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Antibiotics
Antibiotics affect not only pathogenic microorganisms, but many human residential symbiotic and administered probiotic bacterial strains too. Many strains of the most prevalent vaginal lactobacilli species (L. crispatus, L. iners, L. jensenii, and L. gasseri) were all demonstrated to be susceptible to commonly used systemic antibiotics including ampicillin, cefazolin, cefotaxime, and vancomycin, but insensitive to metronidazole and trimethoprim/sulfamethoxazole along with differential sensitivity to others (gentamycin, clindamycin, erythromycin, ciprofloxacin, and tetracycline). For example, treatment with clindamycin was shown to suppress/eradicate L. crispatus and induce the selective accumulation of L. iners and L. gasseri.
Bacterial Vaginosis and Urinary Tract Infections
Many women experience a transient, often recurrent, loss of a lactobacilli-dominated vaginal microbiota and reduced vaginal acidity, which is associated with increased risk of urogenital infections as the reduction in lactobacilli makes for a more conducive vaginal environment for the proliferation of many anaerobic bacteria such as Gardnerella vaginalis (G. vaginalis) and Atopobium vaginae (A. vaginae).
BV and UTIs are common infections, afflicting hundreds of millions of women annually,48,49 with BV the most common cause of vaginal symptoms among women. In the United States, the prevalence of BV (determined by a Nugent score of 7-10) was estimated to be 21.2 million (29.2%) among women aged 14 – 49 years, based on a nationally representative sample of women who participated in the National Health and Nutrition Examination Survey (NHANES) 2001 – 2004.42 BV is a risk factor for acquisition of both bacterial (gonorrhea, chlamydia, and Trichomonas vaginalis infection) and viral (HIV, HSV, and HPV) sexually transmitted diseases as well as adverse obstetric outcomes (e.g., miscarriage, fetal distress syndrome, PROM, preterm birth).3,6,50
G. vaginalis and A. vaginae are commonly associated with BV51,52 whereas the majority (>80%) of UTIs are caused by uropathogenic E. coli (UPEC) and often associated with AV.53 These pathogenic bacteria colonize the vagina via the formation of biofilms, which results in increased tolerance to adverse conditions for better persistence in hostile environments (i.e., protection from the immune system and decreased susceptibility to antibiotics).54,55
Adherent biofilm comprised of mostly G. vaginalis and A. vaginae was observed to persist for three weeks following one-week treatment with orally administered metronidazole in women with BV.52 In the UK, BV is frequently treated with topical clindamycin. The proportion of group B streptococci isolated from neonatal blood cultures that are resistant to clindamycin or erythromycin has risen substantially over recent years in the UK (Health Protection Report 2013, 7:46), most likely as a result of exposure to these antibiotics.
Lactobacillus Strains to Support Women's Urogenital Health
Bacterial migration from the colon to the vagina across the perineum occurs naturally, thus is a source of both potential pathogens as well as certain lactobacilli. Given that lactobacilli are generally recognized as the hallmark of a healthy vaginal microbiota, the rationale for probiotic use in support of women's urogenital tract health is strong.56 Certain lactobacilli strains can safely colonize the vagina after oral as well as vaginal administration, displace and kill pathogens, and modulate host immune responses. Maintenance of a healthy vaginal microbiota could reduce the incidence of urogenital infections, the spread of sexually transmitted infections, and adverse pregnancy outcomes, thus decrease the need for conventional treatments.57
However, it is important to keep in mind that these inhibitory mechanisms and activities are generally strain specific; therefore, not all strains of a given lactobacillus species have the same probiotic potential. Furthermore, strains contained in a multi-strain combination need to be compatible (i.e., not antagonistic) and preferably synergistic for a targeted health condition beyond general gastrointestinal health (e.g., women's urogenital tract health), which must be demonstrated by clinical research. Although administration of vaginal suppositories is the most common way of delivering lactobacilli to the vagina, oral administration represents a more user-friendly alternative that may be more effective as a preventative strategy in the long run, given the recognition of the gastrointestinal tract as a reservoir for vaginal colonization by lactobacilli for the maintenance of a normal vaginal microbiota. It should be noted that any vaginally inserted capsule should not be enteric-coated, common for oral probiotics to protect the live bacteria from stomach acid, thus appropriate for orally administered probiotics to support women's urogenital tract health.
It is worth noting the current internationally endorsed definition of probiotics established by an expert panel commissioned in 2001 by the Food and Agriculture Organization (FAO) of the United Nations and supported by the World Health Organization (WHO), which states, 'Live microorganisms that, when administered in adequate amounts, confer a health benefit on the host." A health benefit to the host, humans in our case, must be realized and demonstrated to be superior to that of placebo/control (i.e., clinical research), but the majority of fermented foods and products labeled as or as containing probiotics on the market have not been appropriately tested and verified as such. How 'probiotic" containing products are regulated, marketed, and sold often has nothing to do with the definition. Many consumers/patients appear to be influenced by the live cell count (quantity) and number of strains offered in products labeled as containing probiotics, naively believing the more of each the better. Companies indulge this naivety and even actively propagate this messaging to consumers, often masquerading as educational, and eluding the lack of clinical validation for these strains (when strains are even identified on the label). Yet, the definition of probiotics militates against excessively high counts (dosing) of strains lacking clinical validation as touted by many commercially available products in favor of efficacious strains and dosing, substantiated by clinical research.
Orally and vaginally administered probiotic lactobacilli strains have been investigated as both an adjuvant and alternative therapy for the treatment and prevention, including recurrence post-treatment, of BV and UTIs. For example, orally administered (twice daily) probiotic lactobacilli strains L. rhamnosus GR-1 (1 billion) and L. reuteri RC-14 (1 billion) for 30 days in conjunction with oral metronidazole (500 mg) treatment during the first week was shown to be significantly more effective at curing BV than metronidazole treatment alone in premenopausal women, with significantly higher abundance of vaginal lactobacilli at day 30 in women receiving oral probiotic supplementation.58 Additionally, oral supplementation with probiotic lactobacilli strains was as effective as daily antibiotics for UTIs.59 Used in conjunction with and following antibiotic treatment helps restore a healthy vaginal microbiota to increase cure rate and reduce relapse.56,58
'Kitchen sink" products marketed to support women's vaginal health often tout a laundry list of different bacterial species and claim as many as 100 billion per capsule, albeit generic, clinically unsubstantiated strains for this indication. These levels have no rationale in light of the fact that the successful clinical studies utilized dosing in the 1 - 10 billion live organisms per day range, the difference being clinically validated strains with probiotic attributes to serve this function. Clinically validated strains are expensive, thus a product containing 100 billion (live organisms guaranteed through the listed 'best used before date" and not at time of manufacture) clinically validated strains per capsule would be prohibitively expensive and excessively dosed. Again, and most importantly, the specific probiotic strain(s) indicated to support women's urogenital tract health must be provided in sufficient quantity as validated by clinical research; otherwise, it does not constitute a true probiotic for this condition.
Not All Strains Are Equal
Again, it should be noted that not all lactobacilli strains, even those recognized more generally as a probiotic to support gastrointestinal health, are effective for supporting women's urogenital tract health. For example, daily oral administration of the widely recognized probiotic strain to support gastrointestinal health, L. rhamnosus GG, for 28 days failed to influence vaginal health despite the administration of 10 billion, whereas oral administration of only 1.6 billion of the combination of L. rhamnosus GR-1 and L. reuteri RC-14 supported a healthy vaginal microbiota.60 Furthermore, daily oral administration of a commercially available dietary probiotic containing L. rhamnosus GG (40 billion) for six months failed to demonstrate vaginal colonization by this specific L. rhamnosus strain or reduce the recurrence of UTIs.61
The majority of probiotic products marketed for support of women's vaginal health, generally multi-strain combinations of lactobacilli with or without strains from additional genera such as Bifidobacteria, are not supported by clinical research for this indication. Additionally, the strain designation for each bacterium within the combination is often not disclosed (only genus and species). It is well recognized scientifically that probiotics are strain, dose, and condition specific. Strains of the same bacterial species can be different as exemplified by aforementioned examples comparing L. rhamnosus GR-1 vs. L. rhamnosus GG (unique strains of the same bacterial genus and species) to support women's urogenital tract health (condition), a functional distinction that was not overcome with administration of markedly greater abundance (dose) of L. rhamnosus GG.
Strain functionality and associated health claims beyond general support of gastrointestinal health in humans require substantiation of efficacy with clinical trials. Strain designation links unique bacterial strains to the scientific research supporting probiotic characteristics and efficacy for a specific condition in target host organisms (e.g., humans).
Guidelines established by an expert working group, convened jointly by the FAO of the United Nations and the WHO, state, 'Proper identification to the level of strain of all probiotics in the product," and Dr. Mary Ellen Sanders of the International Scientific Association for Probiotics and Prebiotics, an internationally recognized consultant in the area of probiotic microbiology, has stated, 'Manufacturers should designate the strains in their products so that consumers know what they're getting. It's pretty much a consensus among probiotic scientists that this is the responsible thing to do."
Four Unique Vaginal Probiotic Lactobacilli Strains
Domig et al.62 demonstrated an extensive, multi-step scientific process to identify candidate probiotic strains, representing the predominant Lactobacillus species colonizing the vagina of healthy pregnant women (L. crispatus, L. jensenii, L. gasseri, L. rhamnosus), for oral administration to support women's urogenital tract health. From 68 isolates belonging to these species, which were derived from 99 isolates from the genus Lactobacillus out of a total of 127 isolates from healthy pregnant women in their late-first trimester, four final candidate strains were selected for targeted formulation based on a battery of criteria such as ability to grow under both aerobic and anaerobic conditions, acidification capacity, glycogen utilization, extracellular hydrogen peroxide production, stability under acidic conditions and resistance to bile salts (important for survival during gastrointestinal transit post-oral administration), anti-microbial activity against multiple strains of common vaginal pathogens (i.e., Candida albicans, Candida krusei, Candida glabrata, E. coli, and G. vaginalis), compatibility, safety (e.g., lack of virulence factors, antibiotic susceptibility/lack of antibiotic resistance), and encapsulated stability of the multi-strain formulation (forecasting shelf-life stability for use in commercial dietary supplements).
The strains of this probiotic formulation representing the predominant Lactobacillus species of the vaginal microbiota of healthy pregnant women have been designated L. crispatus LbV 88, L. jensenii LbV 116, L. gasseri LbV 150N, and L. rhamnosus LbV 96. These strains, as part of multi-strain probiotic formulation, were subsequently demonstrated in multiple clinical studies to increase vaginal lactobacilli abundance and acidification in support of urogenital tract health.
The Neovagina: A Challenging Microbial Environment
The neovaginal microbiota of male-to-female transsexual women is a diverse community of both aerobic and anaerobic species with very limited colonization by lactobacilli, more reflective of the abnormal vaginal microbiota characteristic of BV.63 The neovaginal environment may not adequately support the growth of lactobacilli despite transsexual women having comparable estrogen levels to those of postmenopausal women receiving hormone replacement therapy,63 with one study observing a neovaginal lactobacilli colonization rate of only 4%.64
In a prospective, randomized, placebo-controlled study, twice daily oral supple-mentation with the multi-strain probiotic formulation (2 X 2.5 billion live cells/dose) for only one week significantly enriched lactobacilli and resulted in a lower Nugent score in the neovagina of male-to-female transsexual women compared to placebo.65 Neovaginal lactobacilli abundance was five to six times higher in the intervention group compared to the placebo group. In contrast to previous observations reported in the scientific literature, an unexpectedly high proportion (30%) of the participants in this study had a normal Nugent score of < 3. When those participants with a baseline Nugent score < 3 were excluded from the analysis or only those participants with BV (Nugent score > 7) were included, an improvement in the Nugent score was observed in the intervention group, but not in the placebo group.
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