Metabolomic Signatures of Polyphenol Intervention in Non-Alcoholic Fatty Liver Disease: Pathway-Level Insights into Lipid and Energy Metabolism

Introduction:
Non-alcoholic fatty liver disease (NAFLD) is characterized by profound disturbances in lipid and energy metabolism. While polyphenols have demonstrated therapeutic potential in improving clinical markers of NAFLD, their metabolomic impact remains incompletely characterized. This study aimed to systematically evaluate metabolomic alterations associated with polyphenol interventions in NAFLD and identify key metabolic pathways underlying therapeutic responses.

Methods:
A PRISMA 2020-compliant systematic review was conducted using PubMed, Scopus, and Web of Science databases (2015–2025). Randomized controlled trials and metabolomics-based clinical studies investigating polyphenol supplementation in adult NAFLD patients were included. Studies employing mass spectrometry or NMR-based metabolomic profiling were analyzed. Identified metabolites were categorized into lipidomics, amino acid metabolism, bile acid metabolism, and energy-related pathways. Pathway enrichment analysis was performed using reported metabolite alterations.

Results:
Seventeen studies met inclusion criteria, including nine clinical trials with metabolomic endpoints. Polyphenol supplementation was consistently associated with modulation of acylcarnitines, decreased saturated free fatty acids, and normalization of phosphatidylcholine/phosphatidylethanolamine ratios. Significant reductions in circulating ceramides and diacylglycerols were reported, indicating improved lipid homeostasis. Alterations in branched-chain amino acids and tricarboxylic acid cycle intermediates suggested enhanced mitochondrial function. Several studies demonstrated shifts in bile acid composition and increased short-chain fatty acid production, reflecting gut–liver axis modulation. Pathway analysis identified significant regulation of AMPK-mediated energy sensing, β-oxidation pathways, and inflammatory lipid mediator synthesis.

Conclusions:
Polyphenol interventions induce measurable metabolomic remodeling in NAFLD, particularly within lipid and energy metabolism pathways. The consistent modulation of ceramides, acylcarnitines, and bile acids suggests potential metabolomic biomarkers of therapeutic response. These findings support the integration of metabolomics into nutritional intervention trials to enable precision-based strategies for metabolic disease management.