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The present study aimed to determine the effects of toll-like receptor 4 (TLR4) deletion on high fat diet-induced aortic stiffness and gut microbiota alterations. We hypothesized that a high fat diet would result in perturbation of the gut microbiota in both control and TLR4 knockout mice (TLR4-/-), but that the absence of TLR4 signaling would protect mice from downstream vascular consequences of the high fat diet. Male control mice (CON, n=12) and TLR4-/- mice (KO, n=12) were fed either a standard low-fat diet (SD) or a high fat diet (HFD) (60% kcals from fat) for 6 months, after which time measurements of aortic stiffness (via pulse wave velocity [aPWV]) and gut microbiota composition (16S rRNA sequencing) were determined. Compared to the SD, HFD reduced microbial variability, promoted perturbation of the gut microbiota, and increased intestinal permeability in both CON and KO mice, with no effect of genotype. This increased intestinal permeability in HFD mice was accompanied by increases in plasma lipopolysaccharide binding protein (LBP) levels, an indicator of circulating endotoxin (p