Bilberry Fruit

Health Care Professional Information

Scientific Name
Vaccinium myrtillus, Vaccinium uliginosum, Vaccinium smallii, Vaccinium arctostaphylos, Vaccinium cespitosum
Common Name

Dwarf bilberry, bog bilberry, European blueberry, whortleberry, bog bilberry, Chinese blueberry

Clinical Summary

Bilberry fruit grows on perennial fruit trees or shrubs, and is closely related to the huckleberry and blueberry. It is marketed as a dietary supplement to help improve eyesight and promote overall eye health, and is widely used in herbal therapy. Bilberry anthocyanins are thought to regenerate rhodopsin, a pigment in retinal photoreceptor cells, and bilberry has been used for poor night vision, macular degeneration, glaucoma, and cataracts.

In vitro, isolated bilberry polyphenols appear to protect against neurodegenerative processes and eye disorders (1) (2). Animal models suggest the extract may help visual functioning (3) and protect against retinal diseases (4). Human studies are mixed on whether bilberry anthocyanosides improve visual acuity, night vision, and retinal function (5) (6) and many of the positive studies are poorly designed (7). A small trial suggests bilberry may improve visual function in some individuals with normal tension glaucoma (8), but generally human data on bilberry for eye disorders are lacking (9).

A standardized bilberry extract was shown to reduce disease activity in a pilot study of patients with mild to moderate ulcerative colitis (10). Dietary bilberry produced beneficial changes in serum lipids and lipoproteins in women with higher metabolic risk, but had an unexpected opposite effect in those who were low-risk (11). Another species of bilberry, Caucasian whortleberry, was found to improve glycemic control in type 2 diabetic patients (12). Ingestion of bilberries in a diet that also included whole grain/low-insulin-response grain products and fatty fish also altered lipid profiles and improved glucose metabolism in individuals at high risk for type 2 diabetes (13). Two small randomized trials suggest that bilberry juice may reduce biomarkers of inflammation and improve cardiometabolic risk (14) (15).

In vitro and in vivo studies indicate that bilberry may have anticancer activities (4) (16) (17) (18) (19) (20) (21). A pilot study suggests bilberry extract may significantly reduce proliferation of colorectal cancer tumor tissue (22). Bilberry extract has a protective effect against chemotherapy-induced oral mucositis in an animal model (23). Other small studies of a proprietary extract combination that includes bilberry suggests it may relieve chemotherapy-induced mucositis in cancer patients (24) (25). However, it is unclear the extent to which bilberry itself may be responsible for this effect. More studies are needed to determine what benefits are attributable to bilberry fruit itself, as well as its potential synergy with other berry compounds and food combinations.

Purported Uses
  • Cancer prevention
  • Ocular disorders
  • Circulatory disorders
  • Diabetic retinopathy
  • Diarrhea
  • Mucositis
  • Visual acuity
Constituents
  • Flavonoids: anthocyanins, anthocyanidins (cyanidins, delphinidins, malvidins, peonidins, and petunidins), epicatechins
  • Flavonols: anthocyanosides, trans-resveratrol, flavonol glycosides including quercetin
  • Phenolics: ferulic acid, p-coumaric acid, chlorogenic acid
    (6) (7) (14) (16) (26) (27)
Mechanism of Action

In vitro, bilberry polyphenols inhibited amyloid fibril formation and dissolved preformed toxic aggregates and mature fibrils, suggesting a role in controlling fibril formations of various proteins that occur with neurodegenerative diseases (1). Bilberry anthocyanins modulated oxidative stress defense enzymes heme oxygenase-1 (HO-1) and glutathione S-transferase-pi (GST-pi) in human retinal pigment epithelial cells (2). In vitro and in vivo, bilberry inhibited angiogenesis through inhibition of ERK 1/2 and Akt phosphorylation (4). In an animal model of uveitis and retinal inflammation, pretreatment with bilberry extract prevented photoreceptor impairment, relieved intracellular ROS elevation, activated retinal NF-ĸB in the inflamed retina, and suppressed the decrease of rhodopsin via inhibition of IL-6, which activates STAT3, thereby protecting outer segment length in photoreceptor cells (3). In a monocytic cell line, quercetin, epicatechin, and resveratrol inhibited lipopolysaccharide (LPS)-induced NF-kappaB activation (14).

In individuals with hypercholesterolemia, anthocyanins may improve endothelium-dependent vasodilation by activating the NO-cGMP signaling pathway (28). The polyphenols in bilberry juice can modulate inflammation by decreasing plasma C-reactive protein, interleukin (IL)-6, -15, and monokine induced by INFγ (MIG) (14).

In human colon and liver cancer cell lines, bilberry anthocyanins demonstrated intracellular antioxidant activity even though concentrations applied were very low (29). Bilberry extract can inhibit human leukemia, colon, and breast cancer cells through apoptotic induction and/or inhibition of cell proliferation (17) (30). Delphinidin and other isolated anthocyanidins synergistically enhanced cell-cycle arrest and apoptotic induction in aggressive non-small-cell lung cancer cell lines by modulating Notch, WNT, and NF-ĸB signaling pathways (16). Their malfunction in cancers fuel cell regeneration and chemotherapy-resistance, and delphinidin particularly appeared to be the most effective at Notch1 and NF-ĸB inhibition (16).

Pharmacokinetics

In human studies, bilberry anthocyanins are excreted in the urine either intact or as methylated or glucuronidated metabolites (19) (22). The stomach appears to be the predominant site for anthocyanin absorption (31). Despite unfavorable pharmacokinetics, these anthocyanins appear to have intracellular antioxidant activity (29).

In animal studies, oral administration showed moderate GI absorption with <2% bioavailability (32). Peak levels were achieved within 15 minutes with a three-compartment distribution and elimination shown. Elimination was primarily through urine and bile.

Adverse Reactions

Bilberry is generally reported as safe and well tolerated (10) (22).

Case report
Rectal bleeding with long-term bilberry overconsumption:
In a 77-year-old man on warfarin therapy, requiring 2 emergency department visits, treatment with fresh plasma infusions, and hospitalization to evaluate inconsistent international normalized ratio (INR) values (33) (34).

Herb-Drug Interactions

Anticoagulants / Antiplatelets: Bilberry may potentiate the risk of bleeding (33) (34).
Aspirin and aspirin products: May have added or synergistic antiplatelet effects and increase bleeding risk (35).
Non-steroidal anti-inflammatory drugs (NSAIDs): May have added or synergistic antiplatelet effects and increase bleeding risk (35).
Chemotherapy drugs: Bilberry may interfere with the actions of certain chemotherapy drugs and radiation therapy (25) .

Herb Lab Interactions

Bilberry may increase prothrombin time and partial thromboplastin time (PT/PTT) and inhibit platelet activity (33) (34) (35).

Literature Summary and Critique

Larmo PS, et al. Effects of sea buckthorn and bilberry on serum metabolites differ according to baseline metabolic profiles in overweight women: a randomized crossover trial. Am J Clin Nutr. 2013;98:941-951.
In this randomized crossover trial, 80 overweight women consumed either frozen bilberries, or one of three sea buckthorn formulations for 30 days to compare the effects of these regimens on metabolic profiles, which were quantified from serum samples using 1H nuclear magnetic resonance spectroscopy. Even though most changes in individual metabolites were not statistically significant after correction for multiple testing, clear trends produced significant overall effects: P<.001 to .003 for all interventions on overall metabolic profiles, both in participants who had higher baseline cardiometabolic risk (Group B: P=.001 to .008) and those with lower-risk (Group A: P<.001 to .009). Unexpectedly for those taking bilberry, there were beneficial changes in serum lipids and lipoproteins in Group B but not in Group A. Investigators determined that the effects of bilberry on serum metabolites differed according to baseline metabolic profiles in overweight women, but could not explain the observed opposite effect in women with low-risk metabolic profiles.

Biedermann L, et al. Bilberry ingestion improves disease activity in mild to moderate ulcerative colitis - an open pilot study. J Crohns Colitis. 2013;7:271-279.
This open pilot trial with 9 weeks’ follow-up evaluated a standardized anthocyanin-rich bilberry preparation taken daily by 13 patients with ulcerative colitis. Assessments included clinical, biochemical, endoscopic and histologic parameters. At the end of the 6-week treatment, 63.4% of patients achieved the primary endpoint of remission, and 90.9% of patients had shown a response. All patients had decreased total Mayo scores (mean: screening, 6.5; week 7, 3.6; P<.001). Fecal calprotectin levels also significantly decreased, including 4 patients with undetectable levels post-treatment. Beneficial effects were confirmed by a decrease in endoscopic Mayo score and histologic Riley index. However, increases in calprotectin levels and disease activity were observed after intervention cessation. No serious adverse events were reported, and randomized clinical trials are warranted.

Thomasset S, et al. Pilot study of oral anthocyanins for colorectal cancer chemoprevention. Cancer Prev Res (Phila). 2009 Jul;2(7):625-33.
This unblinded study enrolled 25 patients with colorectal cancer (n=15) or colorectal liver metastases (n=10) who were scheduled to undergo resection of the primary tumor. The patients were randomized to receive a daily dose of mirtocyan, an anthocyanin-rich bilberry extract, until 7 days before surgery. Immunohistochemical observations were made in biopsy samples pre-intervention and compared with resection tissue post-intervention. Plasma concentrations of insulin-like growth factor (IGF-1) were also measured pre- and post-intervention. The proliferation index reflected by Ki-67 staining of colorectal tissue significantly decreased by 7% (P=.003) in all patients receiving mirtocyan extract, and was as high as 9% (P=.021) in one dosage group. After receiving mirtocyan, patients also experienced a small but nonsignificant reduction in circulating IGF-1 concentrations. The investigators also found mirtocyan to be safe and well tolerated.

Dosage (Inside MSKCC Only)
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References
  1. Iwasa H, Kameda H, Fukui N, et al. Bilberry anthocyanins neutralize the cytotoxicity of co-chaperonin GroES fibrillation intermediates. Biochemistry. Dec 23 2013;52(51):9202-9211.
  2. Milbury PE, Graf B, Curran-Celentano JM, et al. Bilberry (Vaccinium myrtillus) anthocyanins modulate heme oxygenase-1 and glutathione S-transferase-pi expression in ARPE-19 cells. Invest Ophthalmol Vis Sci. May 2007;48(5):2343-2349.
  3. Miyake S, Takahashi N, Sasaki M, et al. Vision preservation during retinal inflammation by anthocyanin-rich bilberry extract: cellular and molecular mechanism. Lab Invest. Jan 2012;92(1):102-109.
  4. Matsunaga N, Chikaraishi Y, Shimazawa M, et al. Vaccinium myrtillus (Bilberry) Extracts Reduce Angiogenesis In Vitro and In Vivo. Evid Based Complement Alternat Med. Mar 2010;7(1):47-56.
  5. Muth ER, Laurent JM, Jasper P. The effect of bilberry nutritional supplementation on night visual acuity and contrast sensitivity. Altern Med Rev. Apr 2000;5(2):164-173.
  6. Zadok D, Levy Y, Glovinsky Y. The effect of anthocyanosides in a multiple oral dose on night vision. Eye (Lond). Dec 1999;13 ( Pt 6):734-736.
  7. Canter PH, Ernst E. Anthocyanosides of Vaccinium myrtillus (bilberry) for night vision—a systematic review of placebo-controlled trials. Surv Ophthalmol. Jan-Feb 2004;49(1):38-50.
  8. Shim SH, Kim JM, Choi CY, et al. Ginkgo biloba extract and bilberry anthocyanins improve visual function in patients with normal tension glaucoma. J Med Food. Sep 2012;15(9):818-823.
  9. Gerding H. [Primary or Secondary Prophylaxis of AMD with Anthocyanins?]. Klin Monbl Augenheilkd. Apr 2009;226(4):216-219.
  10. Biedermann L, Mwinyi J, Scharl M, et al. Bilberry ingestion improves disease activity in mild to moderate ulcerative colitis - an open pilot study. J Crohns Colitis. May 2013;7(4):271-279.
  11. Larmo PS, Kangas AJ, Soininen P, et al. Effects of sea buckthorn and bilberry on serum metabolites differ according to baseline metabolic profiles in overweight women: a randomized crossover trial. Am J Clin Nutr. Oct 2013;98(4):941-951.
  12. Kianbakht S, Abasi B, Dabaghian FH. Anti-hyperglycemic effect of Vaccinium arctostaphylos in type 2 diabetic patients: a randomized controlled trial. Forsch Komplementmed. 2013;20(1):17-22.
  13. Lankinen M, Schwab U, Kolehmainen M, et al. Whole grain products, fish and bilberries alter glucose and lipid metabolism in a randomized, controlled trial: the Sysdimet study. PLoS One. 2011;6(8):e22646.
  14. Karlsen A, Paur I, Bohn SK, et al. Bilberry juice modulates plasma concentration of NF-kappaB related inflammatory markers in subjects at increased risk of CVD. Eur J Nutr. Sep 2010;49(6):345-355.
  15. Kolehmainen M, Mykkanen O, Kirjavainen PV, et al. Bilberries reduce low-grade inflammation in individuals with features of metabolic syndrome. Mol Nutr Food Res. Oct 2012;56(10):1501-1510.
  16. Kausar H, Jeyabalan J, Aqil F, et al. Berry anthocyanidins synergistically suppress growth and invasive potential of human non-small-cell lung cancer cells. Cancer Lett. Dec 1 2012;325(1):54-62.
  17. Katsube N, Iwashita K, Tsushida T, et al. Induction of apoptosis in cancer cells by Bilberry (Vaccinium myrtillus) and the anthocyanins. J Agric Food Chem. Jan 1 2003;51(1):68-75.
  18. Bagchi D, Sen CK, Bagchi M, et al. Anti-angiogenic, antioxidant, and anti-carcinogenic properties of a novel anthocyanin-rich berry extract formula. Biochemistry (Mosc). Jan 2004;69(1):75-80, 71 p preceding 75.
  19. Lala G, Malik M, Zhao C, et al. Anthocyanin-rich extracts inhibit multiple biomarkers of colon cancer in rats. Nutr Cancer. 2006;54(1):84-93.
  20. Misikangas M, Pajari AM, Paivarinta E, et al. Three Nordic berries inhibit intestinal tumorigenesis in multiple intestinal neoplasia/+ mice by modulating beta-catenin signaling in the tumor and transcription in the mucosa. J Nutr. Oct 2007;137(10):2285-2290.
  21. Teller N, Thiele W, Marczylo TH, et al. Suppression of the kinase activity of receptor tyrosine kinases by anthocyanin-rich mixtures extracted from bilberries and grapes. J Agric Food Chem. Apr 22 2009;57(8):3094-3101.
  22. Thomasset S, Berry DP, Cai H, et al. Pilot study of oral anthocyanins for colorectal cancer chemoprevention. Cancer Prev Res (Phila). Jul 2009;2(7):625-633.
  23. Davarmanesh M, Miri R, Haghnegahdar S, et al. Protective effect of bilberry extract as a pretreatment on induced oral mucositis in hamsters. Oral Surg Oral Med Oral Pathol Oral Radiol. Dec 2013;116(6):702-708.
  24. Bertoglio JC, Folatre I, Bombardelli E, et al. Management of gastrointestinal mucositis due to cancer therapies in pediatric patients: results of a case series with SAMITAL((R)). Future Oncol. Nov 2012;8(11):1481-1486.
  25. Pawar D, Neve RS, Kalgane S, et al. SAMITAL(R) improves chemo/radiotherapy-induced oral mucositis in patients with head and neck cancer: results of a randomized, placebo-controlled, single-blind Phase II study. Support Care Cancer. Mar 2013;21(3):827-834.
  26. Yamamoto M, Yamaura K, Ishiwatari M, et al. Difficulty for consumers in choosing commercial bilberry supplements by relying only on product label information. Pharmacognosy Res. Jul 2013;5(3):212-215.
  27. Ehala S, Vaher M, Kaljurand M. Characterization of phenolic profiles of Northern European berries by capillary electrophoresis and determination of their antioxidant activity. J Agric Food Chem. Aug 10 2005;53(16):6484-6490.
  28. Zhu Y, Xia M, Yang Y, et al. Purified anthocyanin supplementation improves endothelial function via NO-cGMP activation in hypercholesterolemic individuals. Clin Chem. Nov 2011;57(11):1524-1533.
  29. Bornsek SM, Ziberna L, Polak T, et al. Bilberry and blueberry anthocyanins act as powerful intracellular antioxidants in mammalian cells. Food Chem. Oct 15 2012;134(4):1878-1884.
  30. Nguyen V, Tang J, Oroudjev E, et al. Cytotoxic effects of bilberry extract on MCF7-GFP-tubulin breast cancer cells. J Med Food. Apr 2010;13(2):278-285.
  31. Cai H, Thomasset SC, D PB, et al. Determination of anthocyanins in the urine of patients with colorectal liver metastases after administration of bilberry extract. Biomed Chromatogr. Jun 2011;25(6):660-663.
  32. Morazzoni P, Livio S, Scilingo A, et al. Vaccinium myrtillus anthocyanosides pharmacokinetics in rats. Arzneimittelforschung. Feb 1991;41(2):128-131.
  33. Djuv A, Nilsen OG, Steinsbekk A. The co-use of conventional drugs and herbs among patients in Norwegian general practice: a cross-sectional study. BMC Complement Altern Med. 2013;13:295.
  34. Aktas CSV, Sarikaya S, Karit S. Bilberry potentiates warfarin effect? Turk J Geriatr 2011;14:79-81.
  35. Abebe W. Herbal medication: potential for adverse interactions with analgesic drugs. J Clin Pharm Ther. Dec 2002;27(6):391-401.

Consumer Information

How It Works

Bottom Line: Bilberry is used in traditional medicine to treat eye disorders and support vision health, but clinical data for these purposes are mixed or lacking. There is insufficient evidence to support its other uses.

Compounds in bilberry called anthocyanins can regenerate rhodopsin, a pigment found in retinal cells responsible for eyesight. This is one of the reasons it has gained popularity in traditional medicine to support eye health.

In laboratory studies, bilberry reduces inflammation and fluid accumulation in tissues, acts as an antioxidant, inhibits blood clotting, and strengthens the walls of blood vessels. Bilberry extracts can inhibit the growth of cancer cells in the lab. Initial studies in humans also show that bilberry may have anti-cancer effects, relieve certain types of inflammation, or improve the biological profiles of those at higher risk for heart disease or diabetes. More clinical trials are needed to confirm these effects.

Purported Uses
  • To prevent cancer
    Laboratory studies and one clinical study suggest anti-cancer effects. More studies are needed.
  • To treat eye disorders
    One small study suggests bilberry may improve visual function in some patients with normal tension glaucoma, but human data are generally lacking. The effect of bilberry on other eye conditions has been explored in animal and test tube studies, or in older studies with weak trial designs.
  • To reduce inflammation
    A few preliminary studies suggest that bilberry may be helpful in preventing or treating gastrointestinal mucositis, or for those with mild to moderate ulcerative colitis. Other small studies indicate that bilberry may improve biomarkers of inflammation related to cardiovascular disease. Larger confirmatory studies are needed.
  • To improve vision, especially at night
    Clinical trial results are mixed on whether bilberry can help improve vision, and do not support this use in individuals with good vision.
  • To treat diarrhea
    No scientific evidence supports this specific use, although one small study indicates bilberry may be helpful in mild to moderate ulcerative colitis.
  • To treat circulatory disorders
    Laboratory studies show that bilberry may protect blood vessels and decrease the risk of blood clots. Human data are needed.
Research Evidence

Colorectal cancer
A small study in humans suggests that bilberry extract may decrease tumor growth in colorectal cancer. However, additional studies are needed to confirm this effect.

Ulcerative colitis
A small study in patients with mild to moderate ulcerative colitis suggests that bilberry may be helpful in controlling symptoms. Larger randomized trials are needed to confirm these effects.

Reduce risk for heart disease and diabetes
A preliminary randomized trial that evaluated several berry formulations including frozen bilberries noted an improvement in overall biomarkers for overweight women at a higher risk for heart disease or diabetes.

Patient Warnings
  • Bilberry fruit should not be confused with bilberry leaf, which may lower blood sugar levels.
Do Not Take If
  • You use warfarin or other blood thinners: Bilberry may increase the risk of bleeding.
  • You use aspirin or aspirin products: Bilberry may increase the risk of bleeding.
  • You use non-steroidal anti-inflammatory drugs (NSAIDs): Bilberry may increase the risk of bleeding.
Side Effects
  • Case report of excessive bleeding related to long-term high consumption of bilberry along with taking a newly prescribed blood-thinning drug
E-mail your questions and comments to aboutherbs@mskcc.org.