Probiotic-Fermented Mare’s Milk Ameliorates High-Fat Diet-Induced Dyslipidemia Through Coordinated Gut-Liver Metabolic Remodeling

Dyslipidemia is closely associated with disturbances in hepatic lipid metabolism and gut-liver metabolic homeostasis. This study evaluated the effects of fermented mare’s milk (FMM), produced using an equal-ratio consortium of four cholesterol-lowering Lactiplantibacillus plantarum Ni2 strains, on high-fat diet (HFD)-induced dyslipidemia and characterized the associated gut–liver metabolic responses. Sixty Sprague–Dawley rats were assigned to control, HFD model, simvastatin, and three FMM groups (6, 8, and 10 mL/kg) for 7 weeks. Lipid profiles and liver histology were assessed, and the high-dose FMM group was further analyzed using 16S rRNA sequencing, fecal and hepatic metabolomics, and hepatic transcriptomics, followed by qRT-PCR and Western blot validation. Compared with the HFD model group, high-dose FMM significantly reduced serum TC, TG, and LDL-C levels by 34.2%, 40.1%, and 49.5%, respectively, increased HDL-C by 46.6%, and decreased hepatic TG accumulation by 27.8%. The high-dose FMM group showed lipid-lowering effects similar to those observed in the simvastatin group, particularly in major serum lipid parameters. Compared with the HFD group, high-dose FMM partially restored gut microbial α-diversity and altered the abundance of several bacterial taxa, including Lactobacillus and Roseburia. Fecal and hepatic metabolomic analyses revealed coordinated changes in metabolites associated with lipid metabolism, bile acid metabolism, and bile secretion-related pathways after FMM intervention. Hepatic transcriptomic analysis showed that differentially expressed genes between the FMM and HFD groups were enriched in the PPAR signaling and bile secretion pathways, with increased expression of PPARα, CPT1a, CYP7A1, ABCG5, ABCG8, and MRP2 mRNAs and their corresponding proteins confirmed by qRT-PCR and Western blot analysis. Collectively, FMM ameliorated HFD-associated dyslipidemia and hepatic lipid accumulation, which are accompanied by changes in gut microbial composition, fatty acid oxidation, and cholesterol-bile acid metabolism.