Microbiomes of Pelvic Pain

Interstitial cystitis/painful bladder syndrome (IC) or Chronic Prostatitis/Chronic Pelvic
Pain Syndrome (CP/CPPS) is characterized by chronic pelvic pain and voiding dysfunction. IC
or CP/CPPS remains an enigma within urology, with no known etiology or widely effective
therapies. However, some IC, CP/CPPS, and depressed patients suffer bowel co-morbidities, and
it is well established that the GI tract can influence bladder function, mood and sensation
via pelvic organ crosstalk. Like other body sites, the gut harbors a rich microflora. Studies
characterizing microbial diversity and relative abundance at a particular body site, the
"microbiome," reveal that microbiomes play critical roles in normal cellular and organ
function, and thus this importance is emphasized with the Human Microbiome Project (HMP), an
NIH Common Fund initiative. CPPS patients suffer chronic pelvic pain and dramatically lower
quality of life, yet diagnostic markers and effective therapies remain elusive for these
costly syndromes. IC is a debilitating condition of pelvic pain and voiding dysfunction
afflicting up to 8 million U.S. women where depression is a common co-morbidity, distinct
from over-active bladder (OAB) patients lacking pain. IC etiology remains unknown, but
urothelial lesions and lamina propria mast cells are associated with patient symptoms.
Similarly, CP/CPPS afflicts 1 in 22 men in the U.S. with pain and voiding and sexual
symptoms, again distinct from patients having only irritative voiding from lower urinary
tract symptoms (LUTS). And although leukocytes are observed in prostatic fluid of some
patients, the etiology of CP/CPPS also remains unknown. Hypothalamic-pituitary-adrenal axis
(HPA) dysfunction has been implicated in female and male patients and cats with feline IC,
and thus may be common among CPPS, but a mechanism that integrates pelvic pain, voiding
dysfunction, HPA activity, and depression is lacking.

Microbiomes are also dynamic and subject to skewing, and these changes are increasingly
associated with diseases including Crohn's disease, ulcerative colitis, obesity, and possibly
depression. Antibiotic therapies alter microbiomes, often causing temporary dysfunction and
sometimes resulting in diseases such as colitis. Since IC or CP/CPPS patients often have a
history of urinary tract infection (UTI), they typically receive multiple courses of
antibiotics. This therapeutic history of IC or CP/CPPS patients may have adverse consequences
for two reasons. First, potential skewing of the gut microbiome may alter normal sensory and
functional homeostatic mechanisms, contributing to pain and voiding dysfunction. Second, an
altered gut microbiome may foster uropathogen reservoir expansion, and our preliminary data
demonstrate urinary E. coli isolates can induce chronic pelvic pain persisting long after
microbial clearance. Together these lines of reasoning raise the provocative possibility that
microbiomes contribute to IC, CP/CPPS, and depression directly by supplying uropathogens or
indirectly through organ crosstalk dysfunction. Therefore, is an altered gastrointestinal
tract microbiome associated with IC, CP/CPPS, and/or depression? Our team marries core NIH
and NIDDK missions, digestive diseases and kidney/urologic, to address this novel question
with synergistic expertise in clinical diagnosis of IC, CP/CPPS, and depression, quantifying
GI tract microbiomes, and neural mechanisms of microbe-induced pelvic pain. Stool samples
will be analyzed by 16S rDNA sequence and in silico metagenome analyses to identify taxa,
abundance, and function. Computational tools will be used to identify taxa amenable to rapid
evaluation of stool. Stool, serum, and urine will be evaluated for small molecules specific
to CPPS, and these putative mediators will be tested in mice for effects on pelvic pain and
urinary function.

Inclusion Criteria:

- Any sex

- Between the ages of 18 and 60

- Any ethnicity

- Have provided informed consent

- Physician diagnosis of interstitial cystitis/bladder pain syndrome (IC/BPS),
interstitial cystitis/painful bladder syndrome (IC/PBS), chronic prostatitis/chronic
pelvic pain syndrome (CP/CPPS), Lower Urinary Tract Symptoms, Overactive Bladder, or
Major Depression.

- Report symptoms of discomfort or pain in the pelvic or abdominal region of moderate
severity for at least a three (3) month period within the last six (6) months, who
have been currently diagnosed with major depression

- Are healthy, age matched, controls.

Exclusion Criteria:

For IC/CPPS/LUTS/OAB

- Evidence of facultative Gram negative or enterococcus with a value of ≥ 100,000 colony
forming units (CFU)/milliliter in mid-stream urine (VB2)

- Secondary chronic pain condition which would prevent a clear interpretation of the
study results

- A history of tuberculous cystitis, bladder cancer, carcinoma in situ, or urethral
cancer; history of alcohol abuse, inflammatory bowel disease, pelvic radiation or
systemic chemotherapy, intravesical chemotherapy, intravesical Bacillus
Calmette-Guerin (BCG), active urethral stricture, ureteral calculi, urethral
diverticulum, or neurological disease or disorder affecting the bladder or gut

- Unlikely to be compliant due to unmanaged medical or psychological conditions,
including neurological, psychological or speech/language problems that will interfere
or prevent with their understanding of consent

- Ability to comply with the protocol or ability to complete the study

- Pregnant or Syndromes of Chronic Pelvic Pain (SCPP) symptoms are present only during
menses

- And if there was antibiotic use in the last 6 months

For Depressed Patients:

- Participant is in remission or has recovered from major depression, has substance
abuse in the past 6 months, has been diagnosed with any bipolar or psychotic disorder,
has been diagnosed with any severe cognitive impairment or dementia, history of cancer
(with the exception of skin cancer), has current major psychiatric disorder or other
psychiatric or medical comorbidities that would interfere with study participation
(e.g. dementia, psychosis, upcoming major surgery, lupus, active heart failure,
diabetes, etc., currently has a UTI and/or has had a positive urine culture in the
past 6 weeks, and if there was antibiotic use in the last 3 months.