Energy-controlled high-fat diets effectively ameliorate MASLD and improve overall health

Introduction: Dietary intervention is a promising strategy for improving fatty liver, yet altering dietary habits in individuals on a high-fat diet remains challenging. Objectives This study investigated the efficacy of an energy-controlled high-fat dietary regimen (ECHF) in ameliorating metabolic-associated fatty liver disease (MASLD) using rat and Drosophila models. Methods The role of the hepatointestinal axis in ECHF-mediated improvement of MASLD was identified through the integration of 16S rRNA sequencing, metagenomics, and liver transcriptomics. The interaction between gut microbiota and hepatic genes was further explored using fruit fly models with gene knockdown and fecal microbiota transplantation. Results Multi-omics analysis in rats revealed that ECHF alleviated MASLD by repairing pathological damage and reducing inflammation through downregulation of the arachidonic acid metabolism pathway. Transcriptome profiling identified G6pc as a key gene, negatively correlated with arachidonic acid metabolism enzymes, whose expression was upregulated by ECHF. ECHF also restored gut microbiota homeostasis, increasing Lactobacillus and Turicibacter abundances, which positively correlate with G6pc . Drosophila experiments demonstrated that ECHF's benefits were microbiota-dependent, as microbiota transplantation from ECHF-treated flies improved MASLD in high-fat diet flies. Notably, G6pc RNAi flies lost all ECHF-mediated improvements. Conclusion In conclusion, ECHF ameliorates MASLD in both rat and Drosophila models by mitigating hepatic injury and inflammation, potentially through mechanisms involving the enrichment of Lactobacillus , upregulation of G6pc , and suppression of the pro-inflammatory arachidonic acid pathway.