Crosstalk between Vaginal Microbiome and Female Health: A review

Highlights

• Microbiota plays a fundamental role in the overall development and defences of human beings.

• Disruptions in vaginal microbial environment enhanced the risk of acquiring vaginal infections and diseases.

• This review highlights the recent advancements in the detection of microbiome interactions with the vaginal environment.

Abstract

Microbiota plays a fundamental role in the overall development and defences of human beings. The majority of indigenous microbiota exists in a mutually beneficial relationship with their hosts, while few of these are opportunistic pathogens that can lead to life-threatening diseases and chronic infections. These microbial communities constitute the primary defence against infections induced by non-indigenous invasive organisms. Female vaginal ecosystem thought to have been shaped over the years by co-evolutionary processes occurring between the particular microbial partners and the human host. Vaginal secretions contain numerous microorganisms and the host provides them nutrients for their growth and development. Disruptions in vaginal association with the microbiomes lead to the change in the vaginal environment, which enhanced the risk of acquiring diseases including sexually transmitted infections, bacterial vaginosis, fungal infections, preterm birth etc. The focus of this review is on the detailed analysis of vaginal microbiome interplay and its overall impact on female health. The mutualistic relationship between the vagina and residing microbial species has been well described. Finally, the recent advancements in the detection of microbiome interactions with the vaginal environment have been presented.

Introduction

“The states of health or disease are the expressions of the success or failure experienced by the organism in its efforts to respond adaptively to environmental challenges” [1].

– stated by Rene Dubos (Rockefeller University scientist) in 1965 [2].

Indigenous microorganisms play a very crucial role in the overall maintenance of human health [3]. Multicellular creatures existing as meta-organisms include both the macroscopic host and its commensal symbiotic microbiota [1]. These complex microbial communities include viruses, fungi, bacteria, protozoa etc. [4]. These symbionts have an amazing enzymatic capability and have the capability of expressing 10 fold more unique genes than their host's genome, thus play a crucial role in governing most facets of host physiology [5,6]. In 2001, the announcement of revolutionary sequencing of the human genome has been made [7]. Undoubtedly, it is one among the notable achievements in the physiological and biological worlds, but still it provides only a fractional blueprint of human species [8]. In order to complete this blueprint, the next frontier of research is the critical study and analyses of human microbiota (which includes the microorganisms' communities that inhabit the human body [9]) and microbiome (which represents the genetic profile of all such microorganisms in a combined manner [3,[8], [9], [10]]. Human genome is basically a segment of the cumulative genome of complex symbiotic, commensal and pathogenic microbial association that colonizes and resides inside the human body [11]. The human microbiome consists of almost more than ten thousand diverse species of microorganisms that populate the human body [6]. Until recently, the researchers have studied human microbiome with a primary focus on disease states, however, the research trend has now shifted with the objective of recognition of innate microorganisms as these indigenous microbes have a fundamental role in regulating human health [3].

Similar to the gut and mouth which contains numerous different microbial communities, the female vagina also consists of millions and trillions of tiny microorganisms including bacteria, viruses, and fungi. All such microorganisms together make up the vaginal microbiome. Among these microbiomes, Lactobacillus is one of the primary bacteria colonising inside a healthy vagina [12] and helps in keeping the vaginal environment acidic, thus prevents the thriving of yeast, deadly bacteria and viruses in vagina [[13], [14], [15]]. Some specific types of lactobacilli interact with the host cells and interplay with the genome type of a woman in order to boost the production of right mucus and also maintain the acidic environment of the vagina [16]. Such types of lactobacilli are considered to be the healthiest vaginal microbiota (VMB) or vaginal microflora [17]. Other types of lactobacilli are catastrophic in nature. Presence of these harmful strains or lack of dominant and healthy lactobacillus in vaginal microbiome can put females at a higher risk of getting infected with sexually transmitted infections (STIs) [6,18,19] and also enhance the chances of acquiring several critical conditions like bacterial vaginosis, pelvic inflammatory disease, preterm birth etc. [13,16,20].

Human microbiome study is important for understanding the composition of human body; to determine whether all human beings consist of a core and specific set of microbial communities or they differ from person to person. It has been speculated that human health alterations and the risk of acquiring diseases might be correlated with the variations in the core microbiome [21]. Among the different microbial species, bacteria are present in a vast group of living beings and carry a large domain of life in themselves [22]. On the basis of cell shape, cell wall type, motility, endospore production, energy and oxygen requirements, the bacterial community can be classified biochemically and morphologically by employing DNA-based tests. According to their capability of producing energy in the absence and presence of oxygen, bacteria can also be categorized as anaerobic, aerobic or facultative anaerobic. Facultative anaerobic bacteria are those that can generate ATP both in presence and absence of oxygen while obligated anaerobic bacteria can only survive and perform in anaerobiosis. Staphylococcus, Lactobacillus, and Escherichia coli (E. coli) are all facultative anaerobic bacteria. On the other hand, Bacteroides are examples of obligated anaerobic species. Phylogenetically, bacteria are segregated according to the analysis of small subunits of ribosomal RNA operons’ nucleotide sequences, especially variable regions of 16S rRNA, a bacterial specific ribosomal RNA [[22], [23], [24]]. Presently, bacteria domain is gigantic and is classified into diverse phyla; however, the whole human microbiota consists of majority of microbes that can fall under four major phyla: Bacteroidetes, Proteobacteria, Actinobacteria, and Firmicutes [[25], [26], [27], [28]].

From the comprehensive study of the human vaginal microbial community, it has been found that in the majority of females the vaginal composition is dominated by the Lactobacillus bacterial species [29]. This group of bacteria acts as protective agents in the reproductive tract by producing hydrogen peroxide and also release several compounds like bacteriocins in order to prevent the colonization of harmful bacteria. However, an appreciable percentage of asymptomatic and healthy women, harbouring an array of diversified strictly and facultative anaerobic microbes, have vaginal microbiota that lacks a sufficient number of Lactobacillus sp. [29]. Thus, it can be concluded that there are multiple core microbiomes instead of a single core microbiome for the human vagina [30]. Further, ethnicity is also one of the major factors contributing to vaginal composition. It has been seen that the Asian/Caucasian women have significantly higher levels of Lactobacilli than Black/Hispanic women [31,32]. Though, it is still a mystery that whether this difference in Lactobacilli levels is due to genetic factors or related to the hygiene practice variations, specifically vaginal douching [33,34].

Since the vaginal environment of all females is not same, so the researchers have observed that there are actually five kinds of microbial communities (as shown in Fig. 1(A)), known as Community State types (CST), as per which species of Lactobacillus dominates. The CST I is dominated by Lactobacillus crispatus (L. crispatus), CST II is dominated by L. gasseri, CST III is dominated by L. iners and CST V is dominated by L. jensenli. CST IV lacks Lactobacillus sp. and contains huge amounts of strict anaerobic bacteria like Megasphera, Prevotella, Gardenella and Sneathia which are generally associated with BV [31,35,36]. Every woman in her lifespan is susceptible to transitions from one CST state to another and the most common transition seen in the majority of cases is from CST III to CST IV. Each Lactobacillus sp. has its particular weakness and strength, for example, L. iners can be active over a wider pH range, but are not strong enough to inhibit the growth of strict anaerobes seen in CST IV. These strict anaerobes multiply over a period of time and the concentration of lactobacilli falls due to the lack of fighting capability of L. iners leading to the change in power where the strict anaerobes rule the roost [31].

The recent studies comparing the composition of vaginal microbiome from three vaginal sites viz. cervix, mid-vagina, and introitus have revealed that the female vagina consists of over 200 phylotypes and the most predominant belong to the phyla Firmicutes, Bacteroidetes, Actinobacteria, and Fusobacteria [11,30,37,38]. Fig. 1(B) schematically summarizes the taxonomic distribution, abundance and prevalence of these microbial taxa residing in the female vagina in accordance with the human microbiome projects (HMP) [[39], [40], [41]].

The female vagina in normal situations is acidic in nature i.e. has low pH value because of the presence of hydrogen peroxide and lactic acid secreted by Lactobacillus sp. The vaginal microbiome gets disrupted due to the disturbances experienced by the vaginal environment on a regular basis like the use of various lubricants, sexual activities, semen, menstruation, antibiotics and hormonal contraceptives [[42], [43], [44]]. For instance, in the case of gut bacteria, antibiotics are culpable for eliminating the lactobacillus and for providing the opportunity to harmful microorganisms to thrive and grow [16]. As a consequence of the prolonged use of antibiotics, Peptostreptococcus anaerobius and Gardnerella vaginalis, Atopobium vaginae, Mobiluncus sp. Sneathia, Prevotella sp., Mycoplasma, Ureaplasma, and numerous uncultivated or fastidious anaerobes become more active and can cause BV and other associated disorders due to the decrease in the levels of Lactobacillus [45,46]. Thus, the health status of a female can be predicted by observing the composition of the vaginal microbiome. Vaginal microbiome environment is also age-dependent [47]. As the reproductive status and physiology of female changes, the vital functions and microflora in the reproductive tract also change. From the preliminary evidence, it has been observed that for the ability to conceive and for a successful pregnancy, the composition of microflora in whole reproductive tract play a crucial role [13,48,49],. Further, IVF (In-vitro Fertility) research has shown that at the time of transfer of the embryo, the type of microorganisms present in the uterus interplay resulting in the outcome of pregnancy [13]. Thus, due to constant lifestyle and hormonal changes, the vaginal microbiome experience dramatic shifts throughout a woman's life.