Gut microbiota supportive dietary pattern associated with reduced MASLD risk mediated by metabolomic profiles: a prospective cohort study

BACKGROUND: Metabolic dysfunction-associated steatotic liver disease (MASLD) affects 38% of adults worldwide. While diet influences MASLD development through multiple pathways, the role of gut microbiota-targeted dietary patterns remains unclear. We aimed to investigate the association between Dietary Index for Gut Microbiota (DI-GM) and incident MASLD risk, and to identify metabolomic signatures that may mediate this relationship. METHODS: We analyzed data from 100,953 UK Biobank participants with detailed dietary and metabolomic information. The DI-GM was calculated based on 14 food components with established effects on gut microbiota. Plasma metabolomic profiling was performed using NMR spectroscopy. A metabolic signature was derived through LASSO regression with cross-validation. Cox proportional hazards models were employed to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) for incident MASLD. RESULTS: During a median follow-up of 13.46 years, 1,221 cases of MASLD were documented. Each one-point increase in DI-GM was associated with a 15% reduction in MASLD risk (HR: 0.85, 95% CI: 0.80–0.90). Participants in the highest DI-GM (≥ 7) had a HR of 0.68 (95% CI: 0.58–0.80) compared to the lowest (≤ 4). The metabolomic analysis identified a signature of 92 metabolites strongly correlated with DI-GM (r = 0.30, P < 0.001). This signature was associated with a 26% reduction in MASLD risk per standard deviation increase (HR: 0.74, 95% CI: 0.69–0.79). Mediation analysis revealed that the metabolic signature explained 34.2% (95% CI: 19.3%–60.6%) of the association between DI-GM and MASLD risk. CONCLUSIONS: Higher adherence to a gut microbiota supportive dietary pattern is associated with reduced risk of MASLD. The association is partially mediated through favorable alterations in metabolism. These findings support the implementation of gut microbiota-focused dietary strategies for chronic liver disease prevention.