The Human Urinary Microbiome and Its Potential Role in Urinary Tract Infections.

Introduction and Objective: Urinary tract infections (UTIs) pose a significant burden on individuals with Type II Diabetes Mellitus (T2DM). UTIs are not only more prevalent in T2DM patients but also tend to be more severe. Managing UTIs effectively is crucial to prevent adverse outcomes and improve quality of life. Yet, the biological factors underlying UTI susceptibility associated with T2DM are not well understood. Recent research has highlighted a role for the female urinary microbiome (FUM) in UTI susceptibility. However, if FUM dysbiosis is exacerbated in people with diabetes remains unknown. We hypothesize that differences in FUM composition exist in women with T2DM and that these differences may underlie increased UTI susceptibility. The goal of this study is to define the FUM associated with T2DM in postmenopausal (PM) women with and without UTI. Methods: Following IRB approval and informed consent, urine was collected from 100 PM women passing exclusion criteria of post-void residual >150 mL, immune deficiency, prolapse >stage 2, catheterization, neurogenic bladder, or recent surgery representing four groups: noUTI/noT2DM, UTI/noT2DM, noUTI/T2DM, UTI/T2DM (N=25 each). Genomic DNA was extracted using the Zymo DNA/RNA kit for shotgun metagenomic sequencing on an Illumina NextSeq2000. Trimgalore and KneadData were used for quality control and host read removal, respectively. MetaPhlan 4 was used for read-based taxonomic assignment. Results: Preliminary analysis revealed a prevalence of Lactobacillus spp. in the FUM of noUTI/noT2DM women and an abundance of Gardenerella vaginalis and Fannyhessea vaginae in the noUTI/T2DM group. In women with active UTI, the FUM of patients without T2DM were dominated by one or two uropathogens like Escherichia coli, Klebsiella pneumoniae or Enterococcus faecalis. Conversely, the FUM of UTI patients with T2DM were more polymicrobial with increased species diversity. Conclusion: Urinary microbiomes of PM women with T2DM may harbor more polymicrobial populations compared to non-diabetic counterparts. Disclosure U. Basu: None. M.L. Neugent: None. S.B. Papp: None. C.N. Saenz: None. R.S. Ahmed: None. P.E. Zimmern: None. N.J. De Nisco: None.

The existence of urinary microbiome in healthy individuals is now widely accepted as the longstanding belief in urinary tract sterility was disproved over a decade ago. The urinary microbiome has since been implicated in multiple urologic conditions including urinary tract infection (UTI), urinary incontinence, and bladder cancer. This review relays new findings of urinary microbiome compositional changes associated with aging and UTI susceptibility. Recent advancements have established how the urinary microbiome changes over the lifespan. Studies finding distinct urinary microbiomes in prepubescent, reproductive age, and postmenopausal females have identified sex hormones as potential modulators of urinary microbiome composition and have identified prevalent species that may be markers of dysbiosis. Research in male children finds a cultivable urinary microbiota that varies with age or urologic history but not delivery mode. Emerging research also addresses the function of the urinary microbiota, including genetic factors associated with urinary tract colonization and interactions with uropathogens. The urinary microbiome is a promising therapeutic target for urologic disease. However, a more functional understanding is necessary for the development of microbiome-based therapies. Future research should develop accurate animal models and explore functional relationships between the urinary microbiome and the host environment.

Characterization of urinary bacterial microbiome and antimicrobial peptides after burn injury to identify potential mechanisms leading to urinary tract infections and associated morbidities in burn patients. Retrospective cohort study using human urine from control and burn subjects. University research laboratory. Burn patients. None. Urine samples from catheterized burn patients were collected hourly for up to 40 hours. Control urine was collected from "healthy" volunteers. The urinary bacterial microbiome and antimicrobial peptide levels and activity were compared with patient outcomes. We observed a significant increase in urinary microbial diversity in burn patients versus controls, which positively correlated with a larger percent burn and with the development of urinary tract infection and sepsis postadmission, regardless of age or gender. Urinary psoriasin and β-defensin antimicrobial peptide levels were significantly reduced in burn patients at 1 and 40 hours postadmission. We observed a shift in antimicrobial peptide hydrophobicity and activity between control and burn patients when urinary fractions were tested against Escherichia coli and Enterococcus faecalis urinary tract infection isolates. Furthermore, the antimicrobial peptide activity in burn patients was more effective against E. coli than E. faecalis. Urinary tract infection-positive burn patients with altered urinary antimicrobial peptide activity developed either an E. faecalis or Pseudomonas aeruginosa urinary tract infection, suggesting a role for urinary antimicrobial peptides in susceptibility to select uropathogens. Our data reveal potential links for urinary tract infection development and several morbidities in burn patients through alterations in the urinary microbiome and antimicrobial peptides. Overall, this study supports the concept that early assessment of urinary antimicrobial peptide responses and the bacterial microbiome may be used to predict susceptibility to urinary tract infections and sepsis in burn patients.

Acute pyelonephritis and renal scarring are caused by dysfunctional innate immunity in mCxcr2 heterozygous mice

Urinary tract infections (UTIs) are a common condition in children and often lead to hospitalization. A considerable proportion of children with UTIs (up to 30%) experience at least one recurrence, placing them at risk for long-term complications such as renal scarring. Since the concept of the microbiome was first introduced in 2001, increasing attention has been given to the role of the urinary tract microbiome in maintaining urinary tract homeostasis. Dysbiosis of the urinary microbiome has been recognized as a factor associated with an increased risk of various urinary tract diseases, including UTIs. However, the specific role of the urinary microbiome in the pathophysiology of pediatric UTIs remains incompletely understood. The present review examines recent studies on the urinary microbiome in children and summarizes current strategies for modulating the urinary microbiome to prevent UTI recurrence in the pediatric population.

The application of next generation sequencing techniques has allowed the characterization of the urinary tract microbiome and has led to the rejection of the pre-established concept of sterility in the urinary bladder. Not only have microbial communities in the urinary tract been implicated in the maintenance of health but alterations in their composition have also been associated with different urinary pathologies, such as urinary tract infections (UTI). Therefore, the study of the urinary microbiome in healthy individuals, as well as its involvement in disease through the proliferation of opportunistic pathogens, could open a potential field of study, leading to new insights into prevention, diagnosis and treatment strategies for urinary pathologies. In this review we present an overview of the current state of knowledge about the urinary microbiome in health and disease, as well as its involvement in the development of new therapeutic strategies.

The community of bacteria that colonize the urinary tract, the urinary microbiome, is hypothesized to influence a wide variety of urinary tract conditions. Older adults who reside in nursing homes are frequently diagnosed and treated for urinary tract conditions such as urinary tract infection. We investigated the urinary microbiome of older adults residing in a nursing home to determine if there are features of the urinary microbiome that are associated with specific conditions and exposure in this population. We were also interested in the stability of urinary microbiome over time and in similarities between the urinary and gastrointestinal microbiome. Urine samples were prospectively collected over a period of 10 months from a cohort of 26 older adults (aged >65 years) residing in a single nursing home located in Central Massachusetts. Serial samples were obtained from 6 individuals over 10 months and 5 participants were concurrently enrolled in a study of the gastrointestinal microbiome. Information collected on participants included demographics, medical history, duration of residence in the nursing home, frailty, dementia symptoms, urinary symptoms, antibiotic treatment, urinary catheterization, and hospitalizations over a 10-month period. Clean catch, midstream urine samples were collected and stored at -80°C. DNA was extracted and 16S rRNA gene sequencing was performed. The length of stay in the nursing facility and the Clinical Frailty Scale correlated with significant changes in microbiome composition. An increase in the relative abundance of a putative urinary pathogen, Aerococcus urinae, was the largest factor influencing change that occurred over the duration of residence.

The mechanism by which cranberry-lingonberry juice (CLJ) prevents urinary tract infections (UTI) in children remains unknown. We hypothesized that it alters the composition of the gut or urinary microbiome. Altogether, 113 children with UTIs were randomly allocated to drink either CLJ or a placebo juice for 6 months. We collected urinary samples at 3 months and fecal samples at 3, 6 and 12 months and used next-generation sequencing of the bacterial 16S gene. The children who consumed CLJ had a lower abundance of Proteobacteria (p=0.03) and a higher abundance of Firmicutes phylum (p=0.04) in their urinary microbiome at 3 months than did those in the placebo group. The abundance of Escherichia coli in the urinary microbiome was 6% in the CLJ group and 13% in the placebo group (p=0.42). In the gut microbiome the abundance of Actinobacteria at 3 and 12 months was higher in the children receiving CLJ. The diversity of the urinary and gut microbiome did not differ between the groups. The children drinking CLJ had a different urinary and gut microbiome from those receiving a placebo juice. A healthy urinary microbiome may be important in preventing UTIs in children.

Urinary Tract Infections in Solid Organ Transplant Recipients

Microbial determinants of acute-disease severity and tissue damage have been extensively studied, but less is known about genetic variation influencing host susceptibility. This chapter discusses two candidate genes with strong effects on the innate immune response and the antibacterial defense in the urinary tract and with major but opposite effects on urinary tract infection (UTI) susceptibility. The chapter explains that defects in TLR4 expression are protective and associated with asymptomatic bacteriuria (ABU) while defects in CXCR1 expression promote acute pyelonephritis (APN) and renal scarring. C3H/HeJ mice, then known as lipopolysaccharide (LPS)-nonresponder mice, had an increased susceptibility to UTI, as shown by delayed bacterial clearance. It also had an impaired innate immune response, suggesting that defects in innate immunity are of great importance for the antibacterial defense of the urinary tract. Studies of the murine model showed that the antibacterial defense of the urinary tract mucosa relies on innate immunity and that TLR4 plays a central role in the early host defense against infection. The results suggest that genetic variation of the TLR4 promoter is an essential, largely overlooked mechanism to influence TLR4 expression and UTI susceptibility. It was found that the protein expression was reduced and additionally the level of CXCR1 transcript and protein expression was lower in this new subset of pediatric patients. There is a great clinical need to identify genetic variants that improve resistance or increase susceptibility to infectious pathogens.

Narrowing the Focus: What We Now Know (and Still Don’t Know) About Antibiotic Prophylaxis for Children With Vesicoureteral Reflux

Defining the relationship between vaginal and urinary microbiomes

Introduction. A new paradigm in the diagnosis, treatment, and prevention of urinary tract infections (UTIs) is currently emerging in medical science, based on the understanding that urine is not sterile and the urinary tract is inhabited by a diverse microbiome. Recurrent UTIs remain one of the leadingproblems in the management of patients with neurogenic lower urinary tract dysfunction (NLUTD), but the dependence of UTI recurrence rate on the composition of the urinary microbiome has not been studied. The purpose of the study was to assess the changes in the urinary microbiome in patients with neurogenic bladder and the relationship between these changes and the frequency of recurrent urinary tract infections. Materials and methods. The urinary microbiome was studied in 118 patients with neurogenic bladder without UTI recurrence and 15 healthy volunteers as a control group. Urine cultures were performed using the modified enhanced quantitative urine culture (EQUC) method, with determination of antimicrobial susceptibility of the microorganisms, and real-time PCR analysis of urine samples using the Androflor kit (DNA-Technology, Russia). Results. Bacterial growth was obtained in 72% of urine cultures from NLUTD patients and 80% in the control group. A total of 175 isolates were obtained: from 1 to 6 (on average 1.76±1.22) per patient. PCR analysis of urine samples revealed the presence of microbial DNA in all urine samples, including those that did not show growth on culture media. The most common microorganisms in the microbiome of NLUTD patients were: Escherichia coli (20%), Enterococcus faecalis (19%), Staphylococcus spp. (15%), Streptococcus spp. (12%), and Klebsiella pneumoniae (9%). The microbiome of patients with preserved spontaneous urination was closest to the control group, but differed in an increased proportion of Enterobacteriaceae and Enterococcus spp. The presence of a significant number of representatives of the normal microflora, such as Lactobacillus spp., Streptococcus spp., Staphylococcus spp., and a more diverse composition in general, distinguished the urinary microbiome of patients using intermittent catheterization from those with a permanent drainage. Urine cultures of patients with recurrent UTIs yielded fewer isolates than those without frequent infection exacerbations (1±0.58 and 2.25±1.29, respectively, p=0.001). Conclusions. The urinary microbiome of NLUTD patients is dominated by Enterobacteriaceae. The presence of a significant number of representatives of the normal microflora, such as Lactobacillus spp., Streptococcus spp., Staphylococcus spp., and a more diverse composition in general, distinguish the urinary microbiome of patients with intermittent catheterization from those with cystostomy or a permanent urethral catheter. Species diversity of the microbiome is associated with a lower frequency of recurrent urinary tract infections.

Urinary Tract Infection (UTI) is a common condition often expressed as a bacterial colonization of the bladder that in severe conditions extends to associated structures in the urinary system. The topic of recurrent UTI and antibiotic resistance has prompted several researchers to focus on the relationship gut and urinary microbiome have with recurrent UTI, searching for potential cures to antibiotic-resistant UTIs from the probiotic approach. This study aimed to find regional differences in microbiome studies, including the taxonomies in microbiomes across regions and their relationships to the local UTI conditions. The study reviewed data and findings of two iconic studies, Choi et al. and Huang et al., to examine how their findings would contribute to future research on probiotic treatments and the role of the gut-bladder axis in UTI. It found out that many identified UTI-causing pathogens are opportunistic species, whose relationships with the host are complicated by weakened immune systems, gut-bladder proximity and genetic plasticity. Additionally, the study pointed out several advantages of NGS technology that provide promising insight into microbiome taxonomies previously unreached by culturing methods. It identified several species as potential UTI-curing probiotics, though their wide applications were cautioned. Further research on UTI microbiome across regions and their effects on the local conditions is still warranted.

Recent advances in the analysis of microbial communities colonizing the human body have identified a resident microbial community in the human urinary tract (UT). Compared to many other microbial niches, the human UT harbors a relatively low biomass. Studies have identified many genera and species that may constitute a core urinary microbiome. However, the contribution of the UT microbiome to urinary tract infection (UTI) and recurrent UTI (rUTI) pathobiology is not yet clearly understood. Evidence suggests that commensal species within the UT and urogenital tract (UGT) microbiomes, such as Lactobacillus crispatus, may act to protect against colonization with uropathogens. However, the mechanisms and fundamental biology of the urinary microbiome-host relationship are not understood. The ability to measure and characterize the urinary microbiome has been enabled through the development of next-generation sequencing and bioinformatic platforms that allow for the unbiased detection of resident microbial DNA. Translating technological advances into clinical insight will require further study of the microbial and genomic ecology of the urinary microbiome in both health and disease. Future diagnostic, prognostic, and therapeutic options for the management of UTI may soon incorporate efforts to measure, restore, and/or preserve the native, healthy ecology of the urinary microbiomes.