By Chiara Ghetti, MD

Associate Professor, Obstetrics and Gynecology, Division of Female Pelvic Medicine and Reconstructive Surgery, Washington University School of Medicine, St. Louis, MO

Dr. Ghetti reports no financial relationships relevant to this field of study.

SYNOPSIS: Increased diversity of the microbiota in women is associated with urgency urinary incontinence symptoms but not with stress urinary incontinence symptoms.

SOURCE: Thomas-White KJ, Kliethermes S, Rickey L, et al; National Institute of Diabetes and Digestive and Kidney Diseases Urinary Incontinence Treatment Network. Evaluation of the urinary microbiota of women with uncomplicated stress urinary incontinence. Am J Obstet Gynecol 2017;216:55.e1-55.e16.

The objective of this study was to investigate the relationships between urinary microbiota and characteristics of women undergoing surgery for stress urinary incontinence. Microbiota (or synonymously microbiome) refers to a community of microorganisms. In particular, Thomas-White et al investigated the female urinary microbiota, or in other words, the microbial communities that live in women’s bladders. This was a sub-study of the Value of Urodynamic Evaluation study (VALUE), a National Institutes of Health-sponsored large, multicenter, clinical trial of women with uncomplicated stress urinary incontinence planning to undergo surgery.

Adult women were eligible for the VALUE study if they reported symptoms of stress urinary incontinence for three months with stress predominant urinary incontinence as measured by the Medical, Epidemiologic and Social Aspects of Aging (MESA) questionnaire subscale score, a post-void residual < 150 mL on examination, a negative urinalysis/standard urine culture, a positive provocative stress urinary test, and a desire for stress urinary incontinence surgery. Participants in the main study consented to contributing a single baseline urine specimen to a previously established biorepository of urine samples. Demographic and clinical variables (including stress and urgency urinary incontinence symptoms, menopausal status, and hormone use) were collected. The bacterial content of the urine was determined by sequencing the 16S ribosomal RNA gene.

Bacterial phylogenetic diversity and alpha diversity of urine samples were studied. Phylogenetic diversity refers to the evolutionary relationships between bacteria. This is described as a phylogenetic tree (a branching diagram that shows the evolutionary relationships between organisms). Alpha diversity refers to the measurement of diversity of a single sample, compared to beta diversity, which is the measurement between samples. The phylogenetic diversity and microbial alpha diversity were compared to subject demographics and urinary symptoms using generalized estimating equation models. Generalized estimating equations are a statistical methodology used to analyze correlated data (data where mutual relationships exist).

Samples from 197 of the 630 VALUE study participants were used in this analysis. Demographic and clinical characteristics of the 197 participants were similar to those of the overall trial population. The majority of samples (174) had been obtained by clean catch, with the remaining by catheterization. The majority of participants were non-Hispanic Caucasians. Forty-two percent were premenopausal, 31% postmenopausal without current exogenous hormone use, and 18% were using exogenous hormones.

Subjects reported stress predominant symptoms consistent with study eligibility, and many had concomitant urinary symptoms. The majority of urine samples (86%) had detectable bacterial DNA. Bacterial diversity was significantly associated with higher body mass index (BMI), increased urgency symptoms as measured by the MESA urge index score, and hormonal status. Hormone-positive women (premenopausal and those currently on exogenous estrogen) have predominant bacteria with a higher prevalence of Lactobacillus or Gardnerella types (66%) compared to hormone-negative women. Hormone-negative women (postmenopausal not on exogenous hormones) have a higher bacterial diversity with greater number of nondominant bacteria, which is associated with a lower frequency of Lactobacillus or Gardnerella urotypes (38%) compared to estrogen-positive women. No associations were found between bacterial diversity and stress urinary incontinence symptoms.

COMMENTARY

The findings reported in this study show that women undergoing stress urinary incontinence surgery have measurable urinary microbiota. The analysis suggests that increased urinary bacterial diversity is associated with urgency urinary incontinence symptoms, hormonal status, and increased body mass index and not associated with stress urinary incontinence symptoms.

Studies have shown that in a healthy human body, microbial cells outnumber human cells by 10 to one. This microbiome is thought to be an integral component in the maintaining health and proper function of the immune system.1 Until recently, the community of microbes with which we coexist largely was unstudied. In 2008, the NIH began funding the Human Microbiome Project to help identify and characterize the microorganisms associated with humans and their role in health and disease.2 To date, studies have focused mainly on the gut, vagina, oral cavity, and skin. New data recently have been published, reporting a large number of bacterial genomes from different body sites.3

Very little is still known about the urinary microbiome. In fact, before the last decade, many of us were taught that urine was sterile. The current study and several other prior studies by the authors have demonstrated by DNA analysis and microbial culture that even when urine cultures are negative, detectable bacterial communities containing mixtures of urinary and genital tract bacteria exist in the urine of some adult women.4,5 Studies of urine from women with lower urinary tract symptoms demonstrate that large numbers of bacteria are present, often undetected by routine cultures.6

This study has a number of strengths, including the multicenter nature of the study, extensive characterization of participants, as well as the use of cutting-edge sequencing techniques and state-of-the art analytic approaches. Future studies will benefit from using controls matching for the significant associations found (BMI, hormone status, and lower urinary tract symptoms) and from the addition of vaginal and/or rectal samples to inform how these nearby microbiomes may affect the bladder.

The current study further highlights the diversity of the urinary microbiomes and the likely associations among microbiome characteristics, BMI and hormone status, and urinary symptoms. In particular, urinary urgency symptoms may be associated with increased bacterial diversity in the absence of a predominant bacterial type. A 2008 Cochrane review examining the use of vaginal estrogen in the treatment of women with recurrent urinary tract infections (UTIs) concluded that vaginal estrogens are effective in reducing the number of UTIs in postmenopausal women with recurrent UTIs.7 The current study helps bring to light a significant relationship between hormone status and urinary microbiome that may explain these findings. We are just at the beginning of an exciting new understanding of the urinary microbiome and its effect on the care of women with urinary urgency symptoms and with recurrent UTIs.

REFERENCES

  1. Human Microbiome Project Consortium. Structure, function and diversity of the healthy human microbiome. Nature 2012;486:207-214.
  2. National Institutes of Health. Human Microbiome Project. Expanding Our View of the Human Microbiome. Available at: https://commonfund.nih.gov/hmp. Accessed Nov. 7, 2017.
  3. Lloyd-Price J, Mahurkar A, Rahnavard G, et al. Strains, functions and dynamics in the expanded Human Microbiome Project. Nature 2017;550:61-66. Erratum in: Nature 2017;551:256.
  4. Wolfe AJ, Toh E, Shibata N, et al. Evidence of uncultivated bacteria in the adult female bladder. J Clin Microbiol 2012;50:1376-1383.
  5. Brubaker L, Wolfe AJ. The female urinary microbiota, urinary health and common urinary disorders. Ann Transl Med 2017;5:34.
  6. Khasriya R, Sathiananthamoorthy S, Ismail S, et al. Spectrum of bacterial colonization associated with urothelial cells from patients with chronic lower urinary tract symptoms. J Clin Microbiol 2013;51:2054-2062.
  7. Perrotta C, Aznar M, Mejia R, et al. Oestrogens for preventing recurrent urinary tract infection in postmenopausal women. Obstet Gynecol 2008;112:689-690.