Blueberry Extract Improves Obesity through Regulation of the Gut Microbiota and Bile Acids via Pathways Involving FXR and TGR5.
Guo J, Han X, Tan H, Huang W, You Y, Zhan J.
iScience. 2019 Aug 16;19:676-690. doi: 10.1016/j.isci.2019.08.020

Recent Research on the Health Benefits of Blueberries and Their Anthocyanins.
Kalt W, Cassidy A, Howard LR, Krikorian R, Stull AJ, Tremblay F, Zamora-Ros R.
Adv Nutr. 2019 Jul 22. pii: nmz065. doi: 10.1093/advances/nmz065.

Bioactive Compounds of Strawberry and Blueberry and Their Potential Health Effects Based on Human Intervention Studies: A Brief Overview.
Miller K, Feucht W, Schmid M.
Nutrients. 2019 Jul 2;11(7). pii: E1510. doi: 10.3390/nu11071510.

Blueberry leaves from 73 different cultivars in southeastern China as nutraceutical supplements rich in antioxidants.
Wu H, Chai Z, Hutabarat RP, Zeng Q, Niu L, Li D, Yu H, Huang W.
Food Res Int. 2019 Aug;122:548-560. doi: 10.1016/j.foodres.2019.05.015.

Isolation and Characterization of Blueberry Polyphenolic Components and Their Effects on Gut Barrier Dysfunction.
Polewski MA, Esquivel-Alvarado D, Wedde NS, Kruger CG, Reed JD.
J Agric Food Chem. 2019 Jun 14. doi: 10.1021/acs.jafc.9b01689.

Antiviral effects of blueberry proanthocyanidins against Aichi virus.
Joshi SS, Howell AB, D'Souza DH.
Food Microbiol. 2019 Sep;82:202-208. doi: 10.1016/j.fm.2019.02.001.

Combinatorial effect of blueberry extracts and oxaliplatin in human colon cancer cells.
Lin Y, Li B, Zhao J, Wei L, Wang Y, Wang M, Dia VP, Meng X.
J Cell Physiol. 2019 Aug;234(10):17242-17253. doi: 10.1002/jcp.28341.

Postprandial Effects of Blueberry (Vaccinium angustifolium) Consumption on Glucose Metabolism, Gastrointestinal Hormone Response, and Perceived Appetite in Healthy Adults: A Randomized, Placebo-Controlled Crossover Trial.
Stote K, Corkum A, Sweeney M, Shakerley N, Kean T, Gottschall-Pass K.
Nutrients. 2019 Jan 19;11(1). pii: E202. doi: 10.3390/nu11010202.

Mechanistic insights to the cardioprotective effect of blueberry nutraceutical extract in isoprenaline-induced cardiac hypertrophy.
Eladwy RA, Mantawy EM, El-Bakly WM, Fares M, Ramadan LA, Azab SS.
Phytomedicine. 2018 Dec 1;51:84-93. doi: 10.1016/j.phymed.2018.10.009.

Molecular Mechanism and Health Role of Functional Ingredients in Blueberry for Chronic Disease in Human Beings.
Ma L, Sun Z, Zeng Y, Luo M, Yang J.
Int J Mol Sci. 2018 Sep 16;19(9). pii: E2785. doi: 10.3390/ijms19092785.

Bilberry, Vaccinium myrtillus (Ericaceae)

Vaccinium myrtillus, commonly known as European bilberry or European blueberry, is a small deciduous shrub belonging to the family Ericaceae, widely distributed across the temperate and boreal regions of Europe and northern Asia. It is a characteristic component of acid heathlands, coniferous forests, bogs and montane and subalpine environments, where it forms dense carpets in the understorey. The species prefers acid, well-drained, humus-rich soils and shows a marked ability to colonise nutritionally poor environments, especially in mountain and boreal belts. Morphologically, it is a low shrub with green, angular, strongly branched shoots, small ovate leaves with finely serrated margins, and solitary, nodding, urn-shaped flowers, usually greenish-pink to pink.

The fruit is a small blue-black berry, rich in intensely coloured juice that readily stains skin and mucous membranes. A distinctive feature of European bilberry, compared with related species such as Vaccinium corymbosum (the American highbush blueberry), is the presence of anthocyanin pigments not only in the skin but also in the pulp, giving the fruit a uniformly dark colour in cross-section. The plant propagates both by seed and, very efficiently, through rhizomes and underground stems, which allow it to form extensive clonal colonies and to play an important role in soil stabilisation and understorey structure.

From an ecological perspective, Vaccinium myrtillus is considered a key species in many forest and mountain ecosystems. It contributes to carbon and nutrient cycles, provides a major food source for numerous frugivorous animals (birds, small mammals and large herbivores) and influences the natural regeneration dynamics of tree species. Its occurrence is often used as an indicator of soil conditions, water regime and forest cover, and several ecological studies have modelled its distribution in relation to climatic, hydrological and edaphic factors, particularly in boreal and subalpine environments.

On the chemical and health side, European bilberry is especially noted for its very high content of anthocyanins, among the highest within the genus Vaccinium. These pigments, together with other polyphenols (flavonols, phenolic acids and tannins), are responsible for the marked antioxidant capacity of the fruits. In addition to polyphenols, bilberries provide vitamin C, dietary fibre and a moderate amount of simple sugars, within a relatively low-energy matrix. Scientific interest focuses on the potential role of anthocyanins and other bioactive constituents in various aspects of cardiovascular health, glucose metabolism, oxidative stress and inflammatory responses.

Experimental and clinical studies, with varying levels of evidence, suggest possible beneficial effects of standardised Vaccinium myrtillus fruit extracts on vascular function, modulation of inflammatory and oxidative markers, support of visual function under conditions of fatigue or oxidative stress, and improvement of certain metabolic parameters such as blood glucose and lipid profile. It is important to underline that many of these results come from studies using specific preparations (extracts titrated in anthocyanins) under controlled conditions and cannot be directly extrapolated to occasional consumption of fresh or processed berries. Consumption of the fruit as part of a balanced diet is generally considered favourable, whereas the use of high-dose nutraceutical or phytotherapeutic products calls for critical evaluation of the literature and appropriate professional guidance.

The leaves of Vaccinium myrtillus have also been used in traditional herbal practice, particularly in infusions aimed at supporting glucose metabolism. However, their content of tannins and other constituents raises concerns in the case of prolonged or uncontrolled use, and modern regulatory assessments tend to be more cautious regarding extensive use of leaves than of fruits. For this reason, current attention is focused mainly on fruit-based preparations (dried berries, standardised extracts, juices and derivatives), for which the data set is broader, though still evolving.

Botanical classification (APG IV system)

Indicative nutritional values per 100 g (fresh fruits of Vaccinium myrtillus)
Values refer to fresh bilberries and may vary with origin, growing conditions, cultivar and ripeness.

At typical serving sizes (for example 50–100 g of fruits in yogurt, desserts, smoothies or as a snack), bilberries provide a moderate energy intake, almost entirely from carbohydrates, an interesting amount of dietary fiber, and a variable contribution of vitamin C and phenolic compounds (especially anthocyanins), which are more relevant from a phytochemical than from a strictly macronutrient perspective.

Lipid profile note

Fresh Vaccinium myrtillus fruits have a very low fat content. Saturated fatty acids (SFA) are present only in minimal amounts; when SFA predominate over unsaturated fats in the overall diet, they are generally regarded as less favourable for cardiovascular health.

Most of the small lipid fraction is made up of MUFA and PUFA, which are usually considered more favourable when they replace part of dietary SFA. However, given the very low absolute fat content of bilberries and the relatively small serving sizes, their direct impact on the global dietary fat profile is negligible; the main nutritional interest lies in carbohydrates, fiber, vitamins and phenolic compounds.

Plant Characteristics:

Growth Form: Vaccinium myrtillus is a deciduous shrub that typically grows to a height of 0.3-0.6 meters. It has a spreading habit with a dense network of branches.

Leaves: The leaves are oval, with a glossy, dark green upper surface and a lighter green or reddish underside. They turn red or orange in the autumn.

Flowers: The flowers are small, bell-shaped, and pale pink or white, appearing in clusters. They usually bloom in late spring to early summer.

Fruits: The berries are small, round, and dark blue to black when ripe. They have a sweet and slightly tangy flavor.

Chemical Composition and Structure:

• Anthocyanins: Bilberries are rich in anthocyanins, a type of flavonoid that provides their deep blue color and has strong antioxidant properties.
• Vitamins: The berries are a good source of vitamin C, which supports immune function and skin health.
• Minerals: They contain important minerals like manganese and iron.
• Phenolic Compounds: Bilberries contain various phenolic compounds, including quercetin and catechins, which have antioxidant and anti-inflammatory properties.

Cultivation:

• Soil: Prefers acidic, well-drained soils with a pH between 4.5 and 5.5. It thrives in sandy, loamy, or peaty soils.
• Climate: Grows well in temperate climates with cold winters and moderate summers. It requires a period of winter chill for optimal fruiting.
• Irrigation: Regular watering is needed, particularly in dry periods, but overwatering should be avoided to prevent root rot.
• Fertilization: Use fertilizers that are low in phosphorus, as bilberries are adapted to low-phosphorus soils. A balanced, acidic fertilizer can be applied in the spring.
• Pruning: Pruning helps to maintain plant shape and encourages new growth. Remove old or damaged branches to improve air circulation and fruit production.

Uses and Benefits:

• Culinary Uses: Bilberries are used in a variety of dishes, including jams, jellies, pies, and sauces. They are also enjoyed fresh or dried as a snack.
• Medicinal Uses: Bilberries are known for their potential health benefits, including improved vision, enhanced circulation, and anti-inflammatory effects. They are often used in supplements and traditional remedies.
• Cosmetic Uses: Extracts from bilberries are used in skincare products for their antioxidant properties, which can help protect the skin from damage and promote a healthy complexion.

INCI Functions:

Skin conditioning agent. It is the mainstay of topical skin treatment as it has the function of restoring, increasing or improving skin tolerance to external factors, including melanocyte tolerance. The most important function of the conditioning agent is to prevent skin dehydration, but the subject is rather complex and involves emollients and humectants that can be added in the formulation.

Antioxidant agent. Ingredient that counteracts oxidative stress and prevents cell damage. Free radicals, pathological inflammatory processes, reactive nitrogen species and reactive oxygen species are responsible for the ageing process and many diseases caused by oxidation.

Hair conditioning agent. A significant number of ingredients with specific and targeted purposes may co-exist in hair shampoo formulations: cleansers, conditioners, thickeners, matting agents, sequestering agents, fragrances, preservatives, special additives. However, the indispensable ingredients are the cleansers and conditioners as they are necessary and sufficient for hair cleansing and manageability. The others act as commercial and non-essential auxiliaries such as: appearance, fragrance, colouring, etc. Hair conditioning agents have the task of increasing shine, manageability and volume, and reducing static electricity, especially after treatments such as colouring, ironing, waving, drying and brushing. They are, in practice, dispersants that may contain cationic surfactants, thickeners, emollients, polymers. The typology of hair conditioning agents includes: intensive conditioners, instant conditioners, thickening conditioners, drying conditioners. They can perform their task generally accompanied by other different ingredients.

Skin conditioning agent. It is the mainstay of topical skin treatment as it has the function of restoring, increasing or improving skin tolerance to external factors, including melanocyte tolerance. The most important function of the conditioning agent is to prevent skin dehydration, but the subject is rather complex and involves emollients and humectants that can be added in the formulation.

Cosmetic astringent. This ingredient exerts a direct effect on the skin by tightening dilated pores by contracting stratum corneum cells and removing superfluous oil.

CAS: 84082-34-8

EC number 281-983-5

Applications:

• Food Industry: Bilberries are utilized in making jams, juices, and baked goods. Their flavor and nutritional content make them a popular ingredient in various culinary products.
• Pharmaceutical Industry: Bilberry extracts are used in dietary supplements and herbal remedies for their potential health benefits, including their effects on vision and vascular health.
• Cosmetic Industry: Ingredients derived from bilberries are incorporated into skincare products due to their antioxidant and anti-inflammatory properties.

Environmental and Safety Considerations:

• Environmental Impact: Cultivating bilberries in an environmentally sustainable manner is crucial to minimize the impact on soil and surrounding ecosystems. Using organic practices and avoiding excessive use of chemicals can help preserve the environment.
• Safety: Bilberries are generally safe to consume and use. 

Studies

Blueberry contains a large number of phytochemicals including flavonoids, polyphenols and anthocyanins to which the scientific literature attributes a positive role in limiting the risks of cardiovascular disease, obesity and type 2 diabetes mellitus as they exert antioxidant and anti-inflammatory activity. It can therefore be considered a nutraceutical.

This crossover study conducted on obese or overweight patients with metabolic syndrome confirmed an antioxidant action that manifested itself after three hours from the intake of blueberries during meals (1).

The most abundant flavonoids found in blueberry are, according to this study, quercetin, kaempferol and, among phenolic acids, gentisic acid. These compounds were evaluated on treated cells HCT-116, a tumor model for human colon cancer. Quercetin and kaempferol have shown strong cytotoxic, antioxidant and apoptotic effects, while gentisic acid is mostly effective as an antioxidant polyphenol. The study concludes that these flavonoids have anticancer potential (2).

Based on evidence, blueberry can improve some measures of cognitive performance and mood (3).

In blueberry content, 10.0 μg/mL of phenolic acid present in blueberry has been shown to inhibit the death of retinal pigment epithelial cells. Anthocyanins and flavonoids showed similar results and the consistent activity of flavonoids improved phagocytosis and oxidative cellular stress (4).

An intake of blueberry flavonoids, equivalent to 240 g or 1½ cup of fresh blueberries, can provide acute cognitive benefits in children. These results support the accumulation of evidence that flavonoid-rich products are beneficial to healthy brain function, particularly during critical developmental periods (5).

Blueberry studies

References__________________________________________________________________

(1) Sobolev AP, Ciampa A, Ingallina C, Mannina L, Capitani D, Ernesti I, Maggi E, Businaro R, Del Ben M, Engel P, Giusti AM, Donini LM, Pinto A. Blueberry-Based Meals for Obese Patients with Metabolic Syndrome: A Multidisciplinary Metabolomic Pilot Study. Metabolites. 2019 Jul 10;9(7):138. doi: 10.3390/metabo9070138.

Abstract. A pilot study was carried out on five obese/overweight patients suffering from metabolic syndrome, with the aim to evaluate postprandial effects of high fat/high glycemic load meals enriched by blueberries. Postprandial urine samples were analyzed by 1H-NMR spectroscopy after 2 and 4 h from ingestion to identify potential markers of blueberry intake. Significant decrease of methylamines, acetoacetate, acetone and succinate, known indicators of type 2 diabetes mellitus, were observed after the intake of meals enriched with blueberries. On the other hand, an accumulation of p-hydroxyphenyl-acetic acid and 3-(3'-hydroxyphenyl)-3-hydropropionic acid originating from gut microbial dehydrogenation of proanthocyanidins and procyanidins was detected. Real-time PCR-analysis of mRNAs obtained from mononuclear blood cells showed significant changes in cytokine gene expression levels after meals integrated with blueberries. In particular, the mRNAs expression of interleukin-6 (IL-6) and Transforming Growth Factor-β (TGF-β), pro and anti-inflammation cytokines, respectively, significantly decreased and increased after blueberry supplementation, indicating a positive impact of blueberry ingestion in the reduction of risk of inflammation. The combined analysis of the urine metabolome and clinical markers represents a promising approach in monitoring the metabolic impact of blueberries in persons with metabolic syndrome.

(2) Sezer ED, Oktay LM, Karadadaş E, Memmedov H, Selvi Gunel N, Sözmen E. Assessing Anticancer Potential of Blueberry Flavonoids, Quercetin, Kaempferol, and Gentisic Acid, Through Oxidative Stress and Apoptosis Parameters on HCT-116 Cells. J Med Food. 2019 Nov;22(11):1118-1126. doi: 10.1089/jmf.2019.0098. 

Abstract. In recent years, natural products gained popularity with their anti-inflammatory and antioxidant effects mediated by chemical compounds within their composition. Study results offering them as palliative therapy options in cancer or as anticancer agents with high levels of cytotoxicity brought a new approach to combine cancer treatment protocols with these products. From a different perspective, edible types of these products are suggested in daily diets due to their potential cancer preventive effects. Our preliminary work was on blueberry extracts (Vaccinium myrtillus) as a main representative of these natural products, and the contents of the extracts were analyzed with liquid chromatography tandem mass spectrometry (LC MS/MS) to reveal the composition and distribution of polyphenolic compounds within. The most abundant polyphenols detected in V. myrtillus extracts were quercetin, kaempferol, and a phenolic acid, gentisic acid (GA). The compounds were further evaluated on treated HCT-116 cells for their potential anticancer effects by measuring total antioxidant status, total oxidant status, and 8-hydroxydeoxyguanosine levels for evaluation of oxidative stress and through protein array analysis and flow cytometric analysis for evaluation of apoptosis. In analysis of oxidative stress parameters, reduced total oxidant levels and reduced oxidative stress index levels were found in cells treated with the compounds in comparison with untreated cells. In apoptosis-related protein profiles, at least twofold reduction in various apoptotic proteins was observed after quercetin and kaempferol treatment, whereas a different profile was observed for GA. Overall, results of this study showed that quercetin and kaempferol have strong cytotoxic, antioxidant, and apoptotic effects, although GA is mostly effective as an antioxidant polyphenol on HCT-116 cells.

(3) Travica N, D'Cunha NM, Naumovski N, Kent K, Mellor DD, Firth J, Georgousopoulou EN, Dean OM, Loughman A, Jacka F, Marx W. The effect of blueberry interventions on cognitive performance and mood: A systematic review of randomized controlled trials. Brain Behav Immun. 2020 Mar;85:96-105. doi: 10.1016/j.bbi.2019.04.001. 

Abstract. Blueberries are rich in polyphenols that may be beneficial to cognitive performance and mood. The aim of this systematic review was to evaluate randomized controlled trials investigating the effects of blueberries and blueberry products on measures of cognition and mood. In total, eleven articles (that included 12 studies) were identified using freeze-dried blueberries (n = 9 studies), whole blueberries (n = 2) and blueberry concentrate (n = 1). These studies were conducted in children (n = 5), young adults (n = 1), and older people with either no known cognitive impairment (n = 4) or indicated cognitive impairment (n = 2). Eight studies reported blueberry consumption or supplementation at various doses and time lengths to improve measures of cognitive performance, particularly short- and long-term memory and spatial memory. For mood, one study reported significant between-group improvements in positive affect from blueberry products, whereas four studies reported no improvement. Low risk of bias were observed across all studies. Based on the current evidence, blueberries may improve some measures of cognitive performance. However, considerable differences in study design, dosages, and anthocyanin content hinder between-study comparison. The use of standardized blueberry interventions, consideration of placebo formulations, and consistently reported cognitive performance tools are recommended in future trials. PROSPERO registration no. CRD42018100888.

(4) Liu Y, Liu M, Chen Q, Liu GM, Cao MJ, Sun L, Lu Z, Guo C. Blueberry Polyphenols Ameliorate Visible Light and Lipid-Induced Injury of Retinal Pigment Epithelial Cells. J Agric Food Chem. 2018 Dec 5;66(48):12730-12740. doi: 10.1021/acs.jafc.8b05272. 

Abstract. Although dietary polyphenols are known to be beneficial to vision, the protective distinctions among different types of polyphenols are unclear. In this work, the visual benefits of various blueberry polyphenols were evaluated using an in vitro model of visible light-lipid-induced injury of retinal pigment epithelial cells. Results showed that, at 10.0 μg/mL, the phenolic acid-rich fraction was superior in inhibiting cell death (93.6% ± 2.8% of cell viability). Anthocyanin- and flavonoid-rich fractions shared similar advantages in preventing the expression of senescence-associated β-galactosidase (34.8% ± 11.1% and 32.2% ± 9.7% of aged cells, respectively) and overexpression of vascular endothelial growth factor (51.8 ± 3.5 and 54.1 ± 6.5 pg/mL, respectively). The flavonoid-rich fraction also showed high activity in ameliorating phagocytosis (70.3% ± 12.6%) and cellular oxidative stress. These results were further confirmed by using the corresponding polyphenol standards. Improved inhibitory effects of polyphenol mixture on cell death and senescence-associated β-galactosidase expression were also observed. Therefore, various polyphenols play diverse roles and exert synergistic effects in nourishing the retina.

(5) Barfoot KL, May G, Lamport DJ, Ricketts J, Riddell PM, Williams CM. The effects of acute wild blueberry supplementation on the cognition of 7-10-year-old schoolchildren. Eur J Nutr. 2019 Oct;58(7):2911-2920. doi: 10.1007/s00394-018-1843-6. 

Abstract. Purpose: Previous evidence suggests consumption of flavonoids, a sub-class of polyphenols, is associated with improved cognitive function across the lifespan. In particular, acute intervention of a flavonoid-rich wild blueberry (WBB) drink has been shown to boost executive function (EF), short-term memory and mood 2-6 h post-consumption in 7-10-year-old children. However, confirmation of the aspects of EF and memory susceptible to WBB ingestion is required, particularly during childhood, a critical period of neurological development. In addition, the child literature on berry flavonoid supplementation and cognition highlights the potential for such interventions to elicit positive benefits to real-world educational scenarios, such as reading, a complex ability which relies upon aspects of cognition already known to improve following WBB.....Conclusion: Consumption of WBB was found to significantly improve memory and attentional aspects of EF. This indicates that a flavonoid-rich blueberry product, equivalent to 240 g or 1½ cups of fresh blueberries can provide acute cognitive benefits in children. These findings support accumulating evidence that flavonoid-rich products are beneficial for healthy brain function, particularly during critical developmental periods. However, the lack of findings relating to reading ability suggested acute WBB may not be sufficient to elicit benefits to reading. Chronic supplementation and other more sensitive reading measures should be considered for examining the effects of WBB on such a complex skill in the future.