More Evidence That Probiotics May Prevent UTI

Posted 10:29 AM, April 21, 2011, by Michael Harrison Hsieh

Urinary tract infections (UTI) can recur despite antibiotic treatment. The “dysbiosis” theory postulates that antibiotics and other influences can disturb the commensal microbiota (the non-disease-causing microbes living in and on the body), resulting in overgrowth by disease-causing microbes. The vagina and peri-urethra (the area around the urethra, the tube through which humans urinate) may be reservoirs for bacterial uropathogens, which cause UTI. Consequently, investigators have hypothesized that antibiotic therapy of UTI results in local dysbiosis which predisposes girls and women to recurrent infections. As a result, extensive work has been conducted to determine whether probiotics, “live microorganisms which when administered in adequate amounts confer a health benefit on the host” [1], can replace or augment the vaginal microbiota in order to reduce risks of subsequent UTI. Stapleton et al. recently published a clinical trial of a Lactobacillus crispatus intravaginal suppository to prevent recurrent UTI in young women [2]. L. crispatus is a commensal bacterial species found in the vaginas of many healthy women. The particular strain tested in this study, L. crispatus CTV-05, was isolated from the vagina of a healthy woman and produces hydrogen peroxide, an anti-bacterial molecule. Intravaginal administration of this potential probiotic results in minimal side effects [3]. Stapleton’s study was a placebo-controlled trial, which means that one group of study subjects received the study “medication” (probiotics) and the other group received the vaginal suppository equivalent of a “sugar pill”. Placebo arms for clinical trials are important since many studies have demonstrated that the mind-body connection affects various health outcomes; study subjects in placebo arms can exhibit clinical benefits or side effects by believing they may be receiving therapy. To eliminate potential bias on the part of either study staff or subjects, the clinical trial was double-blinded, where neither the staff nor the subjects were aware of whether subjects received placebo or probiotics.

The investigators recruited 100 UTI-prone women through the University of Washington student health center. Study subjects were randomized to receive either a L. crispatus or placebo intravaginal suppository. By evenly distributing patients between treatment arms, randomization helps reduce the likelihood that any observed effects are due to unforeseen differences between study subjects. For example, if eye color is an unexpected but important factor in UTI risk (I don’t think it is!), randomization would evenly distribute study subjects of different eye colors among the treatment arms. The study also incorporated multiple important secondary study endpoints, such as pelvic examination and PCR (a sensitive DNA-based laboratory detection technique) quantification of L. crispatus levels in the vagina. However, no power calculation (an a priori, or pre-study, estimate of the number of patients required to see a statistically significant effect) is mentioned, suggesting that the 100 study subjects was chosen as an arbitrary number. The authors also categorized study subjects into “low” and “high” L. crispatus colonization levels without a clear rationale and explanation of whether this categorization was decided upon a priori. These issues are particularly important when a clinical trial shows lack of efficacy of a treatment arm but demonstrates positive findings in secondary endpoints. In the case of this study, these considerations may be irrelevant, given the magnitude of effect of the intervention (2-fold reduction in risk of recurrent UTI in women receiving probiotics), and evidence that high levels of L. crispatus colonization correlated with reduced UTI risk for women in the probiotics arm.

For women prone to recurrent UTI, this clinical trial strongly suggests that intravaginal administration of probiotics may be a valid approach to prevent subsequent infections. However, this strategy does not apply to boys and men prone to UTI. Intravaginal suppositories are also not feasible for prepubescent girls, since parents are understandably hesitant to insert medications into the vaginas of their young daughters. Realistic probiotic strategies for prepubescent girls prone to UTI must be based on oral administration. Giving probiotics by mouth in order to exert vaginal effects features several significant challenges. Orally administered probiotics must be able to withstand the highly acidic environment of the stomach. They must also be tolerant of bile acids, which humans produce in the liver and secrete into the intestinal tract. Bile acids act as detergents to help digest food, and many bacteria cannot resist their detergent effect. Orally administered probiotics must also avoid or resist the immune system. Other bacteria produce specific molecules to kill competing bacteria, and probiotics must survive this gauntlet as well. Once probiotics exit the intestinal tract through the rectum, they next need to migrate across the perineal skin (area between the rectum and vagina) to the vagina and peri-urethra. Analogous to their experience in the intestinal environment, probiotics must again resist the immune system and other bacteria in the vagina and peri-urethra in order to successfully colonize these areas and exert their beneficial effects. In short, the biological “bar” for orally administered probiotics to prevent UTI is high. Fortunately, investigators have shown that some probiotics taken by mouth indeed may colonize the vagina and peri-urethra [4]. However, the leap from oral-vaginal colonization to clinical efficacy against UTI remains to be made. Our laboratory is studying the interactions between candidate probiotics and vaginal cells. Through this work we hope to better understand how probiotics interact with the human body, which will be critical to probiotic applications for human diseases such as UTI.

1. Guidelines for the Evaluation of Probiotics in Food. 2002, Joint FAO/WHO Working Group on Drafting Guidelines for the Evaluation of Probiotics in Food: London Ontario, Canada. p. 1-11.
2. Stapleton, A.E., et al., Randomized, Placebo-controlled Phase 2 Trial of a Lactobacillus crispatus Probiotic Given Intravaginally for Prevention of Recurrent Urinary Tract Infection. Clin Infect Dis, 2011.
3. Czaja, C.A., et al., Phase I trial of a Lactobacillus crispatus vaginal suppository for prevention of recurrent urinary tract infection in women. Infect Dis Obstet Gynecol, 2007. 2007: p. 35387.
4. Reid, G., et al., Oral use of Lactobacillus rhamnosus GR-1 and L. fermentum RC-14 significantly alters vaginal flora: randomized, placebo-controlled trial in 64 healthy women. FEMS Immunol Med Microbiol, 2003. 35(2): p. 131-4.

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