肠道菌群失调经肠肝轴驱动代谢相关脂肪性肝病的分子机制

Molecular mechanisms of gut microbiota dysbiosis in driving metabolic dysfunction-associated fatty liver disease via the gut-liver axis

摘要

代谢相关脂肪性肝病 (MAFLD) 已成为全球最常见的慢性肝病, 其病理进程由单纯性脂肪肝向脂肪性肝炎及肝纤维化的转化是决定预后的关键环节, 持续活化的肝脏炎症反应, 正是驱动这一进展的关键因素。 临床尚缺乏针对脂肪性肝炎阶段的特效药物, 促使肠肝轴机制成为研究热点。 本综述系统阐述肠道菌群失调通过肠肝轴驱动 MAFLD 肝脏炎症的分子通路及治疗策略。 肠道屏障损伤导致脂多糖等病原体相关分子模式经门静脉持续入肝, 激活 Kupffer 细胞表面 TLR4 / NF-κB 通路, 诱导 TNF-α、IL-6 等促炎因子释放。 菌群代谢功能偏移表现为短链脂肪酸及次级胆汁酸等保护性产物减少, 而三甲胺 N 氧化物等致病性产物累积, 削弱机体抗炎能力。 此外, MAFLD 患者肠道真菌丰度显著升高, 促进 IL-17 分泌及 Th17/ Treg 比值升高, 进而激活肝星状细胞, 加剧炎症与纤维化。NLRP3 炎症小体活化进一步放大了 IL-1β 介导的级联反应。 基于上述机制, 治疗策略包括益生菌、粪菌移植 (FMT) 及饮食干预以恢复菌群稳态, 以及靶向 FXR、NLRP3 及 IL-17 通路的药物。 然而, FMT 在肠屏障受损患者中存在菌血症风险, 且供体筛选与标准化 FMT 方案尚未建立。 未来需借助单细胞转录组与多组学整合分析, 明确菌群信号与炎症通路间的因果关联, 为 MAFLD 的炎症分层与精准干预提供依据。

Abstract

Metabolic dysfunction-associated fatty liver disease (MAFLD) has emerged as the most prevalent chronic liver disease worldwide. The pathological transition from simple steatosis to steatohepatitis and subsequent liver fibrosis is a key determinant of prognosis, with persistent hepatic inflammation serving as the core driver of this detrimental progression. Currently, no specific pharmacotherapies are approved for the steatohepatitis stage, which has directed research focus toward the gut-liver axis. This review systematically elucidates the molecular pathways by which gut dysbiosis drives hepatic inflammation in MAFLD via the gut-liver axis and discusses corresponding therapeutic strategies. Gut barrier dysfunction leads to continuous translocation of pathogen-associated molecular patterns, such as lipopolysaccharide, into the liver through the portal vein. This activates the TLR4/ NF-κB pathway in Kupffer cells, inducing the release of proinflammatory cytokines, including TNF-α and IL-6. Concomitant shifts in gut microbial metabolic profiles result in reduced production of protective metabolites (e.g., short-chain fatty acids and secondary bile acids) and accumulation of pathogenic metabolites such as trimethylamine-N-oxide, thereby compromising the host's anti-inflammatory capacity. Moreover, the gut mycobiota is significantly enriched in MAFLD patients, promoting IL-17 secretion and elevating the Th17 / Treg ratio, which in turn activates hepatic stellate cells and exacerbates both inflammation and fibrosis. Activation of the NLRP3 inflammasome further amplifies the IL-1β-mediated inflammatory cascade. Based on these mechanisms, therapeutic strategies include probiotics, fecal microbiota transplantation (FMT), dietary interventions to restore gut microbial homeostasis, as well as pharmacological agents targeting the FXR, NLRP3, and IL-17 pathways. However, FMT carries a risk of bacteremia in patients with an impaired intestinal barrier, and standardization of donor selection and FMT protocols remains to be established. Future studies should employ single-cell transcriptomics and integrative multi-omics analyses to clarify causal links between microbial signals and inflammatory pathways, thereby providing a rationale for inflammatory stratification and precision intervention in MAFLD.

关键词

代谢相关脂肪性肝病 / 肠道菌群 / 肠肝轴 / 肝脏炎症 / 脂多糖 / Toll 样受体 4 / 核因子 κB / NLRP3 炎症小体

Key words

metabolic dysfunction-associated fatty liver disease / gut microbiota / gut-liver axis / hepatic inflammation / lipopolysaccharide / Toll-like receptor 4 / nuclear factor kappa B / NLRP3 inflammasome

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基金资助

陕西省创新能力支撑计划项目(2024CX-GXPT-44)

陕西省重点研发计划项目(2024SF2-GJHX-09)