Synbiotic Administration of d ‐Tagatose and Lacticaseibacillus casei ATCC 393 Improves Hyperlipidemia in BALB/c Mice by Modulating Gut Microbiota and Metabolic Parameters

ABSTRACT The search for alternative, cost‐effective, and side‐effect‐free therapies for hyperlipidemia remains a priority. This study evaluated the effects of probiotic Lacticaseibacillus casei ATCC 393, prebiotic d ‐tagatose, and their synbiotic combination on hyperlipidemia induced in BALB/c mice via a high‐fat, high‐cholesterol diet over 12 weeks. During the final 4 weeks, different groups received the respective treatments. Compared to the positive control (PC) group, synbiotic administration (SYN group) significantly reduced serum glucose by 32.8%, total cholesterol by 20.2%, HDL‐C by 28.0%, and triglycerides by 42.5% ( p < 0.05). Although serum albumin, alanine aminotransferase, and aspartate aminotransferase levels decreased by 3.9%, 5.2%, and 16%, respectively, these changes were not statistically significant ( p > 0.05), suggesting preserved liver function without adverse effects. Histological evaluation revealed a significant reduction in microvesicular steatosis and IL‐6 immunoreactivity scores exclusively in the synbiotic group, indicating alleviated hepatic lipid accumulation and inflammation. Although synbiotic treatment did not alter overall gut microbiota diversity or species richness, it selectively enriched certain taxa, resulting in dominance of Coprococcus, Parabacteroides, and Bacteroides genera as identified by LEfSe analysis (LDA score ≥ 4, p < 0.05). Conversely, Streptococcus and [Ruminococcus] abundances significantly declined from 3.59% to 1.1% and 7.25% to 0.75%, respectively ( p < 0.05). Collectively, these findings demonstrate that synbiotic supplementation effectively improves lipid profiles and mitigates hepatic lipid accumulation and inflammation without compromising liver function. The modulation of specific gut microbiota taxa further supports its therapeutic potential. Therefore, the synbiotic formulation investigated herein represents a promising alternative biotherapeutic approach for managing hyperlipidemia.