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

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. The 211 gut microbiota data were obtained from a large-scale human gut microbiome composition study conducted by the MiBioGen consortium. Inverse variance weighting, weighted median, MR-Egger, weighted model, and simple model methods were used to assess the mutual influences among non-alcoholic fatty liver disease, sarcopenia, and gut microbiota-related traits. RESULTS AND CONCLUSION: The inverse variance weighting analysis indicated that walking speed and appendicular muscle mass were negatively correlated with non-alcoholic fatty liver disease, while left and right hand grip strength showed no significant correlation with non-alcoholic fatty liver disease risk. Reverse Mendelian randomization analysis showed that non-alcoholic fatty liver disease was negatively correlated with appendicular muscle mass, but no significant correlation was found between non-alcoholic fatty liver disease and walking speed or left and right hand grip strength. Thirty-nine gut microbiota taxa were significantly associated with sarcopenia onset, and six gut microbiota taxa had a causal relationship with non-alcoholic fatty liver disease. The study suggests that gut microbiota may regulate the 'gut-liver-muscle axis' through short-chain fatty acid metabolism, providing a new direction for cross-organ mechanism research for Chinese scholars. Combined with the unique genetic background of the Chinese population (such as ALDH2 mutations and genes related to high-salt diet), it can further analyze the race-specific pathways of metabolic-muscle comorbidity, providing a scientific basis for formulating dietary recommendations that conform to the Chinese dietary structure (such as high grain intake).

1. Introduction

Sarcopenia is a syndrome closely related to aging, characterized by progressive muscle atrophy and dysfunction, manifesting as abnormalities in skeletal muscle mass, strength, and function, often leading to decreased life expectancy and quality of life [1]. Meta-analysis data show that the prevalence of sarcopenia in people over 60 years old is as high as 27% [2]. Sarcopenia and non-alcoholic fatty liver disease (NAFLD), as common geriatric diseases, have become major public health concerns. NAFLD is the most prevalent liver disease, with a global prevalence of approximately 25% [3]. If not intervened in time, NAFLD can progress to non-alcoholic steatohepatitis, and even cirrhosis and hepatocellular carcinoma [4]. The incidence of muscle mass and strength loss is high in patients with NAFLD. Studies have shown an association between sarcopenia and NAFLD, with several shared risk factors such as obesity, diabetes, hormonal abnormalities, dietary factors, metabolic syndrome, and physical inactivity [5].

Skeletal muscle is one of the important metabolic and endocrine organs in the human body. Defects and deterioration of liver function can affect blood flow and metabolism in skeletal muscle, and skeletal muscle atrophy caused by sarcopenia can aggravate NAFLD. They may promote each other and act as mutual risk factors. Both decreased skeletal muscle mass and hepatic lipid deposition are closely related to insulin resistance. Muscle atrophy leads to decreased glycolipid metabolism, promoting the transfer of free fatty acids to the liver, while NAFLD-related insulin resistance may further exacerbate muscle protein breakdown, creating a vicious cycle.