Overactive bladder: urine is not sterile

Overactive bladder, and the often more painful condition interstitial cystitis (IC) and painful bladder syndrome (PBS) occur in the absence of infection and should be investigated for an autoimmune basis. Most colleagues following reports here will know that asymptomatic bacteriuria (some bacteria detected in urine but without symptoms of urinary tract infection (UTI) is not to be treated. A fascinating paper just published in the Journal of Clinical Microbiology demolishes the dogma that urine is sterile by using advanced methods to prove that the urinary bladder has its own microbiome. The authors note:

"Overactive bladder (OAB) is a highly prevalent syndrome characterized by urinary urgency with or without urge urinary incontinence and is often associated with frequency and nocturia. The etiology of OAB is often unclear and antimuscarinic treatments aimed at relaxing the bladder are ineffective in a large percentage of OAB sufferers, thereby suggesting etiologies outside neuromuscular dysfunction. One possibility is that OAB symptoms are influenced by microbes that inhabit the lower urinary tract (urinary microbiota)."

Dogma of the sterile bladder discredited

Negatives urine cultures have led to the belief that urine and the bladder must be sterile, but this observation was confounded by technical limitations.

"The microbiota of the female urinary tract has been poorly described; primarily, because a “culture-negative” status has been equated with the dogma that normal urine is sterile. Yet, emerging evidence indicates that the lower urinary tract can have a urinary microbiota. For example, our group previously reported the use of 16S rRNA gene sequencing to identify bacterial DNA (urinary microbiome) in culture-negative urine specimens collected from women diagnosed with pelvic prolapse and/or urinary incontinence, as well as from urine of women without urinary symptoms. Our previous study showed that bacterial genomes can be identified using 16S rRNA sequencing in urine specimens of both symptomatic and asymptomatic patients who are culture negative according to standard urine culture protocols.."

In the present study the authors extended their survey of bladder microbial ecology by advanced culture and identification:

"In the present study, we used a modified culture protocol that included plating larger volumes of urine, incubation under varied atmospheric conditions, and prolonged incubation times to demonstrate that many of the organisms identified in urine by 16S rRNA gene sequencing are, in fact, cultivable using an expanded quantitative urine culture (EQUC) protocol. Sixty-five urine specimens (from 41 patients with overactive bladder and 24 controls) were examined using both the standard and EQUC culture techniques. Fifty-two of the 65 urine samples (80%) grew bacterial species using EQUC, while the majority of these (48/52 [92%]) were reported as no growth at 10³ CFU/ml by the clinical microbiology laboratory using the standard urine culture protocol. Thirty-five different genera and 85 different species were identified by EQUC. The most prevalent genera isolated were Lactobacillus (15%), followed by Corynebacterium (14.2%), Streptococcus (11.9%), Actinomyces (6.9%), and Staphylococcus (6.9%). Other genera commonly isolated include Aerococcus, Gardnerella, Bifidobacterium, and Actinobaculum."

Disorders of the urine microbiome can play a role in bladder pathology

Neuroimmune hypersensitivity disorders such as overactive bladder and painful bladder syndrome, as well as recurrent urinary tract infections, may be affected by urine dysbiosis. An experts' comment on this study published in European Urology states:

"“The bladder is sterile, and urinary tract infection starts with invasion by a pathogen from an outside source”—this common belief derives from the fact that the verdict of negative urine culture (<10³ CFU/ml) results when no growth is observed on the culture plate. However, under different culture conditions, the same urine does yield colonies, leading to the conclusion that “urine is not sterile.” At minimum, the female bladder contains a microbiome that consists mainly of species that never cause urinary tract infection (UTI) but can include potential UTI causes...This idea challenges the concept that a UTI always starts with invasion of the urinary tract. A UTI may also start from a microbiome that is given the chance to multiply...The presence of a bladder microbiome also sheds a light on UTI recurrence. For women in whom an uncomplicated Escherichia coli UTI was successfully treated with a 7-d course of pivmecillinam (negative culture at day 10), the strain that caused a new E coli UTI within 35–49 d proved to be identical to the original infecting strain in 77% of all cases. The E coli appears to survive the treatment using mechanisms such as biofilm formation."

Clinical note: Not including interventions to disrupt the biofilm is also a common reason for the failure of treatment for gastrointestinal infections by yeast and other pathogens.

Clear the biofilm and restore immune tolerance

The commentators also state:

"The message for urologists who treat patients with recurrent UTI is that a negative urine culture indicates the cure of the ongoing UTI but not removal of the risk of recurrence."

The authors of the original study conclude:

"Our current study demonstrates that urine contains communities of living bacteria that comprise a resident female urine microbiota."