Microbiota-liver axis and host transcriptomic mechanisms underlying the anti-obesity effects of Bifidobacterium animalis DPU-MWFBA in early-life overfeeding.

Early-life nutritional overfeeding is increasingly recognized as a critical driver of metabolic programming and long-term obesity risk. This study investigated the protective effects and underlying mechanisms of Bifidobacterium animalis DPU-MWFBA, designated as FBA-40, against early-life overfeeding-induced obesity and metabolic dysfunction. An early overfeeding mouse model was established by small-litter rearing, followed by a two-week oral intervention with FBA-40. FBA-40 significantly attenuated excessive body weight gain and adiposity, improved glucose tolerance and insulin sensitivity, and alleviated dyslipidemia, systemic inflammation, and hepatic dysfunction. Histological analyses showed that FBA-40 reduced hepatic lipid accumulation and improved liver morphology. In addition, colonic histology and immunohistochemistry demonstrated that FBA-40 preserved intestinal barrier integrity by increasing ZO-1 and Occludin expression while suppressing TNF-α-associated inflammatory activation. Gut microbiota analysis revealed that FBA-40 restored microbial richness and diversity and reshaped gut microbial composition toward a more metabolically favorable profile. Hepatic transcriptomic analysis further showed that FBA-40 reprogrammed lipid metabolism-, oxidative stress-, and inflammation-related pathways, particularly PPAR signaling, linoleic acid metabolism, cholesterol metabolism, bile secretion, and arachidonic acid metabolism. qRT-PCR and estern blot validation confirmed that FBA-40 suppressed lipogenesis-related targets, including Scd1, Acaca, Lpin1, and SCD1, while restoring PPARα/EHHADH-associated fatty acid β-oxidation and GPX1-mediated antioxidant defense. Collectively, these findings demonstrate that FBA-40 alleviates early-life overfeeding-induced metabolic dysfunction by coordinating gut microbial remodeling, intestinal barrier protection, and hepatic lipid metabolic reprogramming. This study provides mechanistic evidence supporting FBA-40 as a promising early-life probiotic candidate for preventing obesity and associated metabolic disorders.