The Role of Urinary Microbiota in Lower Urinary Tract Dysfunction: A Systematic Review

The traditional view of urine sterility has been challenged by the discovery of the urinary microbiome, meaning a mix of bacteria and microorganisms within the urinary tract. This unique relationship between microbes and humans is still not fully understood but has gained a lot of attention in clinical research in the last decade. Several studies suggest that the urinary microbiome may play a role in many diseases of the urinary system, including urinary tract infection and urgency urinary incontinence . It is believed that with an increased knowledge of the urinary microbiota, prevention strategies can be improved as well as making a better diagnosis and advancing the treatment of common lower urinary tract disorders.

Microbiome & microbiota

Microbiome: the collection of genomes (genetic material) from all the microorganisms found in a particular environment. Microbiomes are individual to each organism and the diversity in microbiomes between individuals is huge. Microbiota: all microorganisms (bacteria, viruses, and fungi) that are found within a specific environment. Refers to bacteria living in the human body both symbiotically or pathologically. Care needs to be taken when talking about where microbiota come from, e.g. the urinary microbiota.

The traditional view of urine sterility has been challenged by the discovery of the urinary microbiome, meaning a mix of bacteria and microorganisms within the urinary tract, analogous with the acknowledged presence in the bowel. This unique relationship between microbes and humans is still not fully understood but has gained a lot of attention in clinical research in the last decade. The old perception of urine sterility is grounded in the lack of bacteria in urine samples using standard culture protocols. Today we know that the culturing methods were insufficient and could not detect anaerobic or slow-growing bacteria. A contributing reason to the increased understanding and knowledge about microorganisms is the improvements within technologies to detect the bacteria.

Two important improvements for this achievement are:

The use of DNA sequencing: a very sensitive test for identification of bacteria, without the need for culture. It cannot determine whether the bacteria are alive or dead.

• Improved techniques for urine culture, allowing for a more complete description of the microbes present, differentiated between live and dead bacteria, in an Enhanced Quantitative Urine Culture (EQUC) protocol.
• The improvements in urine culture techniques offer an alternative that can be implemented immediately in most clinical laboratories. Sequencing is more costly, but more and more used in a clinical setting.

Several studies suggest that the urinary microbiome may play a role in many diseases of the urinary system, including urinary tract infection (UTI) and urgency urinary incontinence (UUI).

It is believed that with an increased knowledge of the urinary microbiota, prevention strategies can be improved as well as making a better diagnosis and advancing the treatment of common lower urinary disorders.

Via the more advanced molecular methods available, several recent studies have shown the enormous diversity, functional capacity, and age-associated dynamics of human microbiota in the urinary tract, contributing to its homeostasis in various ways. Urinary microbiota may produce molecules that interact with the nervous system and can have a role in the regulation and maintenance of epithelial junctions. There is also evidence indicating that the bacteria normally living in the body may create a barrier in uroepithelium, outcompete uropathogens, and produce antimicrobial compounds and/or degrade harmful products! Thus, the bacteria may help us to recover, without need for medications.

At the same time recent studies have shown a link between an imbalance in the composition and function of urinary microbiota and chronic urological conditions, contributing to much attention and a better recent understanding of the urinary microbiota within clinical research, and a potential for novel therapeutic and preventive strategies for many disorders.

This review highlights the role of urinary microbiota in the pathophysiology of several lower urinary tract (LUT) functional disorders.

Overactive bladder (OAB) in relation to microbiota

Overactive bladder (OAB) is a symptom characterized by the presence of urinary urgency, usually accompanied by nocturia and frequency with or without Urgency Urinary Incontinence (UUI). There is no gold standard for the diagnosis of OAB and diagnosis is mainly done by physical examination and voiding diary. A negative urine culture is a prerequisite for the diagnosis of OAB, as urinary tract infection (UTI) must be ruled out.

The discovery of urinary microbiota begs the question of whether bacteria that are part of the natural flora in the lower urinary tract can directly or indirectly contribute to OAB.

Several studies have shown significant differences between urinary microbiomes of women with and without UUI. Depending on the patient’s microbiota (the diversity of microorganisms etc.), the effect of medication in the UUI patients differed. From a clinical point of view, knowledge about the individual urinary microbiota could lead to possibilities to refine and personalize UUI treatment. Thus, potential for prevention and/or better treatment of this disorder.

Bladder pain syndrome and interstitial cystitis in relation to microbiota.

Another clinically relevant patient group for this purpose are those suffering from bladder pain syndrome (BPS) and interstitial cystitis (IC). BPS/IC were traditionally described as a chronic sterile bladder inflammation. In fact, despite the symptoms of this condition being similar to those of UTI, several studies using conventional cultural methods have failed to identify an infectious agent. However, the new molecular-based diagnostics have made it possible to detect important differences in the urinary microbiota. 

Studies showed less microbial diversity in BPS/IC patients in comparison with healthy females, as well as more of the bacteria Lactobacillus in the urine of these patients. Lactobacillus is considered being pathogenic and resistant to widely used antibiotics and may have a direct or indirect role in the development of this inflammatory disease.

Lower Urinary Tract Disorders in relation to microbiota

The detailed knowledge regarding bacteria co-existing with the human body will possibly lead to a change in the therapeutic paradigm. The main focus will no longer be simply killing pathogenic microbes with antibiotics. Instead, evolving therapies are focused on enhancing the role of beneficial microorganisms in the urinary ecosystem and restoring healthy microorganisms in the lower urinary tract.

This may be of particular relevance for patients with persisting Lower Urinary Tract Symptoms (LUTS), whose standard urine cultures show no growth. This is based on the findings that certain microbes have characteristics that protect against uropathogens by producing antibiotics and/or other antimicrobial compounds that inhibit or kill other pathogenic bacteria.

It is well known that the vaginal and gut microbiota are able to rapidly change microbial composition, and these changes may affect the urinary microbiota. It is also believed that by analyzing specific biomarkers (a naturally occurring molecule to identify a disease) from the urinary microbiota we might have new diagnostic, therapeutic, and prognostic tools for LUTS in the future.

Although the following conditions, BPS and interstitial cystitis as well as UUI and prostatitis, are not associated with a bacterial origin, all of them have shown an altered microbiome and specific dominating urotypes in comparison to urine from asymptomatic healthy individuals. Along with the growing understanding of the impact of urinary microbiota on how these disorders develop, we achieve guidance for optimized management and treatment.

Conclusions

At this time, we know for sure that urine is not sterile. The differences found between the urinary microbiota of healthy individuals and patients with LUT dysfunction suggest that a disturbance in the natural bacterial flora may constitute an evolving factor in several functional bladder disorders. The discovery of urinary microbiota will bring profound clinical implications in the near future with potential diagnostic and therapeutic implications for urinary disorders.