Zhang Da-Ya, Li Da, Chen Shi-Ju, Zhang Li-Jun, Zhu Xu-Li, Chen Fa-Di, Chen Chen, Wang Qi, Du Yiping, Xiong Jian-Xin, Huang Shi-Mei, Zhang Xiao-Dong, Lv Yan-Ting, Zeng Fan, Chen Run-Xiang, Huang Xianfeng, Mao Fengjiao, Zhou Shuo, Yao Qicen, Huang Yuliang, Chen Runyu, Mo Ying, Xie Yunqian, Jiang Yue-Hong, Chen Zhai, Mo Cui-Yi, Chen Jia-Jia, Bai Fei-Hu
The Second School of Clinical Medicine, Hainan Medical University, Haikou, China.
Department of Gastroenterology, The Second Affiliated Hospital of Hainan Medical University, Haikou, China.
Gut Microbes. 2025 Dec;17(1):2508433. doi: 10.1080/19490976.2025.2508433. Epub 2025 May 25.
Gut microbiota exerts a pivotal influence on the development of Metabolic Associated Fatty Liver Disease (MAFLD), although the specific contributions of individual bacterial strains and their metabolites remain poorly defined. We conducted stool shotgun metagenomic sequencing and plasma untargeted metabolomics in a large prospective cohort comprising 120 MAFLD patients and 120 matched healthy controls. The mechanisms and microbial-derived metabolites involved in MAFLD were further investigated through multi-omics analyses and . Distinct differences were identified in both the microbial community structure and metabolomic profiles between MAFLD patients and healthy controls. Bacteroides uniformis () was the most significantly depleted species in MAFLD and negatively correlated with hepatic steatosis and BMI. MAFLD was characterized by marked disruptions in fatty acid and amino acid metabolism. Combined analysis of metabolomic and metagenomic data achieved high diagnostic accuracy for MAFLD and hepatic steatosis severity (AUC = 0.93). Transplantation of fecal microbiota from MAFLD subjects into ABX mice led to the onset of MAFLD-like symptoms, whereas administration alleviate disease progression by inhibiting intestinal fat absorption, FFA from eWAT influx into liver via the gut-liver axis, and IRE1α-XBP1s-mediated flipogenesis and ferroptosis, as confirmed by hepatic transcriptomic and proteomic analyses. Hexadecanedioic acid (HDA), potentially identified as a key metabolite produced by , ameliorated MAFLD symptoms. Mechanistically, -derived HDA also inhibited fat absorption and transported, and entered the liver via the portal vein to suppress IRE1α-XBP1s-mediated flipogenesis and ferroptosis. B. uniformis and its potential putative metabolite HDA may contribute to MAFLD progression modulation, through regulation of the IRE1α-XBP1s axis. This study provides new insights into the gut-liver axis in MAFLD and offers promising therapeutic targets based on specific microbes and their metabolites.
肠道微生物群对代谢相关脂肪性肝病（MAFLD）的发展具有关键影响，尽管单个细菌菌株及其代谢产物的具体作用仍不清楚。我们对一个由120名MAFLD患者和120名匹配的健康对照组成的大型前瞻性队列进行了粪便鸟枪法宏基因组测序和血浆非靶向代谢组学分析。通过多组学分析进一步研究了MAFLD中涉及的机制和微生物衍生的代谢产物。MAFLD患者和健康对照之间在微生物群落结构和代谢组学谱方面均存在明显差异。均匀拟杆菌（）是MAFLD中最显著减少的物种，与肝脂肪变性和BMI呈负相关。MAFLD的特征是脂肪酸和氨基酸代谢明显紊乱。代谢组学和宏基因组学数据的联合分析对MAFLD和肝脂肪变性严重程度具有较高的诊断准确性（AUC = 0.93）。将MAFLD受试者的粪便微生物群移植到抗生素处理的小鼠中会导致类似MAFLD症状的出现，而给予[具体物质]可通过抑制肠道脂肪吸收、白色脂肪组织中的游离脂肪酸通过肠-肝轴流入肝脏以及IRE1α-XBP1s介导的脂肪生成和铁死亡来缓解疾病进展，肝脏转录组学和蛋白质组学分析证实了这一点。十六烷二酸（HDA）可能被确定为[某种微生物]产生的关键代谢产物，可改善MAFLD症状。从机制上讲，[某种微生物]衍生的HDA还抑制脂肪吸收和转运，并通过门静脉进入肝脏以抑制IRE1α-XBP1s介导的脂肪生成和铁死亡。均匀拟杆菌及其潜在的推定代谢产物HDA可能通过调节IRE1α-XBP1s轴促进MAFLD进展的调节。这项研究为MAFLD中的肠-肝轴提供了新的见解，并基于特定微生物及其代谢产物提供了有前景的治疗靶点。
