The Rationale for Probiotics in Female Urogenital Healthcare

Gregor Reid PhD MBA, BSc (Hons); Jeremy Burton PhD; Estelle Devillard PhD

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In This Article

Probiotics for Vaginal and Bladder Health

After the commercial introduction of L casei Shirota (Yakult) in Japan in the 1930s, the next probiotic strains to be discovered and extensively studied were L acidophilus NCFM (mid-1970s) for the gut[63] and L rhamnosus GR-1 and L fermentum RC-14 for the urogenital tract (1980 through 1985).[66] Since then, several research groups have attempted to identify suitable candidates for vaginal colonization.[67,68,69]

In vitro selection data are useful to learn more about the organisms but are insufficient to predict efficacy in humans. In addition, simply showing an absence of lactobacilli associated with disease does not mean that application of lactobacilli to the vagina will prevent or treat that ailment. A key factor is whether a strain colonizes over a sufficient period to confer health benefits to the host. Adhesion and colonization of the vaginal epithelium by the strain for days or even weeks may be necessary.[70,71] However, longer-term colonization for months or years may not be necessary if the person's own lactobacilli recolonize or the exogenous therapy is re-administered. Some researchers have paid little attention to these points and have tested Lactobacillus strains not particularly well suited to the vagina.[72,73] Perhaps not surprisingly, the strains had no clinical impact on recurrence of infection. Others have taken products to market with minimal clinical verification of efficacy of a given strain.[74] Although these strains may provide some relief of symptoms and ultimately be a useful treatment option, publication of supportive efficacy data would enhance credibility and acceptance by the medical community and consumers.

Insertion of lactobacilli into the vagina via a pessary or capsule is an effective means of boosting content of the flora and overcoming some pathogens or reducing their ability to dominate. This seems to be true for treatment of BV and possibly UTI pathogens,[44,75,76] but there is only anecdotal evidence to suggest that lactobacilli can treat yeast vaginitis.[77,78] (Whether any effect is attributable to the ability of such strains as GR-1 and RC-14 to inhibit candidal growth and adhesion[79,80] remains to be determined in human trials.) The dried lactobacilli used in vaginal suppositories appear to be capable of hydrating from the capsule and interfering with pathogenic organisms. Use of skim milk-based preparations can also be effective,[81] but compliance may be a problem for some women because of the need to retain the fluid with a tampon. Oral dosage seems to require around 109 viable bacteria once or twice weekly,[52] although a once-per-day vaginal protocol for 3 days might initially be required to displace large pathogen biofilms in the urogenital tract.

Most urogenital microflora originate from the gut and ascend via the rectum. Studies have shown that daily oral intake of L rhamnosus GR-1 and L fermentum RC-14 can modify the vaginal flora.[15,52,53] In a randomized, double-blind, placebo-controlled study of 64 healthy women, daily intake of L rhamnosus GR-1 and L fermentum RC-14 resulted in significantly less yeast and fewer coliforms in the vagina.[15] Vaginal swabs (blinded) were sent to an independent laboratory and cultured. Cultures revealed significantly more lactobacilli and less yeast and fewer coliforms in the lactobacilli-treated group; whereas the swabs obtained from women treated with placebo showed a significant increase in yeast and coliforms, perhaps explaining why the vaginal flora is so commonly "abnormal." Administration of the probiotic organisms even normalized flora in some cases of BV, making it feasible to study this as an approach to long-term therapy for pregnant women and those susceptible to BV and UTI. The ability of these organisms to displace other organisms was shown previously in vitro.[82]

Studies are needed to determine whether healthy people and those prone to recurrent urogenital infections benefit from daily use of dried probiotics, such as L rhamnosus GG, which is the most clinically documented probiotic strain for gut health and is available in the United States. A study using this strain in fermented milk has suggested some reduction in UTI recurrences.[83] The potential for intestinal probiotics to influence bladder and vaginal health through some form of immune modulation has not been fully explored, but a study using L casei Shirota (available from a few stores in California) suggested that it had potential to reduce recurrence of bladder cancer.[84]

The interactions among microbes at the vaginal mucosal surface remain to be elucidated. It is assumed that antiviral, antiyeast, and antibacterial effects shown in vitro[71,80] also occur in vivo, but mechanistic and cause-and-effect studies are required to verify this hypothesis. A recent study on a dextran sulphate-induced mouse colitis model suggested that DNA extracted from probiotic organisms and E. coli could mediate anti-inflammatory activity and ameliorate disease through toll-like receptor 9 signaling.[85] However, the interpretation of the findings by authors and writers who have subsequently reported on the results[86] has been exaggerated and overextended. The experimental model is 1 way of creating and studying colitis, but using the same probiotic organisms, the principal author of the study did not find an effect of the extracted DNA using a different animal model of colitis.[87] Also, there are other ways to influence inflammatory responses; thus, even if it is possible to interfere with toll-like receptor 9 activity, it might not result in a clinically significant outcome for colitis patients. People consume bacteria and bacterial DNA on a daily basis, yet rates of inflammatory bowel disease increase. This latest study provides a useful insight into potential mechanisms of probiotic actions, but clearly much clinical investigation is needed before DNA can be recommended for symptomatic relief of disease in the gut or other mucosal sites.

The actual mechanisms of action of probiotics in the vagina have not been proven and are probably multifactorial. The production of lactic acid, bacteriocins, and hydrogen peroxide seems to be important, but these substances have not been measured in healthy women and compared with those obtained in women immediately before and during a BV or UTI event. Modulation of immunity is another plausible mechanism--for example, in BV IL-1 and IL-8 levels are elevated compared with levels in healthy (lactobacilli-dominated) vaginas.[88] Lactobacilli have been shown to produce biosurfactants and collagen-binding proteins that inhibit pathogen adhesion and to some extent displace pathogens.[89,90] This might explain why vaginal mucosa dominated by lactobacilli but that has much of the surface uncovered by these organisms could still be less receptive to pathogens. Among Lactobacillus by-products, cell-signaling molecules have been discovered, which can downregulate pathogen virulence (unpublished findings). Thus, cell-to-cell communication is another probable mechanism of action. This communication may also involve the signaling of mucus production, which acts as a barrier to pathogens,[91] or signaling of anti-inflammatory cytokine production.[92,93] How normal flora can become conducive to BV so rapidly is still a mystery. Perhaps epithelial cell turnover is involved, exposing new surfaces to pathogens, or perhaps ascension of pathogens from the anus becomes so overwhelming that the microenvironment changes and the pathogens thrive due to rapid multiplication. Clearly, more research is needed.

The concept of using nonviable bacteria as a vaccine in the vagina has also been explored in a study in which a combination of antigens from various uropathogens was tested for its ability to reduce risk for recurrent UTI.[94] The results are encouraging, but again more research is required to confirm the results and to elucidate the mechanisms involved. It seems unlikely that dead pathogens in a vaccine induce immune protection when live pathogens, present in the vagina in large numbers in patients with recurrent UTI, do not. Competitive exclusion also seems unlikely, because although dead pathogens could interfere with adhesion of live ones, the effect would not last long, as the vaccine components would degrade or be sloughed off. Vaccines that specifically interfere with adhesion, such as type 1 fimbriae of E. coli, may have some success. However, these organisms have several mechanisms of attaching to cells, and blocking 1 species may simply lead to infection by another if the environment is not conducive to restoration of a normal flora.

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