Probiotics Womens Health

Feature - Probiotics and women’s health: bacterial vaginosis and vaginal candidiasis

By Alexander Georgiou, AdvDip(Nat), AdvDip(Myo), Scientific Affairs Associate, Life-space Group

Implications for pharmacy practice

Patients may ask pharmacists and pharmacy staff about natural ways to treat bacterial vaginosis and vaginal thrush. It is important for staff to understand how these two conditions develop so that appropriate advice can be provided.

Key points

A healthy vaginal microbiome is dominated by 4 main Lactobacilli species, which restrict the growth of pathogenic microorganisms.
Lactobacillus rhamnosus GR-1 and Lactobacillus reuteri RC-14 have been shown to inhibit the growth of urogenital pathogens, prevent the adhesion of pathogenic bacteria, downregulate inflammation, and enhance immune defences.
The pathogenesis of bacterial vaginosis (BV) involves the loss of healthy Lactobacilli species in the vaginal microbiome, a reduction in lactic acid production, and increasing pH levels in the vaginal environment, rendering the vaginal microbiome vulnerable to pathogenic microorganisms.
Vaginal candidiasis is the second most common vaginal infection after BV and is caused by the overgrowth of the commensal fungal species, Candida albicans.
Beneficial indigenous Lactobacilli produce lactic acid and other short-chain fatty acids which leads to acidification of the vaginal microbiome, inhibiting the invasive overgrowth of this fungal species.
Development of fungal biofilms plays a key role in the pathogenesis, severity, and recurrence of VC.
The probiotic strains L. rhamnosus GR-1 & L. reuteri RC-14 have been shown to prevent fungal biofilm formation involved in the growth of C. albicans, produce fungicidal and fungistatic agents which directly kill and supress C. albicans growth, and lactic acid, which promotes a lower vaginal pH, creating a less conducive environment for Candida growth.

Introduction

In reproductive-aged women, the vaginal microbiome is a microbial ecosystem that is dominated by specific Lactobacillus species. Unlike the high bacterial diversity seen in the gut microbiome, a healthy vaginal microbiome is dominated by only four Lactobacilli species, predominately, Lactobacillus iners, Lactobacillus crispatus, Lactobacillus gasseri and Lactobacillus jensenii. [1,2] These bacterial species act as frontline defenders by actively restricting the growth of pathogenic microorganisms. [3] Lactobacilli species produce various antimicrobial compounds to protect the vaginal microbiome, including lactic acid, hydrogen peroxide and bacteriocins. In addition, lactic acid bacteria work to lower the vaginal pH, making the environment more acidic and in turn, less conducive to pathogenic microorganisms. [4,5]

A healthy, Lactobacillus-dominated vaginal microbiome is dependent on a steady source of freely available glucose in the vaginal lumen. Although glucose is not produced directly by vaginal epithelial cells, oestrogen levels stimulate local epithelial cells to produce a multibranched polysaccharide known as glycogen. [3] However, for vaginal Lactobacilli to utilise the glucose from glycogen, the enzyme alpha-amylase, produced in vaginal secretions, must degrade the polysaccharide bonds into simple glucose molecules. Consequently, vaginal Lactobacilli can then convert glucose to lactic acid to help maintain a healthy vaginal microbiome. [6]

Figure 1: Function of alpha-amylase

Although the vaginal microbiome harbors a small number of pathogens, a Lactobacillus dominated vaginal microbiome keeps these harmful organisms at bay. Consequently, disrupting this dominance of Lactobacilli may lead to excessive proliferation of pathogenic microorganisms. [7]

Therefore, over the past twenty years there has been extensive research conducted to identify probiotics that assist in replenishing beneficial vaginal Lactobacilli. In particular, the strains Lactobacillus rhamnosus GR-1 and Lactobacillus reuteri RC-14, which were individually isolated from the distal urethra and vaginal microbiome of two healthy women (respectively), have been shown to inhibit the growth of urogenital pathogens, prevent the adhesion of pathogenic bacteria, downregulate inflammation, and enhance immune defences. [8,9] Lactobacillus GR-1 in particular has been shown to produce a specialised protein called ‘lectin-like protein 1’, which binds to the vaginal epithelium and prevents the adhesion of pathogenic biofilms without affecting the natural Lactobacillus dominance. [10] These beneficial Lactobacilli are capable of colonising the vaginal microbiome after oral ingestion though migration from the rectum to the vaginal microbiome. [11]

Bacterial Vaginosis

A decrease in vaginal Lactobacilli of the vaginal microbiome can lead to an overgrowth of pathogenic bacteria, including Gardnerella vaginalis, Mycoplasma hominis, Bacteroides, Prevotella species. [5] In a prospective cohort trial of young Australian women, the prevalence of bacterial vaginosis (BV) occurred in 12% of women and has been shown to be more common in women with multiple sexual partners. Other risk factors of BV include smoking and vaginal douching. [12] Symptoms of BV include vaginal discharge, burning sensation during urination, itching and fish-like odour. [8]

Treatments for BV

To decrease the overgrowth of pathogenic bacteria in the vaginal microbiome, oral and topical antibiotics can be used to treat BV. The most common being oral metronidazole and clindamycin. Both metronidazole and clindamycin can also be used intravaginally in a gel (metronidazole) or cream base (clindamycin). For patients with BV during pregnancy, oral clindamycin can be used throughout the whole gestational period. [13]

The pathogenesis of BV involves the loss of healthy Lactobacilli species in the vaginal microbiome. This results in a reduction in lactic acid production, ultimately increasing pH levels in the vaginal environment, rendering the vaginal microbiome vulnerable to pathogenic microorganisms. [5]

The ‘Amsel criteria’ is a common diagnostic technique for BV that involves, microscopic analysis of ‘clue cells’, which are vaginal epithelial cells covered in bacteria (Fig.2). Amsel criteria also analyses pH levels and symptoms to diagnose bacterial vaginosis. [14] Another diagnostic technique for BV is the ‘Nugent Criteria’, which involves gram staining to identify the proportions of bacterial morphotypes in a vaginal smear test. [14,15]

Fig.2 Clue Cells

Vaginal bacterial biofilms are the accumulation of pathogenic microorganisms, which adhere to the vaginal epithelium and become difficult to eradicate with antibiotics alone. [16] The establishment of bacterial biofilms plays a key role in the development and recurrence of BV and occurs in the three main steps. Firstly, the ‘initial contact’ stage occurs when pathogenic anaerobes adhere to the vaginal epithelium. The ‘accumulation stage’ occurs, when pathogenic anaerobes begin to multiply and communicate as a single celled organism. Followed by the ‘dispersion stage’, where pathogenic bacteria become enveloped by a protective extracellular matrix, with the ability to detach bacterial cells to infect other surrounding tissue. [17] While antibiotics are effective at reducing the overgrowth of pathogenic bacteria in BV, antibiotics do little to restore a Lactobacilli dominated vaginal microbiome. In addition, unlike beneficial vaginal Lactobacilli, antibiotics are unable to penetrate and eradicate pathogenic biofilms and restore bacterial homeostasis. [16,18]

Table 1: Clinical Trials for Probiotics and Bacterial Vaginosis

Probiotic strains	Ref	Objective	Type	Daily dose	Study age	Study size and length	Results	Conclusion	Limitations
Lactobacillus rhamnosus GR-1 & Lactobacillus reuteri RC-14	[19]	To observe the effects of GR-1, RC-14, GG & determine the dose required to restore and maintain a normal vaginal flora	Double Blind - Clinical Trial (No placebo utilised)	100 million, 1.6 & 6 billion CFU	Women (17-50)	42 Patients (28 days)	Bacterial vaginosis reverted to normal to intermediate in 64% of patients in all GR-1 & RC-14 groups compared to GG. Subject with history of UTI's has a greater improvement in vaginal flora within 28 days (P<0.04) compared to GG. Greatest improvements seen with dosages of 1.6 billion & 6 billion (P<0.01).	Improved vaginal flora in patients with history of BV.	The study was not designed to determine if the ingested strains were the ones that colonised the vaginal microbiome.
Lactobacillus rhamnosus GR-1 & Lactobacillus reuteri RC-14	[18]	To assess the changes in vaginal microbiota following antimicrobial & probiotic therapy with GR-1 & RC-14	Randomised, double-blind, placebo controlled trial	1 billion CFU of each strain, taken twice daily + 2g tinidazole (single dose)	Women (16-50)	62 Patients - BV trial arm (28 days)	GR-1 & RC-14 was shown to enhance the effectiveness of tinidazole in the treatment of BV by improving abundancy of beneficial indigenous bacteria L. iners & L. crispatus (P<0.007).	Increased relative abundance of indigenous L. iners or L. crispatus in vaginal microbiome.	Not stated.
Lactobacillus rhamnosus GR-1 & Lactobacillus reuteri RC-14	[20]	To assess if the probiotics Lactobacillus rhamnosus GR-1 and Lactobacillus reuteri RC-14 might provide an adjunct to antimicrobial treatment and improve cure rates of bacterial vaginosis.	Randomised, double-blind, placebo controlled trial	1 billion CFU of each strain, taken twice daily + 2g tinidazole (single dose)	Women (16-50)	64 Patients (28 days)	After 28 days of treatment the probiotic group had a significantly higher cure rate of BV (87.5%) compared to the placebo group (50.0%) (p = 0.001). In addition, according to the Gram-stain Nugent score, more women were assessed as having a "normal" vaginal microbiota in the probiotic group (75.0% vs. 34.4% in the placebo group; p = 0.011).	Improved cure rate of BV. Improved vaginal microbiota.	Patients self-reported recurrence of BV in baseline characteristics.
Lactobacillus rhamnosus GR-1 & Lactobacillus reuteri RC-14	[21]	To assess whether long-term oral L. rhamnosus GR-1 & L. reuteri RC-14 supplementation in HIV positive women can prevent bacterial vaginosis (BV) and enhance the cure rate of metronidazole among those with bacterial vaginosis	Randomised, double-blind, placebo controlled trial	1 billion CFU of each strain, taken twice daily + 400 mg of oral metronidazole twice daily for 10 days	Women (18 - 45)	65 HIV positive patients (6 months)	Consistent vaginal pH <4.7 was maintained in patients taking RC-14 & GR-1 compared to placebo control groups (P<0.02), However treatment did not enhance the BV cure rate among women living with HIV.	Maintained a healthy vaginal pH bellow 4.7.	Not stated.

Probiotic strains	Ref	Objective	Type	Daily dose	Study age	Study size and length	Results	Conclusion	Limitations
Lactobacillus rhamnosus GR-1 & Lactobacillus reuteri RC-14	[22]	To assess the augmentation of antimicrobial metronidazole therapy of bacterial vaginosis with oral probiotic L. rhamnosus GR-1 and L. reuteri RC-14 in premenopausal women	Randomised, double-blind, placebo controlled trial	1 billion CFU of each strain, taken twice daily + metronidazole (500 mg) twice daily from days 1 to 7	Women (18-44)	106 Patients (4 Weeks)	BV cure rates in probiotic & antibiotic treated group where 88% vs 40% in the placebo & antibiotic group (P<0.001). Higher counts of Lactobacilli were recovered from the vagina in 96% probiotic-treated subjects compared to 53% in control group at day 30.	Increased BV cure rate success. Increased vaginal lactobacilli.	This study was not designed to understand the mechanisms of action of the therapies.
Lactobacillus rhamnosus GR-1 & Lactobacillus reuteri RC-14	[23]	To assess the efficacy of orally administered capsules containing L. rhamnosus GR-1 & L. reuteri RC-14 compared to placebo in otherwise healthy women diagnosed with bacterial vaginosis	Randomised, double-blind, multicentric, placebo-controlled trial	1 billion CFU of each strain, taken twice daily	Women (18+)	544 Patients (6 Weeks)	GR-1 & RC-14 group showed restored vaginal microbiota after treatment in patients with bacterial vaginosis 61.5% restoration compared with 26.9% in the placebo group (P<0.001).	Restored healthy vaginal microflora in BV patients.	A relatively short follow-up period of 6 & 12 weeks post-baseline. Strain identification in the follow-up vaginal swabs was unavailable.
Lactobacillus rhamnosus GR-1 & Lactobacillus reuteri RC-14	[24]	To assess the effectiveness of the probiotic strains having L. rhamnosus GR-1 and L. reuteri RC-14 in the management of lower genital infections (BV and candidiasis) as an integral therapy with antibiotics (metronidazole)	Randomised, double-blind, placebo controlled trial	1 billion CFU of each strain, taken twice daily for 30 days followed by 1 daily for 30 days + metronidazole 400mg 1-0-1 for 7 days	Women (18-45)	32 Patients (2 months)	According to wet smear and gram straining 81.3% women with BV had a normal vaginal picture after sixty days of treatment as compared to placebo which was only 31.3% (P<0.004).	Restored health vaginal microflora in BV patients Improved cure rate of BV with metronidazole	Small sample size. Women were only followed for a 2-month period.
Lactobacillus crispatus Lbv88, gasseri Lbv150, rhamnosus Lbv96, jensenii Lbv116	[25]	To compare the effect of oral intake of yoghurt containing L. crispatus Lbv88, L. gasseri Lbv150, L. rhamnosus Lbv96, L. jensenii Lbv116 with that of placebo on the rate of recovery from BV after standard treatment with metronidazole. Secondary measure was to compare the effect of probiotics on the symptoms of BV and the vaginal microbiome	Randomised, double-blind, placebo controlled trial (Pilot trial)	1.25 billion CFU x2 (each strain) + metronidazole 500 mg twice daily for 7 days	Women (18+)	36 Patients (4 weeks)	According to Amsel criteria (symptoms & amine test), 17/17 patients in the probiotic verum group where BV free after 4 weeks of supplementation compared to 11/17 in the placebo group (P<0.018). Results for Nugent scoring where insignificant between groups (P<0.158)	Improved BV cure rate	Small sample size.

Vaginal Candidiasis

Vaginal candidiasis (VC) is the second most common vaginal infection after BV and is caused by the overgrowth of the commensal fungal species, Candida albicans. [26] Symptoms include burning sensation, irritation, painful urination, and a white, cottage-cheese like discharge. Diagnosis is based on the presence of symptoms, fungal culture examination and a vaginal pH below 4.5. Non-albicans species can also cause candidiasis, such as Candida glabrata. [27] Although a natural, commensal fungal species, the vaginal microbiome plays a pivotal role in controlling the overgrowth of pathogenic Candida species. Beneficial indigenous Lactobacilli produce lactic acid and other short-chain fatty acids which leads to acidification of the vaginal microbiome, inhibiting the invasive overgrowth of this pathogenic fungus. [28]

In addition, the development of fungal biofilms play a key role in the pathogenesis, severity, and recurrence of VC, and occurs in the following stages. [29] Firstly, in the early stages, single-celled yeast adheres to the vaginal epithelium, followed by hyphae elongation, where cells begin to branch into a root-like structure. As numerous yeast cells begin to elongate, the community forms an extracellular matrix which is constructed by polysaccharides and protein elements, creating a protective biofilm. When the biofilm is established, growth can multiply by the production of daughter yeast cells, which can seed new biofilm formation in other tissues (Fig.3). [30,31]

Fig.3 Fungal biofilm formation

The probiotic strains L. rhamnosus GR-1 & L. reuteri RC-14 have been shown to prevent fungal biofilm formation by interfering with genes involved in the growth of C. albicans. [29] In addition, GR-1 & RC-14 are known to produce fungicidal and fungistatic agents which directly kill and supress C. albicans growth. The strains are also well known lactic acid producers, which promote a lower vaginal pH, creating a less-conducive environment for Candida growth. [29,34]

Treatments for VC

Oral and topical antifungal medications are the current medical treatment for VC. The antifungal fluconazole is the most commonly used oral anti-fungal, followed by topical treatments such as: clotrimazole, miconazole, and nystatin. [32] Patients with frequent VC recurrence commonly require long-term suppression with oral antifungals, which may be prescribed weekly to monthly as C. albicans biofilms demonstrate a high resistance to commonly prescribed antifungals. [33]

Table 2: Human Clinical trials for Probiotics & Vaginal Candidiasis

Probiotic strains	Ref	Objective	Type	Daily dose	Study age	Study size and length	Results	Conclusion	Limitations
Lactobacillus rhamnosus GR-1 & Lactobacillus reuteri RC-14	[35]	To determine if ingestion of these strains is safe in healthy women, and to test whether it can induce changes in pathogen load in the vaginal microbiome.	Randomised, double-blind, placebo controlled trial	1 billion CFU of each strain	Women (19-46)	64 Patients (60days)	The culture findings showed that lactobacilli oral therapy led to a significant (log 10) increase in vaginal Lactobacilli within 4 weeks (P = 0.01), plus a 0.8 log 10 decrease in yeasts (P = 0.01) and coliforms (P = 0.001) compared to the placebo	Decreased vaginal yeast count in vaginal microbiome Increased vaginal lactobacilli	Not stated
Lactobacillus rhamnosus GR-1 & Lactobacillus reuteri RC-14	[36]	To determine the ability of probiotic GR-1 & RC-14 to improve the treatment of vulvovaginal candidiasis	Randomised, double-blind, placebo controlled trial	1 billion CFU of each strain, taken twice daily + 150mg fluconazole (one dose)	Women (16-46)	55 Patients (28days)	GR-1 & RC-14 improved the effectiveness of fluconazole treatment in patients with vaginal thrush by reducing presence of candida 10.3% vs 38.5% (P<0.014) and reducing thrush symptoms 10.3% vs 34.6% (P<0.03) compared with placebo.	Reduced cultures of vaginal candida Reduced symptoms of vaginal thrush Improved effectiveness of fluconazole in thrush treatment	The key mechanism of action was not assessed thus the role of metabolic by-products of the probiotics may or may not have influenced the outcome.
Lactobacillus plantarum CECT 7504 (I101)	[37]	To evaluate the effectiveness of L. plantarum CECT 7504 applied vaginally on Vulvovaginal Candidiasis (VVC) and the time-until recurrence after treatment with single-dose vaginal clotrimazole	Non-randomized, open-label, prospective study	100 million CFU applied 3 times a week	Women (18-50)	33 Patients (2 months)	Probiotic vaginal tablets & clotrimazole use was associated with a three-fold reduction in the risk of recurring vulvovaginal candidiasis when compared with placebo at 3 months (P<0.033).	Improved effectiveness of single-dose vaginal clotrimazole by reducing VC recurrence	Lack of randomisation and an open-label trial. Limited sample size.

Conclusion

Bacterial vaginosis and vaginal candidiasis are the two most common vaginal infections experienced by women worldwide. [26] Although two different microbial infections, both BV and VC are initiated by changes in the vaginal microbiome, marked by a decline vaginal Lactobacilli, and subsequently a change in the vaginal microenvironment. [3] The commensal vaginal Lactobacilli, including Lactobacillus iners, Lactobacillus crispatus, Lactobacillus gasseri and Lactobacillus jensenii are dependent on the steady flow of alpha-amylase to breakdown complex glycogen to simple glucose for energy utilisation. Beneficial Lactobacilli can then produce lactic acid, hydrogen peroxide, antifungal agents and bacteriocins which provide antimicrobial benefits and also work to increase acidification in the vaginal environment to directly inhibit the growth of pathogenic microorganisms, such as Gardnerella vaginalis and Candida albicans. [5,6]

In multiple clinical trials, the restoration of vaginal Lactobacilli with the probiotic Lactobacillus rhamnosus GR-1 and Lactobacillus reuteri RC-14 have shown to restore a Lactobacilli-dominated vaginal microbiome and to enhance the effectiveness of metronidazole and tinidazole for BV and fluconazole for VC. [18,22,24,36]

To a lesser extent, the probiotic strains Lactobacillus crispatus Lbv88, Lactobacillus gasseri Lbv150, Lactobacillus rhamnosus Lbv96, Lactobacillus jensenii Lbv116 have also been shown to improve the effectiveness of metronidazole in the treatment of BV. In addition, Lactobacillus plantarum CECT 7504 has shown to be effective for enhancing the outcome of patients taking clotrimazole for VC. [25,37]

Furthermore, it is known that bacterial and fungal biofilms contribute to the pathogenesis, severity, and recurrence of BV and VC, with mechanistic research revealing that probiotic therapy can help to suppress and prevent the growth of both bacterial and fungal biofilms. [10,38] The combination of high efficacy rates and adjunctive therapy success, makes selective probiotic supplementation an appealing option for improving the management of both BV and VC.

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