Abstract
Introduction and hypothesis
Studies within the past decade have suggested associations among composition of the urinary microbiota, local immune responses, and urinary incontinence symptoms. To investigate these relationships, we evaluated the structure of the urinary microbiome, local inflammatory markers, and patient responses prior to and at 6-weeks after treatment with anticholinergic medication for urgency urinary incontinence (UUI).
Methods
Using a prospective pilot study, we enrolled women who presented with UUI symptoms and were prescribed treatment with anticholinergics. Catheterized urine samples were collected from participants at their baseline and 6-week follow-up visits for microbiological (standard and 16S rRNA gene phylotyping analyses) and cytokine analysis along with the UDI-6 questionnaire and 2-day bladder diary.
Results
Patients were Caucasian, post- menopausal, with a median age of 64 and median BMI of 30.1 kg/m2. Among the patients, 75% had UUI symptoms for less than 2 years, but with a frequency of at least a few times a week or every day. Most women were prescribed 10 mg oxybutynin ER daily at enrollment. Patients had varied urinary microbiota by culture and 16S phylotyping, with species of Lactobacillus being the most common, in six samples, in addition to taxa associated with Enterococcus, Staphylococcus, and mixed flora. Cytokine levels showed no differences before and after treatment with anticholinergics, nor correlation with urinary bacteria or microbiome composition.
Conclusions
Our pilot study suggests factors in addition to the urinary microbiome and local immune responses may be involved in patients’ response to anticholinergics for UUI.
Similar content being viewed by others
Data Availability
Data available upon request from authors.
References
Haylen BT, de Ridder D, Freeman R, Swift S, Berghmans B, Lee J, et al. An International Urogynaecological Association (IUGA)/International Continence Society (ICS) joint report on the terminology for female pelvic floor dysfunction. Neurourol Urodyn. 2010;29:4–20.
Abufaraj M, Xu T, Cao CH, Siyam A, Isleem U, Massad A, et al. Prevalence and trends in urinary incontinence among women in the United States, 2005–2018. Am J Obstet Gynecol. 2021;225:166.e1-166.e12.
Irwin DE, Milsom I, Hunskaar S, Reilly K, Kopp Z, Herschorn S, et al. Population-based survey of urinary incontinence, overactive bladder, and the other lower urinary tract symptoms in five countries: results of the EPIC study. Eur Urol. 2006;50:1306–14.
Aoki Y, Brown H, Brubaker L, Cornu JN, Daly JO, Cartwright R. Urinary incontinence in women. Nat Rev Dis Primers. 2017;3:17042.
Raju R, Linder B. Evaluation and treatment of overactive bladder in women. Mayo Clin Proc. 2020;95:370–7.
Hilt EE, McKinley K, Pearce MM, et al. Urine is not sterile: use of enhanced urine culture techniques to detect resident bacterial flora in the adult female bladder. J Clin Microbiol. 2014;52:871–6.
Curtiss N, Balachandran A, Krska L, et al. A case controlled study examining the bladder microbiome in women with Overactive Bladder (OAB) and health controls. Eur J Obstet Gynecol Reprod Biol. 2017;214:31–5.
Karstens L, Asquith M, Davin S, et al. Does the urinary microbiome play a role in urgency urinary incontinence and its severity? Front Cell Infect Microbiol. 2016;6:78.
Rooks MG, Garrett WS. Gut microbiota, metabolites and host immunity. Nat Rev Immunol. 2016;16:341–52.
Karlsson M, Scherbak N, Reid G, et al. Lactobacillus rhamnosus GR-1 enhances NF-kappaB activation in Escherichia coli-stimulated urinary bladder cells through TLR4. BMC Microbiol. 2012;12:15.
DeNisco NJ, Neugent M, Mull J, et al. Direct detection of tissue-resident bacteria and chronic inflammation in the bladder wall of postmenopausal women with recurrent urinary tract infection. J Mol Biol. 2019;431:4368–79.
Barichello T, Generoso JS, Singer M, et al. Biomarkers for sepsis: more than just fever and leukocytosis-a narrative review. Crit Care. 2022;26:14.
Siddiqui NY, Helfand BT, Andreev VP, et al. Biomarkers implicated in lower urinary tract symptoms: systematic review and pathway analyses. J Urol. 2019;202:880–9.
Ogulur I, Pat Y, Ardicli O, et al. Advances and highlights in biomarkers of allergic diseases. Allergy. 2021;76:3659–86.
Thorsted A, Nielsen EL, Friberg LE. Pharmacodynamics of immune response biomarkers of interest for evaluation of treatment effects in bacterial infections. Int J Antimicrob Agents. 2020;56:1060.
Jhangi S, Gandhi R, Glanz B, Cook S, Nejad P, Ward D, et al. Increased archaea species and changes with therapy in gut microbiome of multiple sclerosis subjects (S24.001). Neurology. 2014;82(10 Supplement):S24.001.
Thomas- White KJ, Hilt EE, Fok C, et al. Incontinence medication response relates to the female urinary microbiota. Int Urogynecol. 2016;27:723–33.
McIver LJ, Abu-Ali G, Franzosa EA, et al. bioBakery: a meta’omic analysis environment. Bioinformatics. 2018;34:1235–7.
Mallick H, Rahnavard A, McIver L, et al. Multivariable association discovery in population- scale meta-omics studies. PLoS Comput Biol. 2021;17:e1009442.
Pearce M, Zilliox MJ, Rosenfeld AB, et al. The female urinary microbiome in urgency urinary incontinence. Am J Obstet Gynecol. 2015;347:e1-11.
Boyanova L, Marteva-Proevska Y, Markovska R, et al. Urinary tract infections: should we think about the anaerobic cocci? Anaerobe. 2022;77:102509.
Jung CE, Brubaker L. Postoperative urinary tract infection after urogynecologic surgery: timing and uropathogens. Int Urogynecol J. 2020;31:1621–6.
Lotte R, Lotte L, Ruimy R. Actinotignum schaalii (formerly known Actinobaculum schaalii): a newly recognized pathogen- review of the literature. Clin Microbiol Infect. 2016;22:28–36.
Gill K, Horsley H, Swamy S, et al. A prospective observational study of urinary cytokines and inflammatory response in patients with overactive bladder syndrome. BMC Urol. 2021;21:39.
Pillalamarri N, Shalom DF, Pilkinton ML, et al. Inflammatory urine cytokine expression and quality of life in patients with overactive bladder. Female Pelvic Med Reconstr Surg. 2018;24:449–53.
Nobles C, Bertone- Johnson ER, Ronnenberg AG, et al. Correlation of urine and plasma cytokine levels among reproductive-aged women. Eur J Clin Invest. 2015;45:460–5.
Ingersoll MA, Albert ML. From infection to immunotherapy: host immune responses to bacteria at the bladder mucosa. Mucosal Immunol. 2013;6:1041–53.
Abernethy MG, Rosenfeld A, White JR, et al. Urinary microbiome and cytokine levels in women with interstitial cystitis. Obstet Gynecol. 2017;129:500–6.
Kirjavainen PV, Pautler S, Baroja ML, et al. Abnormal immunological profile and vaginal microbiota in women prone to urinary tract infections. Clin Vaccine Immunol. 2009;16:29–36.
Vasileiou K, Barnett J, Thorpe S, Young T. Characterising and justifying sample size sufficiency in interview-based studies: systematic analysis of qualitative health research over a 15-year period. BMC Med Res Methodol. 2018;18:148.
Rose GL, Farley MJ, Flemming N, et al. Between-day reliability of cytokines and adipokines for application in research and practice. Front Physiol. 2022;13:967169.
Nearing JT, Comeau A, Langille M. Identifying biases and their potential solutions in human microbiome studies. Microbiome. 2021;9:113.
Funding
This study was supported through a restricted grant from the Medical University of Silesia and the International Urogynecological Association, and by the Harvard Digestive Diseases P30 DK034854 grant from the National Institutes of Health/NIDDK.
Author information
Authors and Affiliations
Contributions
Gabriel I: Project development, data collection, manuscript writing.
Delaney ML: Project development, data analysis.
Au M: Project development, data analysis.
Courtepatte A: Data analysis.
Lynn Bry: Project development, manuscript editing.
Minassian VA: Project development, manuscript writing.
Corresponding author
Ethics declarations
Conflicts of interest
The authors declare that they have no conflict of interest.
Additional information
Publisher’s note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Supplementary Information
Below is the link to the electronic supplementary material.
Rights and permissions
Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.
About this article
Cite this article
Gabriel, I., Delaney, M.L., Au, M. et al. Impact of microbiota and host immunologic response on the efficacy of anticholinergic treatment for urgency urinary incontinence. Int Urogynecol J 34, 3041–3050 (2023). https://doi.org/10.1007/s00192-023-05664-5
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00192-023-05664-5