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High strength cranberry and probiotics for urinary health

Herbs and probiotic strains

Cranberry

Vaccinium macrocarpon, fruit, dry

Lactobacillus gasseri CCFM1201

Lactobacillus reuteri HR7

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  • Pathogen inhibition

Clinical applications

  • Cystitis and urinary tract infections
  • Cellular exfoliation associated with bacterial vaginosis
  • Vulvovaginal candidiasis

Cranberry Photos, Cranberry Images, Nature Wildlife Pictures | NaturePhoto

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Figure 1: Cranberry (vaccinium macrocarpon)[1]

Figure 2: Lactobacillus gasseri (above left): (a) optical microscopy; (b) scanning electron microscopy[2]

A group of chemical formulas

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Figure 3 (above right): Scanning electron micrograph of Lactobacillus reuteri[3]

The use of cranberry to prevent urinary tract infections (UTIs) has a long history that was supported mainly by anecdotal evidence. A body of scientific literature now supports the ability of cranberry to prevent adherence of E. coli bacteria to uroepithelial cells.[4],[5],[6]

Cranberries are composed of a complex mixture of organic acids, vitamin C, flavonoids and anthocyanidins, among others.[7] The anthocyanidins and proanthocyanidins (PACs) are polyphenols with high antioxidant activity,[8] functioning as a natural plant defence system against microbes. The anti-infective efficacy of cranberry depends on the PACs to reduce the bacterial adhesion to uroepithelial cells.[9]

Figure 4: Structures of some of the major anthocyanins (cyanidin and peonidin), flavonols (quercetin and myricetin), phenolic and organic acids (p-coumaric acid, chlorogenic acid, and benzoic acid), flavan-3-ols (epicatechin), and terpenoids (ursolic acid) in cranberry fruit.

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Pathogen inhibition: UTI pathogenesis primarily involves E. coli attaching to the uroepithelia through specific fimbriae. Once adhesion occurs, adjacent endothelial cells of peritubular capillaries get activated and up regulated. Local neutrophil conscription, renal abscess formation and leukocyturia follows.[10]

Two compounds in cranberry are able to block attachment of pathogenic E. coli in UTI patients. The first is fructose, which restrains mannose-sensitive adhesions and the second is proanthocyanidins (PACs), also known as condensed tannins, which inhibit mannose-resistant adhesions. Almost all fruit juices contain fructose, but few contain this specific second compound.[11] A comparison of several PAC-containing foods, including cranberry, apple, grape, green tea, and chocolate, found that cranberry PACs prevented E. coli adhesion at the lowest concentration tested. Among the other foods, grape PACs showed adherence-inhibiting properties, but only at much higher doses, whereas the other foods showed no activity.[12]

Supplemental probiotics may also help prevent UTIs. Probiotics can compete with pathogens for adhesion sites and nutrition, produce bacteriocins which inhibit pathogenic growth, modulate host immune responses, and can modulate the gut and vaginal microbiota.[13]

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A healthy vaginal microbiome predominantly consists of Lactobacilli species.[14] Bacterial vaginosis (BV) is the most common vaginal infection, with prevalence among women of reproductive age range ranging from 23–29%, according to the WHO.[15] Although the exact cause of BV remains unknown, disturbance of the microbial balance is believed to be involved, and Gardnerella vaginalis (G. vaginalis) is the most commonly associated pathogen.[16] G. vaginalis exerts pathogenicity through various factors, including biofilm formation and interactions with the local host immune response. In contrast, researchers have shown that the adhesive abilities of Lactobacilli species contribute to their colonization of the vaginal microbiome, inhibiting the invasion of pathogenic bacteria, and regulating host immune responses. Lactobacillus gasseri CCFM1201 (L. gasseri 1201), isolated from healthy human vaginal tissue, exhibited strain-specific adhesion to HeLa cells and at the same time significant inhibition of G. vaginalis biofilm formation, when compared to other Lactobacilli of human origin.[17]

Figure 5: Effect of various Lactobacilli on G. vaginalis biofilm formation, including CCFM1201 (full black)[18]

Another bacterium found in the human vaginal microbiome is Lactobacillus reuteri HR7 (L. reuteri HR7). This species showed significant inhibitory effects on G. vaginalis, as well as Candida albicans, and Staphylococcus aureus. It’s production of the anti-microbial substance hydrogen peroxide, controlled the pathogens and this contributed to its ability to alleviate vaginal inflammation.[19]

Clinical applications

Cystitis and urinary tract infections: An ex-vivo study evaluated the inhibitory activity of cranberry tablets on the adhesiveness of E. coli to uroepithelial human cells.[20] Women with both a positive and negative history of recurrent cystitis were enrolled and received either the active extract or placebo in a random, cross-over, double-blinded fashion. Urine samples were collected at the beginning and the end of each study period, testing for bacterial adhesiveness. Significant reductions were observed in women who received the extract, regardless of their cystitis history or cross-over period. In contrast, no changes were observed with placebo. The authors determined that supplementation of cranberry extract provides an anti-adhesive effect on uropathogenic E. coli.[21]

An open label pilot study examined a concentrated cranberry extract in preventing UTIs in women with a history of recurrent infections. All participants experienced a minimum of 6 UTIs in the preceding year, and all were available for follow up 2 years later.[22]

None of the women experienced a UTI during the study, and 2 years later, 8 of the 12 women who continued taking the cranberry preparation, remained free of infection. No adverse events were reported.[23]

A 2017 systematic review and meta-analysis was conducted to assess the impact of cranberry on the risk of UTI recurrence in otherwise healthy women. The group identified 7 randomized controlled trials conducted in almost 1500 participants considered at risk of UTI. Their results showed that cranberry did in fact reduce the risk of UTI in generally healthy women.[24]

And a 2024 randomized, placebo-controlled, double-blinded trial looking into the prophylactic use of cranberry in women with recurrent cystitis gleaned similar results.[25]

172 women with a history of recurrent UTIs were randomized to either a high dose cranberry PAC or placebo for 12 months. In response to the intervention, the number of UTIs in the PAC group was significantly lower than placebo. The numbers of E. coli isolates detected in vaginal and rectal swabs were also significantly decreased. The authors concluded that daily use of cranberry PACs was associated with a reduction of UTIs, and a prolongation of UTI-free survival compared to placebo, supporting its use as prophylaxis in this patient population.[26]

Cellular exfoliation associated with BV: A destructive clinical feature of BV is the exfoliation, or shedding, of significant numbers of epithelial cells. The potential cause is believed to be the release of cytotoxic substances such as vaginolysin by G. vaginalis, which directly damages vaginal epithelia.[27]

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Researchers sought to determine the impact of L. gasseri 1201 on vaginal cell exfoliation induced by G. vaginalis and compare this to other Lactic acid bacteria. As shown in Table 1 (right), approximately 36.9 exfoliated cells per field were counted in the model group, while 7.8 cells per field were counted in the unaffected control group. Epithelial exfoliation in the L. gasseri 1201 group was 14.7, significantly lower than that of all other Lactobacillus strains, second only to the unaffected control group.[28]

Table 1: G. vaginalis-induced epithelial cells exfoliation[29]

Vulvovaginal candidiasis: Recurrent vulvovaginal candidiasis (VVC) is a debilitating condition that can severely affect quality of life. Globally, it affects about 138 million women annually.[30] As with other pathogenic microbes, adhesion to surfaces promotes yeast virulence. In addition to this, morphological switch and biofilm-forming abilities are other recognized factors of Candida albicans (C. albicans).[31]

Recent in vitro studies have shown that cranberry extracts may benefit women suffering with vulvovaginal candidiasis. In 2021, Italian scientists investigated the efficacy of two urinary cranberry metabolites, (5-(3′,4′-dihydroxy phenyl)-γ-valerolactone (VAL) and 4-hydroxybenzoic acid (4-HBA)), to inhibit C. albicans adhesion and biofilm formation. Both metabolites were able to interfere with the yeast adhesion by modulating the expression of key genes. A significant dose-dependent reduction in biofilm biomass and metabolic activity was also recorded.[32]

And a 2024 randomised controlled trial investigating the efficacy of cranberry extracts as treatment for VVC was conducted in 300 hospital patients with a confirmed diagnosis.[33]

Patients were randomized into 3 groups: group 1 received standard anti-fungal therapy (oral fluconazole plus vaginal miconazole suppository); group 2 received the cranberry extract – oral A-type proanthocyanidins (A-PACs); and group 3 were given oral A-PACs plus vaginal miconazole suppository. Patients deemed clinically cured at the seventh day of follow-up in group 2 received maintenance therapy of oral A-PACs for 12 weeks.

At follow-up, the vaginal mycological results of all patients in group 2 exhibited negative results. The negative conversion rates of fungal spores and blastospores in group 2 were superior to those in groups 1 and 3. In addition, the symptoms of group 2 ameliorated significantly compared with those in group 1. And finally, the 12-week maintenance therapy was shown to diminish the risk of long-term recurrence. The researchers therefore concluded that cranberry A-PACs combined with azole antibiotics can be considered a viable therapeutic option for the treatment and long-term prevention of recurrent VVC.[34]

Pregnancy: not suitable for pregnancy.

Lactation: not suitable for breastfeeding women.

Warnings: Adults only. If symptoms persist, consult your healthcare professional. If pain or irritation persists for more than 48 hours, consult your doctor. The presence of blood in the urine warrants immediate medical attention.

Drug interactions:

Atorvastatin (Lipitor): Theoretically, cranberry might increase levels and adverse effects of atorvastatin.[35]

Cytochrome P450 2C9 (CYP2C9) substrates: Theoretically, cranberry might increase the levels and adverse effects of CYP2C9 substrates. However, research is conflicting.[36],[37],[38]

Cytochrome P450 3A4 (CYP3A4) substrates: Theoretically, cranberry might increase the levels and adverse effects of CYP3A4 substrates.[39]

Diclofenac (Voltaren, others): Theoretically, cranberry might modestly increase the levels and adverse effects of diclofenac.[40]

Nifedipine (Procardia): Theoretically, cranberry might increase the levels and adverse effects of nifedipine.[41]

Warfarin (Coumadin):

Theoretically, cranberry might increase the levels and adverse effects of warfarin. However, research is conflicting.[42],[43],[44],[45]

  1. https://www.naturephoto-cz.com/cranberry-photo-10372.html
  2. Varela-Pérez A, Romero-Chapol OO, Castillo-Olmos AG, García HS, Suárez-Quiroz ML, Singh J, Figueroa-Hernández CY, Viveros-Contreras R, Cano-Sarmiento C. Encapsulation of Lactobacillus gasseri: Characterization, probiotic survival, in vitro evaluation and viability in apple juice. Foods. 2022 Mar 2;11(5):740.
  3. https://www.sciencephoto.com/media/12129/view/lactobacillus-reuteri
  4. Khalid SB, Sohail A, Wahab KA, Omer MA, Qureshi A, Sajjad H, Nadeem R, Anmol10 S. EFFECTIVE ROLE OF CRANBERRY AGAINST E. COLI URINARY TRACT ADHESIONS; A REVIEW.
  5. Tempera G, Corsello S, Genovese C, Caruso FE, Nicolosi D. Inhibitory activity of cranberry extract on the bacterial adhesiveness in the urine of women: an ex-vivo study. International journal of immunopathology and pharmacology. 2010 Apr;23(2):611-8.
  6. Burleigh AE, Benck SM, McAchran SE, Reed JD, Krueger CG, Hopkins WJ. Consumption of sweetened, dried cranberries may reduce urinary tract infection incidence in susceptible women–a modified observational study. Nutrition journal. 2013 Dec;12:1-7.
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  8. Bors W, Foo LY, Hertkorn N, Michel C, Stettmaier K. Chemical studies of proanthocyanidins and hydrolyzable tannins. Antioxidants and Redox Signaling. 2001 Dec 1;3(6):995-1008.
  9. Jass J, Reid G. Effect of cranberry drink on bacterial adhesion in vitro and vaginal microbiota in healthy females. The Canadian journal of urology. 2009 Dec 1;16(6):4901-7.
  10. Sujata M, Gurpreet K, Argha R. Cranberry: Effects on Oral Health. History. 2015 May 1;17(70):44-9.
  11. Khalid SB, Sohail A, Wahab KA, Omer MA, Qureshi A, Sajjad H, Nadeem R, Anmol10 S. EFFECTIVE ROLE OF CRANBERRY AGAINST E. COLI URINARY TRACT ADHESIONS; A REVIEW.
  12. Howell AB, Reed JD, Krueger CG, Winterbottom R, Cunningham DG, Leahy M. A-type cranberry proanthocyanidins and uropathogenic bacterial anti-adhesion activity. Phytochemistry. 2005 Sep 1;66(18):2281-91.
  13. Sánchez B, Delgado S, Blanco‐Míguez A, Lourenço A, Gueimonde M, Margolles A. Probiotics, gut microbiota, and their influence on host health and disease. Molecular nutrition & food research. 2017 Jan;61(1):1600240.
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  17. Zhang Q, Cheng Q, Cui S, Zhao J, Chen W, Zhang H. Inhibitory effect of Lactobacillus gasseri CCFM1201 on Gardnerella vaginalis in mice with bacterial vaginosis. Archives of Microbiology. 2022 Jun;204(6):315.
  18. Zhang Q, Cheng Q, Cui S, Zhao J, Chen W, Zhang H. Inhibitory effect of Lactobacillus gasseri CCFM1201 on Gardnerella vaginalis in mice with bacterial vaginosis. Archives of Microbiology. 2022 Jun;204(6):315.
  19. https://patents.google.com/patent/CN116751705A/zh?oq=CN+116751705+A. Accessed 5/8/24
  20. Tempera G, Corsello S, Genovese C, Caruso FE, Nicolosi D. Inhibitory activity of cranberry extract on the bacterial adhesiveness in the urine of women: an ex-vivo study. International journal of immunopathology and pharmacology. 2010 Apr;23(2):611-8.
  21. Tempera G, Corsello S, Genovese C, Caruso FE, Nicolosi D. Inhibitory activity of cranberry extract on the bacterial adhesiveness in the urine of women: an ex-vivo study. International journal of immunopathology and pharmacology. 2010 Apr;23(2):611-8.
  22. Bailey DT, Dalton C, Daugherty FJ, Tempesta MS. Can a concentrated cranberry extract prevent recurrent urinary tract infections in women? A pilot study. Phytomedicine. 2007 Apr 10;14(4):237-41.
  23. Bailey DT, Dalton C, Daugherty FJ, Tempesta MS. Can a concentrated cranberry extract prevent recurrent urinary tract infections in women? A pilot study. Phytomedicine. 2007 Apr 10;14(4):237-41.
  24. Fu Z, Liska D, Talan D, Chung M. Cranberry reduces the risk of urinary tract infection recurrence in otherwise healthy women: a systematic review and meta-analysis. The Journal of nutrition. 2017 Dec 1;147(12):2282-8.
  25. Tsiakoulias E, Gravas S, Hadjichristodoulou C, Oikonomou KG, Kyritsi M, Dadouli K, Matziri A, Kola K, Vacthsioli E, Tsiakoulia M, Gianniou M. Randomized, placebo-controlled, double-blinded study of prophylactic cranberries use in women with recurrent uncomplicated cystitis. World Journal of Urology. 2024 Jan 12;42(1):27.
  26. Tsiakoulias E, Gravas S, Hadjichristodoulou C, Oikonomou KG, Kyritsi M, Dadouli K, Matziri A, Kola K, Vacthsioli E, Tsiakoulia M, Gianniou M. Randomized, placebo-controlled, double-blinded study of prophylactic cranberries use in women with recurrent uncomplicated cystitis. World Journal of Urology. 2024 Jan 12;42(1):27.
  27. Nasioudis D, Linhares IM, Ledger WJ, Witkin SS. Bacterial vaginosis: a critical analysis of current knowledge. BJOG: An International Journal of Obstetrics & Gynaecology. 2017 Jan;124(1):61-9.
  28. Zhang Q, Cheng Q, Cui S, Zhao J, Chen W, Zhang H. Inhibitory effect of Lactobacillus gasseri CCFM1201 on Gardnerella vaginalis in mice with bacterial vaginosis. Archives of Microbiology. 2022 Jun;204(6):315.
  29. Zhang Q, Cheng Q, Cui S, Zhao J, Chen W, Zhang H. Inhibitory effect of Lactobacillus gasseri CCFM1201 on Gardnerella vaginalis in mice with bacterial vaginosis. Archives of Microbiology. 2022 Jun;204(6):315.
  30. Denning DW, Kneale M, Sobel JD, Rautemaa-Richardson R. Global burden of recurrent vulvovaginal candidiasis: a systematic review. The Lancet infectious diseases. 2018 Nov 1;18(11):e339-47.
  31. Ottaviano E, Baron G, Fumagalli L, Leite J, Colombo EA, Artasensi A, Aldini G, Borghi E. Candida albicans Biofilm Inhibition by Two Vaccinium macrocarpon (Cranberry) Urinary Metabolites: 5-(3′, 4′-DihydroxyPhenyl)-γ-Valerolactone and 4-Hydroxybenzoic Acid. Microorganisms. 2021 Jul 13;9(7):1492.
  32. Ottaviano E, Baron G, Fumagalli L, Leite J, Colombo EA, Artasensi A, Aldini G, Borghi E. Candida albicans Biofilm Inhibition by Two Vaccinium macrocarpon (Cranberry) Urinary Metabolites: 5-(3′, 4′-DihydroxyPhenyl)-γ-Valerolactone and 4-Hydroxybenzoic Acid. Microorganisms. 2021 Jul 13;9(7):1492.
  33. Wei D, Chen Y, Chen Y, Cui T, Niu X. Assessing the treatment effect of cranberry type A proanthocyanidins on vulvovaginal candidiasis: a randomised controlled clinical interventional study. Gynecology and Obstetrics Clinical Medicine. 2024 Jun 1;4(2).
  34. Wei D, Chen Y, Chen Y, Cui T, Niu X. Assessing the treatment effect of cranberry type A proanthocyanidins on vulvovaginal candidiasis: a randomised controlled clinical interventional study. Gynecology and Obstetrics Clinical Medicine. 2024 Jun 1;4(2).
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  37. Greenblatt DJ, von Moltke LL, Perloff ES, Luo Y, Harmatz JS, Zinny MA. Interaction of flurbiprofen with cranberry juice, grape juice, tea, and fluconazole: in vitro and clinical studies. Clinical Pharmacology & Therapeutics. 2006 Jan;79(1):125-33.
  38. Li Z, Seeram NP, Carpenter CL, Thames G, Minutti C, Bowerman S. Cranberry does not affect prothrombin time in male subjects on warfarin. Journal of the American Dietetic Association. 2006 Dec 1;106(12):2057-61.
  39. Doad GJ, Kabange W. Cranberry juice, atorvastatin and back pain. Journal of the Medical Association of Georgia. 2014;103(1):14.
  40. Ushijima K, Tsuruoka SI, Tsuda H, Hasegawa G, Obi Y, Kaneda T, Takahashi M, Maekawa T, Sasaki T, Koshimizu TA, Fujimura A. Cranberry juice suppressed the diclofenac metabolism by human liver microsomes, but not in healthy human subjects. British journal of clinical pharmacology. 2009 Aug;68(2):194-200.
  41. Uesawa Y, Mohri K. Effects of cranberry juice on nifedipine pharmacokinetics in rats. Journal of pharmacy and pharmacology. 2006 Aug;58(8):1067-72.
  42. Grant P. Warfarin and cranberry juice: an interaction?. The Journal of heart valve disease. 2004 Jan 1;13(1):25-6.
  43. Rindone JP, Murphy TW. Warfarin-cranberry juice interaction resulting in profound hypoprothrombinemia and bleeding. American journal of therapeutics. 2006 May 1;13(3):283-4.
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  45. Mellen CK, Ford M, Rindone JP. Effect of high‐dose cranberry juice on the pharmacodynamics of warfarin in patients. British journal of clinical pharmacology. 2010 Jul;70(1):139-42.

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