Acupuncture for Female Interstitial Cystitis/Painful Bladder Syndrome and Its Effect on the Urinary Microbiome: A Randomized Controlled Trial
Phase: NA
Conditions: Painful Bladder Syndrome, Interstitial Cystitis
Sponsor: Loyola University

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Acupuncture for Female Interstitial Cystitis/Painful Bladder Syndrome and Its Effect on the Urinary 
Microbiome: A Randomized Controlled Trial 
Larissa Bresler, MD Colleen M. Fitzgerald, MD, MS, Alan Wolfe, PhD 
 
Version 4  
11/09/2020 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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A. BACKGROUND AND CLINICAL SIGNIFICANCE: 
 
Interstitial Cystitis/Painful Bladder Syndrome (IC/PBS), affecting nearly 7.9 million US adult women1, is a 
complex chronic pelvic pain (CPP) condition characterized by suprapubic pain related to bladder filling and 
associated with urinary urgency and frequency in the absence of urinary infection or other obvious pathology2. 
Quality of life with IC/PBS is significantly reduced particularly in those with concomitant pain comorbidities3. 
Proposed etiologies have included bladder glycsosaminoglycan (GAG) layer injury with resultant neurogenic 
inflammation, autoimmune basis with mast cell infiltration, epithelial dysfunction, infectious (4) and peripheral 
and/or central sensitization. The presentation of symptoms can be quite variable5,6, suggesting that IC/PBS is a 
multi-factorial disease with overlapping etiologies7 driven by complex pelvic neural circuitry8. Definitive diagnostic 
criteria for IC/PBS and research measures that correlate with treatment outcomes are lacking4. Additionally, 
etiologic and contributing factors to symptom manifestation are not well defined.  
 
Recent IC/PBS guidelines9 advocate first and second line treatment directed at pain management. Over 80% of 
patients with IC/PBS seek complementary and alternative medical (CAM) treatment10. There is mounting 
evidence to support acupuncture as an alternative therapy in various types of chronic pain11. Several 
mechanisms of action have been proposed for acupuncture treatment effect. Various models have implicated 
cytokines, hormones (eg, cortisol and oxytocin), biomechanical effects, electromagnetic effects, the immune 
system, and the autonomic and somatic nervous systems (Andew C Ahn, Acupuncture. UpToDate). Current 
understanding of acupuncture’s analgesic effect thought to be associated with neurotransmitters release at both 
the spinal and supraspinal levels. Recent preliminary evidence documents the efficacy of acupuncture in lower 
urinary tract symptom reduction in men with chronic prostatitis/CPPS12. Yet there is a significant knowledge 
gap regarding its effect in women with IC/PBS.   
 
The Urinary Microbiota. Within internal surfaces, which are defined as existing outside the body (e.g. the 
intestinal epithelium or the vaginal epithelium), there exist commensal microbial communities. These microbiota 
are believed to be beneficial to human health, facilitating efficient removal of improperly functioning immune cells 
and protecting the host from pathogen infection13-15. The human bladder is a core component of the human 
urinary tract. It is a hollow muscular organ lined with transitional epithelium, which functions as the storage site 
for metabolic wastes in the form of urine.  Given that the bladder’s luminal space is also considered outside the 
body, it would seem reasonable that a urinary microbiota would be present. Yet, the historic dogma has 
maintained that urine is “sterile,” based on culture-dependent methods of bacterial detection. This paradigm is 
shifting, however, based on our newly published data noting the presence of a urinary microbiota in adult women 
without clinical urinary tract infections16,17. Furthermore, we have recently discovered that the microbiota of 
women with overactive bladder (specifically with associated urgency incontinence) is distinguishable from the 
microbiota of women with stress urinary incontinence. These findings suggest that IC/PBS may be influenced by 
an alteration to the urinary microbiota. Indeed, recent evidence reports a difference in the urinary microbiome 
dominated by Lactobacillus in subjects with IC/PBS compared with healthy controls18. This work is limited by 
lack of correlative clinical symptomatology, small sample size and urinary samples that may have been 
contaminated. 
Cytokines and Pain. Upon exposure to a pathogen, dramatic metabolic changes occur within the infected cell. 
One consequence of these alterations is the initiation of the innate immune response. This immune response is 
the first line of defense against the infection. It is comprised of cells and mechanisms that defend the host from 
infection by organisms in a non-specific manner.  The innate immune response is initiated immediately upon 
infection, by the binding of proteins, e.g. toll like receptors (TLR), nucleotide-binding oligomerization domain-
containing proteins (NOD), and retinoic acid-inducible (Rig)-like proteins to specific pathogen associated 
molecules. These proteins can be found on the cell surface, on the surface of internal vesicle and organelle 
membranes, or freely within the cytoplasm of the cell including cells of the nervous system. Each protein 
recognizes a different pattern molecule associated with specific types of pathogens. For example, the proteins 
TLR 2, 4 and 5 recognize bacterial cell surface components lipoteichoic acid (LTA), lipopolysaccharide (LPS) 
and bacterial flagellin, respectively (24). Binding of bacterial ligands to host receptors activates signaling 

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pathways that result in the production of pro-inflammatory proteins, e.g. type I interferons, tumor necrosis-factor 
alpha (TNF-α), interleukin-1 (IL-1) and numerous chemokines.  
The inability of the ligand to bind its cognate receptor, the lack of or aberrant activation of the downstream 
signaling cascades, or decreased production of pro-inflammatory proteins are known to influence neuronal 
function and pain symptoms (13-14). The central nervous system regulates systemic inflammatory responses to 
many pathogens including Gram-negative bacteria (15). Afferent fibers from the central nervous system 
innervate the bladder and the surrounding detrusor muscle. LPS and various cytokines can activate these 
afferent fibers, consequently stimulating the hypothalamic-pituitary-adrenal anti-inflammatory response (16). The 
efferent fibers of the central nervous system, which also innervate the bladder and detrusor muscle, then mediate 
the parasympathetic anti-inflammatory response. It is during this response that the brain modulates the systemic 
inflammatory pathway (17). Stimulation of these nerve fibers in the presence LPS inhibits the production of tumor 
necrosis factor (TNF-), potent symmetric inflammatory cytokine. This inhibition is thought to occur via both the 
nicotinic and muscarinic acetylcholine receptors (17). Conjugation of TLRs and other pathogen-specific sensing 
molecules stimulate the production of type I interferons, IL-6, IL-10, MCP1, IL-1α and other pro-inflammatory 
cytokines. Receptors for these molecules are present on the efferent central nervous system nerve fibers.  
Results of studies of acupuncture have suggested that analgesia is mediated by regulating production of 
cytokines including pro and anti-inflammatory mediators19,20. Various models have implicated cytokines, 
hormones (eg, cortisol and oxytocin), biomechanical effects, electromagnetic effects, the immune system, and 
the autonomic and somatic nervous systems (Andew C Ahn, Acupuncture. UpToDate, updated 12/2013).  
Prior research has also noted a differential expression of several urinary cytokines between women with 
interstitial cystitis and asymptomatic controls, pointing to the relationship between their expression and symptom 
development21,22. Irritative bladder symptoms in IC/PBS may result by aberrant signaling from the central nervous 
system due to the presence cytokines and other pathogen-associated molecules during initiation of the innate 
immune response. 
The reports that acupuncture’s influence may be partially expressed through immune mechanisms are reinforced 
by the understanding that beta endorphin and met-enkephalin seem to be mediators between the central nervous 
system and immune system. The two substances have been shown to enhance natural killer cell activity and 
met-enkephalin increases in vitro T-lymphocyte rosette formation from human T-lymphocytes (Josef M. Helms. 
Acupuncture energetics 1995 | ISBN-10: 1572507063 | ISBN-13: 978-1572507067 | Edition: 1st).  
It seems logical to theorize that acupuncture treatment may lead to urinary microbiome change. 
We propose that changes in bladder microbiota leading to this enhanced cytokine response may result in 
symptoms associated with IC/PBS and that acupuncture, by modulating cytokine response, in turn has effect on 
the urinary microbiome. 
Our long term goal is to determine pelvic pain mechanisms that will inform clinically-relevant classification and 
evidence-based treatment of women with IC/PBS and CPP. The short term goal of this application is to 
determine the safety, tolerability and efficacy of acupuncture in women with IC/PBS as a neuromodulative 
treatment and to characterize the urinary microbiome before and after acupuncture treatment. Our approach will 
advance the understanding of the contribution and consequences of peripheral pelvic nociception in IC/PBS. 
Our central hypothesis is that women with IC/PBS will benefit from acupuncture compared with sham treatment 
and acupuncture will have an effect on the urinary microbiome. 
 
This proposed work impacts public health with contributions of rigorous clinical and translational methods, 
suitable for future NIH clinical research networks, to evaluate and assess treatment outcomes in women with 
IC/PBS. It is likely that these methods will have impact beyond this group of affected patients, such as CPP 
related to irritable bowel syndrome, vulvodynia, pregnancy, and endometriosis. 
 

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B. INNOVATION: We believe that the proposed research is innovative, as current pharmacologic strategies for 
IC/PBS have limited success and/or problematic side effects, yet  acupuncture has not been studied in this 
population to date despite its proven efficacy in other chronic pain disorders11. In addition, no study to date has 
correlated the urinary microbiome in IC/PBS with clinical characteristics or with response to acupuncture 
treatment.  
 
C. STUDY POPULATION: Women presenting with IC/PBS at the Urogynecology/Urology clinics at Loyola 
University Medical Center will be approached for research participation. A certified research team member will 
explain the purpose and procedures of the study. Potential participants who meet inclusion criteria and agree to 
participate will indicate their consent by signing the informed consent document. Consistent with prevalent 
research regulations and policies, a signed copy of the research consent document will be given to the participant 
and the investigator will keep the original research consent document. Enrolled participants with IC/PBS must 
meet all the following eligibility criteria: Inclusion: 1) Females, age 21 to 65 years (no racial/ethnic restrictions); 
2) Symptoms of urinary frequency, urgency and suprapubic/bladder pain for > 6 months; 3) Generally stable 
health 4) An average bladder pain score of at least >3/10. Exclusion: 1) Patients with pacemaker or other 
neurostimulator (gastric/spinal) 2) History or current symptomatic urethral stricture, cystitis caused by 
tuberculosis, radiation therapy or Cytoxan/cyclophosphamide therapy; 3) Prior augmentation cystoplasty or 
cystectomy; 4) Systemic autoimmune disorder (such as Crohn's Disease, Ulcerative Colitis, Lupus, Rheumatoid 
Arthritis, or Multiple Sclerosis); 5) Systemic neuromuscular disease known to affect the lower urinary tract; 6) 
History of urogenital cancer (with the exception of minor skin cancer); 7) Current or imminent planned 
pregnancy/recent delivery <6 months; 9) Current pelvic floor physical therapy; 10) Current use of opioid 
medications (short or long acting) for pain; 11) Abdominal or pelvic surgery within the last 6 months12) No 
symptoms or diagnosis of UTI within the past 3 months 
 
 
Additionally 20 control women will be recruited for primary comparison of urinary microbiome data with IC/PBS 
cases. Inclusion for controls: : 1) Females, age 21 to 65 years (no racial/ethnic restrictions); 2) No history of or 
current bladder or pelvic pain; 3) Generally stable health 4) English speaking Exclusion: 1) Patients with 
pacemaker or other neurostimulator (gastric/spinal) 2) History or current symptomatic urethral stricture, cystitis 
caused by tuberculosis, radiation therapy or Cytoxan/cyclophosphamide therapy; 3) Prior augmentation 
cystoplasty or cystectomy; 4) Systemic autoimmune disorder (such as Crohn's Disease, Ulcerative Colitis, 
Lupus, Rheumatoid Arthritis, or Multiple Sclerosis); 5) Systemic neuromuscular disease known to affect the lower 
urinary tract; 6) History of urogenital cancer (with the exception of minor skin cancer); 7) Current or imminent 
planned pregnancy/recent delivery <6 months; 9) Current pelvic floor physical therapy; 10) Current use of opioid 
medications (short or long acting) for pain; 11) Abdominal or pelvic surgery within the last 6 months.  12) No 
symptoms or diagnosis of UTI within the past 3 months. These women after screening for eligibility will complete 
a basic demographics form for controls (see attached) and provide one voided clean catch urine specimen. They 
will not be required to undergo physical examination or vaginal swab or complete any other additional 
questionnaires. Women will be recruited from the LUC Health Sciences campus and will be provided a parking 
sticker for their participation.  
 
D. DESIGN OVERVIEW: This prospective randomized single blinded study will compare the effect of true 
acupuncture compared with sham/minimal acupuncture in women with IC/PBS (n=30). Symptomatic IC/PBS 
participants will not be asked to stop taking standing medications such as neurological agents in order to 
participate in the study. All current medications will be recorded and will measured using the Medication 
Quantification Scale (MQS III)23,24. They will be asked to refrain from use of short-acting 
opioids/acetaminophen/non-steroid anti-inflammatory medications during study visits. IC/PBS participants will 
engage in 7 acupuncture sessions once weekly.  Initial visit would assess participant’s response to needle 
insertion. Standard classical/true acupuncture treatment will be administered during 6 following visits to 
treatment group (n=15) and sham/minimal acupuncture will be administered to control group. Menstrual cycle 
time points will be recorded for each visit. Clean catch voided urine samples and vaginal swab will be obtained 
prior to initiation of intervention, on completion of intervention and 12 weeks post onset of study visits. 
E. RESEARCH STRATEGY:  

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Specific Aim 1: To determine the safety and tolerability of acupuncture in women with IC/PBS. 
Hypothesis 1: Acupuncture treatment (true and sham) will be safe and tolerable in women with IC/PBS.  
Specific Aim 2: To determine if acupuncture is effective in reducing pain in women with IC/PBS 
compared to sham treatment. 
Hypothesis 2: True acupuncture treatment will be effective in the treatment of pain in women with IC/PBS 
compared with sham/minimal treatment. 
 
Specific Aim 3: To determine the association between acupuncture responders and the urinary 
microbiome.  
Hypothesis 2: Acupuncture responders will exhibit change in the urinary microbiome compared with 
nonresponders after acupuncture treatment.  
 
STUDY DESIGN/METHODS: 
Acupuncture Component: 
This is a randomized, controlled, single-blinded, pilot trial to study the feasibility, safety, and efficacy of 
acupuncture in IC/PBS women. Women will be recruited from the patient population of the Loyola University 
Medical Center who meet criteria for diagnosis of IC/PBS. This trial had 2 arms comparing the treatment of 
IC/PBS symptoms with acupuncture or sham/minimal acupuncture (placebo).Thirty (30) patients with IC/PBS 
will be enrolled as study participants into the study. Fifteen (15) will be allocated in the treatment classical 
acupuncture + medical management of IC and fifteen (15) will be allocated in the control sham/minimal 
acupuncture + standard medical treatments of IC.  The acupuncturist will interview each patient and perform 
an exam. A standardized acupuncture treatment will be assigned, and both groups will receive 7 acupuncture 
treatments that follow a standardized protocol on classical acupuncture points, with or without mild electrical 
stimulation versus sham/minimal acupuncture. Acupuncture needles are single use, sterile and disposable. 
Standard acupuncture treatment protocol will include 4 gates plus GV 20 to reduce anxiety and help with 
relaxation and to assess acupuncture naïve patient’s response to needles during their first acupuncture 
encounter. Subsequent visits would include administration of curious meridian Chong Mo paired with Yang 
Ming. 4 Hz low level electrical stimulation will be applied. Control group will receive sham/minimal acupuncture 
with low level electrical stimulation. The sham intervention (also described as minimal intervention) will use 
superficial needle insertion at body locations not recognized as true acupoints. Patients will be explained that 
various acupuncture treatment protocols will be tested including “minimal acupuncture”, therefore, the control 
group will not be aware of receiving sham acupuncture. These described acupuncture treatments are well 
accepted treatment protocols for women with pelvic pain and bladder complaints.  
Acupuncture or sham needle treatments will be performed once a week for 7 weeks. All subjects will be 
reassessed following the 7-week intervention phase and then 12 weeks from initiation of study. All subjects will 
be treated by single acupuncture practitioner (Dr. Bresler) who is also a board certified urologist specializing in 
IC/PPS and is a current associate member of American Academy of Medical Acupuncture and board eligible 
for the American Board of Medical Acupuncture. 
 
Clinical Measurements:  
The following clinical parameters will be assessed in all participants at baseline and repeated at follow-up 12 
weeks after initiation of PFPT: 
Demographics: age, self-reported race and ethnicity, vaginal parity, body mass index, menopausal and hormone 
replacement status, prior treatment for IC/PBS and other pelvic floor disorders, tobacco and alcohol use, prior 
medical and surgical history, medications including pain medications measured by the Medication quantification 
scale (MQS III)23,24), allergy history, social history 
Standardized physical exam: Abdominal exam with vaginal assessment of pelvic floor muscle function 
generalized muscle tenderness exam25 
Pain location, duration, intensity: Brief Pain Inventory – Short form (BPI-SF)26, VAS pain scale27, Short Form 
McGill Pain Questionnaire28, Body Pain Diagram 
Pain functional impact: Pain disability index29; Patient Global Response Assessment (GRA)30  

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Urinary/Pain Symptoms: Female Genitourinary Pain Index (FGuPI)31, Interstitial Cystitis Symptom Index and 
Problem Index (ICSI, ICPI)32  
Sexual Dysfunction: Female Sexual Function Index33  
Psychological impact/Coping style: Pain Catastrophizing Scale (PCS)34, Beck Depression Inventory, second 
version (BDI-II)35, Beck Anxiety Inventory (BAI)36  
Clean catch voided urine specimen: for urinalysis, culture and microbiome analysis 
Vaginal Swab: to exclude vaginal bacteria from voided urine specimen. 
 
Urinary Microbiome Approach: 
In order to elucidate changes in the bladder’s microbiota and to understand how the host’s immune response 
may contribute to IC/PBS, we propose a multidisciplinary approach that blends molecular biology, immunology, 
genomics and clinical assessment. We will use de novo sequencing to determine the composition of the bacterial 
community present in the urine of women with IC/PBS undergoing acupuncture treatment. Urine will be collected 
at three time points via clean catch voided urine specimen and vaginal swab: at baseline, post intervention 
completion and 12 weeks after the onset of the intervention. 
Preliminary Data: In April, 2012, we published data concluding that bacteria are present in the bladders of 
culture-negative women without symptoms of UTI16. More recently, we completed an analysis of 13 urine 
samples from individual women with either stress urinary incontinence (SUI) or urgency/frequency (U/F) or both. 
From this preliminary analysis, we found that the urine 
microbiota differs between patients with predominately 
SUI symptoms compared to those with predominately 
U/F symptoms.  Figure 1 shows the illustrative results 
of our microbiota analysis of these 13 samples. The 
composition of the microbiota for each patient was 
determined by sequencing 150 nucleotides of the DNA 
encoding for the RNA molecule found within the small 
unit of the bacterial ribosome. These sequences 
identify the bacterial species present in each patient’s 
urine. Principle component analysis (PCA) was used 
to determine the amount of difference between the 
groups of patients. This graph depicts the result of this 
examination, which suggests the microbiota of women 
with SUI or SUI>U/F significantly differ from that of 
women with U/F or U/F>SUI. This difference has the 
potential to be used as biomarker for various types of 
bladder dysfunction. Our results clearly indicate that 
the urine microbiota may be related to the etiology of 
different UI subgroups. Subsequently, we hypothesize 
that measurable biological changes in the urinary 
microbiota and/or urinary cytokine levels correlate with 
irritative bladder symptoms in women with IC/PBS.  
 
 
 
 
Analysis of Urinary Bacterial Communities by De Novo Whole Genome DNA Sequencing (WGS) 
Rationale.  Most microbiome studies define a catalog of bacterial species present in the microbial community 
on the basis of the sequence of one or more variable regions of the 16S ribosomal RNA (16S rRNA) gene. This 
assay is based upon a similarity between what is present in the sample and what bacterial species are already 
known. Therefore, many bacterial species present in the community may not be identified. De novo whole 
genome sequencing eliminates this bias. Genome assembly is based upon the presence of overlapping 
sequence between the assayed DNA fragments. Thus, the entire bacterial community can be identified, 
exponentially increasing our understanding of the relationship between the bladder’s bacterial community and 
Figure. 1: PCA- patients of different UI subgroups can 
be distinguished by their microbiota. SUI (orange) and 
SUI >U/F (lime) are different than U/F (aqua) and U/F 
>SUI (blue) along Axis 2.  

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OAB. The rapidly decreasing cost of WGS makes this more comprehensive approach feasible and thus 
desirable. 
 
Sequencing Approach. Bacterial DNA will be isolated from 0.5 ml of each urine sample, randomly fragmented, 
modified for and sequenced using Illumina’s MiSeq technology. This technology allows for sequence of more 
than 200 nucleotides of DNA from each strand of the DNA duplex to be generated, facilitating the downstream 
bioinformatics analysis. WGS by MiSeq technology is expected to generate more than 100X coverage, the 
average number of sequences representing a given nucleotide from the generated sequence, for each sample. 
This magnitude of data allows for samples to be multiplexed, individually barcoded, and sequenced at once. 
 
Bioinformatics Approach.  Quality control & de-multiplexing, the separation of each individual sample from the 
group based upon their barcode, the sequence data can be readily achieved with MiSeq Reporter software from 
Life Technologies (current version: 2.0). Only high quality reads (≥Q20) will be kept for analysis. Reads will be 
aligned and assembled using open source algorithms such as the AMOS and CABOG assembler packages to 
bioinformatically generate the genome of a specific bacterium. 
 
 
Table 1. Schedule of measures for the proposed study. 
Schedule of Measures: 
Baseline 
 
Post 
Acupuncture 
Completion 
12 Weeks from 
Baseline 
Demographics 
X 
X 
X 
Questionnaires 
X 
X 
X 
Physical exam 
X 
X 
X 
Urine Specimen 
X 
X 
X 
 
 
F. DATA ANALYSIS/SAMPLE SIZE ESTIMATION:  
The primary objective is to compare the mean BPI-SF worst pain score at following acupuncture between 
groups. All other analyses are secondary outcomes. A separate linear mixed effects model will regress each 
pain score outcome on  group (minimal versus electro-acupuncture), time (baseline, end of treatment, or end of 
follow-up), and a group by time interaction.  Random intercepts will be included to account for within-patient 
correlation.  Adjusted means and standard errors will be estimated, and main effects and the group by time 
interaction will be formally tested within the mixed model.  A similar linear mixed effects model will regress 
relative abundance of uropathogen on group, time, and the group by time interaction.   Based on the prior work 
of Crew KD et al.37, a sample size of 30 participants (15 per arm) was calculated to yield 90% power to detect 
a reduction of 2.5 on the BPI-SF worst pain item at a 5% significance level, assuming a standard deviation of 
difference in score between treatment groups of 2.5 points. This includes a dropout rate of 10% A reduction of 
at least 2 points on the BPI-SF worst pain item is considered to be a clinically meaningful decrease based on 
the literature38. All statistical analyses will be two-sided and performed using SAS 9.4 (SAS Institute, Cary, 
NC).   
 
G. FUTURE DIRECTIONS: The impact and potential benefits of identifying new nonpharmacologic treatment 
in women with IC/PBS will be critical to reduce disease severity and improve quality of life across female 
IC/PBS and all CPP subtypes. These same methods will be employed for future clinical trials in IC/PBS and 
other CPP subtypes. In future studies, participants could be reassessed monthly for 6 months after post-
intervention assessment (6 months after completing the treatment protocol), and subjects who relapse could 
receive one to two booster/maintenance acupuncture sessions with additional studies performed on the urinary 
microbiome. 
 

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H. TIMELINE: 
 
 
 
 
 
 
 
 
 
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Research Activity 
Year 1 
(2013 – 2014) 
Qt 1 
Qt 2 
Qt 3 
Qt 4 
Recruitment and Evaluation of Participants 
X 
X 
X 
 
Data Collection 
X 
X 
X 
 
Data Analysis/Manuscript writing/editing 
 
 
X 
X 

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