 NAFLD 小鼠的肝功能，减少了肝内脂肪滴的积累。LG 逆转了 HD 破坏的肠道微生物群落结构，改善了肠道屏障功能。同时，LG 组的总血胆汁酸（BAs）浓度较低，BAs 组成发生变化，粪便短链脂肪酸（SCFAs）浓度升高。此外，LG 还可以调节与初级 BAs 生物合成途径和过氧化物酶体增殖物激活受体（PPAR）信号通路相关的肝基因表达。我们的研究表明，LG 通过改变肠道微生物群落的结构和代谢来改善 NAFLD，而 BAs 和 SCFAs 被认为是可能的介导物质。
到目前为止，在非酒精性脂肪性肝病（NAFLD）小鼠模型中，还没有关于苓桂术甘汤（LG）的肠道微生物群和代谢组学的研究。我们的研究首次报道了 LG 对肠道微生物群落结构和代谢的重塑，并探讨了改善 NAFLD 的潜在机制。具体来说，我们的研究证明了肠道微生物衍生的短链脂肪酸（SCFAs）和血胆汁酸（BAs）作为 LG 治疗 NAFLD 动物模型的潜在介导物的可能性。基于转录组学的结果，我们进一步证实，LG 通过上调回肠 Fgf15/FXR 和下调肝脏 CYP7A1/FXR 来恢复 BAs 的代谢紊乱，从而减轻 NAFLD。LG 还通过调节过氧化物酶体增殖物激活受体（PPAR）信号通路，减少 NAFLD 小鼠的脂肪生成，从而有助于减轻肝内炎症，改善肠道屏障功能，治疗 NAFLD。
