Urinary Microbiota Research Articles

Pre- and postmenopausal women have different core urinary microbiota

Recent studies suggest that alterations in the female urinary microbiota is associated to development of bladder disease. However, the normal microbiota composition and variation in healthy women are poorly described. Moreover, the effects of hormonal changes on microbiota during menopause is not well understood. The aim of our study was to investigate the urinary microbiota in healthy pre- and postmenopausal women without urinary tract symptoms. Microbiota composition in catheterized urine samples was mapped using 16S rRNA gene sequencing. In total, 41 premenopausal and 42 postmenopausal women were initially included. Samples with first PCR amplification concentration below level of the negative control were excluded, resulting in 34 premenopausal and 20 postmenopausal women included in data analysis. Urine from postmenopausal women showed significantly higher alpha diversity compared to premenopausal women. Lactobacillus was the most abundant bacteria in both groups, however the relative abundance of Lactobacillus accounted for 77.8% in premenopausal versus 42.0% in postmenopausal women. In conclusion, urine from premenopausal mostly presented with Lactobacillus dominated urotypes, whereas urine from postmenopausal women presented a more diverse urinary microbiota with higher abundance of the genera Gardnerella and Prevotella. The clinical and pathophysiological implications of this difference remain to be elucidated.

The Urinary Tract Microbiome in Male Genitourinary Diseases: Focusing on Benign Prostate Hyperplasia and Lower Urinary Tract Symptoms.

The human body is sterile during gestation; however, but during and after birth, the entire body surface becomes host to an enormous variety of microorganisms. Urine in the urinary tract was once considered sterile based on the lack of cultured microorganisms. Many recent studies have revealed evidence of microorganisms in human urine in the absence of clinical infection. Sequencing methods and analytical techniques are rapidly evolving to improve the ability to detect bacterial DNA and living bacteria and to understand the microbiota of the urinary tract. In women, fascinating evidence associates urinary tract microbiota with lower urinary tract symptoms. However, in men, the relevance of urinary tract microbiota in low urinary tract symptoms and prostate disease has not been established. In this review, we highlight a recent study that increases our ability to understand the urinary tract microbiota in men with lower urinary tract symptoms.

Polymicrobial interactions in the urinary tract: is the enemy of my enemy my friend?

The vast majority of research pertaining to urinary tract infection has focused on a single pathogen in isolation, and predominantly Escherichia coli. However, polymicrobial urine colonization and infection are prevalent in several patient populations, including individuals with urinary catheters. The progression from asymptomatic colonization to symptomatic infection and severe disease is likely shaped by interactions between traditional pathogens as well as constituents of the normal urinary microbiota. Recent studies have begun to experimentally dissect the contribution of polymicrobial interactions to disease outcomes in the urinary tract, including their role in development of antimicrobial-resistant biofilm communities, modulating the innate immune response, tissue damage, and sepsis. This review aims to summarize the epidemiology of polymicrobial urine colonization, provide an overview of common urinary tract pathogens, and present key microbe-microbe and host-microbe interactions that influence infection progression, persistence, and severity.

Dysbiosis of urine microbiota in obstructive urinary retention patients revealed by next-generation sequencing

BackgroundUrinary retention (UR) is a common urinary system disease can be caused by urinary tract obstruction with numerous reasons, however, the role of urine microbes in these disorders is still poorly understood. The aim of this study was to identify the urine microbial features of two common types of obstructive UR, caused by urinary stones or urinary tract tumors, with comparison to healthy controls.MethodsUrine samples were collected from a cohort of 32 individuals with stone UR, 25 subjects with tumor UR and 25 healthy controls. The urine microbiome of all samples was analyzed using high-throughput 16S rRNA (16S ribosomal RNA) gene sequencing.ResultsWe observed dramatically increased urine microbial richness and diversity in both obstructive UR groups compared to healthy controls. Despite different origins of UR, bacteria such as Pseudomonas, Acinetobacter and Sphingomonas were enriched, while Lactobacillus, Streptococcus, Gardnerella, Prevotella and Atopobium were decreased in both UR groups in comparison with healthy controls, exhibited an approximate urine microbial community and functional characteristics of two types of obstructive UR. Furthermore, disease classifiers were constructed using specific enriched genera in UR, which can distinguish stone UR or tumor UR patients from healthy controls with an accuracy of 92.29% and 97.96%, respectively.ConclusionWe presented comprehensive microbial landscapes of two common types of obstructive urinary retention and demonstrated that urine microbial features of these patients are significantly different from that of healthy people. The urine microbial signatures would shed light on the pathogenesis of these types of urinary retention and might be used as potential classification tools in the future.

Evaluation of Correlations Between Bladder Detrusor Overactivity and Lower Urinary Tract Infections

Lower Urinary Tract Infections (LUTIs) are regarded as the most frequent form of bacterial infections and bladder Detrusor Overactivity (DO) are considered to contribute to (OAB), including urinary urgency, urinary frequency, with or without Urgency Incontinence (UI), which is common disorder and influences patient's health and quality of life. Since 1960s, studies had focused on whether DO is the etiological factors of recurrent LUTIs or the inverse. Although the definite correlation between DO and LUTIs have not been proved, urinary microbiota may play a role in genesis of DO that was found by mounting evidences using enhanced urine culture technique and pathophysiological variations of bladder detrusor facilitates bacterial colonization in bladder urothelium. In the future, clarification of correlation between DO and LUTIs needs more scheduled studies and more researches that link the urinary microbiota with Central Nervous System (CNS) function to provide accurately information to help us manage the patients more appropriately.

Vagococcus fluvialis isolation and sequencing from urine of healthy cattle.

While the gram-positive bacterium Vagococcus fluvialis has been isolated from the environment as well as fish, birds, and mammals, very little is known about the species. V. fluvialis is believed to be a probiotic in fishes. However, within mammals, it is more frequently isolated from infectious tissue, including on rare occasions human and livestock lesions. Prior to the study described here, V. fluvialis had never been found in healthy bovine animals. Here, we present the complete genomes of V. fluvialis UFMG-H6, UFMG-H6B, and UFMG-H7, novel strains isolated from urine samples from healthy bovine females. These are the first genomes of mammalian isolates and the first description of V. fluvialis from urine. The genomes did not encode for any known virulence genes, suggesting that they may be commensal members of the urine microbiota.

The female urinary microbiota in relation to the reproductive tract microbiota.

Human urine is traditionally considered to be sterile, and whether the urine harbours distinct microbial communities has been a matter of debate. Potential links between female urine and reproductive tract microbial communities is currently not clear. Here, we collected urine samples from 147 Chinese women of reproductive age and explored the nature of colonization by 16S rRNA gene amplicon sequencing, quantitative real-time PCR, and live bacteria culture. To demonstrate the utility of this approach, the intra-individual Spearman's correlation was used to explore the relationship between urine and multiple sites of the female reproductive tract. PERMANOVA was also performed to explore potential correlations between the lifestyle and various clinical factors and urinary bacterial communities. Our data demonstrated distinct bacterial communities in urine, indicative of a non-sterile environment. Streptococcus-dominated, Lactobacillus-dominated, and diverse type were the three most common urinary bacterial community types in the cohort. Detailed comparison of the urinary microbiota with multiple sites of the female reproductive tract microbiota demonstrated that the urinary microbiota were more similar to the microbiota in the cervix and uterine cavity than to those of the vagina in the same women. Our data demonstrate the potential connectivity among microbiota in the female urogenital system and provide insight and resources for exploring diseases of the urethra and genital tract.

Balanopreputial sac and urine microbiota in patients with male genital lichen sclerosus.

Male genital lichen sclerosus (MGLSc) is a chronic inflammatory scarring dermatosis associated with penile carcinoma. The prepuce is pivotal in its etiology. Other proposed etiological factors are the subject of dispute and include occluded urinary exposure, autoimmunity, immunodysregulation, and infectious agents. To determine whether the bacterial microbiota of the balanopreputial sac and urine are associated with MGLSc. Twenty uncircumcised patients with MGLSc and 20 healthy uncircumcised males were enrolled in a prospective case-control study. Balanopreputial swabs and urine specimens were subjected to 16S rRNA gene amplicon sequencing. Microbiota analysis indicated differences between the groups. In the balanopreputial sac, the median relative abundance of Finegoldia spp. was lower (9% [range 0-60%]) in MGLSc patients than in controls (28% [range 0-62%]). Conversely, the median relative abundance of Fusobacterium spp. was higher in MGLSc patients (4% [range 0-41%]) than in controls (0% [range 0-28%]). In the urine, the median relative abundance of Finegoldia spp. was comparable between groups, whereas that of Fusobacterium spp. was higher in MGLSc patients (0% [range 0-18%] vs. 0% [range 0-5%]). There was a strong association between the microbiota composition of the balanopreputial sac and urine in MGLSc. Dysbiosis could be involved in the etiopathogenesis of MGLSc. Further studies are required to confirm the association suggested herein and to determine its nature.

Deciphering the Urinary Microbiota Repertoire by Culturomics Reveals Mostly Anaerobic Bacteria From the Gut.

Human urine was considered sterile for a long time. However, 416 species have been previously cultured, including only 40 anaerobic species. Here, we used culturomics, particularly those targeting anaerobes, to better understand the urinary microbiota. By testing 435 urine samples, we isolated 450 different bacterial species, including 256 never described in urine of which 18 were new species. Among the bacterial species identified, 161 were anaerobes (35%). This study increased the known urine repertoire by 39%. Among the 672 bacterial species isolated now at least once from urine microbiota, 431 (64.1%) were previously isolated from gut microbiota, while only 213 (31.7%) were previously isolated from vagina. These results suggest that many members of the microbiota in the urinary tract are in fact derived from the gut, and a paradigm shift is thus needed in our understanding.

Monitoring of urinary microbiota and uropathogens' antibiotic resistance in one urological hospital

Introduction. There is no consensus on the management of patients with recurrent uncomplicated lower urinary tract infection (uLUTI), which makes it difficult to carry out effective therapy. Purpose of the study . To study the microbial patterns of urine and uropathogens' antibiotic resistance in a urological hospital from 2010 to 2017. Materials and methods . The results of bacteriological studies and the data of individual antibiotic susceptibility testing of patients with recurrent uLUTI (n = 502) were retrospectively analyzed. Inclusion criteria of the study: consent of patients to participate in the study, the presence of clinical manifestations of recurrent uLUTI in anamnesis, two episodes within six months or three during the year, leukocyturia in the urinalysis, the absence of sexually transmitted diseases at the time of the study and in anamnesis and also vaginal discharge. Bacteriological studies of the midstream morning urine sample before the prescription of antibiotic therapy were carried out with the determination of antibiotic sensitivity/resistance and production of extended-spectrum p-lactamases. In addition to the standard set of culture media, chromogenic media, aerobic and anaerobic culturing conditions were used. Statistical analysis was performed in the statistical processing and data visualization environment «R ver 3.2» («R Foundation for Statistical Computing», Vienna, Austria). Results. During the 8-year monitoring of the microbiota, the urine of patients with recurrent uLUTI was characterized by a microbial pattern certain constancy, but with the predominance (94.1% - 99.1%) of anaerobic-aerobic associations. The antibiotic resistance of most causative and debatable uropathogens increased, and the detection frequency of enterobacteria producing extended-spectrum p-lactamases also increased. Significant differences in the average levels of bacteriuria in the study period for most taxa of microorganisms were not detected. Conclusion. The detection frequencies of E. coli vary around 50.0%, for other causative pathogens a lower detection rate is noted, while non-clostridial anaerobic bacteria are excreted in 96.6% of cases in patients with recurrent uLUTI. The antibiotic resistance of causative and debatable pathogens and the detection frequencies of enterobacteria producing extended-spectrum p-lactamases are increasing, which necessitates a revision of the etiological structure and approaches to empirical therapy of recurrent uLUTI.

Recurrent cystitis and bacterial vaginosis: how to avoid polypharmacy

Background. The structure of lower urinary tract infections has clear sex-based differences. The vaginal microbiota is a key factor in the pathogenesis of lower urinary tract infections: aerobic vaginitis predisposes to infection and increases the incidence of cystitis by 2.9 times.
 Aim. To determine the effectiveness of Nifuratel as monotherapy in patients with chronic cystitis and concomitant bacterial vaginosis (BV).
 Materials and methods. Study design: an open-label, non-comparative, pilot, single-center, prospective study, which included 23 patients with recurrent cystitis and BV. All women received monotherapy with Nifuratel (Macmiror manufactured by Doppel Farmaceutici S.r.l., Italy) in tablets of 200 mg 3 times a day for 7 days. Control visits were performed in 7.90 and 180 days.
 Results. BV was diagnosed in all patients; 19 (82.6%) women also had vaginal candidiasis. At the end of therapy, 17 (73.9%) patients showed an excellent outcome, 4 (17.4%) a significant improvement, 2 (8.7%) no effect. After the end of three-month therapy, 18 (81.8%) out of 22 patients who left in the study had no complaints of urinary disorders or vaginal discharge. Their urinalyses were normal. Molecular genetic analysis of the vaginal biocenosis showed moderate dysbiosis; Candida spp. was revealed only in 3 (13.6%) cases. 18 patients came for the 4th visit. Within six months after the end of monotherapy with Nifuratel, the patients had no complaints. They all achieved the recovery of vaginal normocenosis with a sufficient amount of Lactobacillus spp.
 Conclusion. Monotherapy in patients with recurrent cystitis and BV is highly effective for both diseases: 73.9% of women achieved stable normalization of urine and vaginal microbiota analyzes, removal of bacteriuria. The bi-directional action of Nifuratel allows to avoid polypharmacy in this category of patients.

Ureteral Stent Microbiota Is Associated with Patient Comorbidities but Not Antibiotic Exposure

SummaryUreteral stents are commonly used to prevent urinary obstruction but can become colonized by bacteria and encrusted, leading to clinical complications. Despite recent discovery and characterization of the healthy urinary microbiota, stent-associated bacteria and their impact on encrustation are largely underexplored. We profile the microbiota of patients with typical short-term stents, as well as over 30 atypical cases (all with paired mid-stream urine) from 241 patients. Indwelling time, age, and various patient comorbidities correlate with alterations to the stent microbiota composition, whereas antibiotic exposure, urinary tract infection (UTI), and stent placement method do not. The stent microbiota most likely originates from adhesion of resident urinary microbes but subsequently diverges to a distinct, reproducible population, thereby negating the urine as a biomarker for stent encrustation or microbiota. Urological practice should reconsider standalone prophylactic antibiotics in favor of tailored therapies based on patient comorbidities in efforts to minimize bacterial burden, encrustation, and complications of ureteral stents.

Voided Urinary Microbiota Is Stable Over Time but Impacted by Post Void Storage.

Background: New sensitive techniques have revealed a thriving bacterial community in the human urinary tract, challenging the perception that urine in healthy humans is sterile. While the functional role of this urinary microbiota is unknown, dysbiosis has been linked to urgency urinary incontinence and risk of urinary tract infections. When comparing studies, it is crucial to account for possible confounders introduced due to methodological differences. Here we investigated whether collection and storage conditions had any impact on the urinary microbial composition.Results: For comparison of different storage conditions, midstream urine was collected from five healthy adult female donors and analyzed by 16S rRNA gene sequencing. Samples stored at −80 and −20°C, but not 4°C, were found to be comparable to freshly handled voided urine. Using the same methods, the daily or day-to-day variation in urinary microbiota was investigated in 19 healthy donors, including four women, five men, five girls, and five boys. Apart from two male adult donors, none of the tested conditions gave rise to significant differences in alpha and beta diversities between individuals.Conclusion: The composition of voided urinary microbiota was found to be effectively maintained by freezing, but not storage at 4°C. In addition, we did not observe any intrapersonal daily or day-to-day variations in microbiota composition in women, girls or boys. Together our study supports present methodologies that can be used in future studies investigating the urinary microbiota.

Discovery and predictive modeling of urine microbiome, metabolite and cytokine biomarkers in hospitalized patients with community acquired pneumonia

Pneumonia is the leading cause of infectious related death costing 12 billion dollars annually in the United States alone. Despite improvements in clinical care, total mortality remains around 4%, with inpatient mortality reaching 5–10%. For unknown reasons, mortality risk remains high even after hospital discharge and there is a need to identify those patients most at risk. Also of importance, clinical symptoms alone do not distinguish viral from bacterial infection which may delay appropriate treatment and may contribute to short-term and long-term mortality. Biomarkers have the potential to provide point of care diagnosis, identify high-risk patients, and increase our understanding of the biology of disease. However, there have been mixed results on the diagnostic performance of many of the analytes tested to date. Urine represents a largely untapped source for biomarker discovery and is highly accessible. To test this hypothesis, we collected urine from hospitalized patients with community-acquired pneumonia (CAP) and performed a comprehensive screen for urinary tract microbiota signatures, metabolite, and cytokine profiles. CAP patients were diagnosed with influenza or bacterial (Streptococcus pneumoniae and Staphylococcus aureus) etiologies and compared with healthy volunteers. Microbiome signatures showed marked shifts in taxonomic levels in patients with bacterial etiology versus influenza and CAP versus normal. Predictive modeling of 291 microbial and metabolite values achieved a + 90% accuracy with LASSO in predicting specific pneumonia etiology. This study demonstrates that urine from patients hospitalized with pneumonia may serve as a reliable and accessible sample to evaluate biomarkers that may diagnose etiology and predict clinical outcomes.

Culture-Dependent and Sequencing Methods Revealed the Absence of a Bacterial Community Residing in the Urine of Healthy Cats.

A growing number of studies suggest that the lower urinary tract of humans and dogs can harbor a urinary microbiota. Nevertheless, a certain concern has developed that the microbiota reported could be due to unaccounted contamination, especially in low-biomass samples. The aim of this study was to investigate the bacterial community which populates the urine of healthy cats using two approaches: a culture-dependent approach which consisted of the expanded quantitative urine culture (EQUC) techniques capable of identifying live bacteria not growing in standard urine cultures, and a culture-independent approach which consisted of 16S ribosomal RNA next generation sequencing (16S rRNA NGS) capable of identifying bacterial DNA and exploring microbial diversity with high resolution. To avoid confounding factors of possible bacterial contamination, the urine was sampled using ultrasound-guided cystocentesis, and several sample controls and negative controls were analyzed. The urine sampled from the 10 cats included in the study showed no bacterial growth in the EQUC procedure. Although several reads were successfully originated using 16S rRNA NGS, a comparable pattern was observed between urine samples and the negative control, and no taxa were statistically accepted as non-contaminant. Taken together, the results obtained allowed stating that no viable bacteria were present in the urine of healthy cats without lower urinary tract disease and urinary tract infections, and that the bacterial DNA detected was of contaminant origin.

Bladder cancer-related microbiota: examining differences in urine and tissue samples.

The microbiota isolated from the urine of bladder carcinoma patients exhibits significantly increased compositional abundance of some bacterial genera compared to the urine of healthy patients. Our aim was to compare the microbiota composition of cancerous tissues and urine samples collected from the same set of patients in order to improve the accuracy of diagnostic measures. Tissue samples were collected from patients during cancer tissue removal by transurethral resection. In parallel, urine samples were obtained by transurethral resectoscopy from the same patients. The V3–V4 region of the bacterial 16S rRNA gene was sequenced and analyzed using the Kraken pipeline. In the case of four patients, duplicate microbiota analysis from distant parts of the cancerous tissues was highly reproducible, and independent of the site of tissue collection of any given patient. Akkermansia, Bacteroides, Clostridium sensu stricto, Enterobacter and Klebsiella, as “five suspect genera”, were over-represented in tissue samples compared to the urine. To our knowledge, this is the first study comparing urinary and bladder mucosa-associated microbiota profiles in bladder cancer patients. More accurate characterization of changes in microbiota composition during bladder cancer progression could provide new opportunities in the development of appropriate screening or monitoring methods.

Factors of bacteriuria in children and young adults following hematopoietic stem cell transplantation

Presence of bacteriuria and urinary microbiota composition is an important index of immunocompromised conditions. These parameters are scarcely studied in patients undergoing hematopoietic stem cell transplantation (HSCT). The aim of this work was to evaluate detection rates of cultured aerobic microbiota from urine samples taken by clinical indications before HSCT and within 4 months after the treatment. The study was approved by the Independent Ethics Committee and the Scientific Council of the I.P. Pavlov First Saint Petersburg State Medical University. We evaluated results of bacterial cultures from 734 urine specimens taken in 50 patients with oncohematological and inborn diseases at the age ranging from 1 to 21 years who were subjected to allogeneic HSCT. The analysis was performed for 3 age groups: 1–5, 6–14, and 15–21 years old. The bacterial cultures proved to be positive with 37.6% of urine samples. The following microbes were revealed at highest rates: K. pneumoniae, 95/734 (12.9%); E. faecalis, 90/734 (12.3%); E. coli, 65/734 (8.9%); E. faecium, 50/734 (6.8%). The bacteriuria rates have shown distinct time dependence, with significantly decreased K. pneumoniae and E. coli detection at earliest terms (1st month) after myeloablative conditioning, which could be explained by effective antibacterial prophylaxis over the time of conditioning and in early posttransplant period. We have shown that the frequency of positive tests for K. pneumoniae и E. coli in these samples were different for distinct age groups, i.e., the positivity rates were significantly higher in youngest children (up to 5 years old) as compared with older age groups, being sufficiently increased 2–3 months after HSCT which may be an index of antibiotic resistance as well as a risk factor for infectious complications of other organs. We have also shown a highly significant increase in K. pneumoniae и E. coli positivity rates when using myeloablative conditioning regimen before HSCT. The immunotoxic effects of cytostatic therapy in HSCT deserve further studies, including biodiversity analysis of urinary microbiota by means of new-generation DNA sequencing. These results may serve as a basis for rational antibacterial therapy in HSCT.

855 - Urine and vaginal microbiota are mutually dependent in recurrent uncomplicated lower urinary tract infections

855 - Urine and vaginal microbiota are mutually dependent in recurrent uncomplicated lower urinary tract infections

Recurrent urinary tract infection in women and overactive bladder - Is there a relationship?

Overactive bladder (OAB) in women has similar symptomatology with other common urologic diseases such as recurrent urinary tract infection (UTI). Recent evidence showed that chronic low-grade bacterial bladder colonization might exacerbate OAB symptoms and could be the etiology of recurrent UTI. The high prevalence of lower urinary tract dysfunction is associated with OAB. Women with urgency urinary incontinence refractory to antimuscarinic therapy had more bacteria and a more diverse urinary microbiome. The bacterial reside in the superficial urothelial cells to form intracellular bacterial community and outbreak when the host innate immunity is low. Women with recurrent UTI are found to have highly prevalent voiding dysfunction and detrusor overactivity. These functional abnormalities will further damage the urothelial barrier integrity and create vulnerable to uropathogen invasion. The defective urinary microbiota is less common in women with recurrent UTI, suggesting that the normal flora in the urine might inhibit uropathogen growth and invasion. The defective urothelial barrier function, deficient basal proliferation, and deficient maturation might be owing to chronic suburothelial inflammation, resulting in activation of sensory nerves (causing OAB) and failure elimination of intracellular bacterial communities (causing recurrent UTI). Precision diagnosis and multidisciplinary treatment of the underlying pathophysiology of OAB and recurrent UTI is necessary.

The urothelium, the urinary microbioma and men LUTS: a systematic review.

The pathophysiology and management of male patients with lower urinary tract symptoms (LUTS) is still a matter of debate. In the past few years, the urothelium and the urinary microbiota represented important areas of research to improve the understanding and management of these patients. Aim of the present review was to summarize the available data on the urothelium and the microbiota related to male LUTS. A National Center for Biotechnology Information (NCBI) PubMed search for relevant articles published between January 2000 and December 2019 was performed using the medical subjects heading "urothelium," "microbioma," "microbiota," "urobioma," "urobiota," "benign prostatic hyperplasia," "benign prostatic enlargement," "lower urinary tract symptoms," "lower urinary tract dysfunction," "men," "male," "overactive bladder," "receptors." Exclusion criteria included: animal studies and studies on muscarinic and adrenergic pathways. The urothelium has been recently evaluated in humans to evaluate new possible markers and pathways. New possible targets for the treatment of male LUTS include the neural growth factor, the cannabinoid, the vanilloid and the ATP pathways. However, studies in humans are still needed to elucidate the exact role of these pathways in the management of male patients with LUTS. The available evidence on the urinary microbioma in male is poor. Standing to the available, urinary microbioma is evident in healthy urine in males. Moreover, the urinary microbioma varies depending on the method of collection, sexually transmitted disease status, inflammation and urinary symptoms. A possible role of probiotics in the management of LUTS in women has been proposed and may have a role in male patients as well. The urothelium and the urinary microbiota are still poorly studied in men with LUTS. Most of the evidence and the hypothesis on the relationship between urothelium/urinary microbiota and LUTS comes from animal/in-vitro evidence while clinical trials are lacking. These pathways seem interesting even in LUTS pathogenesis in men but their possible role as a new therapeutic target is still an open debate.