Colletti A, Sangiorgio L, Martelli A, Testai L, Cicero AFG, Cravotto G. Highly active cranberry's polyphenolic fraction: New advances in processing and clinical applications. Nutrients. July 2021;13(8):2546. doi: 10.3390/nu13082546.
Cranberries (Vaccinium macrocarpon, Ericaceae) have a long history of use in traditional medicine for the treatment of urinary tract infections (UTIs) and wounds. Observational and interventional studies have also found cranberries to promote overall gut and oral health, reduce or prevent cardiovascular risk factors and chronic conditions such as hyperglycemia, dyslipidemia, and type 2 diabetes, as well as cancer. However, some studies show conflicting or contradictory results. The purpose of this review was to describe the main bioactive components of cranberry, types of extraction and purification methods, and clinical applications. Lastly, the study presented future perspectives for cranberry extraction.
A keyword search was performed using PubMed, MEDLINE, the Cochrane Register of Controlled Trials, Scopus, EMBASE, and ClinicalTrials.gov. Randomized controlled trials were preferred but open-label and animal studies printed in English were also eligible. A flow diagram was not included.
The phytochemical composition of cranberries is complex and includes polyphenols like procyanidins (PACs), anthocyanins, benzoic acid, flavanols, as well as terpenes like ursolic acid (UA). The bioactive compounds in cranberries are dependent on the variety and exact life phase of the plant. For example, PACs and flavanols are highest in the earliest life stages and decrease during the growth of the fruit. Anthocyanins, on the contrary, are richest as the fruit finishes growing and continues to ripen. Cranberries are consumed as juice, sauce, dried fruit, and extracts and processing has significant effects on the bioactive compounds of cranberries. For example, anthocyanins can lose up to 50% of their total content due to removal of skins and seeds, high temperatures, and oxidation of polyphenols but PACs and flavanols are more resistant.
Several extraction methods are used to make cranberry extracts, and these may have substantially different chemical profiles. Cranberry juice is pressed or decanted from frozen berries, and the resultant solids (skins and seeds), or pomace, is rich in proteins, insoluble polymers, and polyphenols. The juice is rich in flavonoids, organic acids, and sugars. The concentrated syrup may be further sweetened or blended with other fruit juices. Extraction methods can be improved by adding pectinase enzymes.
Cranberry extract is extremely variable due to flavonoid degradation during processing. This variability could influence the results of cranberry extracts used in clinical practice. For this reason, unconventional extraction techniques have been explored. Treatment techniques include blanching, ultrasound, pulsed electric field, sonication, and microwave-vacuum drying. Aqueous ethanol and methanol were found to be the best extraction solvents. Recently, supercritical carbon dioxide extraction has been used to extract lipophilic compounds.
Pharmacological interventions for treating UTIs include the use of antibiotics; however, antibiotic resistance and damage to the intestinal microbiota are real risks. Escherichia coli is responsible for 85% of lower UTIs. The A-type PACs found in cranberry have the greatest influence on the efficacy of cranberry extracts on UTIs with an inhibitory effect against E. coli adhesion to uroepithelial cells. Randomized controlled trials (RCTs) have confirmed the efficacy of cranberry juice and extracts for the treatment and prevention of UTIs. The first RCT included 153 females with frequent bacteriuria. Two groups were randomized to receive 300 mL of cranberry juice or placebo. Results showed a reduction of > 50% of bacteriuria in the cranberry group over the placebo. Another RCT demonstrated A-type PACs inhibited ex vivo adherence of both P-type and type 1 uropathogenic E. coli. A similar result was shown against Candida albicans. The minimum daily dose of PACs found to be effective was 36 mg.
Results of two separate meta-analyses reported that cranberry consumption reduced the risk of recurrence of UTIs. Combination therapy using cranberry and probiotic strains have been proposed as effective management of recurrent UTIs. However, the use of cranberry extracts alone or in combination with probiotic strains remains inconclusive when treating recurrent UTIs.
In vitro and animal studies have investigated the use of cranberry on gastrointestinal tract disorders. Supplementation was shown to protect gut inflammation by reducing oxidative stress and intestinal triglyceride content in mice. In a human study, consumption of 42 g/day of dried cranberries was shown to positively affect human gut microbiota (n = 10). Cranberry powder supplementation (30 g/day) enhanced the production of short-chain fatty acids (SCFAs) demonstrating a post-biotic effect (details of the study were not disclosed).
Helicobacter pylori has been shown to be a major cause of peptic ulcer disease and gastric cancer. Several RCTs investigated the efficacy of cranberry juice on H. pylori with positive results. One RCT conducted in China included 189 patients diagnosed with an H. pylori infection. Results showed that the consumption of cranberry juice (250 mL) over 90 days resulted in negative results for the 13C-urea breath test (P < 0.05). Consumption of high-proanthocyanidins cranberry juice twice daily (44 mg proanthocyanidin/240 mL serving) resulted in a significant reduction in H. pylori (P < 0.05; details of the trial were not disclosed). Another study involving 200 patients diagnosed with an H. pylori infection and peptic ulcer disease were treated with a triple therapy of lansoprazole, clarithromycin, and amoxicillin. The addition of cranberry to the triple therapy resulted in a significantly higher rate of eradication compared to the conventional therapy alone (P value not disclosed). In a similar study, 177 patients with an H. pylori infection received 250 mL of either the triple therapy (omeprazole, amoxicillin, and clarithromycin) plus a placebo (n = 88) or the triple therapy plus cranberry juice (n = 89). Participants received the intervention twice daily for one week, followed by only cranberry juice or the placebo for the following two weeks. Results showed a significantly higher eradication rate in the cranberry arm for the female patients, but results were not significant for the male patients (P values not disclosed). A RCT including 295 asymptomatic children (aged 6 to 16 years) who tested positive for H. pylori showed significant eradication rates in the groups that consumed cranberry juice (P < 0.01).
PACs found in cranberries have been demonstrated to prevent the formation of Porphyromonas gingivalis biofilm; thus, useful in oral health. Other studies found that cranberry extract reduced the proliferation of P. gingivalis, Tannerella forsythia, and T. denticola in periodontal pockets. Additional studies showed that cranberry juice mouthwash decreased salivary counts of oral Streptococci mutans and cranberry polyphenols used in various oral products prevented dental plaque formation, although specific study details were not included.
Cranberry juice and extracts have been studied as possible treatment for cardiovascular diseases (CVDs). Cranberry juice (240 mL/day) was shown to reduce fasting plasma glucose and homeostatic model assessment-insulin resistance (HOMA-IR) in patients diagnosed with type 2 diabetes (study details not provided). In a study with eight overweight or obese men and women with abdominal adiposity, consumption of 450 mL/day of high polyphenol cranberry extract resulted in a reduction of endothelin-1, fasting C-reactive protein, and oxidized glutathione ratio, and nitric oxide (NO) was improved (P < 0.05 for all). In the same study, serum insulin was significantly reduced, and high-density lipoprotein cholesterol significantly increased (P < 0.05 for both).
In terms of insulin improvement following cranberry supplementation, data were contrasting. One RCTs showed significant reductions in lipid peroxidation with consumption of 450 mL of a low-calorie cranberry beverage compared to the placebo (P = 0.02) as well as improvements in triglyceride levels (P = 0.04) and nitrates (P = 0.02). However, no impact on insulin sensitivity was reported. Another RTC with 41 overweight patients diagnosed with non-alcoholic fatty liver disease evaluated the efficacy of cranberry extract (288 mg/day equivalent to 26 g of dried cranberry) or a placebo over a 12-week period. The study reported a significant decrease in aminotransferase (P < 0.05) compared to the placebo at the end of the study, a significant reduction in insulin within the cranberry group compared to baseline (P < 0.05), and in the cranberry group compared to the placebo (P = 0.02). None of the RCTs demonstrated lipid-lowering properties. Some studies reported a decrease in low-density lipoprotein cholesterol (LDL-C), inflammatory markers, and an increase in NO.
An important limitation within the studies evaluated included a generally high dropout rate (< 30%) owing to the low palatability of cranberry juice, especially the sugar-free juices. Another limitation included the high costs to titrate PACs for standardized extracts. Future studies are needed to find new non-conventional extraction methods to improve the quality of cranberry extracts as well as reduce the overall costs of extraction. Additional studies are needed to confirm the efficacy and safety of long-term RCTs, including mechanisms of action. Notwithstanding these limitations and recommendations, the authors conclude that cranberry extract supplementation may serve as a functional food and nutraceutical. It also may also act as an adjuvant for the prevention of UTIs and exert beneficial effects for cardiovascular and gastroenteric disease prevention.
The authors declare no conflict of interest.