Bilberry Fruit

• How It Works

  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.
• 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
  • A case of excessive bleeding related to long-term consumption of bilberry along with a newly prescribed blood-thinning drug has been reported.
• Scientific Name

  Vaccinium myrtillus, Vaccinium uliginosum, Vaccinium smallii, Vaccinium arctostaphylos, Vaccinium cespitosum

• 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. The anthocyanins in bilberry are thought to regenerate rhodopsin, a pigment present in retinal photoreceptor cells.

  In vitro, bilberry polyphenols appear to protect against neurodegenerative processes and eye disorders ^(1) (2). Animal models suggest bilberry 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, or retinal function ^(5) (6) ; 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⁾.

  In other studies, a standardized bilberry extract was shown to reduce disease activity in 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 at 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 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 that bilberry extract may significantly reduce proliferation of colorectal cancer cells ⁽²²⁾. Bilberry extract also showed 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 such effects. More studies are needed to determine what benefits are attributable to bilberry fruit, 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
• 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 a 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 inhibited human leukemia, colon, and breast cancer cells through apoptotic induction and/or inhibition of cell proliferation ^(17) (30). Delphinidin and other anthocyanidins synergistically enhanced cell-cycle arrest and apoptotic induction in aggressive non-small-cell lung cancer cells by modulating Notch, WNT, and NF-ĸB signaling pathways ⁽¹⁶⁾.

• Adverse Reactions

  Case report
  Rectal bleeding following long-term overconsumption of bilberry has been reported in a 77-year-old man on warfarin therapy, requiring two emergency room 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: Bilberry can have added or synergistic antiplatelet effects, and increase the risk of bleeding ⁽³⁵⁾.
  Non-steroidal anti-inflammatory drugs (NSAIDs): Bilberry may have added or synergistic antiplatelet effects, and increase the risk of bleeding ⁽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)}.

• 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.