2′-Fucosyllactose Alleviates Metabolic Hypertension in Mice via Gut Microbiota Modulation and Involvement of the LPS/TLR4 Signaling

2′-Fucosyllactose (2′-FL) shows promise in ameliorating metabolic disorders. However, the role of 2′-FL in metabolic hypertension (MH) remains unclear. This study aimed to evaluate the effects of 2′-FL on MH and explore its underlying mechanisms. 2′-FL treatment (1000 mg/kg) reduced systolic blood pressure (SBP) by 16.6% and alleviated dyslipidemia, microglial activation, and neuroinflammation in MH mice. 2′-FL markedly increased short-chain fatty acids (SCFAs)-producing beneficial bacteria, e.g., Akkermansia and Bifidobacterium by 3.9-fold and 19.5-fold, accompanied by increased fecal acetate and butyrate. Notably, the benefits of 2′-FL for MH were transferable via fecal microbiota transplantation (FMT). Particularly, 2′-FL-mediated attenuation of vascular dysfunction was associated with the inhibition of the lipopolysaccharide/toll-like receptor 4 (LPS/TLR4) signaling, a protective effect that could be transferred via FMT. The antihypertensive and metabolic benefits of 2′-FL in mice were accompanied by gut-brain axis modulation. These findings suggest that 2′-FL represents a promising dietary strategy for preventing hypertension-associated complications.