Blueberry improves components of metabolic syndrome in animal studies: a systematic review and meta-analysis

doi:10.21203/rs.3.rs-1612980/v1

Metabolic syndrome (MetS) is the co-occurrence of several interconnected metabolic disorders and its prevalence is rising in the world. We hypothesized that blueberry (BB) feeding will have positive effects on components of MetS according to studies which used animal subjects. A systematic search for the studies in Science Direct, Embase, Cochrane and PubMed databases was done. The Studies which investigated effects of BB on components of MetS in animal models were included. Of 1030 potentially relevant studies, after investigation, 28 animal studies remained for further investigation. Of these, 1 study was conducted using pigs, one study using hamsters, 15 studies using mice and 11 studies using rats. 18 studies were eligible for the meta-analysis, and others were included in systematic review. The meta-analysis was done by Comprehensive Meta-analysis Software.The results of the meta-analysis demonstrated no significant effect of blueberry feeding on body weight [p = 0.65 CI95%: (-3.029, 1.892)]. However, a statistically significant improvement of systolic blood pressure [p < 0.001, CI95%: (-0.916, -0.283)], diastolic blood pressure[p = 0.01, CI95%: (-1.10, -0.13)], triglycerides[p = 0.01, CI95%: (-1.018, -0.109], total cholesterol [p < 0.001 CI95%: (-1.693, -0.782)], low density lipoprotein(LDL) [p = 0.008, CI95%: (-2.182, -0.334)], high density lipoprotein(HDL) [p = 0.02, CI95%: (0.077, 1.057)], blood glucose [p < 0.001, CI95%:( -1.638, -0.623)] and insulin level [p < 0.001, CI95%: (-1.711, -0.688)] was reported.

Conclusion: this study showed that blueberry can be effective in ameliorating some components of metabolic syndrome in animal models. There is a need to conduct more studies on this subject in humans.

Nutrition & Dietetics

Integrative & Complementary Medicine

Endocrinology & Metabolism

Preventive Medicine

Clinical Pharmacology

Pharmacodynamics

Pharmacokinetics

blood pressure

body weight

glucose

insulin

triglyceride

Metabolic syndrome (MetS) is a complex condition which has different definitions according to the different criteria. It is a cluster of dyslipidemia, elevated blood pressure, insulin resistance, obesity and low grade inflammation [1, 2]. In addition to their harmful nature, insulin resistance and hyperinsulinemia are also contributors to hyperstension which makes the need for urgent and efficient interventions [3]. The prevalence of this syndrome is estimated to be 4.8 to 7% in the young age population in the world, and it is mostly attributed to changes in lifestyle factors such as diet and activity status in individuals [4–6]. Higher consumption of fats and sugar are a deleterious trend worldwide which together with a sedentary lifestyle account for higher burden of MetS worldwide[5]. Increasing prevalence of this condition and its association with type 2 diabetes and cardiovascular disease risk and mortality, which count as the number one cause of morbidity throughout the world, warn us to take serious steps toward preventing and treating this syndrome or its components [7–9]. Different treatment policies have been proposed for MetS which include modulation of gut microbiome, active lifestyle, healthy diet, use of functional foods and even surgery to treat its components such as obesity [6, 10–12] .

According to WHO ( world health organization) MetS is defined as hyper-insulinemia (the upper fourth of the fasting insulin level among non-diabetic subjects) or hyperglycemia (fasting blood sugar ≥ 110 mg/dl) in addition to at least two of: waist girth ≥ 94 cm, dyslipidemia (triglycerides ≥ 150 mg/dl or HDL cholesterol < 40 mg/dl), and blood pressure ≥ 140/90 mmHg or taking BP lowering medications [13]. The International Diabetes Federation (IDF) has defined MetS as central obesity in addition to any two of : 1.triglycerides ≥ 150mg/dl, 2. HDL < 40mg/dl in males and < 50 mg/dl in females, 3. systolic blood pressure ≥ 130mmHg and diastolic blood pressure ≥ 85mmHg and 4.fasting blood glucose ≥ 100mg/dl [14]. The National Cholesterol Education Program (NCEP ATP III-2001) and The AHA/NHLBI 2005 have proposed the MetS criteria as having any three of the following: Waist Circumference > 102cm in men and 88cm in women, fasting plasma glucose ≥ 110mg/dl, blood pressure ≥ 130/85mmHg, triglycerides ≥ 150mg/dl and HDL < 40 and < 50 in men and women respectively [15].

Functional foods have gained wide popularity among health care professionals and the people, because it has been revealed that that can be helpful in the prevention of chronic diseases [16]. Berries, as an example of functional foods are rich in several nutritious compounds including fiber, vitamins ( C ), minerals and fatty acids in addition to their polyphenols [17–19].

Blueberry, native to north America, belongs to the genus Vaccinium, subgenus Cyanococcus and family Ericaceae or Heath which has five major grown types including: wild or lowbush, Highbush, Southern Highbush, Rabbiteye and Halfhigh Blueberries [19]. The polyphenols of blueberry have anti-inflammatory and anti-oxidative, anti-bacteria, anti-cancer and anti-allergic characteristics.[18, 20] These compounds have beneficial effects in preventing cardiovascular diseases (CVD), cancer, liver damage, neurodegenerative diseases and psychiatric conditions such as depression [17].

The effects of different functional foods including blueberry on components of metabolic syndrome is investigated in different studies using animal models, but there is a not enough comprehensive reviews about this topic. To the best of our knowledge, there is no systematic review and meta-analysis or meta-analysis about the role of blueberry feeding on metabolic syndrome in animal models. We hypothesized that blueberry is a beneficial option for MetS components in animal subjects and in this review we aimed to test this hypothesis.

2.1. Search plan

The search for this review was done from February 21 2021 to March 5 2021, and relevant articles were recognized through Science Direct, Cochrane, Embase and PubMed databases. Another complementary search was done in December 2021 for any relevant article. Search terms were blueberry or blueberries [MeSH term] and Metabolic Syndrome [MeSH term], blueberry and blood pressure [MeSH term] or hypertension [MeSH term] or high blood pressure, blueberry and dyslipidemia or lipids/blood [MeSH term] or cholesterol/blood [MeSH term] or triglyceride/blood [MeSH term] or HDL/blood [MeSH term] or LDL/blood [MeSH term], blueberry and insulin [MeSH term] or insulin resistance, blueberry and body weight or obesity [MeSH term]. The search included animal studies and only the word blueberry, not different kinds.

2.2. Study selection criteria

Studies which investigated the effects of blueberry on systolic and diastolic blood pressure, obesity, cholesterol (LDL and HDL) level, triglyceride level, blood glucose, and body weight were selected. The selection process had two phases: 1. Title and abstract assessment and 2.Full text assessment. Any essay having the following criteria was included: a. feeding with blueberry b. studies which investigated metabolic syndrome or its components c. availability of English full text.

This process was done by all researchers and all studies were investigated; in cases of indecisiveness, articles qualification was discussed, until a decision was made finally. Time range of assessed studies was from January 2006 to August 2021.

2.3. Data collection

A comprehensive database was created by gathering the data about the design, amounts, time, materials and population. Additionally, blood glucose, HDL cholesterol, triglyceride, blood pressure measures and body weight amounts were extracted.

2.4. Statistical analyses

Meta-analysis was done by Comprehensive meta-analysis [21] software version 2.2.064. For homogeneous studies fixed effect model, and for heterogeneous studies random effect model was used. The effect size index which was used in all analysis was standard difference in means.

In total, 1030 potentially relevant articles were recognized from the following databases: 131 from PubMed, 353 from Science Direct, 138 from Cochrane library and 408 from Embase. After the primary evaluation, articles with unsuitable title or abstract were excluded (N=851). After removing duplicate articles (N=147), 32 articles remained for further assessment and 4 other articles were excluded due to: book chapters (2 studies) [22, 23], short communication (1 study) [24] and letter (1 study) [25] . We scrutinized the full text of remaining 28 articles (Figure 1).

Study characteristics

The features of 28 animal studies evaluated in this meta-analysis are demonstrated in Table 1. These studies were carried out in Asia[26-33], South America [34, 35] , Australia [36] , the USA [37-46] , Canada [47-51]and Europe, [52, 53] and published between 2007 and 2021. One study was done on pigs [47] , one on hamsters[28] , 15 on mice [27, 29-33, 35, 36, 38, 40, 42, 43, 45, 46, 51, 54] and 11 on rats [26, 34, 37, 39, 41, 44, 48-50, 52, 53]. Among these 28 studies, 5 studies were about hyperstension, 8 were about obesity, 8 were about insulin resistance and 7 were about lipid profile. The studies utilized different kinds of blueberry that included blueberry powder [36, 41, 46] , freeze-dried blueberry [26, 37-40, 43-45, 48, 49] , freeze-dried fermented blueberry [52] , blueberry purified anthocyanin [31], fermented blueberry beverage[42] , juice [29, 32, 51, 53] , puree [50] , blueberry extract [27, 28, 30, 33-35].Furthermore, blueberry dosage varied among different studies (shown in table 1) with different units. Study duration was different and varied between 2 and 21 weeks, and animal age was between 3-13 weeks.

Findings

Effects of blueberry on blood pressure

In the studies about blood pressure which were included in this review, there was a significant effect of blueberry on blood pressure reduction. For instance, Ahren et al. reported a significant decrease in both systolic and diastolic blood pressure (p = 0.008 and 0.013 respectively) after 4 weeks of blueberry feeding[52]. Shaughnessy et al. reported a 30 percent reduction in systolic blood pressure following 6 weeks of blueberry feeding[48] .

Systolic blood pressure Meta-analysis: Five studies [26, 37, 48, 49, 52] were eligible for this outcome, according to assessment of study homogeneity results, I²=40.88 and p=0.14 in Cochrane test, the studies were homogenous. The standardized mean difference between control and intervention groups was -0.59 (p<0.001, CI95%: (-0.916, -0.283). It was confirmed that the intervention had a significant effect on decreasing systolic blood pressure (Figure2.a, b)

Diastolic blood pressure Meta-analysis: Three studies [48, 49, 52] were eligible for this outcome. According to assessment of study homogeneity results, I²=62.11and p=0.07 in Cochrane test, the studies were homogenous. The standardized mean difference between control and intervention groups was -0.61 (p=0.01, CI95%: (-1.10, -0.13). It was confirmed that the intervention had a significant effect on decreasing diastolic blood pressure.

Distribution bias was not significant according to Kendall tau test (Begg-Mazumdar: Kendall's tau = 0, P = 1) (Figure3.a, b).

Effects of blueberry on Insulin Resistance and glucose

Lee et al., demonstrated that providing 10g/100g diet BB for 8 weeks for rats did not affect fasting glucose and insulin (p>0.05), but stimulated insulin sensitivity and signaling. Blood insulin and glucose had lower concentrations in the blueberry fed group after oral-glucose-challenge test (p<0.05 and p=0.07, respectively) [39] . Seymour et al, reported that 90days supplementation with 2% blueberry powder in obesity‐prone Zucker Fatty rats remarkably reduced fasting insulin and glucose(p<0/05) [41] .

Blood insulin and glucose meta-analysis: Regarding these outcomes four studies [29, 30, 40, 46]were eligible for meta-analysis. According to assessment of study homogeneity results, I²=37.76and p=0.18 in Cochrane test, the studies were homogenous. The standardized mean difference between control and intervention groups was -1.20 (p<0.001, CI95%: (-1.711, -0.688) and p< 0.001, CI95 %:( -1.638, -0.623) for insulin and glucose respectively. It was confirmed that the intervention had a significant effect on decreasing insulin and glucose.

Distribution bias was not significant according to Kendall tau test (Begg-Mazumdar: Kendall’s tau = -.83, P = 0.08 and Begg-Mazumdar: Kendall’s tau = -.16, P = 0.73 for glucose and insulin respectively) (Figure 4.a,b,c,d).

Effects of blueberry on Lipid Profile

Prior et al, reported that supplementing high-fat fed male mice with 10 % blueberry freeze-dried powder along with drinking water for 85 days caused a significant decline in triglycerides level(p<0.012) .[45] In the study conducted by Si et al, it was observed that blueberry caused a significant decrease in triglycerides (23.48%) and total cholesterol (23.29%) and a significant increase in HDL (33.06%) amounts [30].

Tg meta-analysis: Five studies [28, 29, 34, 35, 38] were eligible for meta-analysis of this outcome. According to assessment of study homogeneity results, I²=23.046and p=0.26 in Cochrane test, the studies were homogenous. The standardized mean difference between control and intervention groups was -0.56 (p=0.01, CI95%: (-1.018, -0.109). It was confirmed that the intervention had a significant effect on decreasing triglycerides.

Distribution bias was not significant according to Kendall tau test (Begg-Mazumdar: Kendall's tau = -.7, P = .08) (Figure5.a,b).

HDL meta-analysis: five studies [28, 29, 34, 38, 47]were eligible for meta-analysis. According to assessment of study homogeneity results, I²=40.84 and p=0.14 in Cochrane test, the studies were homogenous. The standardized mean difference between control and intervention groups was 0.56 (p=0.02, CI95%: (0.077, 1.057). It was confirmed that the intervention had a significant effect on increasing HDL.

Distribution bias was not significant according to Kendall tau test (Begg-Mazumdar: Kendall's tau =.5, P = .22) (Figure 5.c,d)

LDL meta-analysis: five studies [28, 29, 34, 38, 47]were eligible for meta-analysis. According to assessment of study homogeneity results, I²=64.59 and p=0.02 in Cochrane test, the studies were heterogeneous. The standardized mean difference between control and intervention groups was -1.26 (p=0.008, CI95%: (-2.182, -0.334). It was confirmed that the intervention had a significant effect on decreasing LDL.

Distribution bias was not significant according to Kendall tau test (Begg-Mazumdar: Kendall's tau =-.9, P = .02) (Figure 5.e,f).

TC meta-analysis: Six studies [28, 29, 34, 35, 38, 47]were eligible for the meta-analysis.. According to the results of study homogeneity assessment, based on Cochrane test (p=0.62) and I²=0.00, studies were considered homogeneous. Standardized mean difference between control and intervention groups was -1.23 (p<0.001 CI95%: (-1.693, -0.782)). It was confirmed that the intervention had a significant effects on reduction of TC.

Distribution bias was significant according to Kendall tau test (Begg-Mazumdar: Kendall's tau = -.9, P = .01) (Figure 5.g,h)

Effects of blueberry on body weight

In a study carried out by Wu et al., it was demonstrated that supplementation with 200mg/kg blueberry purified anthocyanin for 12 weeks in 60male mice prevented body weight gain by 55/4% (p<0.05) [31].

Also another study conducted by Wu et al, showed that consumption of blueberry juice for 12 weeks in 48 male mice reduced body weight by 7.3 % [32]. In another study Johnson et al, reported that 72 diet-induced obese mice fed with 30% blueberry beverage for 12 weeks had the lowest body weight gain in comparison to other groups(p<0.05)[42]. Wu et al, reported that 200 mg/kg artificial planting blueberry supplementation for 8 weeks in male high-fat diet-induced obese mice caused body weight gain to be effectively reduced by 19.4% [33]. In another study conducted by Liu et al., it was reported that 54 high-fat diet mice fed with 1% and 2% blueberry extract had decreased body weight gain by 20–23% (p<0.05).[27] DeFuria et al., found that 8 week supplementation with 20g/d blueberry powder in male mice did not influence high fat diet induced body weight gain(p<0.05) [27].

Body weight meta-analysis: Four studies [36, 44, 51, 53] were eligible for meta-analysis. According to the results of study homogeneity assessment, based on Cochrane test (p<0.001) and I²=93.27, studies were considered heterogeneous. Standardized mean difference between control and intervention groups was -0.57 (p=0.65 CI95%: (-3.029, 1.892)). It was confirmed that the intervention had no significant effects on reduction of body weight.

Distribution bias was not significant according to Kendall tau test (Begg-Mazumdar: Kendall's tau = 0.0, P = 1)(Figure 6.a,b).

The results of this study show that, blueberry supplementation in animals has positive effects on TG, HDL-c, LDL-c, TC, SBP, DBP, blood glucose and insulin; but no significant effects were reported in terms of body weight reduction. So, we can say that our hypothesis is generally accepted and BB feeding has beneficial effects on animal subjects of MetS.

According to the results of this study, blueberry supplementation caused a significant reduction in SBP and DBP. It has been understood that oxidative stress and inflammation are two important contributors to hypertension. In the study conducted by Elks et al., it was revealed that blueberry feeding in rats diminished the production of free radicals and maintained the concentration of glutathione and catalase, which in turn improved blood pressure. Blueberries are known to be Reactive oxygen species/reactive nitrogen species (RONS) scavengers. Superoxide is a RONS, and when scavenged or decreased causes improvement of blood pressure [36, 37, 55]. It has also been proposed that in the oxidative stress state reactive oxygen species react with Nitric Oxide (NO) in the endothelium and they reduce its bioavailability, resulting in increased blood pressure, and blueberry has anti-oxidative effects so it reduces blood pressure[26, 48, 52, 56]. Furthermore, blueberry feeding increases NO production which in turn causes vasodilation and decreases blood pressure[26, 49].

This review showed that blueberry feeding in animals improved insulin resistance and glucose metabolism. Blueberry feeding causes changes in gut microbiota and makes Gammaproteobacteria more prevalent in the ileum, and this in turn increases villus height, increases goblet cells and expression of Muc2 Defb2 in the ileum cells and finally causes more integrity of the gastrointestinal tract[31, 39, 57]. Additionally, liver oxidative stress and p-IRS1 hepatic level will be reduced which will improve insulin signaling and improve insulin resistance [31, 39, 57]. Blueberry increases the expression of GLUT-4, GCK, IR and IRS and activates AKT, but decreases GSK-3 and finally improves insulin sensitivity[29]. Moreover, insulin resistance is induced by obesity, in which there is increased expression of TNF-α, IL-1β, and IL-6 and low grade systemic inflammation; blueberry feeding decreases this inflammation and impedes the expression of these inflammatory cytokines and thereby prevents death of adipocytes, increases beta0cell survival and improves insulin resistance[29, 40]. It has also been proposed that diacylglycerol (DAG) blocks the insulin signaling pathway, and blueberry anthocyanins prevent this blockade[30].

As mentioned before, blueberry feeding is effective in improving the lipid profile. Blueberry increases oxidation of fatty acids in the liver and prevents steatosis in the liver tissue, and it also increases the excretion of bile acids and neutral sterols through feces [28]. Liang et al., reported no effect of blueberry anthocyanins feeding on expression of CYP7A1 and LXRa which regulate the pathway of converting cholesterol into bile acids [28]. Expression of genes of tPAI-1 and IL-6 (excreted by adipocytes) are decreased by cyanidin-3-glucoside which is an anthocyanin abundant in blueberry. Blueberry decreases oxidative stress by decreasing lipid peroxidation too[34]. It has been known that there is an association between hypercholesterolemia and increased concentration of Malondialdehyde (MDA) and ROS which is ameliorated by blueberry antioxidant characteristics [34, 35].

It has been shown that blueberry can reduce hyperphagia, and as a result it decreased cumulative body weight gain in mice[51]. Adiponectin gene expression is restricted in the presence of inflammation, and the anti-inflammatory and anti-oxidative features of blueberry polyphenols cause an increased secretion of adiponectin which in turn Improves insulin sensitivity and prevents weight gain[51]. Wu et al., reported that blueberry feeding may suppress the fatty acid synthesis related gene( FAS and PPARγ) and cause the expression of beta-oxidation related gene which in result regulated lipid metabolism[32]. It has also become known that blueberry feeding causes a decline in the leptin level which again modulates lipid metabolism in the obese subjects[32]. Blueberry anthocyanins decrease the size of fat adipose tissue cells, decrease the secretion of leptin and prevent lipid accumulation[33]. Gram-negative bacteria secret Lipopolysaccharides (LPS) which can increase intestinal permeability and result in inflammatory condition and weight gain, and it has been shown that blueberry polyphenols can reduce the inflammation caused by the LPS and prevent weight gain[27].

The results of this review cannot be applied to human subjects without future thorough investigations because in animal studies, environment can be manipulated and intervention and control groups may have similar situations in majority of experiments, whereas humans in different studies have diverse lifestyles and baseline characteristics, and metabolic mechanisms between animals and humans are different.

In conclusion, despite the fact that several studies showed no benefit of blueberry consumption on body weight, the majority of studies included in this meta-analysis demonstrated that blueberry will improve components of metabolic syndrome in animal models by different mechanisms. According to the beneficial effects of blueberry feeding on components of MS in animal models, there is a need for further well-designed clinical trials and comprehensive reviews about the effects of blueberry in human subjects with MS to approve this finding.

Source of support

The authors of this study want to express their gratitude to vice chancellor of research in Tabriz University of Medical Sciences for their financial supports.This work was supported by the Tabriz University of Medical Sciences under grant number: 67677, 1400.02.26. We declare that Tabriz University of Medical Sciences supported this work, but they did not have any role in study design; in the collection, analysis and interpretation of data; in the writing of the report; and in the decision to submit the article for publication.

Author contributions

Conceptualization, and data acquisition: H. A, A. M, and B. P. G; funding acquisition and project administration: B. P. G; investigation: all the authors; writing - original draft: H. A, and A. M; writing –review & editing: all the authors; formal analysis: P. S.

Author Declarations

This manuscript has been read and approved by all the authors, and the requirements for authorship have been met, and that each author believes that the manuscript represents honest work. This manuscript has not been published previously, and it is not under consideration for publication elsewhere.

Conflict of interest

The authors of this systematic review have no conflict of interest to declare.

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Data availability statement:

The data that support the findings of this study are available from the authors upon reasonable request.

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Seymour M, Tanone I, Lewis S, Urcuyo-Llanes D, Bolling SF, Bennink MR. Blueberry‐Enriched Diets Reduce Metabolic Syndrome and Insulin Resistance in Rats. The FASEB Journal. 2009;23:563.31-.31.
Johnson MH, Wallig M, Vital DAL, de Mejia EG. Alcohol-free fermented blueberry–blackberry beverage phenolic extract attenuates diet-induced obesity and blood glucose in C57BL/6J mice. The Journal of Nutritional Biochemistry. 2016;31:45–59.
DeFuria J, Bennett G, Strissel KJ, Perfield JW, Milbury PE, Greenberg AS, et al. Dietary blueberry attenuates whole-body insulin resistance in high fat-fed mice by reducing adipocyte death and its inflammatory sequelae. The Journal of nutrition. 2009;139(8):1510–6.
Khanal RC, Howard LR, Wilkes SE, Rogers TJ, Prior RL. Effect of dietary blueberry pomace on selected metabolic factors associated with high fructose feeding in growing Sprague–Dawley rats. Journal of medicinal food. 2012;15(9):802–10.
Prior RL, Wu X, Gu L, Hager T, Hager A, Wilkes S, et al. Purified berry anthocyanins but not whole berries normalize lipid parameters in mice fed an obesogenic high fat diet. Molecular nutrition & food research. 2009;53(11):1406–18.
Elks CM, Terrebonne JD, Ingram DK, Stephens JM. Blueberries improve glucose tolerance without altering body composition in obese postmenopausal mice. Obesity. 2015;23(3):573–80.
Kalt W, Foote K, Fillmore S, Lyon M, Van Lunen T, McRae K. Effect of blueberry feeding on plasma lipids in pigs. British Journal of Nutrition. 2008;100(1):70–8.
Shaughnessy KS, Boswall IA, Scanlan AP, Gottschall-Pass KT, Sweeney MI. Diets containing blueberry extract lower blood pressure in spontaneously hypertensive stroke-prone rats. Nutrition Research. 2009;29(2):130–8.
Blanton C, He Z, Gottschall-Pass KT, Sweeney MI. Probiotics blunt the anti-hypertensive effect of blueberry feeding in hypertensive rats without altering hippuric acid production. PloS one. 2015;10(11):e0142036.
Gillespie D, Gottschall-Pass K, Sweeney M. Blueberry Puree Increases HDL‐cholesterol in Rats. The FASEB Journal. 2015;29:922.17.
Vuong T, Benhaddou-Andaloussi A, Brault A, Harbilas D, Martineau L, Vallerand D, et al. Antiobesity and antidiabetic effects of biotransformed blueberry juice in KKA y mice. International journal of obesity. 2009;33(10):1166–73.
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Li H, Park H-M, Ji H-S, Han J, Kim S-K, Park H-Y, et al. Phenolic-enriched blueberry-leaf extract attenuates glucose homeostasis, pancreatic β-cell function, and insulin sensitivity in high-fat diet–induced diabetic mice. Nutrition Research. 2020;73:83–96.
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Johnson SA, Figueroa A, Navaei N, Wong A, Kalfon R, Ormsbee LT, et al. Daily blueberry consumption improves blood pressure and arterial stiffness in postmenopausal women with pre-and stage 1-hypertension: a randomized, double-blind, placebo-controlled clinical trial. Journal of the Academy of Nutrition and Dietetics. 2015;115(3):369–77.

Table 1 Main features of studies included in this review

Main Result	Published	Age of subjects	Type of Blueberry	Study duration	Dosage of administration	Number of subjects	Reference
In 6 and 12 week studies, blueberry fed hypertensive rats had lower systolic and mean arterial blood pressures compared to control group.(P<0/05)	2011	7 weeks	Freeze-dried	12 weeks	20g/kg	80 {48 hypertensive and 32 Normotensive} Rats	Carrie M. Elks[37]	1
Week4:19% reduction in SBP(p=0/022) Week6:30% reduction in SBP(p=0/013) Week7and8:18% reduction in SBP(p=0/0586)	2009	7-8 weeks	freeze-dried blueberry	8 weeks	30g/kg	24 male Wistar rats(12 normotensive and 12 hypertensive)	Kevin S. Shaughnessy[48]	2
Diastolic blood pressure decreased significantly(p=0/046), systolic blood pressure decreased but not significantly(p=0/220)	2015	8 weeks	Freeze-dried	8 weeks	3 % blueberry	32 male spontaneously hypertensive rats	Cynthia Blanton[49]	3
Week8:11%reduction in systolic blood pressure(p=0/018) Week10:14%reduction in systolic blood pressure(p<0/0001)	2012	8 weeks	Freeze-dried blueberry	10 weeks	2% blueberry	32 male Wistar rats	Ana Rodriguez-Mateos[26]	4
Fermented blueberry lowered systolic(p<0/008) and diastolic(p<0/013) blood pressure significantly	2014	12-13 weeks	Freeze-dried fermented blueberry	4 weeks	2 g/day	54 adult male rats	Irini Lazou Ahren[52]	5
did not affect fasting glucose and insulin(p>0/05), but stimulated insulin sensitivity and signaling(p<0/05)	2017	8 weeks	freeze-dried blueberry	8 weeks	10 g /100 g diets	24 maleWistar rats	Sunhye Lee[39]	6
Blueberries improve glucose tolerance And blueberry fed mice had significantly lower blood glucose (p= 0.0259)	2015	4 weeks	Blueberry powder	12 weeks	4% BB powder	18 female mice	Carrie M. Elks[46]	7
Total cholesterol: decreased significantly(p<0/05) LDL: decreased significantly(p<0/05) Improved insulin sensitivity significantly(p<0/05)	2020	6 weeks	blueberry juice	17 weeks	1:10 Diluted blueberry juice in tap water	75 healthy male mice	Hao Zhong[29]	8
Improve in insulin sensitivity and glucose tolerance was significant (p<0/01)	2019	4 weeks	freeze-dried blueberry	14 weeks	4% blueberry powder	10 mice	Weixiang Liu[40]	9
Significant decrease in triglycerides(23/48%) and total cholesterol(23/29%) and significant increase in HDL(33/06%) (p<0/05)	2020	4 weeks	blueberry anthocyanin-rich extract	8 weeks	Intra-gastric dose of 100 mg/kg	24 healthy male mice	Xu Si[30]	10
significantly reduced triglycerides, total cholesterol, fasting insulin, and fasting glucose (p<0/05)	2009		blueberry powder	90 days	2% blueberry powder	obesity‐prone Zucker Fatty rat	Mitchell Seymour[41]	11
T1:Decreased total cholesterol (P=0/004), LDL (P=0/001) and HDL (P=0/022) T2: higher total cholesterol (P=0/043)	2008	32–41 d,	freeze-dried BB	8 weeks in T1 and 12 weeks in T2	In T1, BB powder was added to diets at a concentration of 0, 10, 20 and 40 g/kg and in T2 at 0, 15, 0 ,15 g/kg.	healthy male castrated pigs	W. Kalt[47]	12
Total cholesterol and LDL significantly increased(p<0/05) but atherosclerotic lesion area decreased(p<0/001)	2010	4 weeks	Freeze-dried BB	20 weeks	10g/kg freeze-dried BB powder	Female mice	Xianli Wu[38]	13
Significant decrease in total cholesterol and non-HDL cholesterol (p=0/012)	2013	2/5 month	blueberry anthocyanins	6 weeks	0/5% blueberry (BL) and 1% blueberry (BH)	30 Male Golden Syrian hamsters	Yintong Liang[28]	14
prevented the development of dyslipidemia in mice by lowering triglycerides in serum( p<0/01)	2009	3 weeks	Freeze-dried powder	85 days	10% BB	Male C57BL/6 mice	Ronald L. Prior[45]	15
Serum total cholesterol, triglyceride and LDL significantly decreased and HDL significantly increased (p<0/05)	2015	1 month	blueberry extract	2 weeks	25 , 50 mg/kg	36 male Wistar rats	Deise Jaqueline Stro¨ her[34]	16
Prevented increase of serum triglyceride and total cholesterol(p<0/05)	2017	3 weeks	blueberry hydroalcoholic extract,	150 days	200mg/kg/d	4 groups of mice	Pathise Souto Oliveira[35]	17
10% increase in serum HDL cholesterol concentration(p=0/002)	2015		Blueberry puree	8 weeks	5ml/kg	7 Male Wistar‐Kyoto rats	Daniel Gillespie[50]	18
Significantly decreased cumulative body weight gain(p<0/05)	2009	4 weeks	Blueberry juice	3 weeks	40 ml/kg per day in drinking water	40 Male non-diabetic mice	T Vuong[51]	19
Inhibited body weight gain by 55/4%(p<0/05)	2018	24 days	blueberry purified anthocyanin	12 weeks	200 mg/kg food	Sixty male mice	Tao Wu[31]	20
blueberry juice reduced body weight by 7/3%	2013	4 weeks	Blueberry juice	12 weeks	consumption of blueberry juice instead of water	48 male mice	Tao Wu[32]	21
Caused increase in body weight (p<0/05)	2019	6 weeks	blueberry powder	8 weeks	6.4 g/kg	80 Male mice	Min Shi[36]	22
Marked attenuation of body weight gain(p<0/05)	2015	3 weeks	Fermented berry beverages	12 weeks	30% blueberry AFFB	72 diet-induced obese mice	Michelle H. Johnson[58]	23
Did not affect high fat induced body weight gain (p<0/05)	2009	5 weeks	freeze-dried blueberry	8 weeks	20 g/d of BB powder	Male mice	Jason DeFuria[43]	24
200mg/kg dosage blueberry effectively reduced body weight gain by 19/4%	2016	4 weeks	artificial planting blueberry	8 weeks	doses of 50, 100, and 200 mg/kg	72 male high-fat diet-induced obese mice	Tao Wu[33]	25
Reduced body weigh by 20-23%(p<0/05)	2021	-	blueberry extract	-	1% blueberry extract , 2% blueberry extract	54 high-fat diet mice	Jianhui Liu[27]	26
Plasma cholesterol was significantly reduced (p=0.05)	2012	46 days	Freeze dried blueberry	8 weeks	3% blueberry	Thirty-six male Sprague Dawley rats	Khanal[44]	27
No significant effect on serum glucose and insulin was reported( p>0.05)	2020	16 weels	Blueberry juice	14 weeks	25g/kg/day	16 male Wistar rats	Nunes[53]	28

AHA : American Heart Association
BB: blueberry
CVD : cardiovascular diseases
DAG : Diacylglycerol
HDL : high density lipoprotein
IDF : International Diabetes Federation
LDL : low density lipoprotein
LPS : Lipopolysaccharides
MDA : Malondialdehyde
MetS : Metabolic Syndrome
NCEP : National Cholesterol Education Program
NHLBI : National Heart, Lung, and Blood Institute
RONS: Reactive oxygen/nitrogen species
ROS: Reactive oxygen species
TC : total cholesterol
WHO : world health organization

Blueberry improves components of metabolic syndrome in animal studies: a systematic review and meta-analysis

Status:

Version 1

Abstract

Figures

1. Introduction

2. Methods

2.1. Search plan

2.2. Study selection criteria

2.3. Data collection

2.4. Statistical analyses

3. Results

4. Discussion

5. Conclusions

Declarations

References

Tables

Abbreviations

Status:

Version 1