Division of Gastroenterology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1277 Jiefang Avenue, Wuhan, 430022, China.
Health Management Center, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
Atherosclerosis. 2024 May;392:117526. doi: 10.1016/j.atherosclerosis.2024.117526. Epub 2024 Mar 22.
BACKGROUND: Metabolic associated fatty liver disease (MAFLD) is a novel concept proposed in 2020, which is more practical for identifying patients with fatty liver disease with high risk of disease progression. Fatty liver is a driver for extrahepatic complications, particularly cardiovascular diseases (CVD). Although the risk of CVD in MAFLD could be predicted by carotid ultrasound test, a very early stage prediction method before the formation of pathological damage is still lacking. METHODS: Stool microbiomes and plasma metabolites were compared across 196 well-characterized participants encompassing normal controls, simple MAFLD patients, MAFLD patients with carotid artery pathological changes, and MAFLD patients with diagnosed coronary artery disease (CAD). 16S rDNA sequencing data and untargeted metabolomic profiles were interrogatively analyzed using differential abundance analysis and random forest (RF) machine learning algorithm to identify discriminatory gut microbiomes and metabolomic. RESULTS: Characteristic microbial changes in MAFLD patients with CVD risk were represented by the increase of Clostridia and Firmicutes-to-Bacteroidetes ratios. Faecalibacterium was negatively correlated with mean-intima-media thickness (IMT), TC, and TG. Megamonas, Bacteroides, Parabacteroides, and Escherichia were positively correlated with the exacerbation of pathological indexes. MAFLD patients with CVD risk were characterized by the decrease of lithocholic acid taurine conjugate, and the increase of ethylvanillin propylene glycol acetal, both of which had close relationship with Ruminococcus and Gemmiger. Biotin l-sulfoxide had positive correlation with mean-IMT, TG, and weight. The general auxin pesticide beta-naphthoxyacetic acid and the food additive glucosyl steviol were both positively correlated with the increase of mean-IMT. The model combining the metabolite signatures with 9 clinical parameters accurately distinguished MAFLD with CVD risk in the proband and validation cohort. It was found that citral was the most important discriminative metabolite marker, which was validated by both in vitro and in vivo experiments. CONCLUSIONS: Simple MAFLD patients and MAFLD patients with CVD risk had divergent gut microbes and plasma metabolites. The predictive model based on metabolites and 9 clinical parameters could effectively discriminate MAFLD patients with CVD risk at a very early stage.
背景：代谢相关脂肪性肝病（MAFLD）是 2020 年提出的新概念，更适用于识别有疾病进展高风险的脂肪性肝病患者。脂肪肝是肝外并发症的驱动因素，尤其是心血管疾病（CVD）。虽然颈动脉超声检查可以预测 MAFLD 患者的 CVD 风险，但仍然缺乏在形成病理损伤之前的非常早期预测方法。
方法：对 196 名经过充分特征描述的参与者（包括正常对照组、单纯 MAFLD 患者、MAFLD 患者颈动脉病理改变和 MAFLD 患者诊断为冠心病（CAD））的粪便微生物组和血浆代谢物进行比较。使用差异丰度分析和随机森林（RF）机器学习算法对 16S rDNA 测序数据和非靶向代谢组学图谱进行探究性分析，以识别有区别的肠道微生物组和代谢组。
结果：具有 CVD 风险的 MAFLD 患者的特征性微生物变化表现为梭菌和厚壁菌门与拟杆菌门比值的增加。粪杆菌与平均内膜中层厚度（IMT）、TC 和 TG 呈负相关。巨单胞菌、拟杆菌、副拟杆菌和大肠杆菌与病理指标恶化呈正相关。具有 CVD 风险的 MAFLD 患者的特征是石胆酸牛磺酸结合物减少，乙基香草醛丙二醇缩醛增加，这两者与真杆菌属和 Gemmiger 密切相关。生物素 l-亚砜与平均 IMT、TG 和体重呈正相关。一般生长素农药萘氧基乙酸和食品添加剂葡萄糖基甜菊醇都与平均 IMT 的增加呈正相关。结合代谢物特征和 9 项临床参数的模型可准确区分在个体和验证队列中具有 CVD 风险的 MAFLD。发现柠檬醛是最重要的鉴别代谢标志物，通过体外和体内实验进行了验证。
结论：单纯 MAFLD 患者和具有 CVD 风险的 MAFLD 患者的肠道微生物和血浆代谢物存在差异。基于代谢物和 9 项临床参数的预测模型可以在非常早期阶段有效区分具有 CVD 风险的 MAFLD 患者。
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