Incontinence medication response relates to the female urinary microbiota

Abstract

Introduction and hypothesis: Many adult women have resident urinary bacteria (urinary microbiome/microbiota). In adult women affected by urinary urgency incontinence (UUI), the etiologic and/or therapeutic role of the urinary microbiome/microbiota remains unknown. We hypothesized that microbiome/microbiota characteristics would relate to clinically relevant treatment response to UUI medication per os.

Methods: Adult women initiating medication treatment orally for UUI and a comparator group of unaffected women were recruited in a tertiary care health-care system. All participants provided baseline clinical data and urine samples. Women with UUI were given 5 mg solifenacin, with potential dose escalation to 10 mg for inadequate UUI symptom control at 4 weeks. Additional data and urine samples were collected from women with UUI at 4 and 12 weeks. The samples were assessed using 16S ribosomal RNA (rRNA) gene sequencing and enhanced quantitative urine culturing. The primary outcome was treatment response as measured by the validated Patient Global Symptom Control (PGSC) questionnaire. Clinically relevant UUI symptom control was defined as a 4 or 5 score on the PGSC.

Results: Diversity and composition of the urinary microbiome/microbiota of women with and without UUI differed at baseline. Women with UUI had more bacteria and a more diverse microbiome/microbiota. The clinical response to solifenacin in UUI participants was related to baseline microbiome/microbiota, with responders more likely to have fewer bacteria and a less diverse community at baseline. Nonresponders had a more diverse community that often included bacteria not typically found in responders.

Conclusions: Knowledge of an individual's urinary microbiome/microbiota may help refine UUI treatment. Complementary tools, DNA sequencing, and expanded urine culture provide information about bacteria that appear to be related to UUI incontinence status and treatment response in this population of adult women.

Trial registration: ClinicalTrials.gov NCT01642277.

Keywords: Clinical microbiology; Solifenacin; Urinary incontinence.

Conflict of interest statement

All Authors have completed and submitted ICMJE Form for Disclosure of Potential Conflicts of Interest. All authors report that this study was funded in part by a grant from Astellas Scientific and Medical Affairs (ASMA). Alan J. WOLFE, Ph.D. – Scientific Study/Trial: Investigator Initiated Grant from ASMA for certain aspects of this study. Linda BRUBAKER, MD – Scientific Study/Trial: Grants from NICHD and NIDDK during conduct of a different study. Health Publishing: Personal fees from Up-To-Date. Elizabeth R. MUELLER, M.D. reports grants from ASMA, during the conduct of the study; grants and personal fees from ASMA, personal fees from Peri-Coach, and personal fees from Allergan, outside the submitted work. Reprints will not be available.

Figures

Figure 1. Flow of Study Participants

Figure 2. Diversity of cultivatable bacteria is distinct between cohorts and response groups at baseline

Species accumulation analysis illustrates the number of unique species cultured and identified (using EQUC) with each new patient sampled. When the curve plateaus, it indicates that the community is fully sampled and few, if any, new species will be identified. Therefore, it also measures the overall diversity of the population by total number of unique species isolated. The UUI group isolated 80 unique species at baseline and the control cohort isolated 36 unique species. Therefore, the species isolated from UUI is far more diverse that the species isolated from controls. There is statistical difference in the median number of isolates collected from each individual in each cohort [M=3 (IQR: 1–7) versus M=1 (IQR: 1–2), p<0.001]. The UUI curve represents samples at baseline from individuals who will respond or not. When we divide this curve into each stratified by response group we see that the baseline diversity of each groups is distinct, suggesting that baseline diversity could be predictive of treatment response. 5mg responders (grey triangles) had low diversity, with a total of 32 unique species isolated. 10mg responders (dark “x”) had high diversity with a total of 54 unique isolates. Non-responders (light “x”) had high diversity with a total of 42 unique isolates. The median number of unique species was not significant between 10mg and non-responders [5 (IQR: 3–6) versus 8 (IQR: 3–15), p-value= 0.25], but was significant between the 5mg and 10mg and between 5mg and non-responders [1 (IQR: 0–5) versus 5 (IQR: 3–6), p-value= 0.03; and 1 (IQR: 0–5) versus 8 (IQR: 3–15), p-value= 0.02].

Figure 3. Frequency of Detection of Genera and Significant Species Between Response Groups

Comparison of the frequency of culture-based detection at the genus (A) and species level (B) for baseline urines by response group. Fisher’s Exact Test was used to calculate the p-values. * p=0.05 ** p=0.00