Here we report the results of a modified observational clinical trial of two-week SDC consumption for the prevention of UTIs in susceptible women. Using two different methods to determine efficacy, consumption of SDC was shown to be beneficial in reducing the occurrence of UTIs in susceptible women. The significant decrease in six-month UTI rates per individual patient and the comparison of UTI recurrences to a previous control group of women with equivalent UTI histories provide evidence of the potential prophylactic effect of SDC.
Based on the significant decrease in UTI incidence, potential mechanisms of SDC action were investigated. We examined whether the reduction in UTIs could be accounted for by significant changes in the numbers or prevalence of intestinal E. coli or other bacterial species following SDC. E. coli was the only bacteria that showed a significant decrease in overall numbers over the course of the study. It is possible that polyphenols from SDC blocked adherence of E. coli to the intestinal surface and thus decreased their overall numbers, rather than exerting a bactericidal effect. The lack of SDC toxicity is also supported by the observation of no significant changes in the numbers of the other intestinal bacteria surveyed. It is thus likely that SDC are not affecting the growth of commensal bacteria, which is contrary to what would occur if patients were taking prophylactic antibiotics. The lower numbers of intestinal E. coli, combined with the lack of interference with other types of bacteria, may provide a potential benefit since it produces no adverse effects and results in decreased likelihood of UTI.
Although there were no changes in the heterogeneity of intestinal E. coli strains after SDC consumption, we questioned whether there were differences in the intestinal E. coli phylotypes or virulence gene profiles after SDC consumption. The proportion of E. coli with A and D phylotypes was higher after SDC consumption than E. coli with B1 and B2 phylotypes. Phylotypes A and B1 are considered to be less uropathogenic than D and B2. Thus, the increased presence of the A phylotype and decreased presence of the B2 phylotype could be beneficial; however, this does not explain the increased and decreased presence of E. coli with D and B1 phylotypes, respectively. Although there were changes in the phylotypes of E. coli pre- and post-consumption, there was little change in the proportions of strains carrying VF genes associated with UTI. The prevalence of only the iutA and PAI ICFT VF genes in strains differed by more than ten percent after SDC consumption. Overall, the heterogeneity of E. coli and the presence of VFs did not change as a result of SDC consumption, which suggests that SDC do not directly influence the underlying make-up of E. coli in the intestinal flora.
Because the significant reduction in the number of UTIs following SDC consumption is most likely not related to reducing the prevalence or heterogeneity of intestinal uropathogenic E. coli
or other potential uropathogens, alternative mechanisms whereby cranberry phytochemicals could directly influence bacterial phenotypes should be considered. One intriguing possibility is that some components of cranberries may be able to modulate expression of E. coli
VF genes and reduce infectivity and pathogenicity. Support for this concept comes from several studies. Trans-cinnamaldehyde was shown to decrease E. coli
attachment to uroepithelial cells and to reduce cellular invasion in vitro by downregulating expression of the fimH
gene coding for the adhesin of type 1 pili [25
]. Cinnamaldehyde and some of its derivatives were also shown to reduce the virulence of Vibrio
species by decreasing the quorum sensing response [26
]. It has also been reported that compounds in crushed cranberries or cranberry proanthocyanidins inhibited expression of the fliC
flagella structural gene in the CFT073 UPEC strain, with subsequent loss of motility [27
]. Resveratrol, which is present in cranberries, decreased the pathogenicity of Proteus mirabilis
by inhibiting swarming as well as reduced hemolysin production and urothelial cell invasion [28
]. It is possible that these, or other compounds found in cranberries could similarly decrease the virulence of intestinal E. coli
by gene modulation that reduces motility as well as uroepithelial cell adherence and invasion, thereby reducing uropathogenic E. coli
persistence and infectivity in the vagina and bladder.
Another potential mechanism to consider for the observed clinical benefits of SDC consumption is that cranberry phytochemicals may boost mucosal immunity to uropathogens in the gastrointestinal tract. A recent study has shown that cranberry proanthocyanidins can be used as an adjunct to increase intestinal sIgA
levels in mice receiving enteral nutrition [29
]. A clinical investigation found that consuming a cranberry beverage for ten weeks resulted in a five-fold increase in proliferation of T cells ex vivo, a 30% increase in NK cell proliferation, and a 20% reduction in IL-17 secretion, as well as a significant reduction in cold and flu symptoms compared to placebo [30
]. Further studies on the immune enhancing effects of SDC in vivo could define which components of the intestinal immune system are targeted by cranberry phytochemicals.
Although SDC consumption did not prevent UTIs in every patient, none of the patients reported any adverse effects. Therefore, it may be suggested that SDC be used as a prophylactic supplement for patients with recurrent UTIs, since the potential benefits greatly outweigh the risks. A larger, randomized, placebo-controlled study is needed to confirm that daily consumption of SDC is beneficial in the reduction of recurrent UTIs.
One of the limitations of the efficacy assessment is the comparison of patients consuming SDC in this study to a control group from a previous study. We are confident, however, that this comparison between groups is applicable and informative even though it is not the most appropriate comparison for rigorous statistical analysis. Because the women in the current trial and the previous placebo-controlled study had equivalent UTI histories and similar demographics, we would expect women in both groups to acquire UTIs at the same rate over a six-month period without treatment interventions. Randomized, placebo-controlled studies are necessary to further determine the efficacy of SDC consumption.