Blueberry phytochemicals modulate the gut-vascular axis through microbiome-metabolome interaction

Dietary phytochemicals are metabolized by gut microbes into bioactive metabolites that mediate their physiological effects. This study investigated whether microbiome-metabolome interactions contribute to the vascular benefits of blueberry phytochemicals via the gut-vascular axis. Both conventionally raised and germ-free mice received freeze-dried blueberries via oral gavage, and plasma metabolites were analyzed at multiple time points. In other cohorts, mice were fed a standard or high-fat diet (HFD) with or without freeze-dried blueberry powder (∼1.5 human servings) and treated with or without antibiotics (Abx; to deplete gut microbes) for 12 weeks. Metabolic parameters, vascular endpoints, plasma metabolites, and the gut microbiome were assessed. Blueberry intake increased plasma blueberry-derived metabolites in conventionally raised but not germ-free mice, indicating that gut microbes are essential for metabolizing phytochemicals. This was also confirmed in Abx-treated mice. Blueberries reduced HFD-induced vascular inflammation. However, microbial depletion reduced plasma blueberry metabolites and abolished the benefits of blueberries in reducing vascular inflammation. HFD-enriched genera such as Faecalimonas were positively associated, whereas blueberry-derived metabolites (hippuric acid and 3-hydroxy hippuric acid) were negatively associated with vascular inflammation. Furthermore, Turicibacter and Clostridia UGC-014 (incertae sedis), which are enriched by dietary blueberries, were positively associated with hippuric acid. These findings provide insight into the importance of the interaction between the microbiome and metabolome in regulating the benefits of dietary phytochemicals on vascular inflammation via the gut-vascular axis.