Reaching the End of the Line

Tamadonfar, Kevin O.; Omattage, Natalie S.; Spaulding, Caitlin N.; Hultgren, Scott J.

doi:10.1128/9781683670261.ch6

Cited by 14 publications

(14 citation statements)

References 140 publications

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“…Nur77 is a druggable target, with several ligands being explored for treatment of diseases such as cancer, metabolic disorders, hyperinflammatory responses and endometriosis (Wu and Chen, 2018;Mohankumar et al, 2020). If our findings translate to rUTI in humans, this could open up a therapeutic avenue that is much needed in the current climate of increasing antibiotic resistance (Tamadonfar et al, 2019). Future studies will more closely examine the mechanism(s) for Nur77-mediated response to Gardnerella in the bladder, will investigate whether IE responses impact UTI phenotypes in other mouse models, and will test whether Nur77 could also play a role in host response to Gardnerella in the vagina.…”

Section: Discussionmentioning

confidence: 84%

Bladder Exposure to Gardnerella Activates Host Pathways Necessary for Escherichia coli Recurrent UTI

O’Brien

Lewis

Gilbert

2021

Front. Cell. Infect. Microbiol.

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Recurrent urinary tract infections (rUTI) are a costly clinical problem affecting millions of women worldwide each year. The majority of rUTI cases are caused by uropathogenic Escherichia coli (UPEC). Data from humans and mouse models indicate that some instances of rUTI are caused by UPEC emerging from latent reservoirs in the bladder. Women with vaginal dysbiosis, typically characterized by high levels of Gardnerella and other anaerobes, are at increased risk of UTI. Multiple studies have detected Gardnerella in urine collected by transurethral catheterization (to limit vaginal contamination), suggesting that some women experience routine urinary tract exposures. We recently reported that inoculation of Gardnerella into the bladder triggers rUTI from UPEC bladder reservoirs in a mouse model. Here we performed whole bladder RNA-seq to identify host pathways involved in Gardnerella-induced rUTI. We identified a variety host pathways differentially expressed in whole bladders following Gardnerella exposure, such as pathways involved in inflammation/immunity and epithelial turnover. At the gene level, we identified upregulation of Immediate Early (IE) genes, which are induced in various cell types shortly following stimuli like infection and inflammation. One such upregulated IE gene was the orphan nuclear receptor Nur77 (aka Nr4a1). Pilot experiments in Nur77-/- mice suggest that Nur77 is necessary for Gardnerella exposure to trigger rUTI from UPEC reservoirs. These findings demonstrate that bladder gene expression can be impacted by short-lived exposures to urogenital bacteria and warrant future examination of responses in distinct cell types, such as with single cell transcriptomic technologies. The biological validation studies in Nur77-/- mice lay the groundwork for future studies investigating Nur77 and the Immediate Early response in rUTI.

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Section: Discussionmentioning

confidence: 84%

Bladder Exposure to Gardnerella Activates Host Pathways Necessary for Escherichia coli Recurrent UTI

O’Brien

Lewis

Gilbert

2021

Front. Cell. Infect. Microbiol.

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“…About 35-40% of women experience at least one UTI episode requiring antibiotic treatment, and the most common bacteria is E. coli in 85% of cases [28]. The increase of antibiotic resistance represents an additional emerging issue, particularly for E. coli, Klebsiella, and Enterobacteria strains as they are already resistant to third-generation cephalosporins and carbapenems [2,29,30]. Because of the above, researchers are finding suitable adjuvant therapies for UTIs in order to halt this trend.…”

Section: Discussionmentioning

confidence: 99%

Prevention and treatment of cystitis during menopause: efficacy of a nutraceutical containing D-mannose, inulin, cranberry, bearberry, Olea europaea, Orthosiphon and Lactobacillus acidophilus

Mainini¹,

Passaro²,

Schiattarella³

et al. 2020

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Aim of the study: To evaluate the efficacy of a nutraceutical compound containing Uticlin® (D-mannose, cranberry, bearberry, Olea europaea), inulin, Orthosiphon and Lactobacillus acidophilus, in preventing recurrent urinary tract infections (UTIs) in menopausal women. Material and methods: This was a prospective cohort study of menopausal women recruited with a history of recurrent UTIs in the previous twelve months and who intended to treat their bladder problem without the use of antibiotics and/or anti-inflammatories. Women were proposed the use of an oral nutraceutical compound. The drug was taken for ten days, every month. Women were assigned to two parallel cohorts: patients using (group 1) or not using (group 2) this nutraceutical compound. The primary objective of the study was to evaluate the number of women with less than two infective episodes in the 6-month follow-up and less than three episodes in the 12-month follow-up. The secondary endpoints were to evaluate the reduction of related symptoms at 12-month follow-up, according to the Visual Analog Scale (VAS). Results: At 6 months of therapy, the reduction in the number of patients with ≥ 2 UTIs was statistically significant (p < 0.05) compared to baseline only in group 1. At 12 months, the number of patients who were disease-free was significantly higher (p < 0.05) in group 1 compared to group 2. Moreover, the improvement of related symptoms was statistically significant (p < 0.05) in group 1, as shown by the reduction in the VAS scale value. Conclusions: In menopausal women, the combination of D-mannose, inulin, cranberry, bearberry, Olea europaea, Orthosiphon and Lactobacillus acidophilus SGL 11 per os represents a useful therapy for recurrent UTIs in women wanting a natural approach.

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“…Urinary tract infections (UTIs) are reported as the most common infections worldwide, that occur more frequently in women than men due to anatomical differences, and its incidence increases with age or sexual activity [1][2][3][4] . Although several bacterial species are reported as causative agents of UTIs (e.g., Escherichia coli, Klebsiella sp., Proteus sp., Staphylococcus saprophyticus), E. coli is responsible for the majority (up to 75%) of both uncomplicated and complicated UTIs 2,[5][6][7] .…”

Section: Introductionmentioning

confidence: 99%

“…Additionally, the existence of intracellular bacterial communities or quiescent intracellular reservoirs that may silently persist within epithelial cells of urogenital tract also contribute to recurrent UTI (rUTI) development 7,22 .…”

Section: Introductionmentioning

confidence: 99%

The darkest place is under the candlestick - healthy urogenital tract as a source of UTI-relatedEscherichia colilineages

Ksiezarek

Novais

Peixe

2021

Preprint

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Since the discovery of the urinary microbiome, including identification of Escherichia coli in healthy hosts, its involvement in UTI development is a subject of high interest.We explored population diversity and antimicrobial resistance of E. coli from urogenital microbiome of asymptomatic and recurrent UTI (rUTI) women. We also evaluated the genomic relationship between extraintestinal pathogenic E. coli (ExPEC) strains from healthy and diseased hosts, particularly of the ST131 lineage.E. coli was highly prevalent in asymptomatic women (48%) with slightly higher prevalence in vaginal samples comparing to urine, and occasionally with multiclonal population in the same individual. B2 was the most frequent phylogenetic group, with most strains classified as ExPEC. We demonstrated that virulence associated genes profile does not allow to distinguish strains isolated from healthy and rUTI host. We identified E. coli widespread lineages e.g., sequence types (ST) 127, ST131 (asymptomatic cohort) and ST73, ST131 (rUTI), frequently resistant to at least one antibiotic. Phylogenomics of ST131 and other ExPEC lineages revealed close relatedness between healthy and diseased host.These findings demonstrate that healthy urogenital microbiome is a source of potentially pathogenic and antibiotic resistant E. coli strains, including globally spread E. coli lineages causing UTI including ST131.

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Reaching the End of the Line

Cited by 14 publications

References 140 publications

Bladder Exposure to Gardnerella Activates Host Pathways Necessary for Escherichia coli Recurrent UTI

Bladder Exposure to Gardnerella Activates Host Pathways Necessary for Escherichia coli Recurrent UTI

Prevention and treatment of cystitis during menopause: efficacy of a nutraceutical containing D-mannose, inulin, cranberry, bearberry, Olea europaea, Orthosiphon and Lactobacillus acidophilus

The darkest place is under the candlestick - healthy urogenital tract as a source of UTI-relatedEscherichia colilineages

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