Exercise is a key component of lifestyle management in patients with metabolic dysfunction-associated steatotic liver disease (MASLD), but neither its therapeutic effect on the active stage of the disease, that is metabolic dysfunction-associated steatohepatitis (MASH) nor the mediating mechanisms have been characterized. Therefore, we performed multi-omic phenotyping of patients with MASLD-MASH on an exercise program.

Fifteen patients with MASLD conducted high-intensity interval training (HIIT) combined with home-based training for 12 weeks. MASLD was evaluated using histology, transient elastography, and multiparametric magnetic resonance imaging (MRI) before and after the intervention. Change in maximal oxygen consumption (VO_2max) and MRI-determined liver fat were compared with a control group of patients with MASLD (n = 22). RNA sequencing was performed on liver, muscle, and fat biopsies of patients in the exercise group. Stool was analyzed by shotgun metagenomics and untargeted metabolomics was performed on plasma, urine, adipose, and stool.

HIIT increased VO_2max by 10.1% and improved mitochondrial metabolism in skeletal muscle, indicating improved cardiorespiratory fitness and adherence. VO_2max increased significantly in the exercise group compared with controls. Histologically, no reduction in steatosis, MASH, or liver fibrosis was observed; however, transient elastography tended to improve. MRI-determined liver fat did not change in the exercise group compared with controls. HIIT induced changes in mRNA expression of genes related to beiging of adipose tissue and fibrogenesis in liver. In addition, specific gut microbial taxa and metabolites changed.

HIIT increased cardiorespiratory fitness and induced beneficial gene expression changes in muscle, adipose tissue, and liver, but without translation into histological improvement of MASLD. Longer exercise intervention trials are warranted to validate or refute current recommendations for exercise as a cornerstone treatment for MASLD-MASH.