Blueberry Anthocyanins Ameliorate Obesity‐Induced Dysfunction of Lipid Metabolism and Gut Microbiota by Inhibiting TLR4 Pathway

Blueberry anthocyanins demonstrate promising anti-obesity potential, however, their mechanism remains underexplored. This investigation revealed Toll-like receptor 4 (TLR4), an immune receptor recently found to involve in insulin resistance, as a critical mediator of these effects. Male wild-type (WT) and TLR4 gene knockout (TLR4^-/-) mice were used to establish obesity model and investigate the anti-obesity effects of blueberry anthocyanin extracts (BAE) based on TLR4. Body weight, glucose tolerance, liver lipid metabolism, TLR4/adenosine monophosphate-activated protein kinase (AMPK) signaling pathway, gut microbiota, and their metabolite levels were evaluated. The results demonstrated that BAE significantly attenuated weight gain, hepatic steatosis, and dyslipidemia in WT mice. However, these therapeutic benefits were abolished in TLR4^-/- mice despite observing baseline reductions in hepatic lipid accumulation with TLR4 knockout alone. Moreover, BAE regulated gut microbiota composition and enhanced short-chain fatty acids (SCFAs) production in WT mice. Notably, TLR4 deficiency independently induced gut microbiota alterations. These findings revealed a novel mechanism whereby BAE ameliorate obesity-associated metabolic dysfunction through TLR4 pathway inhibition, concurrently addressing lipid metabolism impairments and gut microbiota dysbiosis. This study advances TLR4-targeted therapeutic strategies using blueberry anthocyanins, offering a multimodal approach to obesity management that integrates metabolic regulation with microbiome modulation.