Wild blueberries and cardiometabolic health: a current review of the evidence

Wild blueberries feature a complex and diversified profile of polyphenols, including anthocyanins, flavonols, phenolic acids, flavan-3-ols, and proanthocyanidins (see Table 1 ) ( Gibson et al. 2013 ; Rathinasabapathy et al. 2022 ). Anthocyanins are one of the largest polyphenol subclasses and include about 27–30 distinct anthocyanin moieties. Anthocyanins are considered to have the greatest impact on functions that promote human health. This rich diversity of anthocyanins contributes to their blue color as well as their versatility and utility for human health maintenance ( Kalt et al. 2008 ). In addition, other wild blueberry polyphenols include but are not limited to flavonols, phenolic acids, and tannin polyphenols, which have also been shown to contribute to their functionality and potential health effects ( Rothwell et al. 2013 ). Aside from their polyphenols, wild blueberries are also rich in nutrients including dietary fiber, manganese, zinc, and vitamins C and K ( Blueberries, wild, raw (Alaska Native), 2025 ; Blueberries, wild, frozen (Includes foods for USDA’s Food Distribution Program), 2025 ). Wild blueberry polyphenols have relative degrees of bioavailability after consumption. Upon ingestion, only 5–10% of polyphenols are absorbed in the small intestine. Following ingestion of a single dose of wild blueberry powder, parent anthocyanins and chlorogenic acids were found to have 1.1% and 0.2% bioavailability, respectively, in healthy adults. These bioavailable compounds were rapidly absorbed with peak concentrations appearing in plasma about 2 h after ingestion ( Zhong et al. 2017 ). Subsequently, phase II and gut microbial-derived metabolites became the predominant blueberry compounds and peaked at varying times up to 24 h post-ingestion ( Zhong et al. 2017 ). Likewise, other research in young healthy males has demonstrated dose-dependent and time-dependent effects on circulating polyphenol metabolites. Following wild blueberry powder consumption, metabolites peaked at 1–2 and 6 h post-consumption and these peaks were linked to beneficial modulation of vascular function, as measured by flow-mediated dilation (FMD) ( Rodriguez-Mateos et al. 2013 ). These and other studies suggest that both the intrinsic capacity of enterohepatic xenobiotic metabolism and the gut microbiota, contribute to the pharmacokinetics of blueberry polyphenols and their metabolites. Examples of commonly detected polyphenol metabolites produced from gut microbial and hepatic metabolism are in Table 1 . Bioavailable blueberry anthocyanins and metabolites, including those from wild blueberries, are distributed to tissues and have been detected in liver, eye, brain, and other tissues in animal studies ( Kalt et al. 2008 ; Bò et al. 2010 ). Several studies have investigated the individual and collective impact of blueberry polyphenols, their metabolites and catabolites on mechanisms relevant to cardiometabolic health. For example, phenolic acids from blueberries activate antioxidant responses in cultured human endothelial cells at nutritionally relevant concentrations ( Tang et al. 2018 ). Mixtures of anthocyanin metabolites reduced soluble vascular cell adhesion molecule-1 (VCAM-1) and interleukin (IL)-6 in cultured human endothelial cells exposed to a pro-inflammatory stimulus ( Warner et al. 2017 ). Blueberry phenolic catabolites also inhibited palmitate-induced dysfunction in cultured human aortic endothelial cells ( Bharat et al. 2018 ). Thus, the health benefits of wild blueberry consumption are likely mediated through the bioavailability of polyphenols as well as their metabolites. Wild blueberries are primarily consumed frozen or processed because fresh berries are highly perishable. Processing methods such as freezing, drying, juicing or pureeing disrupt blueberry cell walls, release anthocyanins and other polyphenols, and change polyphenol-fiber interactions ( Hotchkiss et al. 2021 ; Zhang et al. 2023 ). Freeze-drying is a method known to best preserve the phytochemical and nutritional contents ( Bhatta et al. 2020 ), and this form has been used in most published intervention studies. Optimizing juicing, drying, or thermal processing methods can increase the retention of blueberry polyphenols ( Lee et al. 2002 ; Kim et al. 2021 ; Zhang et al. 2023 ). Co-ingredients within food products, such as proteins or fiber, have potential to improve blueberry polyphenol stability during gastrointestinal digestion ( Herrera-Balandrano et al. 2021 ; Chima et al. 2022 ; Wu et al. 2023 ). There are limited studies, particularly on wild blueberries, that have directly investigated the impact of the blueberry matrix on health outcomes. Additionally, there is limited information regarding how food processing impacts the bioactivities associated with blueberry intake. One study demonstrated that the antiproliferative effect of cultivated blueberries against cancer cell lines was higher following freeze drying and high-intensity ultrasound treatment when compared to thermal processing ( Liović et al. 2022 ). Process-induced changes to the polyphenol, fiber, or nutrient profile of wild blueberry products could plausibly impact the bioavailability and metabolism of these components, but further research is needed to delineate these effects.

To strengthen the evidence base, future studies should consider key aspects such as dosing, methodological rigor, and standardization. Research should evaluate both acute and chronic interventions to determine optimal dosing strategies. Dosing may need to be higher in the presence of cardiometabolic diseases and for cognitive health benefits, with potential needs for multiple doses per day. Furthermore, the specific dose of wild blueberry polyphenols should be carefully assessed to better understand their impact on health outcomes. Recently an expert panel recommended daily consumption of 300–600 mg of flavan-3-ols for cardiovascular benefits ( Crowe-White et al. 2022 ). While this recommendation pertains to flavan-3-ols, a similar benchmark is needed for anthocyanins, given their emerging role in cardiometabolic health. As discussed in this perspective, anthocyanins are increasingly being linked to the health benefits of blueberries on cardiometabolic health. Further work is needed to understand benchmark levels for anthocyanin consumption, factoring in the impact of the food matrix and dose response, for cardiometabolic health benefits. Strengthening the evidence with more high-quality, large, and longer-term RCTs will allow for systematic reviews and meta-analyses of high quality to be performed with the intention of answering questions related to dosing. This is needed for dietary guidelines targeted at dietary intake of anthocyanins for human health. To improve the methodology used, translational research should address metabolism, gene expression, and signaling pathways in animal models and humans to bridge preclinical and clinical findings. The background diet of participants should be considered to minimize the influence of other dietary factors that might confound the results of the study. High-quality, well-designed RCTs should account for sex differences and prioritize primary outcomes in sample size calculations. Study reports should clearly communicate the primary outcome for which the sample size was determined. The use of placebo controls is critical for ensuring study validity, and placebo composition is an important consideration. Researchers should also explore innovative research avenues, such as incorporating additional arms into ongoing observational studies and examining responder vs. non-responder differences. Additionally, the methodology should incorporate certain elements to help strengthen the study design. Research should prioritize examining the food matrix and the form of delivery, such as frozen whole fruit versus freeze-dried powder versus juice, and their interactions with other foods and nutrients. Investigating whether wild blueberries replace other foods or nutrients in the diet and interactions with other foods and nutrients is another essential area. The stability and bioaccessibility of polyphenols and other common blueberry-derived metabolites, such as anthocyanins, is increased in a whole food matrix ( Kumkum et al. 2024 ) so one aspect of research to improve personalized nutrition could focus on optimizing the absorption of these compounds through recommended food and nutrient pairings, preparation methods, timing of consumption, and optimal dosing strategies. It would also be relevant to identify habitual dietary patterns that differ across populations, especially baseline consumption of dietary polyphenols at levels that might promote or offset observed cardiometabolic benefits of wild blueberries. Finally, large-scale clinical studies are essential to validate findings and address these evidence gaps comprehensively. Such research will enhance our understanding of the health benefits of wild blueberries and provide a stronger foundation for developing dietary recommendations. To ensure consistency across studies, protocols should include standardized equipment and methods while accounting for interindividual variability and subgroup differences. Research should aim to evaluate the influence of multiple factors (e.g., background diet, baseline health, gut microbiome, genetics, environment) on interindividual and subgroup variability in responses to wild blueberry consumption to advance personalized and precision nutrition. Additionally, reporting should include standardized units for blueberry and bioactive measurements, as well as details on blueberry species, polyphenol types, and concentrations. These steps will improve the comparability and reliability of findings across studies. To strengthen research outcomes and expand the public health impact of wild blueberries, future efforts should consider intentional diversity in study designs and integration into community nutrition programs. Recruiting individuals from a wide range of backgrounds is essential for ensuring that findings are inclusive and applicable to diverse populations. Populations that warrant particular attention in future studies include individuals with prediabetes, type 2 diabetes, metabolic syndrome, and metabolically obese individuals. Other important groups include children, aging adults, individuals with osteoarthritis and chronic diseases, athletes (recreational and professional), and those with subjective cognitive impairment. Women’s health across the reproductive lifespan, including pregnancy, endometriosis, and menopausal/postmenopausal health, also warrants further investigation. Moreover, research should prioritize underrepresented populations, such as different racial and ethnic minority groups and indigenous communities, including Native American and Alaska Native populations. In parallel, public health efforts should explore the incorporation of wild blueberries into food assistance programs (e.g., Supplemental Nutrition Assistance Program (SNAP), women, infants, and children (WIC)), school meal programs, and community-based outreach initiatives. The growing momentum behind the “Food Is Medicine” movement ( Volpp et al. 2023 ) presents a timely opportunity to integrate wild blueberries into nutritional strategies aimed at reducing the burden of diet-related diseases. Initiatives such as medically tailored meals, produce prescriptions, and nutrition incentive programs can help improve access to and affordability of wild blueberries. Partnering with food banks, schools, and local organizations will be key to increasing the cultural relevance and acceptability of wild blueberries across diverse settings. Additional research and implementation efforts are needed to evaluate the specific health impacts of wild blueberry consumption within the “Food Is Medicine” framework. Finally, expansion of research that applies omics technologies (e.g., metagenomics, transcriptomics, metabolomics, genomics) is needed. In particular, foodomics can uncover previously unidentified compounds in wild blueberries and post-ingestion metabolites and link them to biological pathways. Ultimately, this can help advance precision and personalized nutrition approaches and tailor dietary recommendations based on individual needs. Databases such as USDA databases (e.g., Database for the Flavonoid Content of Selected Foods), Phenol-Explorer, and others should be expanded to include comprehensive polyphenol and other phytochemical information for wild blueberries. The Periodic Table of Food Initiative is a global effort to provide standardized tools, data, and training to map food quality to improve these databases ( Jarvis et al. 2024 ). Foodomics can facilitate an improved understanding of wild blueberry phytochemicals, including those that are known (e.g., polyphenols), and those unknown, which may be unique to wild blueberries. Better characterization of these compounds can support an enhanced understanding of their mechanisms of action, especially in relation to cardiometabolic health, and inform the development of precision nutrition strategies tailored to individual or population-specific needs.

Wild blueberries are unique in their geographic origin, growing conditions, and history. They are rich in nutrients and phytochemicals, particularly polyphenols like anthocyanins which along with their bioactive metabolites, have been demonstrated to exert cardiometabolic benefits in in vitro , preclinical, and clinical studies. Overall, these data support that acute and chronic wild blueberry consumption can favorably affect measures of cardiometabolic health, predominately vascular function, with data more mixed for outcomes such as BP, blood lipids, glycemic control/insulin resistance. Related outcomes such as gut microbiome composition and function and cognitive function have also been shown to improve with wild blueberry consumption. One clinical study suggests a beneficial interaction with exercise related to fat and carbohydrate metabolism, suggesting more work is needed related to interactive effects of wild blueberry consumption with exercise. Data from in vitro , preclinical, and clinical studies suggest that wild blueberry polyphenols mediate the cardiometabolic benefits of dietary blueberries by acting on multiple targets, such as eNOS/NO/cGMP signaling, endothelial inflammation, redox signaling, lipid metabolism, glucose metabolism, and vascular glycocalyx. With regard to vascular function, clinical and translational evidence suggests that wild blueberry anthocyanins and their circulating metabolites are major mediators of beneficial impacts, though more research is needed. Nonetheless, variability in cardiometabolic health benefits of wild blueberries is prevalent, and future research should aim to understand factors and mechanisms contributing to responses to wild blueberry consumption. Studies should aim to evaluate foodomics, as well as omics-related outcomes including the gut microbiome, circulating polyphenol metabolites, genetic factors including gene polymorphisms, and others. Future studies should investigate comprehensive biomarkers of cardiometabolic health and function, while applying standardized methodological and precision nutrition approaches where appropriate. Additional priorities include confirming the phytochemical composition of wild blueberries and post-ingestion metabolites, optimizing dosing strategies and food matrix interactions, strengthening clinical trial designs, and expanding research to support community-based interventions, dietary guidelines, and broader public health initiatives.

True blueberries (i.e., wild, Vaccinium angustifolium Ait.; and cultivated highbush, V. corymbosum L. or rabbiteye, V. virgatum Ait.) are native to North America, while the closely related wild bilberries ( V. myrtillus ) are native to Europe ( Negruşier et al. 2024 ). Also known as lowbush blueberries, wild blueberries are perennial plants that grow in unique soil and environmental conditions endemic to the state of Maine and the maritime provinces of Canada, and few other regions in North America ( Tirmenstein 1991 ). Wild blueberry plants colonize vast expanses of irregular terrain through the spread of their rhizome systems. Because these plantings are endemic and naturally colonize their terrain, they do not require the extensive inputs (e.g., transplanting, pesticide applications, herbicides, fertilizers) that most cultivated plants require to compete and thrive. Typically, commercial treeless wild blueberry fields (i.e., wild blueberry barrens) are cared for through disturbance practices such as mowing or fire, which increase yields. The berry plants spread to cover all the surrounding terrain, so the soil is not tilled as in conventional, cultivated plantings. In the northern climates in which they grow, they are exposed year-round to environmental stressors characteristic of their habitat – bitter winter cold, fierce winds and short daylengths in the winter, salty coastal spray, and longer days during the summertime. These stressors provoke the accumulation of a diverse array of secondary metabolites, particularly polyphenols including flavonoids, in wild blueberry plants, a phenomenon known as elicitation. This process triggers more diversified secondary metabolite profiles and is often deliberately used industrially to provoke metabolite accumulation in various plants ( Shakya et al. 2019 ; Roy et al. 2022 ). The diversity and concentration of polyphenols, particularly flavonoids in wild blueberry fruits (including anthocyanin pigments), may be responsible for many of their human health-relevant properties ( Wood et al. 2019 ; Martini et al. 2023 ; Woolf et al. 2023 ). At the same time, research suggests that wild blueberry anthocyanins and their circulating metabolites may be primary drivers of functional modulation of the vasculature ( Rodriguez-Mateos et al. 2019 ). Historically, wild blueberries were consumed by native peoples, birds, and other wildlife. Evidence indicates that wild blueberries were dried in the sun and ground into a powder that was used in soups, stews, and meat curation ( Wood 2004 ). Wild blueberries were combined with other foodstuffs for preservation throughout the year (e.g., dried berries and meat; pemmican or bread made with cornmeal and beans; manna in winter) ( Hummer 2013 ). Indigenous traditional ecological knowledge included multiple additional uses of wild blueberries such as a naturally sourced dye for fabric, as a tea, and as medicine ( Rojo et al. 2017 ). Medicinal uses included gynecological treatments, wound healing preparations, and remedies for gastrointestinal disorders. Subsequently, early European colonizers harvested and used wild blueberries and practiced crop management to maintain fields and facilitate new field development. This led to commercial berry harvesting and use in the food industry, more sophisticated management practices, and marketing. Industry leaders from Maine in the United States and Canada formed the Wild Blueberry Association of North America (WBANA) in 1981 to bring together growers and producers for the purpose of raising awareness of wild blueberries and promoting wild blueberry product quality ( Wood 2004 ). For the past several decades, wild blueberries have been investigated for their human health effects. They were initially recognized to be rich in various polyphenols, notably flavonoids with demonstrated in vitro antioxidant effects inversely associated with chronic diseases such as cardiovascular disease (CVD), stroke, and cancer ( Häkkinen et al. 1999 ). Initial research directions focused on the evaluation of wild blueberries for their in vitro antioxidant and anticar-cinogenic effects, in vivo antioxidant effects in humans, and in vivo cardiovascular health effects in animal models. Since then, our understanding of the health effects of food-based interventions—particularly polyphenol-rich foods including wild blueberries—has evolved. Evidence now suggests that their cardiovascular benefits are unlikely to stem from direct antioxidant activity ( Hollman et al. 2011 ), prompting a shift toward evaluating their physiological relevance through more mechanistic and translational approaches. Several cardiovascular and metabolic (i.e., cardiometabolic) risk factors are predictive of CVD risk and events and can be clinically assessed to understand and improve human cardiovascular health and reduce disease risk. Cardiometabolic risk factors such as elevated blood pressure (BP), obesity, metabolic syndrome, and dyslipidemia predispose individuals to CVD, in large part due to adverse effects on the vascular system including development of endothelial dysfunction and arterial stiffening ( Johnson et al. 2019 ). Wild blueberries are rich in numerous nutrients and polyphenols linked to cardiometabolic health. Since initial research efforts with wild blueberries, numerous studies have been performed to evaluate different aspects of human health such as those related to cardiometabolic, cognitive, and gut health ( Della Lucia et al. 2023 ; Soveid et al. 2023 ; Woolf et al. 2023 ). A Cardiometabolic Health Symposium took place in Bar Harbor, Maine (August 13–15, 2024) supported by WBANA to discuss current research and gaps in the evidence surrounding wild blueberries and cardiometabolic health, and identify future directions needed to more comprehensively understand their human cardiometabolic health effects and applications. Experts that participated in the symposium encompassed fields of nutrition, food science, dietetics, nutrition metabolism and physiology, cardiovascular and cognitive function and health, gut health and microbiology, and pre-clinical, clinical, and translational research. The current article provides a summary of the evidence presented at the symposium and the perspectives of the expert participants.

There is no established definition of cardiometabolic health, but it is characterized by optimal function of cardiovascular and metabolic systems related to blood vessels, the heart, pancreas, liver and brain. The American Heart Association has defined optimal cardiometabolic health by the presence of ideal health behaviors such as nonsmoking, dietary patterns consistent with guidelines, and optimal levels of adiposity, blood glucose, blood lipids, BP, and absence of prior clinical CVD events. Cardiometabolic health is inversely associated with cardiometabolic disease and related risk factors such as obesity, insulin resistance and type 2 diabetes, hyperlipidemia, hypertension, and CVD ( Lloyd-Jones et al. 2010 ; O’Hearn et al. 2022 ). Human clinical studies, including feeding trials of whole blueberries, as well as trials involving blueberry extracts have shown multiple benefits on cardiometabolic health in adults with one or more metabolic impairments or cardiovascular risk factors. Several well-conducted systematic reviews, meta-analyses and/or narrative reviews have been recently published and are summarized and interpreted in this section on the role of blueberries in cardiometabolic health, especially addressing metabolic syndrome and vascular function. Due to their comprehensive nature, these reviews and meta-analyses describe the body of evidence for the cardiometabolic health effects of all blueberries, including both wild and highbush blueberries and derivative products. Endothelial dysfunction, i.e., impaired endothelium-dependent dilation caused by reduced bioavailability of vasodilatory molecules, underlies the initiation and progression of atherosclerotic CVD ( Gimbrone and García-Cardeña 2016 ; Jensen and Mehta 2016 ). Accumulating evidence suggests a consistent beneficial role of blueberries in promoting endothelial function. In a systematic review and meta-analysis of 11 clinical trials, Deng et al. (2024) reported significant improvements in endothelial function measures including 1.5% improvement in FMD (95% CI: 0.81, 2.20), and 0.26% decrease in reactive hyperemia index (RHI) (95% CI: 0.09, 0.42) in adults following dietary supplementation of blueberries ( Deng et al. 2024 ). This report also revealed significant decreases in systolic BP (SBP) by −3.92 mmHg (95% CI: −0.97, −6.88) and diastolic BP (DBP) by −2.20 mmHg (95% CI: −0.27, −4.13) among a sub-group of smokers who experience a higher risk of endothelial dysfunction than nonsmokers ( Deng et al. 2024 ). The dose administered in these studies ranged from 300 g whole blueberries, 13–45 g freeze-dried blueberry powder, or 766 mg blueberry polyphenols for acute (0 to 24 h postprandial) to chronic (1 week to 6 months) timeframes. Among the 11 clinical trials evaluated in that systematic review, 6 were conducted in metabolically healthy adults, 3 in adults with the metabolic syndrome, 1 in adults with regular smoking habit (vs nonsmokers), and 1 in postmenopausal women with above-normal BP. Interestingly, the report revealed no significant improvements in SBP and lipid profiles in a pooled analysis of all studies ( Deng et al. 2024 ). Overall, this meta-analysis revealed low risk of bias in different elements of a rigorous study design, but a publication bias was indicated, and the quality of the evidence was graded to be moderate. FMD is a measure of macrovascular endothelium-dependent dilation that reflects the ability of blood vessels to respond to physical and chemical stimuli in the lumen including nitric oxide (NO) and can predict risk of CVD ( Corretti et al. 2002 ). RHI is a complex measure of microvascular endothelial function that partly reflects NO bioavailability and is correlated with FMD. Based on the site of FMD assessment, it has been demonstrated that a 1% increase in FMD using the distal cuff can cause a 9% decreased risk of CVD, whereas using the proximal cuff can be associated with a 17% risk reduction of CVD ( Inaba et al. 2010 ; Green et al. 2011 ). Thus, the overall 1.50% increase in FMD with blueberry intervention is of clinical relevance in CVD management. In another systematic review and meta-analysis focusing on the role of blueberries and cranberries on SBP and DBP as outcomes of cardiometabolic health and CVD risk, less pronounced beneficial effects were observed ( Delpino et al. 2024 ). There, Delpino et al. (2024) summarized 9 clinical studies using blueberry interventions (out of 17 total studies including blueberry and/or cranberry interventions), and their meta-analysis revealed no overall significant effects on SBP and DBP in adults with one or more cardiometabolic risk factors. The dose ranged from 22 g to 50 g of freeze-dried blueberries administered for 4 to 24 wks. It is important to note that baseline SBP and DBP levels in these studies were relatively normal or slightly elevated, and included confounding factors such as use of antihypertensive medications, which may explain the overall non-significant findings. Additionally, these studies reported a one-time office BP measurement and not a 24-h ambulatory BP which may provide greater insight into diurnal and activity-induced fluctuations and should be examined in future studies ( Delpino et al. 2024 ). Delpino et al. reported that only 1 study evaluated had a low risk of bias, 1 had a high risk of bias, and the other 15 studies reviewed had at least one concern within the Cochrane risk of bias tool. Furthermore, an earlier systematic review and meta-analysis by Carvalho et al. (2021) of 18 clinical studies in adults with metabolic syndrome, of which 12 were included in the meta-analysis, found that blueberry supplementation improved DBP and total- and LDL-cholesterol, but had no effects on glycemic and anthropometric parameters ( Carvalho et al. 2021 ). The magnitude of decrease in DBP, total-, and LDL-cholesterol following blueberry supplementation were as follows: −2.04 mmHg (95% CI: −3.8, −0.2), −0.22 mmol/L (95% CI: −0.39, −0.04), and −0.24 mmol/L (95% CI: −0.37, −0.10), respectively ( Carvalho et al. 2021 ). From the cardiovascular perspective, a reduction of SBP ~ 10 mmHg has been associated with a risk reduction of major cardiovascular events ( Ettehad et al. 2016 ). Thus, compared to the effects on FMD, the effects of blueberry intervention on SBP and DBP are less robust and inconsistent. Woolf et al. (2023) provided a comprehensive mechanistic review on the role of blueberries in vascular function encompassing translational models spanning cell, animal, and human studies ( Woolf et al. 2023 ). A summary of studies in animal models of hypertension and endothelial dysfunction demonstrate a decrease in vasoconstriction, and an increase in vasorelaxation in animals on blueberry supplemented diets versus controls. Molecular pathways reveal increased NO bioavailability, and decreased oxidative stress and inflammation, primarily via downregulating inflammatory enzyme expression, such as cyclooxygenase (COX). In addition, blueberry supplementation decreased monocyte-endothelial cell binding in animal models, which is one of the key steps in endothelial dysfunction and the development of atherosclerosis ( Woolf et al. 2023 ). Together, these pathways may partially explain the observed clinical effects of blueberries in mitigating endothelial dysfunction and vascular outcomes in humans and these deserve further investigation in future long-term dose-dependent studies. In the same narrative review, Woolf et al. described results from 10 clinical studies involving acute blueberry supplementation and their effects on vascular outcomes in adults with or without metabolic syndrome. A summary of their findings shows acute improvements in FMD and/or RHI up to 6 hours following blueberry consumption when compared to the control phase in 8 studies, while the other 2 observed no effects. Chronic blueberry intervention ( n = 11 studies) also saw similar improvements in FMD and RHI in eight studies, while the remaining 3 observed no effects ( Woolf et al. 2023 ). Impaired fasting glucose and dyslipidemia are components of the cardiometabolic risk profile and have been strongly correlated with increases in CVD and type 2 diabetes risk, therefore justifying these outcomes to be examined in response to blueberry exposure. Azari et al. (2022) reported a systematic review and meta-analysis focused on the effects of blueberries on individual components of the metabolic syndrome in adults ( Azari et al. 2022 ). Summarizing a total of 25 clinical studies over a period of 14 years (2007–2021), this meta-analysis revealed no significant effect of blueberry intervention on waist circumference, body mass index (BMI), glycosylated hemoglobin (HbA1c), glucose concentrations and homeostatic model assessment for insulin resistance (HOMA-IR). On the other hand, blueberry consumption was associated with significantly improved SBP and DBP, triglycerides, total cholesterol, LDL- and HDL-cholesterol, and insulin concentrations. While these data provide evidence for the role of blueberries in the management of metabolic syndrome, the summarized studies exhibited large variations in participant characteristics, as well as in blueberry product and dose tested, study duration, and mean differences in the clinical variables examined. Additionally, Azari et al. performed quality assessment of the human studies included and rated 8 studies as high quality, approximately 12 studies were considered to be low or moderate quality. These factors must be considered in making effective recommendations for adults with metabolic syndrome which represents a constellation of risk factors for type 2 diabetes ( Grundy et al. 2005 ). Martini et al. (2023) conducted a systematic review examining the effects of blueberry intervention on cardiovascular risk factors, including biomarkers of oxidative stress and inflammation in adults from 2010 to 2021 ( Martini et al. 2023 ). Among the 26 clinical studies reviewed in this report, 8 studies reported decreases in SBP, serum triglycerides and total cholesterol, insulin sensitivity, and/or BMI, 9 studies reported data on vascular function in which blueberry intervention improved measures of endothelial function (i.e., FMD, RHI) and measures of arterial stiffness (i.e., augmentation index (AIx), pulse wave velocity (PWV)), while most studies observed no effects on glucose and lipid markers. Inflammatory markers were mostly unaffected in these studies, except in two trials that demonstrated decreases in inflammatory cytokines, specifically tumor necrosis factor-α (TNF-α) and IL-6 following blueberry intervention. On the other hand, among the 17 studies that reported data on oxidative stress markers, 9 revealed decreases in oxidative stress biomarkers and/or increases in antioxidant biomarkers following blueberry supplementation when compared to the control group ( Martini et al. 2023 ). Much of this heterogeneity can be attributed to baseline participant characteristics, as half of these studies were conducted in adults with cardiometabolic risk, including diabetes, arthritis and cognitive decline, while the remaining studies were performed in sedentary but overall healthy adults ( Martini et al. 2023 ). Risk of bias was not evaluated in that review and only provided the direction of changes (or no changes) in these variables and did not provide a quantitative summary of observed changes which makes it challenging to draw clinical conclusions for dietary recommendations. In addressing the role of blueberries in adults with and without type 2 diabetes, Delpino et al. (2022) reported a systematic review and meta-analysis in which blueberry and cranberry supplementation was statistically associated with a reduction of 2.37 mg/dL (95% CI: −4.72, −0.02) in fasting blood glucose. However, no significant effects in insulin resistance and HbA1c were noted when the meta-analysis was stratified by blueberry treatment ( Delpino et al. 2022 ). The authors noted risk of bias in the included studies, with 10 studies out of 22 having risk of bias noted and others having risk of bias in areas such as random sequence generation, allocation concealment, and blinding. This study largely combined results from studies conducted in adults with diabetes risk or with clinical diagnosis of type 2 diabetes; out of a total of 22 clinical studies, only 7 studies included adults with type 2 diabetes. Blueberries have twice as many polyphenols as cranberries and various mechanisms have been identified in their anti-diabetic effects including decreased intestinal glucose absorption, inhibition of carbohydrate digestion, stimulation of insulin secretion, modulation of glucose release from the liver, and activation of insulin receptors ( Delpino et al. 2024 ). Addressing a similar hypothesis, de Oliveira et al. (2022) reported a systematic review of 8 clinical studies and 23 preclinical studies on the effects of blueberries (or bilberries) on obesity, diabetes and related markers ( de Oliveira et al. 2022 ). Among these 8 clinical studies, seven were conducted in adults with metabolic syndrome, obesity, and/or insulin resistance, and 1 was conducted in adults with type 2 diabetes. Results revealed improvements in BP, dyslipidemia, and oxidative stress in most studies, whereas blood glucose and HbA1c improved in only 2 clinical studies in these at-risk adults. No effects were noted on body weight and/or adiposity. This systematic review did not evaluate the strength of the evidence of outcomes. Altogether, these critically summarized systematic reviews and/or meta-analyses show a consistent effect of blueberries in increasing FMD in most clinical studies, followed by improvements in BP, serum lipids, and oxidative stress in selected studies, and modest reductions in postprandial glucose, and no effects in HbA1c, insulin, HOMA-IR, fasting blood glucose, or anthropometric variables were revealed in overall studies. Quality assessment for bias in these systematic reviews and meta-analyses revealed some evidence for publication bias, and significant heterogeneity between studies was observed, and these were mostly explained by the small number of studies examining the effects of blueberries on each component of the metabolic syndrome or cardiometabolic risk in adults. Study design assessment revealed low risk of bias, and most studies revealed concerns in at least one domain of bias assessment. Only 1 meta-analysis indicated a moderate strength of the evidence regarding FMD ( Chima et al. 2022 ), but other variables need to be further examined when assessing the clinical relevance of blueberry intervention. It is important to note that many of the outcomes evaluated in clinical trials were secondary outcomes and thus studies may not have had adequate statistical power to detect significant differences, and populations studied may not be appropriate for our outcomes evaluated (e.g., antihypertensive effects in populations with normal blood pressure). Readers are referred to these systematic reviews and meta-analyses for additional information regarding quality assessment and risk of bias of clinical studies evaluated. Acute (i.e., single dose) wild blueberry consumption has been investigated for improving cardiometabolic health in humans in 7 published studies ( Kay and Holub 2002 ; Rodriguez-Mateos et al. 2013 ; Rodriguez-Mateos et al. 2014 ; Bell et al. 2017 ; Stote et al. 2019 ; Whyte et al. 2021 ; Cheng et al. 2024 ). ( Table 2 ). The impact of acute wild blueberry consumption on FMD, and potential underlying mechanisms including assessment of circulating metabolites and neutrophil NADPH oxidase (NOX) activity, was investigated in a dose-dependent study. In healthy males, 14-, 28-, and 34-g doses of freeze-dried wild blueberry powder led to a dose-dependent increase in FMD 1-hour after consumption. No additional benefits were observed with higher doses of 57 and 80 g. Further, decreases in neutrophil NOX activity (a major source of vascular oxidative stress) were associated with improvements in FMD and were predicted by plasma polyphenol metabolites ( Rodriguez-Mateos et al. 2013 ). Another study was performed to evaluate the impact of food processing on FMD and circulating polyphenol metabolites where 34 g freeze-dried wild blueberry powder was provided alone or in a baked product, or as a matched control baked product. Despite changes to the polyphenol composition in the baked product and in circulating polyphenol metabolites, there were no major differences in beneficial increases in FMD with wild blueberry powder alone compared to when incorporated into a baked product on beneficial increases in FMD ( Rodriguez-Mateos et al. 2014 ). Beneficial effects on biomarkers of antioxidant defense were also reported by Kay and Hollub in 2002 . They demonstrated that the acute intake of a freeze-dried wild blueberry powder (100 g) increased postprandial serum antioxidant status following the consumption of a high-fat meal in healthy men ( Kay and Holub 2002 ). In healthy older adults who ingested either 111, 222, 444, or 888 mg wild blueberry extract or placebo, a 4-h post-lunch dip in executive function occurred in the placebo group, while the 222 mg dose led to acute reductions in SBP and DBP (study 1) and faster executive functioning compared to placebo (study 2) ( Cheng et al. 2024 ). One study involving healthy adults investigated acute effects of incorporating 140 g of wild blueberries into a high-carbohydrate breakfast on postprandial glucose metabolism. Results indicated no significant changes in glucose metabolism following blueberry consumption, nor in gastrointestinal hormone responses and perceived appetite ( Stote et al. 2019 ). In line with these findings, another study reported that the acute intake of a freeze-dried wild blueberry powder (100 g) did not affect postprandial glucose or lipid responses (i.e., triglycerides, total cholesterol, LDL- and HDL-cholesterol) following the consumption of a high-fat meal ( Kay and Holub 2002 ). In contrast, consumption of anthocyanin-rich wild blueberry beverages (34 and 80 g powder) versus an equivalent sugar dose beverage improved glucose responses in healthy young adults ( Bell et al. 2017 ). Beneficial effects on postprandial glucose metabolism and cognitive performance were also observed following a single freeze-dried wild blueberry drink (25 g powder) with a breakfast meal in middle-aged adults ( Whyte et al. 2021 ). Chronic (i.e., more than 1 dose for greater than 1 day) wild blueberry consumption has been investigated for improving cardiometabolic health in humans in 7 published studies ( Table 2 ). One study investigated the chronic impact of daily consumption of 25 g of freeze-dried wild blueberry powder mixed in water over a period of 6 wks on RHI in healthy men who had at least 1 CVD risk factor. Biomarkers of oxidative stress including oxidative DNA damage improved, but no statistically significant effects were observed on vascular function measurements, circulating glucose or lipid concentrations (triglycerides, total cholesterol, LDL- and HDL-cholesterol), liver enzymes, or BMI ( Riso et al. 2013 ). Another study involving adults at risk for type 2 diabetes found that consuming 240 mL of wild blueberry juice daily for 7 days also did not result in significant improvements in RHI although increases were noted in circulating NO metabolites (i.e., nitrate and nitrite) ( Stote et al. 2017 ). In healthy older adults, consuming 26 g per day of freeze-dried wild blueberry powder mixed in water for 12 wks led to improved FMD and 24-h SBP compared to a placebo. Furthermore, chronic wild blueberry intake improved cognitive performance and total urinary polyphenol metabolites increased, although no major effects were noted on measures of circulating glucose, lipids, cerebral perfusion, or gut microbiome ( Wood et al. 2023 ). Another study investigated the effects of wild blueberries on composition of the gut microbiota, although not specifically in the context of cardiometabolic health. In brief, chronic wild blueberry consumption over 6 wks increased Bifidobacterium species and other health-associated bacterial taxa in healthy adult men. These findings suggest that wild blueberry intake may modulate the gut microbiota ( Vendrame et al. 2011 ) which is implicated in cardiometabolic health and disease risk ( Tang and Hazen 2024 ). In women at risk for type 2 diabetes, 1 week of daily consumption of a daily 240 mL serving of wild blueberry juice increased circulating NO metabolites (i.e., nitrate and nitrite) and there was a statistical trend for lower SBP, but no effects were observed on blood glucose, insulin, lipid profiles, or biomarkers of oxidative stress and inflammation ( Stote et al. 2017 ). In another study, beneficial effects on BP were also observed in older adults. Briefly, a significant reduction of SBP was found 3 and 6 months after the intake of a commercially available, proprietary wild blueberry extract (providing 50 mg polyphenols and 7 mg anthocyanins), and cognitive benefits were observed ( Whyte et al. 2018 ). Additionally, consuming another wild blueberry extract (222 mg) for 5 wks improved not only SBP and DBP levels, but also demonstrated improvements in cognitive performance ( Cheng et al. 2024 ). Overall, chronic intervention studies involving wild blueberry consumption have generally not reported beneficial effects on glucose, lipid metabolism, body weight, body composition, or anthropometric outcomes ( Riso et al. 2013 ; Stote et al. 2017 ; Wood et al. 2023 ). Moreover, several studies did not assess glucose or lipid outcomes. However, a study in healthy aerobically trained males demonstrated that consumption of 25 g per day of wild blueberry powder for 2 weeks increased fat oxidation and decreased carbohydrate oxidation following an exercise protocol cycling at 65% of VO 2peak for 40 min ( Pilolla et al. 2023 ). Clinical and translational evidence suggests that wild blueberry anthocyanins and their circulating metabolites are major mediators of their cardiovascular benefits. For instance, an acute study in healthy males evaluating 11 g freeze-dried wild blueberry powder compared to control drink, control drink + fiber, control drink + vitamins/minerals, and pure anthocyanin drink found that pure anthocyanins had similar effects on FMD as wild blueberry powder ( Rodriguez-Mateos et al. 2019 ). They also observed that numerous plasma anthocyanin metabolites were found to correlate with acute and chronic improvements in FMD, and injection of those metabolites into mice led to improvements in FMD ( Rodriguez-Mateos et al. 2019 ). Overall, these data support that acute and chronic wild blueberry consumption can favorably affect measures of cardiometabolic health, particularly endothelial function, and limited evidence supports additional beneficial health outcomes, such as improved gut microbiota and cognitive function. Evidence suggests beneficial health effects are mediated by polyphenols and their circulating metabolites, particularly anthocyanins and anthocyanin-derived metabolites. Emerging evidence indicates that blueberry polyphenols mediate the cardiometabolic benefits of dietary blueberries by acting on multiple targets, such as endothelial NO synthase (eNOS)/NO/cyclic guanosine monophosphate (cGMP) signaling, endothelial inflammation, redox signaling, lipid metabolism, glucose metabolism, and vascular glycocalyx. See Figure 1 . Supporting studies using highbush blueberries and other relevant interventions (e.g., pterostilbene) are highlighted to compare research findings with wild blueberries. NO produced in the endothelium by eNOS helps maintain vascular homeostasis by acting as a vasodilatory and signaling molecule ( Gielis et al. 2011 ). NO also exhibits anti-proliferative, anti-inflammatory, and anti-platelet properties ( Su 2015 ). Endothelial NO activates soluble guanylate cyclase (GC) to produce cGMP, which induces smooth muscle relaxation in the vasculature ( Quillon et al. 2015 ). An impairment in eNOS activity and reduced NO production and/or bioavailability enhances atherosclerosis risk by increasing the binding of monocytes to the vascular endothelium, leading to arterial stiffness and increased BP ( Ponnuswamy et al. 2012 ). Hence, eNOS/NO/cGMP activation is critical to vessel relaxation and vascular tone. Emerging evidence from in vitro , in vivo and clinical studies indicates that wild blueberries mediate their beneficial effects on endothelial function through endothelium-dependent pathways, specifically by acting on eNOS/NO/cGMP and COX signaling, to ameliorate endothelial dysfunction. Blueberry polyphenols are extensively metabolized in humans and an in vitro study assessed the effect of metabolites on palmitate-induced NO production impairement ( Bharat et al. 2018 ). Consumption of wild blueberry has been shown to increase NO metabolites (i.e., nitrate and nitrite), activate NO, increase cGMP, and increase endothelium-dependent vasorelaxation ( Norton et al. 2005 ; Kalea et al. 2009 ; 2010 ; Kristo et al. 2010 ; Del Bo et al. 2012 ; Kristo et al. 2013 ; Rodriguez-Mateos et al., 2013 ; 2013 ; Vendrame et al. 2014 ; Johnson et al. 2015 ; Stote et al. 2017 ; Petersen et al. 2022 ). In clinical studies, wild blueberry consumption (240 mL wild blueberry juice for 7 days) increased the concentration of NO plasma levels in participants with overweight or obesity and risk factors for type 2 diabetes ( Stote et al. 2017 ). Consumption of 22 g freeze-dried highbush blueberry powder for 8 wks (equivalent to 1 cup of fresh blueberries) decreased SBP and DBP and reduced arterial stiffness while increasing NO metabolite concentrations in postmenopausal women with pre- and stage-1 hypertension ( Johnson et al. 2015 ). These clinical studies are supported by preclinical studies. For instance, experiments on endothelium-denuded and intact aortic rings in Sprague-Dawley (SD) rats fed 8% (w/w) wild blueberry supplemented diets (equivalent to 2 cups of blueberries) for 13 wks demonstrate the role of wild blueberries as inhibitors of adrenergic receptor-mediated vascular responses ( Norton et al. 2005 ). Wild blueberries suppressed alpha 1-adrenergic agonist-induced vasoconstriction via NO-mediated pathway and this effect was mediated through the endothelium ( Kalea et al. 2009 ; 2010 ; Kristo et al. 2010 ; Kristo et al. 2013 ; Del Bo et al. 2012 ). In other studies, utilizing spontaneously hypertensive rats (SHR) with inhibitors to target and dissect the different steps of the eNOS/NO/cGMP and COX pathways, diet incorporation with 8% (w/w) wild blueberry (equivalent to 2 cups of blueberries) for 8 wks improved vascular reactivity in young and adult SHRs by activating the NO-mediated pathway ( Kalea et al. 2010 ). Further, wild blueberries suppressed α-adrenergic-induced vasoconstriction in SHRs, which was associated with increased cGMP ( Kalea et al. 2010 ; Kristo et al. 2010 ; 2013 ). These studies suggest that both pathways may be involved in the beneficial vascular effects of wild blueberries – activation of the NO-mediated pathway and suppression of the COX-dependent vasoconstriction pathway. Inhibitors that target GC, enzyme that synthesizes cGMP from guanosine triphosphate (GTP), and cGMP-specific phosphodiesterase (PDE)-5M, enzyme that breaks down cGMP, were used to determine the effect of wild blueberry-supplemented diets on the NO-cGMP pathway. Wild blueberries preserved vascular cGMP by activating GC and reducing PDE ( Kristo et al. 2013 ). Further, obese Zucker rats (OZR) fed wild blueberry supplemented diets had downregulated gene expression of inducible NO synthase (iNOS) and increased plasma NO metabolite concentrations supporting improvements in endothelial function via the eNOS/NO pathway. These findings are consistent with studies on Wistar rats fed a high-fat, high-cholesterol diet enriched with 2% (w/w) highbush blueberries for 8–10 wks which resulted in significant decreases in contractile responses to L-phenylephrine and in SBP, which is indicative of the role of wild blueberries in improving endothelial dysfunction induced by high-fat diets ( Rodriguez-Mateos et al. 2013 ). Wild blueberry supplementation at a physiologically relevant dosage (3.8% freeze-dried blueberry powder for 10 wks which is equivalent to 1.5 cups) increased endothelial NO-dependent vasorelaxation in diabetic mice ( Petersen et al. 2022 ). Thus, based on studies in animal models, wild blueberries improve vascular function through modulation of eNOS/NO and/or COX pathways ( Vendrame et al. 2014 ). Collectively, in vitro , pre-clinical, and clinical studies indicate that consumption of wild blueberries and their polyphenols preserve endothelial function and confer their beneficial effects on the vascular tree by modulating the eNOS/NO/cGMP and/or the COX signaling pathways, based on the animal model (SHR, OZR) and age. Endothelial inflammation and resulting endothelial dysfunction play a pivotal role in developing vascular complications and atherosclerosis. Cardiometabolic disease risk factors (e.g., diabetes, dyslipidemia, hypertension) activate the endothelium to secrete pro-inflammatory chemokines and adhesion molecules like monocyte chemotactic protein (MCP)-1, IL-8, VCAM-1, intracellular adhesion molecule (ICAM)-1, and E-selectin ( Thompson et al. 1995 ; Ridker et al. 2000 ; Pearson et al. 2003 ; Danesh et al. 2004 ). These inflammatory factors promote leukocyte rolling, enhance adhesion to endothelial cells, and facilitate migration to the subendothelial layer ( Pearson et al. 2004 ; Whelton 2006 ; Menzaghi et al. 2014 ). Once in the inner vascular layer, the migrated leukocytes differentiate into macrophage foam cells through the uptake of lipids and lipoproteins ( Libby 2002 ). The foam cells further secret proinflammatory molecules including TNF-α, IL-8, and E-selectin, amplifying the inflammatory response and driving vascular complications such as atherosclerosis ( Libby 2002 ; Nallasamy et al. 2014 ). Nuclear factor kappalight-chain-enhancer of activated B cells (NF-κB), a pro-inflammatory transcription factor, is activated by reactive oxygen species (ROS) produced by NOXs ( Savoia and Schiffrin 2007 ). p50/p65 is the most abundant form of NFκB, sequestered in the cytoplasm by binding to the inhibitor IκBα under normal conditions ( Bouwmeester et al. 2004 ). However, pro-inflammatory conditions induce phosphorylation of IκBα by IκB kinase (IκKβ), resulting in the degradation of IκBα and the subsequent nuclear translocation of p50/p65 ( Bouwmeester et al. 2004 ). In the nucleus, the p50/p65 dimer binds to the promoter regions of NFκB-dependent genes, thereby upregulating those involved in vascular inflammation and atherosclerosis ( Yerneni et al.1999 ; Bartchewsky et al. 2009 ). Dietary intake of wild blueberries reduced pro-inflammatory markers and ameliorated vascular inflammation in preclinical models ( Vendrame et al. 2013 ; 2016 ; Petersen et al. 2022 ). Supplementation with wild blueberry powder (8% freeze-dried in the diet for 8 wks, equivalent to 2 cups of blueberries) improved the pro-inflammatory status associated with metabolic syndrome in OZR ( Vendrame et al. 2013 ). Wild blueberry reduced plasma pro-inflammatory markers (TNF-α, IL-6, and C-reactive protein (CRP)), and downregulated NF-κB expression and pro-inflammatory markers (MCP-1, IL-8, and TNF-α) in obese rats ( Vendrame et al. 2013 ; 2016 ). Further, wild blueberries attenuated local inflammation in perivascular adipose tissue (PVAT), which is linked to vascular inflammation ( Petersen et al. 2022 ). Wild blueberry supplementation (3.8% freeze-dried powder in the diet for 10 wks and this dosage is equivalent to 1.5 cups) reduced vascular inflammation in diabetic db/db mice as shown by reduced circulating chemokines (MCP-1 and IL8/KC), reduced mRNA expression of inflammatory molecules (MCP-1, IL-8/KC, and VCAM-1) in the aortic vessel and vascular endothelial cells, and suppression of the binding of monocytes to the vasculature ( Petersen et al. 2022 ). In that study, wild blueberries reduced the expression of NOX4 and IκKβ in the aortic vessel and vascular endothelial cells, indicating dietary wild blueberries possibly mediate the vascular benefits by suppressing endothelial inflammation via the NOX4 mediated NFκB pathway. Further, that study investigated whether the vascular benefits of wild blueberries are mediated through their circulating metabolites ( Petersen et al. 2022 ). Mouse aortic endothelial cells were treated with high glucose and palmitate to induce endothelial inflammation and were incubated with serum obtained from standard diet fed mice (control serum) or wild blueberry fed mice (blueberry metabolites serum). Serum blueberry polyphenol metabolites reduced high glucose and palmitate-induced endothelial inflammation, as shown by reduced monocyte binding and reduced secretion of IL-8/KC ( Petersen et al. 2022 ). A dose- and time-dependent study demonstrated that wild blueberries dose-dependently (3.7% freeze-dried powder in the diet, which is equivalent to 1.5 cups, but not 1.23% or 2.46%) suppresses vascular inflammation as shown by reduced monocyte binding to the vasculature and mRNA expression of inflammatory molecules (MCP-1 and IL-8) in diabetic db/db mice ( Satheesh Babu et al. 2023 ). Together, preclinical studies suggest that wild blueberries efficiently suppress endothelial inflammation by suppressing NOX/NFκB signaling. Oxidative stress and changes in redox signaling contribute to the development of cardiovascular complications by activating endothelial inflammation and subsequent atherosclerosis ( Park and Park 2015 ). NOXs play a dual role in vasculature as they are essential for normal physiological function and contribute to vascular pathology ( Konior et al. 2014 ). NOX-mediated redox signaling and superoxide production are reported in vascular homeostasis, endothelial dysfunction, atherosclerosis, and hypertension ( De Marchi et al. 2013 ). eNOS produces NO in the healthy vasculature, whereas uncoupled eNOS produces ROS under pathological conditions ( Park and Park 2015 ). ROS also mediates peroxynitrite production by interacting with NO and reducing NO bioavailability. Hence, impaired redox signaling leads to endothelial dysfunction via uncoupled eNOS, peroxynitrite, and reduced NO bioavailability ( Symons 2013 ; Park and Park 2015 ; Cutler et al. 2017 ). Additionally, ROS activates the endothelium to enhance the binding of monocytes to the vasculature. By oxidizing LDL, ROS also mediates the formation of foam cells and atherogenic plaques. Consumption of wild blueberries (34 g freeze-dried powder) reduced neutrophil NOX activity in healthy males and was associated with increased FMD ( Rodriguez-Mateos et al. 2013 ). Wild blueberry intake (8% freeze-dried powder in the diet which is equivalent to 2 cups of blueberries for 8 wks) partially restored phenylephrine-induced constriction and attenuated exaggerated response to acetylcholine-induced vasorelaxation, which is associated with downregulation of inducible iNOS in OZR ( Vendrame et al. 2014 ). These findings suggest that blueberry can suppress NO overproduction, which mediates peroxynitrite radical production. Wild blueberry supplementation (3.8% freeze-dried powder in the diet, equivalent to 1.5 cups for 10 wks) to diabetic db/db mice reduced the expression of NOX4 in vascular endothelial cells and aortic vessels ( Petersen et al. 2022 ). Overall, evidence indicates that wild blueberries improve vascular complications by suppressing NOX-mediated redox signaling. Dyslipidemia, characterized by increased plasma total cholesterol, triglycerides, and non-HDL, contributes to vascular complications by enhancing endothelial inflammation, impairing NO synthesis, reducing NO bioavailability, and forming foam cells. Evidence from limited human studies indicates wild blueberry consumption has negligible effects on blood lipids. However, in animal models, wild blueberries modulate lipid metabolism by affecting synthesis and lysis pathways, which has been largely attributed to their anthocyanin content. Vendrame et al. ( Vendrame et al. 2014 ) observed that dietary incorporation of wild blueberry (8% freeze-dried powder in diet for 8 wks) significantly reduced total cholesterol and triglycerides levels in male OZR. These were accompanied by a downregulation in the gene expression of sterol regulatory element-binding protein (SREBP)-1, which promotes the synthesis and accumulation of triglycerides, and fatty acid synthase (FAS). Further, administration of 200 mg/kg body weight blueberry extract daily for 4 wks, significantly reduced serum total cholesterol and triglyceride levels in 28-month-old male Wistar rats ( Albrahim and Alonazi 2022 ). This was accompanied by a significant increase in hepatic antioxidant markers including glutathione, catalase, superoxide dismutase, glutathione peroxidase and reductase, as well as a reduction in hepatic inflammatory markers including TNF-α, IL-1β, and NFκB, and transforming growth factor (TGF)-β, a marker of fibrosis. Similarly, rabbiteye blueberry anthocyanin extract (400 mg/kg/day) significantly lowered serum total cholesterol and triglyceride levels in mice with streptozotocin (STZ)-induced diabetes ( Herrera-Balandrano et al. 2021 ). The same study indicated that blueberry anthocyanin extract (5 μg/mL) attenuated the increase in protein expression of SREBP-1, prevented the increase in acetyl-CoA carboxylase (ACC) and 3-hydroxy-3-methylglutaryl-CoA reductase (HMGCR), rate-limiting enzymes in fatty acid and cholesterol synthesis, respectively, while preventing the decrease in hormone sensitive lipase (HSL), a major controlling enzyme in lipolysis, in HepG2 cells. In another study, dietary incorporation of wild blueberries (1% in the diet) for 20 wks attenuated aortic sinus atherosclerotic lesion area and improved the expression of aortic, hepatic, and serum antioxidant markers in female ApoE −/− female mice ( Wu et al. 2010 ). The interaction between wild blueberry compounds and lipid metabolism extends to adipose tissue based on data from studies with animal models. In the study by Vendrame et al. ( Vendrame et al., 2014 ) mentioned above, dietary incorporation of wild blueberries also upregulated the gene expression of peroxisome proliferator-activated receptor (PPAR)α, which promotes the activation of enzymes involved in fatty acid oxidation, uptake and transport, in adipose tissue. Gene expression of SREBP-1 and ATP-binding cassette transporter A1 (ABCA1), which code for key regulatory proteins in cholesterol synthesis and reverse transport, respectively, were downregulated as was FAS expression. Blueberry supplementation, 10% in the diet for 8 wks, increased PPARα and PPARδ gene expression and prevented the increase in IL-1β and TNF-α while reducing the expression of cluster of differentiation (Cd)11d, a marker of macrophage infiltration in mesenteric fat tissue of male Wistar rats fed a high-fat diet ( Lee et al. 2018 ). Altogether, these findings provide evidence for wild blueberry-mediated improvement in dyslipidemia by regulating the expression of key enzymes and transcription factors involved in lipid metabolism in the liver and adipose tissue. Insulin resistance can lead to chronic hyperglycemia which induces oxidative stress and activation of pro-inflammatory pathways and endothelial cell damage ultimately contributing to the development and progression of cardiometabolic disorders. Evidence from acute clinical intervention studies ( Bell et al. 2017 ; Whyte et al. 2021 ) and animal studies indicate that dietary intake of wild blueberries and their polyphenols reduce blood glucose and insulin concentrations. Highbush blueberries have been shown to attenuate the increase in pancreatic β-cell mass induced by a high-fat diet ( Liu et al. 2019 ) and preserve pancreatic islets structure in diabetic mice. Additionally, they favorably affect glucose metabolism by modulating multiple signaling pathways in animal and cell culture models. For example, Shi et al. ( Shi et al. 2022 ) documented that dietary incorporation of rabbiteye blueberries (6.4 g/kg body weight/day for 8 wks) downregulated FoxO1, responsible for suppressing glucose uptake and glycolysis, and upregulated AMPK gene expression, which stimulates glucose uptake, through GTUT4 translocation, and oxidation, in the extensor digitorum longus muscle while increasing GLUT4 gene expression in the soleus of C57BL/6 male mice fed a high fat diet and 30% fructose in water. Also, Seymour et al. ( Seymour et al. 2011 ) demonstrated that highbush blueberry supplementation (2% in the diet for 90 days) suppressed skeletal muscle PPAR expression and activity in OZR. In diabetic male mice, wild blueberry intake (250 mg/kg body weight for 6 wks) increased the expression of genes associated with insulin signaling pathways (i.e., Egfr, Insr, Irs-1, Akt, Pi3k) and increased phosphorylation of PI3K and AKT proteins ( Qin et al. 2024 ). Wild blueberry intake also attenuated reduced hepatic glycogen storage accompanied by enhanced gene expression of enzymes involved in glycogen synthesis and a downregulation of genes coding for major enzymes in the gluconeogenic pathways (i.e., phosphoenolpyruvate carboxykinase, glucose-6-phosphatase). Furthermore, pterostilbene, a polyphenol found in blueberries, reduced the expression of genes required for gluconeogenesis including PPARδ coactivator (PGC)1α and FoxO1 in H4IIE cells ( Ren et al. 2018 ). In addition, supplementation with blueberry anthocyanins, cyanidin-3-glucoside, cyanidin-3-rutinoside, and peonidin-3-glucoside (200 mg/kg food for 12 wks) increased levels of serum and hepatic antioxidant markers while also downregulating the gene expression of pro-inflammatory markers in the liver of C57BL/6 male mice fed a high-fat diet ( Wu et al. 2018 ). Collectively, these findings support the role of wild blueberries and their polyphenols in improving insulin sensitivity and hyperglycemia and are supported by research with highbush blueberries. Evidence suggests these effects are due to modulation of the expression of major enzymes and transcription factors involved in insulin signaling and glucose metabolism in the liver and skeletal muscle. The glycocalyx is a carbohydrate-rich layer and biologically active barrier that covers the vascular endothelium, composed of proteoglycans [PG], core proteins with glycosaminoglycan (GAG) side chains, glycoproteins, and plasma proteins ( Kolarova et al. 2014 ; Kolsen-Petersen 2015 ). GAGs are polysaccharides composed of alternating disaccharide units of hexosamine (glycosamine or galactosamine) and uronic acid. The glycocalyx is critical in increasing NO bioavailability and vasodilation by translating shear stress to eNOS activation (mechanotransduction), preventing endothelial inflammation, maintaining endothelial cell permeability and lipoprotein binding and retention. Furthermore, the sulfation pattern, degree of sulfation, chain length, and domain organization also determine the functions of GAGs. Studies have reported that increased GAG sulfation enhances the LDL binding affinity to proteoglycans ( Tannock and King 2008 ; Babu et al. 2011 ; Becker et al. 2015 ). Altered glycocalyx thickness and composition are associated with pathological states, such as diabetes, hypertension and metabolic disorders leading to vascular complications ( Noble et al. 2008 ; Hiebert et al. 2014 ; Yen et al. 2015 ; Gowd et al. 2016 ). Targeting the preservation and restoration of the vascular glycocalyx with therapeutic modalities, e.g., medications and/or dietary approaches is one of the novel strategies for the treatment of chronic vascular complications. Even though studies on the effect of wild blueberry polyphenols on endothelial glycocalyx are limited, a few studies suggest that whole wild blueberry and polyphenol metabolites confer vascular benefits due to their effects on the structure and sulfation of the vascular glycocalyx. Animal studies have documented that dietary supplementation with wild blueberries modulates the structure and function of GAGs in the aortic vessels of SD rats and SHRs ( Kalea et al. 2006 ; Kristo et al. 2010 ). Wild blueberry-enriched diets (8% in diet equivalent to 2 cups) for 13 wks increased total GAGs and decreased the sulfation of GAGs in SD rats ( Kalea et al. 2006 ). In SHRs exhibiting abnormal GAG profile associated with a thicker subendothelial matrix and increased BP ( Kristo et al. 2012 ), consumption of wild blueberry-enriched diets (8% in diet equivalent to 2 cups) for 8 wks, normalized their abnormal GAG profile by redistributing GAG populations with an increased amount of hyaluronic acid (HA) and heparan sulfate (HS), and reduced GAG sulfation with implications in atheroprotection ( Kristo et al. 2012 ). This suggests that the reported anti-hypertensive effect of wild blueberries may be mediated through improved GAG profile ( Klimis-Zacas and Kristo 2012 ). Blueberry anthocyanins are extensively metabolized in humans suggesting the bioactivities of wild blueberries are mediated through their circulating metabolites ( De Marchi et al. 2013 ). Exposure of diabetic endothelial cells to a wild blueberry metabolite cocktail at physiologically relevant concentrations, restored normal levels of cell surface GAGs, which was associated with reduced endothelial inflammation ( Petersen et al. 2022 ). Thus, the cardioprotective role of wild blueberry consumption may be mediated through the effects of their metabolites on GAG structure and metabolism. Future clinical studies should validate the in vivo and ex vivo anti-hypertensive and atheroprotective role of wild blueberries and their metabolites as well as further explore the molecular mechanisms mediated via the vascular glycocalyx. Direct measurement of glycocalyx thickness in future clinical studies using sublingual imaging of the endothelial glycocalyx would be beneficial ( Klimis-Zacas and Kristo 2012 ). The rich and diversified profiles of wild blueberry bioactive polyphenols, including flavonoids, are not solely responsible for the health-protective effects of consumption. In fact, most parent polyphenol compounds present in wild blueberries are poorly bioavailable in human gastrointestinal systems after consumption. It is now well-recognized that wild blueberry polyphenols transit the human gastrointestinal tract after ingestion and are biotransformed by commensal microbiota in the gut into bioactive and more highly bioavailable circulating phenolic metabolites ( Jennings et al. 2020 ). Recent studies have estimated that microbial metabolites could account for up to 40% of active compounds in the blood ( Piccolo et al. 2018 ; Zheng et al. 2024 ). Evidence reinforces the hypotheses that gut microbial-derived metabolites of dietary polyphenols are anti-inflammatory and immunomodulatory, can have greater bioactivity than their parent/precursor structures, and have additive or synergistic effects collectively ( Nieman et al. 2017 ; Warner et al. 2017 ; Williamson et al. 2018 ; Cheatham et al. 2022 ; Zhang et al., 2023 ; Cheng et al. 2024 ). The breakdown of wild blueberry polyphenols into more bioaccessible and bioactive metabolites and concurrent modulation of the gut microbial community by these metabolites contribute to positive health outcomes. The human gut microbiome plays a crucial role in the host’s physiology and pathophysiology by producing vitamins, metabolizing dietary components, modulating metabolism, and regulating the immune system. Gut microbial enzymes metabolize most dietary phytochemicals including polyphenols which human digestive enzymes cannot process ( Satheesh Babu et al. 2023 ; Petersen et al. 2025 ). The resulting metabolites enter circulation and can mediate biological effects, including cardiovascular benefits, indicating that the impact of dietary phytochemicals on the host largely depends on gut microbes. Indeed, recent evidence demonstrates a strong association between dietary berries, gut microbes, phytochemical-derived microbial metabolites, and cardiovascular health ( Petersen et al. 2025 ). Only 5–10% of anthocyanins, including those in wild blueberries, are metabolized in the small intestine, and the remaining compounds are processed by gut microbes in the large intestine ( Cutler et al. 2017 ; Rodriguez-Mateos et al. 2019 ). This indicates that the biological effects of phytochemicals are mediated by their metabolites. The carbohydrates released during this metabolism support the growth of commensal microbes, emphasizing a symbiotic relationship between gut microbes and dietary phytochemicals like anthocyanins ( Satheesh Babu et al. 2024 ). Indeed, wild blueberry supplementation positively affects gut microbes in preclinical models ( Lacombe et al. 2013 ; Petersen et al. 2022 ; Satheesh Babu et al. 2023 ; 2024 ). It is important to note that wild blueberry benefits for cardiovascular health may not entirely rely on levels of circulating bioactive metabolites. Blueberry-induced changes to the gut microbiome and intestinal environment can modulate circulating immune factors and reduce systemic inflammation that can lead to cardiovascular benefits. For example, high levels of the mucosa-associated bacteria, Akkermansia muciniphila , are associated with protective effects against numerous diseases such as obesity, type 2 diabetes, and cardiovascular diseases ( Yan et al. 2021 ; Pellegrino et al. 2023 ). In contrast, high levels of Akkermansia combined with low dietary fiber has also been linked to adverse outcomes such as damage to the intestinal epithelium. Wild blueberry consumption, which provides prebiotic dietary fiber and polyphenols, has been shown to increase Akkermansia muciniphila in murine models and also suggesting that people with cardiometabolic disorders and lower levels of Akkermansia may benefit from increasing their intake of wild blueberries ( Li et al. 2016 ; Luo et al. 2022 ). The association between wild blueberries, gut microbes, and cardiovascular health has been reported in recent studies ( Satheesh Babu et al. 2023 ; 2024 ). A dose- and time-dependent study assessed the effect of wild blueberries on cardiovascular health and their relationship with gut microbes ( Satheesh Babu et al. 2023 ). In this study, male diabetic mice were given a diet supplemented with different doses of freeze-dried wild blueberries (equivalent to ½, 1, and 1.5 human servings) for 4, 8, or 12 wks. Wild blueberries suppressed vascular inflammation and improved gut dysbiosis in diabetic mice depending on the dosage and treatment duration. Most importantly, wild blueberries reduced the relative abundance of an opportunistic microbe that was positively associated with vascular inflammation ( Desulfovibrio ) and increased a commensal microbe that was negatively associated with vascular inflammation ( Akkermansia ) ( Satheesh Babu et al. 2023 ). This study suggests that wild blueberries may exert some cardiovascular benefits by modulating gut microbial populations. Trimethylamine-N-oxide (TMAO) is derived from a gut microbial metabolite, and human studies indicate it is strongly linked to an increased risk of developing cardiovascular disease ( Agus et al. 2021 ). Nutritional interventions utilizing phenolic compounds have been proposed as an effective strategy to reduce circulating TMAO ( Iglesias-Carres et al. 2021 ). In a recent preclinical study, dietary incorporation of wild blueberries at a dose equivalent to 1.5 human servings reduced TMAO, and this effect was associated with specific gut microbes ( Satheesh Babu et al. 2024 ). Wild blueberries increased the relative abundance of an unclassified genus of the family Coriobacteriaceae and showed a trend for increased relative abundance of Oscillospira , and an unclassified organism in the eS24-7 family. Notably, these taxa were negatively associated with circulating TMAO. This suggests that the beneficial effect of wild blueberries on TMAO could be mediated by increasing the relative abundance of gut microbes that are negatively associated with TMAO. In humans, there are few studies that have examined the impacts of wild blueberry consumption on the gut microbiome. One study provided evidence that wild blueberry consumption beneficially modulates the gut microbiota, specifically by acting as a prebiotic. Analysis of fecal microbial profiles from a crossover dietary intervention that included 15 middle-aged males consuming 25 g of wild blueberry powder daily showed increased relative abundance of Bifidobacterium spp ., which was not observed during the placebo period ( Vendrame et al. 2011 ). In a follow-up analysis, the authors identified that the increases were specifically attributed to B. infantis subsp, infantis , a probiotic organism with immunomodulatory effects ( Guglielmetti et al. 2013 ). In a separate investigation, Canipe et al. ( Canipe et al. 2021 ) found that wild blueberry consumption by older adults for 3–6 months increased the alpha diversity of the gut microbiome, which was linked to improved cognitive outcomes in the study participants. Evidence indicates that the human gut microbiome is an important determinant of interindividual variation in responses to dietary polyphenol intake which could have important implications on cardiovascular health benefits of wild blueberry consumption. As previously stated, individual differences in gut microbiome can result in differing metabolites with altered bioaccessibility and bioavailability ( Williamson 2025 ). Future research should consider whether baseline gut microbiome profiles predict who will benefit most from a blueberry dietary intervention as it relates to specific health outcomes. Additionally, further evaluation is needed to determine whether long-term wild blueberry consumption can shift gut microbial composition in ways that enhance effectiveness of the intervention. Evidence in a human study suggests that chronic wild blueberry intake may enhance polyphenol metabolite bioavailability based on plasma metabolites following acute and chronic (4 wks) intake of wild blueberries, which could be related to changes in the metabolizing capacity of enzymes and gut microbiota with consistent exposure ( Feliciano et al. 2016 ). Overall, these preclinical and clinical data suggest a connection between wild blueberries, gut microbes, and cardiovascular health. However, the role of gut microbes in metabolizing wild blueberry phytochemicals is largely unexplored. Further, the relationship between dietary wild blueberries, gut microbes, wild blueberry-derived metabolites, and cardiovascular health has yet to be determined. There are several knowledge gaps regarding the effects of wild blueberries on cardiometabolic health. These include limited research on dosing in healthy populations and those with disease or disease risk factors, food matrix interactions, the impact of wild blueberry consumption on vascular health and BP in specific populations, as well as their influence on glycemic control in individuals with prediabetes and diabetes. There is also limited information on approaches for enhancing beneficial human health effects of wild blueberries through food- and technology-based approaches. The food matrix is one of the first factors that must be considered. The stability and bioaccessibility of polyphenols and other common blueberry-derived metabolites, such as anthocyanins, are increased in a whole food matrix ( Kumkum et al. 2024 ). Therefore, one aspect of research aimed at advancing personalized and precision nutrition could focus on optimizing the absorption of these compounds through recommended food and nutrient pairings, preparation methods, timing of consumption, and optimal dosing strategies. Studies that include the use of wearables (e.g., continuous glucose monitoring, 24-h ambulatory BP monitoring), and measure hemoglobin A1c and insulin resistance are needed to more comprehensively assess cardiometabolic effects. Furthermore, though blueberry consumption in general has been demonstrated to improve inflammation, oxidative stress, and vascular function, wild blueberry-specific effects remain underexplored and results are mixed. Similarly, additional understudied areas requiring further investigation include the potential health benefits of phytochemicals in wild blueberries and their effects on other health outcomes and disease process-associated end-organ damage (e.g., kidneys, brain, and eyes). Long-term adherence to wild blueberry consumption, along with potential barriers and an individual’s perceived health benefits, remains poorly understood. Integrative approaches that connect different areas of health and disease pathophysiology and risk are needed, such as evaluation of the gut-brain-axis and linkages with cardiometabolic health. Research evaluating interindividual and subgroup variability in response to wild blueberry consumption and underlying factors and mechanisms are lacking. Precision nutrition is an emerging approach that considers individual variability in dietary responses and nutritional needs. This strategy aims to tailor dietary recommendations based on genetic, environmental, and lifestyle factors to optimize health outcomes. The role of factors such as the gut microbiome, habitual dietary patterns, health status, lifestyle choices, and environmental exposures need evaluation in the context of responsiveness to wild blueberry consumption. Precision nutrition offers an emerging framework to address this gap by considering how genetic, environmental, and lifestyle factors influence dietary responses and nutrient metabolism. Factors such as the gut microbiome, habitual dietary patterns, health status, genetic variability, and other factors likely contribute to differences in the bioavailability and efficacy of blueberry-derived polyphenols. Future studies should examine these influences collectively to better understand the determinants of individual and subgroup responsiveness to wild blueberry intake and their implications for cardiometabolic health. Nutrigenetics, or the impact of genetic polymorphisms on nutrient metabolism, is also a key pillar of precision nutrition. Once ingested, polyphenols such as anthocyanins undergo extensive metabolism by the liver and individual genetics can significantly influence their metabolism, leading to variations in bioavailability and efficacy. For instance, polymorphisms in genes encoding enzymes such as UDP-glucuronosyltransferases (UGTs) and sulfotransferases (SULTs) alter the conjugation and subsequent excretion of polyphenols. A study by Manach et al. (2004) highlighted genetic variations in UGT1A1 can affect the glucuronidation of flavonoids like quercetin, impacting their bioavailability and biological activity ( Manachet al. 2004 ). Similarly, studying individuals with polymorphisms in the catechol-O-methyl-transferase (COMT) gene, which can influence the methylation of flavonoids (2013), showed that individuals with the COMT Val158Met polymorphism exhibited different metabolic responses to green tea catechins ( Miller et al. 2012 ). Such genetic differences underscore the importance of understanding gene-nutrient interactions in personalized and precision nutrition approaches. Ideally, research should consider the impact of multiple factors simultaneously on the efficacy of wild blueberry consumption for cardiovascular health and interindividual variation in responses.