Dietary Blueberry Ameliorates Vascular Complications in Diabetic Mice Possibly through NOX4 and Modulates Composition and Functional Diversity of Gut Microbes

Abstract

Scope: In diabetes, endothelial inflammation and dysfunction play a pivotal role in the development of vascular disease. This study investigates the effect of dietary blueberries on vascular complications and gut microbiome in diabetic mice. Methods and Results: Seven-week-old diabetic db/db mice consume a standard diet (db/db) or a diet supplemented with 3.8% freeze-dried blueberry (db/db+BB) for 10 weeks. Control db/+ mice are fed a standard diet (db/+). Vascular inflammation is assessed by measuring monocyte binding to vasculature and inflammatory markers. Isometric tension procedures are used to assess mesenteric artery function. db/db mice exhibit enhanced vascular inflammation and reduced endothelial-dependent vasorelaxation as compared to db/+ mice, but these are improved in db/db+BB mice. Blueberry supplementation reduces the expression of NOX4 and I𝜿K𝜷 in the aortic vessel and vascular endothelial cells (ECs) isolated from db/db+BB compared to db/db mice. The blueberry metabolites serum reduces glucose and palmitate induced endothelial inflammation in mouse aortic ECs. Further, blueberry supplementation increases commensal microbes and modulates the functional potential of gut microbes in diabetic mice. Conclusion: Dietary blueberry suppresses vascular inflammation, attenuates arterial endothelial dysfunction, and supports the growth of commensal microbes in diabetic mice. The endothelial-specific vascular benefits of blueberries are mediated through NOX4 signaling.

Preclinical Studies of Natural Products Targeting the Gut Microbiota: Beneficial Effects on Diabetes

“…As described above, the gut microbiota is an important player in the physiology and pathology of DM. Therefore, many animal and clinical experiments are conducted to explore preventive and therapeutic strategies for DM that target the gut microbiota. − Meaningfully, some foods and herbal medicines have been shown to have beneficial uses for different types of DM. − They contain abundant natural products and exert antidiabetic effects by improving the intestinal microecological environment (Figure ).…”

Daily blueberry consumption for 12 weeks improves endothelial function in postmenopausal women with above-normal blood pressure through reductions in oxidative stress: a randomized controlled trial

“…Rodriguez-Mateos et al 89 previously demonstrated acute blueberry consumption reduced neutrophil NADPH oxidase activity which was associated with increased FMD in healthy men. In diabetic db/db mice, Petersen et al 90 showed that blueberry consumption for 10 weeks improved endothelial function through reductions in NADPH oxidase 4 gene expression in aortic vessels and vascular endothelial cells. Several investigators have explored the effects of blueberry consumption on biomarkers of oxidative stress and antioxidant defense, and reported results have been mixed.…”

“…Rodriguez-Mateos et al 89 previously demonstrated acute blueberry consumption reduced neutrophil NADPH oxidase activity which was associated with increased FMD in healthy men. In diabetic db/db mice, Petersen et al 90 showed that blueberry consumption for 10 weeks improved endothelial function through reductions in…”

“…Evidence in animal models and limited human studies indicate blueberries modulate the gut microbiota, and emerging evidence suggests beneficial effects on endothelial function may be mediated by the gut microbiota. 90 Research evaluating the impacts on the gut microbiota and the extent to which and how the gut microbiome mediates beneficial health effects of blueberries in humans is needed.…”

Scientific Evidence for the Beneficial Effects of Dietary Blueberries on Gut Health: A Systematic Review

“…[ 14 ] Additionally, microbial hydrolases act on the anthocyanidins to produce metabolites such as phenolic acids which are more easily absorbable. [ 15 ] Blueberry bioactive components are extensively metabolized by intestinal microbiota in humans suggesting that microbiota‐induced metabolites might mediate the health beneficial effects of dietary blueberry. [ 15 ] Studies from our lab and others indicate that dietary blueberries impact gut health by improving gut dysbiosis.…”