Cranberries and Urinary Tract Infections

Cranberries and Urinary Tract Infections Urinary tract infections (UTIs) are a widespread and serious problem infecting millions of people each year. In the United States, 34% of adults over 20 self-reported having at least one occurrence of a urinary tract infection between 1988 and 1994 i, and 1 in 5 women in America will develop UTI in their lifetime i. UTIs are infection of any organs in the urinary system, which include: the kidneys, ureters, bladder and urethra. The urinary tract is a sterile environment, which means that no bacteria should be present. A urinary tract infection typically occurs when bacteria from the gastrointestinal tract get into the opening of the urethra and multiply; from there the bacteria can travel up to the bladder or the kidneys. Most infections are caused by the bacteria Escherichia coli (E. coli), which is commonly found in the colon. The most common symptoms include the frequent urge to urinate, a painful, burning feeling while urinating, and blood and pus in urine. ii Individuals more susceptible to developing urinary tract infections include: women since the urethra is shorter than in males, individuals with a catheter placed in the urethra and bladder, those with a suppressed immune system, pregnant women, individuals with diabetes, people with an obstruction or an inability to completely urinate, and those who have had a previous UTI. The primary treatment of UTIs is antibiotics, which work to kill the bacteria; pain relievers may also be taken to alleviate some of the pain. If the infection is serious enough the individual may have to be hospitalized. ii, Most women suffer from recurrent UTIs, and each infection a woman has increases her risk for another infection. There are also preventative measures that can be done to help reduce the incidence and reoccurrence of UTIs, which include: drinking plenty of water every day so urination is common, urinating when necessary and not holding it in, after urinating wiping from front to back to prevent bacteria from the anus getting into the urethra or vagina, taking showers instead of baths, cleansing the genital areas before sexual intercourse, and drinking cranberry juice. ii There is much debate about drinking cranberry juice and its effectiveness in preventing UTIs. This paper will look at the current research to help assess the home remedy of cranberries to prevent urinary 1

tract infections. A literature search was completed by searching PubMD and academic search complete, which looked at several papers on the topic. The North American cranberry, Vaccinium macrocarpon, is in the Ericaceae family. Cranberries consist primarily of water with a mixture of organic acids, vitamin C, flavanoids, anthocyanidins, proanthocynidin, catechins, and triterpinoids. The active ingredients are proanthocynidins (PACs), which are a type of plant flavonoid with antioxidants and other medicinal functions. Cranberries contain A-type PACs, while other foods have B-type PACs. It is this unique A-type form of PACs that functions as a natural defense system against microbes. iii It used to be thought that the acidity of cranberries was responsible for its protective effects. However, it has been proven that consumption of cranberries does not alter the ph of urine and cranberries lack bacteriostatic * properties. iv Studies have indicated that PACs modify the structure of the fimbriae inhibiting bacterial adherence to uroepithelial cells. The fimbriae are a thin and short appendages in bacteria, that helps facilitate bacteria attachment to cells. Sixty percent of the E. coli that can infect the urinary tract have P-frimbriae. v PACs do not inhibit the expression of fimbriae, instead there is a conformational change induced, which decreases the length of the fimbriae by about 33%, iv thus making it more difficult for bacteria to adhere to the urinary tract and colonize, which causes an infection. v This effect was seen for both the cranberry juice cocktail and pure PACs, with no statistically significant difference between treatments. iv It should be noted that this alteration in the fimbriae is transient, and the fimbriae returned to a normal length once the PACs exposure was removed. Additionally, it was shown that PACs exhibit this action on multi-drug resistant strains of uropathogenic e. coli. v Another possible mechanism of the PACs is that they inhibit the expression of the flagellin gene. vi The flagellin gene expresses the proteins for the flagellum, which is a tail-like projection that helps facilitate bacterial locomotion. This hinders the bacteria s ability to swim and swarm the urinary tract, thus bacteria have a harder time making it up the urinary tract to * An agent that stops bacteria from reproducing 2

cause an infection. vi Future research about the inhibition of the flagellin gene needs to be done, since there was little evidence for this mechanism. There is a dose-dependent effect of the PACs ability to inhibit bacteria. The antiadherence bioactivity of the PACs was detected at concentrations of 10-50 µg/ml when a significant amount of bacteria was present. v With 50 µg/ml of PACs, 0.9 x 10 5 bacteria adhered to uroepithelial cells and with 20 µg/ml 2.0 x 10 5 bacteria adhered to cells. These values can be compared to the control with no PACs where 2.5 x 10 5 bacteria adhered to cells. v Not only does this finding affirm the mechanism of action, it also indicates that the higher the dose of PACs, the less bacteria can adhere to cells. While the PACs do not have the capacity to completely eliminate bacteria from the cells, the reduction in bacteria that can adhere is statically significant and can impact the bacteria s ability to colonize the urinary system and cause infection. Not only are PACs dose dependent, they are also time dependent. The antiadhesion activity was observed within 2 hours of intake of PACs and persisted for up to ten hours. v In a study done in humans, several doses of PACs were administered and urine samples where collected at different intervals after ingestion to assess the antiadhesion activity (AAA) conjured by the different dose and their length of effectiveness. Within the first 6 hours of taking the 36 mg dose of PACs, the AAA rose to a range of 80-100% and then dropped down to 12.5% at 24 hours. In comparison, for all groups who took the 72 mg dose their AAA rose to 100% within the first 6 hours then dropped down to a range of 25-75% in 24 hours. vii While a high AAA for both doses is reached with the first six hours, the AAA for the 36mg dose quickly dropped down. The 72mg dose was more effective since it was able to maintain a higher AAA for a longer time period, which is important since high PAC levels are needed to induce the conformational change of the fimbriae. Thus, the study recommends that two 36 mg of cranberry PAC equivalents should be taken per day since it maintains higher PAC levels and antiadhesion in the body for longer. vii While cranberries are effective at preventing UTIs, it should be noted that study results indicated that antibiotics are more effective in preventing UTIs. viii Antibiotics 3

work by killing bacteria, where PACs only inhibit bacterial adherence to the urinary tract. However, the overuse of antibiotic can lead to antibiotic resistance, in which the bacteria are no longer affected by antibiotics. Then when antibiotics are really needed to treat UTIs, they are less effective. Also, antibiotic resistance can lead to new strains, which are less responsive to antibiotics. Thus, cranberries are an effective and safer option. Also, the use of cranberries is a more cost effective method than antibiotics, and may help reduce the amount spent to eradicate infections; which currently exceeds $2 billion each year. iv Inspite of this strong evidence, some other studies were found that indicated that cranberries were not effective at preventing UTIs, and were found to have major flaws that eliminated their credibility. Research is not perfect and there are strengths and weaknesses to all studies. One of the strengths of the studies was that they were double blind, randomized, placebocontrolled trials, which are the gold standard in experimental studies. They provide the strongest evidence for causality. The randomization reduces selection bias and removes confounders, and bias is reduced by double blinding the trial. The studies used varied concentration of PACs, which allowed the most effective dose to be uncovered. The duration of most of the trials was 6-12 months, which is appropriate since it may take time for a UTI to develop. The trials used commercially available products for UTIs which makes the results easily transferable to the general public. The major weakness of the majority of the studies was that they were done in vitro, which doesn t always translate to the same results in vivo. It is very difficult to do truly in vivo studies and it is almost impossible to recreate the environment of the urinary tract in vitro. The studies that did use humans did a good job of balancing the use of in vivo and in vitro methods. In conclusion, cranberries are effective at preventing urinary tract infections. PACs anti-adhesions and inhibition of flagellum-mediated motility properties help prevent bacteria from colonizing and infecting the urinary tract. Data suggests that 36 mg of cranberry PAC equivalents per day is effective at preventing UTIs, but two doses of 36mg of PACs a day (total of 72 mg) is more effective since it keeps the PAC levels higher throughout the entire day. Some examples of cranberry products that can be 4

consumed to get PACs include: raw cranberries, cranberry juice cocktail (CJC) *, 100% cranberry juice, and cranberry pills. Eight ounces of CJC usually contain 55 mg of PACs (130 kcals). The same amount of PACs can also be obtained from 1/4 cup of fresh or frozen cranberries (12 Kcals), 1/3 cup of sweetened dried cranberries (138 Kcals), or 1/3 cup of cranberry sauce (145 Kcals). iii When talking to clients about incorporating more cranberry products into their diet, it is important to keep in mind the calories found in the different products. The eight-ounce glass of CJC, sweetened dried cranberries, and cranberry sauce have about 130-140 kcals. Two servings of these items can add an additional 260-280 kcals to an individual s diet, which may not be acceptable for all clients. For clients concerned about their intake the fresh or frozen cranberries are the best option since they only have about 12 kcals per quarter cup and would total only 24 kcals for the two serving day. If clients cannot tolerate the bitter taste of fresh cranberries a cranberry supplement can also be recommended. i "Prevalence and Incidence of Urinary Tract Infections - RightDiagnosis.com." Right Diagnosis. 23 Aug. 2011. Web. 06 Nov. 2011. <http://www.rightdiagnosis.com/u/urinary_tract_infections/prevalence.htm>. ii "Urinary Tract Infections in Adults - National Kidney and Urologic Diseases Information Clearinghouse." Home Page - National Kidney and Urologic Diseases Information Clearinghouse. Web. 02 Nov. 2011. iii Cranberry Proanthocyanidins (PACs): Facts for Media. cranberry-infocenter.ch/m/mandanten/188/download/pacs_qa.pdf Accessed on Oct 20, 2011. iv Paola A. Pinzón-Arango, Yatao Liu, and Terri A. Camesano (2009) Role of Cranberry on Bacterial Adhesion Forces and Implications for Escherichia coli Uroepithelial Cell Attachment. J Med Food 12(2):259 270. v Gupta A, Dwivedi M, Mahdi AA, Nagana Gowda GA, Khetrapal CL, Bhandari M (2011) Inhibition of adherence of multi-drug resistant E. coli by proanthocyanidin. Urol Res. * Cranberry cocktail is 27% juice. 5

vi Hidalgo G, Chan M, Tufenkji N (2011) Inhibition of Escherichia coli CFT073 flic expression and motility by cranberry materials.appl Environ Microbiol 77(19):6852-7. vii Howell AB, Botto H, Combescure C, Blanc-Potard AB, Gausa L, Matsumoto T, Tenke P, Sotto A, Lavigne JP (2010) Dosage effect on uropathogenic Escherichia coli anti-adhesion activity in urine following consumption of cranberry powder standardized for proanthocyanidin content: a multicentric randomized double blind study. BMC Infect Dis 10:94. viii Mariëlle A. J. Beerepoot, MD; Gerben ter Riet, MD, PhD; Sita Nys, PhD; Willem M. van der Wal, MSc; Corianne A. J. M. de Borgie, PhD; Theo M. de Reijke, MD, PhD; Jan M. Prins, MD, PhD; Jeanne Koeijers, MD; Annelies Verbon, MD, PhD; Ellen Stobberingh, PhD; Suzanne E. Geerlings, MD, PhD (2011) Cranberries vs Antibiotics to Prevent Urinary Tract Infections: A Randomized Double-blind Noninferiority Trial in Premenopausal Women. Arch Intern Med 171(14):1270-1278. 6