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Chronic inflammation promotes the development of several types of solid cancers and might contribute to prostate carcinogenesis. This hypothesis partly originates in the frequent observation of inflammatory cells in the prostate microenvironment of adult men. Inflammation is associated with putative prostate cancer precursor lesions, termed proliferative inflammatory atrophy. Inflammation might drive prostate carcinogenesis via oxidative stress and generation of reactive oxygen species that induce mutagenesis. Additionally, inflammatory stress might cause epigenetic alterations that promote neoplastic transformation. Proliferative inflammatory atrophy is enriched for proliferative luminal epithelial cells of intermediate phenotype that might be prone to genomic alterations leading to prostatic intraepithelial neoplasia and prostate cancer. Studies in animals suggest that inflammatory changes in the prostate microenvironment contribute to reprogramming of prostate epithelial cells, a possible step in tumour initiation. Prostatic infection, concurrent with epithelial barrier disruption, might be a key driver of an inflammatory microenvironment; the discovery of a urinary microbiome indicates a potential source of frequent exposure of the prostate to a diverse number of microorganisms. Hence, current evidence suggests that inflammation and atrophy are involved in prostate carcinogenesis and suggests a role for the microbiome in establishing an inflammatory prostate microenvironment that might promote prostate cancer development and progression.

Key Points An overarching theme of the immune system in the bladder seems to be balancing the need to respond promptly to microbial challenge with the need to rapidly curtail inflammatory responses, as the structural integrity of the epithelial barrier is disrupted during prolonged immune responses. Bladder epithelial cells not only alert the immune system during infection but also directly mediate bacterial clearance by secreting antimicrobial compounds into the urine and by expelling invading bacteria back into the bladder lumen to reduce intracellular load. Crosstalk between different subsets of macrophages in the bladder coordinates the precise recruitment and onset of neutrophil responses, and thereby reduces harmful inflammatory reactions. Mast cells seem to have a dual role in immune regulation in the urinary tract. They promote early mobilization of immune cells into the bladder and are central to terminating these pro-inflammatory responses presumably when the bladder epithelial barrier is disrupted. However, this homeostatic action often results in blunted adaptive immune responses. Although neutrophils are the predominant immune cells mediating bacterial clearance in the bladder, excessive neutrophil responses can cause damage to the bladder tissue and predispose this organ to persistent infections. Several unconventional, but potentially effective, strategies have been described that can boost immune defences of the bladder to contain or prevent urinary tract infections. This Review describes our current understanding of innate and adaptive immune responses in the urinary tract and how immunomodulatory therapies could provide benefit in an era of increasing antibiotic resistance among uropathogens. The urinary tract is constantly exposed to microorganisms that inhabit the gastrointestinal tract, but generally the urinary tract resists infection by gut microorganisms. This resistance to infection is mainly ascribed to the versatility of the innate immune defences in the urinary tract, as the adaptive immune responses are limited particularly when only the lower urinary tract is infected. In recent years, as the strengths and weaknesses of the immune system of the urinary tract have emerged and as the virulence attributes of uropathogens are recognized, several potentially effective and unconventional strategies to contain or prevent urinary tract infections have emerged.

Key Points Contrary to doctrine, the urinary tract is inhabited by a unique urinary microbiota; further research is needed to characterize this microbial community in health and disease Alterations in the urinary microbiota have been linked to urologic disease, such as neurogenic bladder dysfunction, interstitial cystitis and urgency urinary incontinence The microbiome, particularly that of the gut, has a key role in the development and progression of disease within the urinary tract Although early studies of probiotics in patients with nephrolithiasis or bladder cancer have demonstrated variable effectiveness, such alternative treatment strategies focused on reconstituting the microbiome should be further explored New research indicates that the microbiota at many sites in the body, including the urinary tract, might influence urological health. Whiteside et al . review our current knowledge on the microbiome–host relationship and examine its role in the maintenance of urinary homeostasis, its utility as a predictor of the risk of disease and as a basis for the development of novel therapeutic strategies. Urologists rarely need to consider bacteria beyond their role in infectious disease. However, emerging evidence shows that the microorganisms inhabiting many sites of the body, including the urinary tract—which has long been assumed sterile in healthy individuals—might have a role in maintaining urinary health. Studies of the urinary microbiota have identified remarkable differences between healthy populations and those with urologic diseases. Microorganisms at sites distal to the kidney, bladder and urethra are likely to have a profound effect on urologic health, both positive and negative, owing to their metabolic output and other contributions. Connections between the gut microbiota and renal stone formation have already been discovered. In addition, bacteria are also used in the prevention of bladder cancer recurrence. In the future, urologists will need to consider possible influences of the microbiome in diagnosis and treatment of certain urological conditions. New insights might provide an opportunity to predict the risk of developing certain urological diseases and could enable the development of innovative therapeutic strategies.

Key Points UTIs are increasingly caused by multidrug-resistant organisms as a result of the overuse of empirical, broad-spectrum antibiotic therapy Antimicrobial susceptibility, determined by the phenotypic response to antibiotic exposure, is key for clinical decision making for treating the wide variety of uropathogens and identifying resistance markers Existing technologies (such as PCR, fluorescence in situ hybridization, and mass spectrometry) and new technologies (such as droplet microfluidic and biosensor platforms) need to focus on direct urine testing to expedite objective diagnoses Integrated biosensor–microfluidic platforms have the most potential for point-of-care testing, as they facilitate direct urine analysis and can encompass all assay steps in a compact device New technologies are a key step towards improved antimicrobial stewardship Timely and accurate identification and determination of the antimicrobial susceptibility of uropathogens is central to the management of UTIs and antimicrobial stewardship. In this Review, Davenport and colleagues discuss emerging technologies including biosensors, microfluidics, and other integrated platforms that could improve UTI diagnosis and treatment choice. Timely and accurate identification and determination of the antimicrobial susceptibility of uropathogens is central to the management of UTIs. Urine dipsticks are fast and amenable to point-of-care testing, but do not have adequate diagnostic accuracy or provide microbiological diagnosis. Urine culture with antimicrobial susceptibility testing takes 2–3 days and requires a clinical laboratory. The common use of empirical antibiotics has contributed to the rise of multidrug-resistant organisms, reducing treatment options and increasing costs. In addition to improved antimicrobial stewardship and the development of new antimicrobials, novel diagnostics are needed for timely microbial identification and determination of antimicrobial susceptibilities. New diagnostic platforms, including nucleic acid tests and mass spectrometry, have been approved for clinical use and have improved the speed and accuracy of pathogen identification from primary cultures. Optimization for direct urine testing would reduce the time to diagnosis, yet these technologies do not provide comprehensive information on antimicrobial susceptibility. Emerging technologies including biosensors, microfluidics, and other integrated platforms could improve UTI diagnosis via direct pathogen detection from urine samples, rapid antimicrobial susceptibility testing, and point-of-care testing. Successful development and implementation of these technologies has the potential to usher in an era of precision medicine to improve patient care and public health.

Escherichia coli is the leading cause of urinary tract infection, one of the most common bacterial infections in humans. Despite this, a genomic perspective is lacking regarding the phylogenetic distribution of isolates associated with different clinical syndromes. Here, we present a large-scale phylogenomic analysis of a spatiotemporally and clinically diverse set of 907 E. coli isolates, including 722 uropathogenic E. coli (UPEC) isolates. A genome-wide association approach identifies the (P-fimbriae-encoding) papGII locus as the key feature distinguishing invasive UPEC, defined as isolates associated with severe UTI, i.e., kidney infection (pyelonephritis) or urinary-source bacteremia, from non-invasive UPEC, defined as isolates associated with asymptomatic bacteriuria or bladder infection (cystitis). Within the E. coli population, distinct invasive UPEC lineages emerged through repeated horizontal acquisition of diverse papGII -containing pathogenicity islands. Our findings elucidate the molecular determinants of severe UTI and have implications for the early detection of this pathogen. Escherichia coli is a major cause of urinary tract infection. Here, Biggel et al. provide a phylogenomic analysis of 907 clinical E. coli isolates and identify the P-fimbriae-encoding locus associated with invasive uropathogenic E. coli isolates.

Metabolomics has emerged as a mainstream approach for investigating complex metabolic phenotypes but has yet to be integrated into routine clinical diagnostics. Metabolomics-based diagnosis of urinary tract infections (UTIs) is a logical application of this technology since microbial waste products are concentrated in the bladder and thus could be suitable markers of infection. We conducted an untargeted metabolomics screen of clinical specimens from patients with suspected UTIs and identified two metabolites, agmatine, and N6-methyladenine, that are predictive of culture-positive samples. We developed a 3.2-min LC-MS assay to quantify these metabolites and showed that agmatine and N6-methyladenine correctly identify UTIs caused by 13 Enterobacterales species and 3 non- Enterobacterales species, accounting for over 90% of infections (agmatine AUC > 0.95; N6-methyladenine AUC > 0.89). These markers were robust predictors across two blinded cohorts totaling 1629 patient samples. These findings demonstrate the potential utility of metabolomics in clinical diagnostics for rapidly detecting UTIs. Microbial catabolites in urine provide a rapid method for detecting urinary tract infections (UTIs). Here, the authors describe an LC-MS metabolomics approach for detecting two catabolites collectively produced by 90% of UTI microbes.

Rising rates of antibiotic resistance in uropathogenic bacteria compromise patient outcomes and prolong hospital stays. Consequently, new strategies are needed to prevent and control the spread of antibiotic resistance in uropathogenic bacteria. Over the past two decades, sizeable clinical efforts and research advances have changed urinary tract infection (UTI) treatment and prevention strategies to conserve antibiotic use. The emergence of antimicrobial stewardship, policies from national societies, and the development of new antimicrobials have shaped modern UTI practices. Future UTI management practices could be driven by the evolution of antimicrobial stewardship, improved and readily available diagnostics, and an improved understanding of how the microbiome affects UTI. Forthcoming UTI treatment and prevention strategies could employ novel bactericidal compounds, combinations of new and classic antimicrobials that enhance bacterial killing, medications that prevent bacterial attachment to uroepithelial cells, repurposing drugs, and vaccines to curtail the rising rates of antibiotic resistance in uropathogenic bacteria and improve outcomes in people with UTI.Antibiotic-resistant uropathogenic bacteria are becoming increasingly prevalent. In this Review, strategies for clinicians and researchers to address this challenge are delineated, including implementation of policies, stewardship practices, and the exploration of emerging therapeutic targets aimed at mitigating antibiotic resistance.

Key Points Multidrug-resistant Gram-negative pathogens are rapidly emerging and spreading globally These multidrug-resistant pathogens are frequently associated with major pathologies, including urinary tract infections Routine urological practices are affected by multidrug-resistant pathogens Knowledge of the local epidemiology of multidrug-resistant Gram-negative bacteria is essential for determining empirical antimicrobial therapy Urinary tract infections (UTIs) are very common and are a major contributor to global antibiotic use and resistance. Without effective antibiotics active against common uropathogens, many urological procedures would carry excessive risk. In this article, Zowawi and coauthors describe the current global epidemiology of resistance in Gram-negative uropathogens and discuss the genetic and molecular mechanisms underlying the resistance of these phenotypes. They also examine the effect of resistance on common urological procedures and summarize various preventive and therapeutic options. Antibiotic resistance in Gram-negative uropathogens is a major global concern. Worldwide, the prevalence of Enterobacteriaceae that produce extended-spectrum β-lactamase or carbapenemase enzymes continues to increase at alarming rates. Likewise, resistance to other antimicrobial agents including aminoglycosides, sulphonamides and fluoroquinolones is also escalating rapidly. Bacterial resistance has major implications for urological practice, particularly in relation to catheter-associated urinary tract infections (UTIs) and infectious complications following transrectal-ultrasonography-guided biopsy of the prostate or urological surgery. Although some new drugs with activity against Gram-negative bacteria with highly resistant phenotypes will become available in the near future, the existence of a single agent with activity against the great diversity of resistance is unlikely. Responding to the challenges of Gram-negative resistance will require a multifaceted approach including considered use of current antimicrobial agents, improved diagnostics (including the rapid detection of resistance) and surveillance, better adherence to basic measures of infection prevention, development of new antibiotics and research into non-antibiotic treatment and preventive strategies.

Urinary tract infection (UTI) is the most common type of community-acquired and hospital-acquired bacterial infection. In this Review, Prof. Foxman describes the prevalence, incidence and bacteriology of UTI, the transmission mechanisms and the development of antibiotic-resistant strains of uropathogenic bacteria, and discusses whether we need to change the way we treat patients with uncomplicated or catheter-associated UTI. Urinary tract infections (UTIs) are among the most common bacterial infections acquired in the community and in hospitals. In individuals without anatomical or functional abnormalities, UTIs are generally self limiting, but have a propensity to recur. Uropathogens have specialized characteristics, such as the production of adhesins, siderophores and toxins that enable them to colonize and invade the urinary tract, and are transmitted between individuals both through person-to-person contact and possibly via food or water. Although generally self limiting, treatment of UTIs with antibiotics leads to a more rapid resolution of symptoms and is more likely to clear bacteriuria, but also selects for resistant uropathogens and commensal bacteria and adversely affects the gut and vaginal microbiota. As uropathogens are increasingly becoming resistant to currently available antibiotics, it may be time to explore alternative strategies for managing UTI. Key Points Urinary tract infection (UTI) is diagnosed using a combination of urinary symptoms and urine culture; ∼20% of women presenting with symptoms indicative of UTI will have a negative urine culture Escherichia coli are the bacteria most frequently implicated in uncomplicated UTI and catheter-associated UTI, and are becoming increasingly resistant to antibiotics Positive urine culture in the absence of symptoms should not be treated, except in pregnant women or those undergoing invasive genitourinary procedures

Diabetes is known to increase susceptibility to infections, partly due to impaired granulocyte function and changes in the innate immunity. Here, we investigate the effect of diabetes, and high glucose on the expression of the antimicrobial peptide, psoriasin and the putative consequences for E. coli urinary tract infection. Blood, urine, and urine exfoliated cells from patients are studied. The influence of glucose and insulin is examined during hyperglycemic clamps in individuals with prediabetes and in euglycemic hyperinsulinemic clamped patients with type 1 diabetes. Important findings are confirmed in vivo in type 2 diabetic mice and verified in human uroepithelial cell lines. High glucose concentrations induce lower psoriasin levels and impair epithelial barrier function together with altering cell membrane proteins and cytoskeletal elements, resulting in increasing bacterial burden. Estradiol treatment restores the cellular function with increasing psoriasin and bacterial killing in uroepithelial cells, confirming its importance during urinary tract infection in hyperglycemia. In conclusion, our findings present the effects and underlying mechanisms of high glucose compromising innate immunity. Patients with diabetes have an increased susceptibility to infections. Here the authors show that high glucose impairs innate immunity through reduced levels of the antimicrobial peptide psoriasin and impaired epithelial barrier function, resulting in an increased risk of urinary tract infection.