Integration of transcriptomics and gut microbiomics reveals walnut septum polyphenols alleviate HFD-induced lipid disorders

Walnut septum, an underutilized agricultural by-product, exhibits anti-obesity potential. However, the in vivo hypolipidemic mechanisms of walnut septum polyphenols (WSP) remain unexplored. We investigated the effects of WSP on lipid metabolism in high-fat diet (HFD)-fed mice using integrated transcriptomic and gut microbiomic analyses. The results indicated that WSP inhibited lipid accumulation in HFD mice and ameliorated HFD-induced oxidative stress, inflammation, and gut barrier impairment. Further studies revealed that WSP positively regulated FoxO1 expression by suppressing the PI3K/AKT signaling pathway, which in turn inhibited hepatic lipid synthesis in HFD mice. Furthermore, WSP concurrently remodeled gut microbiota via selective enrichment of beneficial Akkermansia and depletion of inflammation-associated norank_f__Desulfovibrionaceae. This microbial shift correlated with enhanced intestinal barrier integrity, reduced endotoxemia, and a predicted upregulation of propanoate metabolism. This study provides the first evidence of the synergistic regulation of the PI3K/AKT/FoxO1 pathway and gut microbiota restructuring by WSP, establishing a scientific foundation for valorizing walnut-processing waste into nutraceuticals against obesity.