A cohort study of physical activity, gut microbiota, serum metabolites, and the risk of steatotic liver disease.

INTRODUCTION AND

OBJECTIVES

Prospective evidence on the association between physical activity (PA) and steatotic liver disease (SLD) risk is limited. Gut microbiota profiles and metabolites associated with PA remain unclear.

PATIENTS AND

METHODS

We investigated the association between PA and SLD risk in a cohort of 2,942 free-living adults, where PA and SLD were measured using a validated self-reported questionnaire and transient elastography, respectively. We further identified 1-year gut microbial changes and serum metabolites related to moderate-to-vigorous PA (MVPA), and examined their associations with SLD in a subset of the cohort (n=754), where fecal samples for 16S rRNA sequencing were collected twice (1-year apart), species-level microbial profiles were generated using shotgun metagenomics, targeted metabolomics was performed using baseline serum samples, and PA was assessed by accelerometer.

RESULTS

From 2020 to 2025, 565 SLD cases were newly diagnosed. MVPA levels were inversely associated with SLD risk (HRT3vs.T1=0.78, 95% CI: 0.63-0.98), while sedentary hours were positively associated with SLD (HRT3vs.T1=1.26, 95% CI: 1.00-1.58). Twelve genera showed longitudinal changes in relation to MVPA (pFDR<0.05). Proteus was positively associated with SLD risk (OR=1.32, 95% CI: 1.01-1.72), supported by species-level shotgun metagenomics for Proteus cibarius. L-valine concentrations were inversely correlated with MVPA (β=-0.23, pFDR=0.031), while demonstrating a positive association with SLD risk (OR=1.78, 95% CI: 1.22-2.63). L-valine was also correlated with the MVPA-associated genus Synergistes.

CONCLUSIONS

MVPA is associated with changes in the gut microbiota and microbiota-related metabolites that are linked to a more favorable SLD profile, whereas sedentary behavior is associated with higher SLD risk.