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. Author manuscript; available in PMC: 2018 May 1.
Published in final edited form as: Curr Opin Urol. 2017 May;27(3):282–286. doi: 10.1097/MOU.0000000000000396

The Female Urinary Microbiota

Elizabeth R Mueller 1, Alan J Wolfe 2, Linda Brubaker 1
PMCID: PMC5521999  NIHMSID: NIHMS863939  PMID: 28234750

Abstract

Purpose of review

The newly discovered female urinary microbiota has the potential to deepen our understanding of urinary tract health and disease, including common lower urinary tract conditions such as urinary incontinence and urinary tract infection. The spectrum of painful bladder disorders and other less common conditions also may benefit from additional research that includes consideration of the resident bacterial community of the female bladder. This review provides a clinical context for the rapidly emerging research regarding the female urinary microbiota and its relationships with urinary tract conditions of interest.

Recent findings

Studies using culture-independent techniques confirm prior reports of bacteria that reside in the female urinary bladder. These resident communities, the female urinary microbiota, possess characteristics that differ between women affected by urgency urinary incontinence and matched, unaffected controls. Enhanced urine culture techniques permit cultivation of organisms, including uropathogens, missed by standard urine culture, but detected by culture-independent sequencing techniques.

Summary

Clinical laboratories can modify traditional standard urine culture methods to enhance detection of uropathogens. However, given the existence of the female urinary microbiota, the simple presence of bacteria in the lower urinary tract should not be taken as evidence of infection.

Keywords: Urinary Microbiota, Urinary Incontinence, Urinary Tract Infection, Lower Urinary Tract Disorders

Introduction

The vast majority of urinary health research has been conducted without knowledge or consideration of the female urinary microbiota (FUM), communities of microbes present in the lower urinary tract of most adult women. The FUM was initially described in 2012 [1] and subsequently confirmed by others [2–6]. Prior to the discovery of the FUM, clinicians relied on the assumption of bladder sterility and depended on the standard urine culture to be the “gold-standard” for detection of clinically relevant urinary organisms [7]. They can no longer depend on either. What has changed? This review will provide context for emerging research that should begin to inform the clinical care of adult women with lower urinary tract disorders in the context of the ‘normal’ microbiota of the urinary tract in health.

The standard urine culture, a very common clinical test, has been used to determine whether living uropathogens are present in a tested urine sample. Standard urine culture was designed in the 1950s to detect specific uropathogens, especially uropathogenic strains of Escherichia coli that cause pyelonephritis [8,9]. As medicine costs have come under increased scrutiny, standard urine cultures have been conducted on a more selective basis (reflex cultures), based on screening tests that suggest the likelihood of uropathogen detection by standard urine culture techniques. Unfortunately, the standard urine culture does not detect most members of the FUM [3,6], including many uropathogens [10].

Bacterial Detection

An important technical advance has been the availability of culture-independent techniques, such as sequencing, that detect the DNA of microbes within a tested sample. These highly sensitive, high-throughput techniques have been used to describe the microbial communities of multiple microbial niches of the human body, most notably as part of the Human Microbiome Project [11]. Multiple studies have now used DNA sequencing to delineate the microbiota in urine collected from the bladders of women with and without lower urinary tract symptoms [1–4,6,12,13].

Sequencing and culture techniques can be complementary. Sequencing is highly sensitive but cannot quantify the detected organisms; it also cannot determine whether the DNA came from a live microbe. However, sequencing can inform culture-based approaches, detecting the presence of microbes that require “non-standard” culture conditions. This information has been used to enhance urine culture protocols; most clinical microbiology laboratories can perform this refined approach, called enhanced quantitative urine culture (EQUC). The improved protocol includes larger urine volume, additional growth media, and longer incubation in the presence of CO2 [3,5,6,10] (Table 1). A streamlined version is recommended for use in clinical microbiology laboratories [10].

Table 1.

Summary of Urine Cultivation Protocols

Protocol Urine Volume (μl) Media Incubation Conditions Microbial Identification
Standard Urine Culture 1 BAP1, MacConkey Aerobic 35°C 24 h
EQUC 100 BAP, MacConkey Aerobic 35°C 24 h
48 h
BAP, Chocolate, CNA2 5% CO2 35°C 24 h
48 h
CDC Anaerobic BAP Anaerobic 35°C 48 h
BAP, MacConkey, CNA Microaerophilic gas mixture (5% O2, 10% CO2, 85% N) 35°C 48 h
Streamlined EQUC 100 BAP, MacConkey, CNA 5% CO2 35°C 48 h
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1

BAP = Blood agar plate

2

CNA = Colistin Naladixic Acid agar

Unlike some other human microbial niches, the bladder microbiota are low biomass [6,10,14]; EQUC generally detects 102–105 colony-forming units per milliliter of urine obtained from the bladder as compared to the gut, which can contain as much as 1014 colony-forming units per gram of feces. This low microbial abundance is a major reason why sensitive sequencing techniques can help advance our understanding of the microbes that reside in the bladder [6], permitting us to detect rare FUM members that may not be detected by EQUC and other enhanced culture methods. Unfortunately, the combination of this low biomass, the ubiquity of bacterial DNA, and the high sensitivity of modern DNA sequencing methods can lead to the erroneous reporting of bacterial contamination as members of the FUM. Thus, we advise extreme caution and extensive use of negative controls [6]. As we step away from the old “sterile urine” paradigm, other challenges remain; for example, investigators may find that many urine samples contain microbial communities that are below our current detection thresholds. Based on current evidence, however, it is unlikely that these samples are actually “sterile,” but rather extremely low abundance [14,15]. Indeed, a recent study used large amounts of urine and detected bacteria in almost of all the tested samples [4].

Female Urinary Microbiota Characteristics

Now that we know that the FUM exist, the composition of these communities requires study. For urine samples with detectable microbial communities, we can now begin to describe them. An important descriptor is microbial diversity, which can be described by two features: richness and evenness. Richness is a measure of the total number of unique taxa within a given individual, but does not take into account the distribution of those taxa. In contrast, evenness is a measure of distribution, or equality of representation, of taxa within an ecological niche, such as the female bladder. A urine sample with 5 unique microbes would be considered richer than a sample with only 2. A sample with 5 equally abundant microbes would be considered more even than another 5-microbe sample that was predominated by one of those microbes.

Based on the available data, it appears that the FUM are similar to other human microbial niches in there is no one “normal” state, but rather variable between individuals. However, there are distinct trends. Most urine samples studied to date are not rich and contain one or two microbes that are substantially more abundant than others. These samples can be categorized on the identity of that or predominant microbe. Each category has been termed a “urotype” similar to the “enterotype” used by many gut microbiome researchers. At the genus level, the most common urotype is Lactobacillus. The next most common urotypes are Gardnerella, Corynebacterium, Streptococcus and Staphylococcus; other less common urotypes exist. Notably, these are all Gram-positive bacteria, quite unrelated to the Gram-negative bacteria, such as E. coli, responsible for the vast majority of acute uncomplicated urinary tract infection (UTI). Some samples are not predominated by a single organism or even two; they are placed in a urotype called “diverse.” The biological significance of predominance by any specific organism or the lack of a predominant microbe is not yet known. However, FUM diversity appears to have associations with the host’s hormonal status, body mass index and certain clinical conditions [4,6,12,13,15,16].

Clinical Associations

Despite hopes of a finding a single “causative” organism (similar to H. pylori for stomach ulcers), community characteristics may be more important that the presence or absence of a particular microbe. This would be expected if the FUM play a protective role. For example, FUM diversity appears to relate to the presence of urgency urinary incontinence (UUI). A recent report suggests that treatment response may be related to the number of unique organisms (richness) present prior to solifenacin treatment for UUI [14]. Following replication of this work, it may be possible to refine clinical estimates of treatment efficacy, based on a pre-treatment assessment of that individual patient’s urinary microbial community characteristics. Another report identified an association between UUI symptoms and several bacterial species, including a number of emerging Gram-positive pathogens; this report also found that Lactobacillus crispatus associates with the lack of symptoms [6], suggesting the possibility that L. crispatus may be beneficial to maintaining bladder health.

A refined estimate of risk may also be possible in women who will undergo urinary tract instrumentation (catheterization, cystoscopy, surgical procedures). Currently, the population is treated as having a “pooled” risk of UTI; often, this risk is approached with a single protocol for peri-procedure antibiotic. Despite these common clinical protocols, post-instrumentation UTI remains a common event, and is typically associated with a course of treatment antibiotic. There is DNA evidence that the FUM plays a role in within this population [13,16]. Further study is required, but indications are that sequencing (and EQUC) can assist in refining the estimate of this risk. Such information may allow modifications to peri-procedure antibiotic protocols, reducing overall antibiotic use and individualizing specific risk-reduction techniques, based on pre-instrumentation urinary microbial assessment.

The strongest evidence to date supports the hypothesis that the FUM differ in women with UUI, compared to unaffected women [4,6]. At this early stage of investigation, however, it is not known whether this intriguing association is a cause or an effect of the condition. There are many biological possibilities; for example, it is possible that the urinary frequency typically associated with UUI alters the microbial community. Yet, it is prudent to consider this association with a wider lens that takes into account other understudied aspects of lower urinary tract function. For example, significant new information has highlighted the non-barrier role of the urothelium, especially its sensory functions [17]. Evidence exists of communication between the gut microbiota and the central nervous system [18]. Given clear evidence of the communication between bladder and brain [19], it is certainly biologically plausible that a similar mechanism could be present in the urinary system, and that the urinary microbiota play some role in this communication, perhaps involving the urothelial sensory signaling.

Immune Functions of the Bladder

Another intriguing development in our understanding is the emerging evidence regarding the immune functions of the bladder, an understudied aspect of lower urinary tract health. Little is known about the immune functions of the lower urinary tract. Elegant work describes establishment of intracellular communities by uropathogenic strains of E. coli [20]; however, little is known about the role of most other members of the FUM in regulating immune function within the bladder. The potential for certain (“good”) microbes to have an inhibitory effect on other (“bad”) microbes is evident in multiple human microbial niches, where the presence of an organism clearly has a role in maintaining homeostasis [21]. Disruption of that homeostatis can cause a dysbiosis that allows an imbalance of organisms or the overt dominance of a pathogen associated with clinical infection. Unlike the conventional view of UTI that assumes invasion of a sterile field by a single uropathogen, it is more likely that there is a spectrum of urinary dysbioses. This spectrum may more appropriately explain the clinical situations that have been termed “asymptomatic bacteriuria.” This new paradigm of a spectrum of microbial community health may allow clinicians to understand the risk of meaningful clinical conditions of interest, such as UTI, UUI and, perhaps, some forms of bladder pain syndromes.

Anti-microbial peptides (AMPs) exist throughout the body and have been studied extensively in the skin and gut; AMPs have been documented in the urine [22]. Understanding the roles these peptides play in the lower urinary tract requires significantly more study; however, they are likely to play a key role in microbial community regulation, resilience following dysbiotic/infection episodes and response to treatment for lower urinary tract disorders. Similarly, the recent detection of IL-22 receptors in the urothelium allows consideration of interactions between the microbial community, known urothelial cholinergic receptors, the non-barrier role of the urothelium, and AMPs [23]. Interpretation of these interactions may provide new insights into important immune functions of the bladder.

Clinical Potential

Might there be a role for new forms of treatment for common lower urinary tract disorders? Fecal transplants have been rapidly translated from the laboratory setting to the clinic; treatment of refractory Clostridrium difficile infection has saved lives [24]. Some work exists to support this notion for treatment of recurrent UTI. Investigators have instilled non-pathogenic strains of E. coli into the bladders of men with spinal cord injury to effectively reduce subsequent clinical UTI [25]. More recently, researchers reported that intravaginal administration of a probiotic strain of Lactobacillus crispatus reduced episodes of recurrent UTI [26]. In the laboratory setting, Rudick et al. have demonstrated efficacy using a mouse model [27]. The possibility of this clinical treatment is enticing; it requires further rigorous testing to optimize the treatment protocol prior to widespread clinical implementation.

There are many exciting developments in lower urinary tract research that are related to the FUM. Although most studies have concentrated on bacteria, there is also preliminary evidence of viral [28] and fungal community members. As this preliminary work is replicated and published, our understanding will be expanded further.

Based on the clinical insights that the FUM can provide, the involved research community will need to ensure that foundational studies optimize specimen collection, storage and analysis.

Conclusion

The limitations of standard urine culture may affect clinical care, especially for certain subgroups of affected patients. The FUM can be assessed by enhanced urine culture techniques (EQUC) and culture-independent methods (DNA sequencing). Especially in patients with refractory symptoms, clinicians and their patients may benefit from clinical studies that more fully describe the FUM.

Many questions remain. What roles do detected bacteria play: which ones are beneficial? Which ones detrimental? How do they interact with each other and the host? What about non-bacterial microbes? How stable/resilient is the FUM? When does it become established? Does it change with life events?

Key points.

  1. Standard urine culture does not detect most members of the existing female urinary microbiota (FUM), including many uropathogens.

  2. Microbial detection using enhanced urine culture techniques correlates with DNA sequencing, a culture-independent method.

  3. Similar to other human microbial niches, there is no one “normal” state, but rather variable between individuals.

  4. Characteristics of the FUM, such as microbial diversity and predominance, vary based on hormonal status, body mass index and certain clinical conditions, especially urinary urgency incontinence.

  5. Differences exist in the FUM of women with urinary urgency incontinence compared to unaffected women.

Acknowledgments

We would like to thank the members of the Loyola Urinary Education and Research Collaborative for their contributions to the work described.

Financial support and sponsorship

ERM, AJW and LB have been supported by NIH grants R01DK104718 2U10 HD41250, U01 DK58229, R21 DK097435, R56 DK104718 and P20 DK108268, a translational grant from the Falk Foundation and by RFC LU206998 from Loyola University Chicago. AJW has received funding for Investigator Initiated Studies VESI-12D01 and MYRB-15A01 from Astellas Scientific and Medical Affairs Inc. Our funding sources have had no role in design or conduct of our studies; collection, management, analysis, and interpretation of our data; or in preparation, review, or approval of this or any other manuscript.

Footnotes

Conflicts of Interest

Dr. Mueller reports research support and advisory board role with Astellas Scientific and Medical Affairs, Inc. Dr. Brubaker has received editorial honoraria from UpToDate and, as Editor in Chief, for Female Pelvic Medicine and Reconstructive Surgery. Dr. Wolfe has received research support from Astellas Scientific and Medical Affairs, Inc. and Kimberly Clark Corporation for urinary microbiome research. All three authors have received funding from the NIH and Loyola University Chicago for urinary microbiome research (see funding acknowledgements).

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