Sarcopenia and non-alcoholic fatty liver disease: analysis of the gut microbiota

doi:10.12307/2026.318

Abstract

Abstract: BACKGROUND: Previous studies have established a correlation between non-alcoholic fatty liver disease and sarcopenia; however, their causal relationship remains uncertain. The gut-muscle-liver axis hypothesis posits intricate interactions between the gut microbiota and both sarcopenia and non-alcoholic fatty liver disease, yet the precise pathogenic mechanisms underlying these interactions remain poorly elucidated.
OBJECTIVE: To investigate the potential causal relationship between sarcopenia and non-alcoholic fatty liver disease using Mendelian randomization analysis and to delve into the potential role of the gut microbiota in mediating or influencing the interplay between non-alcoholic fatty liver disease and sarcopenia.
METHODS: Sarcopenia data were sourced from the UK Biobank (the UK National-Level Biomedical Database, supported by the UK government and developed in 2006 in collaboration with institutions such as the University of Oxford and the University of Manchester, which encompasses multidimensional data including genes, imaging, and health records from 500 000 participants), with relevant traits including appendicular muscle mass, grip strength, and walking speed. The non-alcoholic fatty liver disease dataset was derived from a publicly accessible GWAS summary dataset compiled by Ghodsian et al., comprising aggregated statistics from GWAS cohorts including eMERGE and FinnGen, updated GWAS data of non-alcoholic fatty liver disease from the UK Biobank, and newly conducted GWAS data from the Estonian Biobank. Gut microbiota data for 211 taxa were obtained from the MiBioGen consortium’s large-scale human gut microbiota composition study. Analytical methods included inverse-variance weighted, weighted median, MR-Egger, weighted mode, and simple mode approaches to evaluate the interplay between non-alcoholic fatty liver disease, sarcopenia and gut microbiota-related traits.
RESULTS AND CONCLUSION: (1) The inverse-variance weighted analysis revealed a negative association between walking speed, appendicular muscle mass, and risk of non-alcoholic fatty liver disease, whereas no significant association was observed between left/right hand grip strength and non-alcoholic fatty liver disease. Reverse Mendelian randomization analysis indicated a negative causal relationship between non-alcoholic fatty liver disease and appendicular muscle mass, but no significant causal links were found between non-alcoholic fatty liver disease and walking speed or grip strength. Additionally, 39 gut microbiota taxa showed significant associations with sarcopenia onset, and causal relationships were identified between 6 gut microbiota taxa and non-alcoholic fatty liver disease. (2) The study suggests that the gut microbiota may regulate the “gut-liver-muscle axis” through the metabolism of short-chain fatty acids, which provides Chinese scholars with a new direction for the study of cross-organ mechanisms. Combined with the unique genetic background of the Chinese population (e.g., ALDH2 mutation and genes related to high salt diet), we can further analyze the race-specific pathways of metabolic-muscle co-morbidities, providing a scientific basis for the development of dietary recommendations that are consistent with the dietary structure of the Chinese population (e.g., high cereal intake).

Key words: sarcopenia, non-alcoholic fatty liver disease, gut microbiota, intestinal flora, Mendelian randomization analysis, causality

CLC Number:

Zhang Zheng, Zhang Yibo, Xu Bin, Yan Shichao, Guo Hui. Sarcopenia and non-alcoholic fatty liver disease: analysis of the gut microbiota[J]. Chinese Journal of Tissue Engineering Research, 2026, 30(23): 6000-6009.

Figures/Tables 7

2.2.2 肠道菌群与肌肉减少症关联的孟德尔随机化分析结果逆方差加权法分析结果表明，39种肠道菌群与肌肉减少症发病具有显著相关性，见图2。其中，9种肠道菌群与步行速度显著相关，放线菌目(P=0.040，OR=0.986，95%CI=0.972-0.999)、放线菌科(P=0.040，OR=0.986，95%CI= 0.972-0.999)、红蝽菌纲(P=0.037，OR=0.984，95%CI=0.969-0.100)、红蝽菌科(P=0.037，OR=0.984，95%CI= 0.969-0.100)、红蝽菌目(P=0.037，OR=0.984，95%CI=0.969-0.999)、肠杆菌属(P=0.044，OR=0.993，95%CI= 0.986-0.100)与步行速度呈负相关，戴阿利斯特杆菌属(P=0.003，OR=1.018，95%CI=1.006-1.030)、乳酸细菌科(P=0.024，OR=1.021，95%CI=1.003-1.041)、毛螺菌属NC2004组(P=0.033，OR=1.010，95%CI=1.001-1.020)与步行速度呈正相关。 14种肠道菌群与四肢肌肉质量具有相关性，副拟杆菌属(P=0.035，OR=0.976，95%CI=0.954-0.998)、优杆菌属(P=0.044，OR=0.983，95%CI=0.967-0.100)、γ-变形菌纲(P=0.049，OR=0.972，95%CI=0.946-0.100)与四肢肌肉质量呈负相关性，拟杆菌科(P=0.007，OR=1.069，95%CI=1.019-1.122)、拟杆菌属(P=0.007，OR=1.069，95%CI=1.019-1.122)、放线菌科(P=0.016，OR= 1.029，95%CI=1.005-1.052)、放线菌目(P=0.017，OR=1.029，95%CI=1.005- 1.053)、埃斯谷菌纲(P=0.023，OR= 1.026，95%CI=1.004-1.049)、月形单孢菌目(P=0.023，OR=1.026，95%CI= 1.004-1.049)、考拉杆菌属(P=0.034，OR=1.022，95%CI=1.002-1.042)、毛螺菌属(P=0.034，OR=1.062，95%CI= 1.004-1.124)、丹毒丝菌UCG003属(P=0.036，OR=1.043，95%CI=1.003-1.085)、霍尔德曼氏菌属(P=0.042，OR=1.014，95%CI=1.001-1.028)、马文布赖恩特菌属(P=0.045，OR=1.023，95%CI=1.000-1.046)与四肢肌肉质量呈正相关性。 7种肠道菌群与右手握力之间存在因果关系，副普氏菌属(P=0.007，OR=0.987，95%CI=0.977-0.996)、普拉梭菌属(P=0.021，OR=0.980，95%CI=0.964-0.997)可降低右手握力，塞利莫纳斯菌属(P=0.002，OR=1.013，95%CI=1.005-1.021)、梭菌纲(P=0.008，OR=1.020，95%CI=1.005-1.036)、普雷沃氏菌属(P=0.025，OR=1.011，95%CI= 1.001-1.020)、梭菌目(P=0.036，OR=1.019，95%CI=1.001-1.036)、艾森伯格菌属(P=0.046，OR=1.012，95%CI= 1.000-1.023)可增加右手握力。 9种肠道菌群与左手握力之间存在因果关系，普拉梭菌属(P=0.002，OR=0.977，95%CI=0.963-0.992)、奥尔森内拉菌属(P=0.036，OR=0.988，95%CI=0.977-0.100)可降低左手握力；嗜黏蛋白阿克曼氏菌属(P=0.032，OR=1.020，95%CI=1.002-1.038)、塞利莫纳斯菌属(P=9.61×10-5，OR= 1.015，95%CI=1.007-1.023)、瘤胃球菌UCG005属(P=0.004，OR=1.020，95%CI=1.006-1.034)、口腔真杆菌属(P=0.013，OR=1.100，95%CI=1.002-1.017)、疣微菌科(P=0.032，OR=1.020，95%CI=1.002-1.038)、疣微菌门(P=0.032，OR=1.020，95%CI=1.002-1.038)、疣微菌目(P=0.032，OR=1.020，95%CI=1.002-1.038)可增加左手握力。 2.2.3 肠道菌群与非酒精性脂肪肝关联的孟德尔随机化分析结果逆方差加权法分析表明，6种肠道菌群与非酒精性脂肪肝之间存在因果关系，见表3、图3。克里斯滕森内拉塞菌属(P=0.005，OR=0.752，95%CI= 0.617-0.916)、瘤胃球菌科(P=0.040，OR=0.828，95%CI=0.691-0.991)可降低非酒精性脂肪肝发病风险，放线菌目(P=0.014，OR=1.260，95%CI=1.047-1.517)、放线菌科(P=0.015，OR=1.260，95%CI=1.047-1.516)、伯克氏菌目(P= 0.021，OR=1.230，95%CI=1.032-1.466)、β-变形菌纲(P=0.031，OR= 1.198，95%CI=1.017-1.411)可增加非酒精性脂肪肝发病风险。 2.3 敏感性分析结果 2.3.1 肌肉减少症与非酒精性脂肪肝关联的敏感性分析结果使用Cochran’s Q统计量测试异质性，逆方差加权分析表明，步行速度与非酒精性脂肪肝(P=0.001)、四肢肌肉质量与非酒精性脂肪肝(P=0.000)、左手握力与非酒精性脂肪肝(P=0.016)、右手握力与非酒精性脂肪肝(P=0.035)间的因果关系存在异质性，见表4。MR-Egger截距结果表明，步行速度与非酒精性脂肪肝(P=0.559)、四肢肌肉质量与非酒精性脂肪肝(P=0.598)、左手握力与非酒精性脂肪肝(P=0.220)、右手握力与非酒精性脂肪肝(P=0.841)间的因果关系均不存在水平多效性，见表4。使用Cochran’s Q统计量测试异质性，逆方差加权分析表明，非酒精性脂肪肝与四肢肌肉质量(P=0.074)、非酒精性脂肪肝与左手握力(P=0.164)、非酒精性脂肪肝与右手握力(P=0.139)间的因果关系均不存在异质性，非酒精性脂肪肝与步行速度(P=0.001)间的因果关系存在异质性，见表4。MR-Egger截距结果表明，非酒精性脂肪肝与四肢肌肉质量(P=0.438)、步行速度(P=0.776)、左手握力(P=0.511)、右手握力(P=0.290)间的因果关系均不存在水平多效性，见表4。"

散点图通过不同方法显示了肌肉减少症与非酒精性脂肪肝之间的因果关系(图4)，图中的每个黑点表示一个单核苷酸多态性，线条对应于使用不同孟德尔随机化方法时肌肉减少症对非酒精性脂肪肝的影响。漏斗图显示每个单核苷酸多态性的因果效应在逆方差加权法估计值周围对称分布，表明因果关联不受到潜在偏差的影响(图5)。 2.3.2 肠道菌群与肌肉减少症敏感性分析结果使用Cochran’s Q统计量测试异质性，逆方差加权分析表明，9种与步行速度相关的肠道菌群中，乳酸细菌科(P=3.66×10-5)、红蝽菌目(P=0.020)、红蝽菌纲(P=0.020)、红蝽菌科(P=0.020)与步行速度间的因果关系存在潜在异质性，其余5种肠道菌群与步行速度间的因果关系均不存在异质性(P > 0.05)；采用MR-Egger法的截距项对水平多效性进行评估，9种肠道菌群与步行速度间的因果关系均不存在水平多效性(P > 0.05)，见表5。 14种肠道菌群与四肢肌肉质量间的因果关系均不存在水平多效性，其中埃斯谷菌纲(P=0.036)、丹毒丝菌UCG003属(P=3.54×10-15)、γ-变形菌纲(P=0.000)与四肢肌肉质量间的因果关系存在潜在异质性，其余9种肠道菌群与四肢肌肉质量间的因果关系无异质性。7种肠道菌群与右手握力间的因果关系均不存在水平多效性及异质性；9种肠道菌群与左手握力间的因果关系均不存在水平多效性，其中嗜黏蛋白阿克曼氏菌属(P=0.042)、疣微菌科(P=0.042)、疣微菌门(P=0.042)、疣微菌目(P=0.042)与左手握力间的因果关系存在潜在异质性，其余5种肠道菌群与左手握力间的因果关系未发现异质性的证据，见表5，表明结果具有稳健性。 2.3.3 肠道菌群与非酒精性脂肪肝关联的敏感性分析结果使用Cochran’s Q统计量测试异质性，6种肠道菌群与非酒精性脂肪肝间的因果关系均不存在异质性，克里斯滕森内拉塞菌属(逆方差加权法P=0.959，Q=3.118；MR-Egger检验P=0.956，Q=2.611)、放线菌目(逆方差加权法P=0.573，Q=2.909；MR-Egger检验P=0.530，Q=2.212)、放线菌科(逆方差加权法P=0.572，Q=2.917；MR-Egger检验P=0.527，Q=2.226)、伯克氏菌目(逆方差加权法P=0.859，Q=6.215；MR-Egger检验P=0.803，Q=6.147)、β-变形菌纲(逆方差加权法P=0.920，Q=6.643；MR-Egger检验P=0.899，Q=6.330)、瘤胃球菌科(逆方差加权法P=0.826，Q=5.095；MR-Egger检验P=0.774，Q=4.843)，见表6。采用MR-Egger法的截距项对水平多效性进行评估，克里斯滕森内拉塞菌属(P=0.497，MR-Egger截距=0.018)、放线菌目(P=0.465，MR-Egger截距= -0.021)、放线菌科(P=0.467，MR-Egger截距=-0.021)、伯克氏菌目基于(P=0.800，MR-Egger截距=-0.005)、β-变形菌纲(P=0.586，MR-Egger截距=-0.011)、瘤胃球菌科(P=0.629，MR-Egger截距=-0.010)与非酒精性脂肪肝间的因果关系无水平多效性，见表6。"

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