The Urinary Fungal Mycobiome and Host Responses in Patients with Interstitial Cystitis
Abstract
Interstitial cystitis/painful bladder syndrome (IC/PBS) is a debilitating, chronic condition characterized by a range of symptoms, such as bladder pain, urinary urgency, frequency, nocturia, and small voided volumes. This disease, which is often highly resistant to treatment, can substantially degrade physical and social activity and quality of life. Community-based surveys estimated that approximately 3-8 million women (up to 7% of women in the United States) meet the diagnostic criteria. Despite the great burden of IC/PBS on public health, diagnosis of these conditions remains challenging and subjective in current clinical practice; as many as 9 in 10 women with bladder pain symptoms may never receive an accurate diagnosis. Even in those who seek attention for their symptoms, the diagnosis of IC/PBS is also often delayed because it presents with nonspecific symptoms that may reflect unrelated disorders. Thus, differentiating IC/PBS from other pain-related or irritative voiding conditions is still a diagnostic challenge, and objective diagnostic markers are urgently needed. Treatment and prevention options are also suboptimal, likely due in part to our poor understanding of disease pathophysiology. Recent studies of the gut and other human organs and body surfaces have resulted in the startling discovery that humans are host to an enormous web of interacting microbial networks of great diversity and complexity. These microbial communities live in symbiosis with the human host in the absence of disease, but are frequently altered in disease. The role of these alterations is as yet unclear, but a growing body of knowledge suggests that microbial components and their breakdown products may interact with human tissues to alter organ function, tissue permeability, and even central nervous system responsivity. Recent reports from several groups using state-of-the-art DNA sequencing methods have definitively disproven the historical claim that normal human urine is sterile. These early studies have identified global differences in the bacterial communities in urine in IC/PBS, but have yet to understand how these differences impact bladder health and contribute to the symptoms of IC/PBS. We hypothesize that perturbations in this community of microorganisms may underlie or otherwise reflect IC/PBS symptoms. We also postulate that the interactions of these altered microbial communities with the host will alter protein expression in both the urine and blood, generating a protein signature characteristic of IC/PBS. In this research project, we will identify alterations in the uncultivated microbial communities, both bacterial and fungal, in the urine that are associated with the development of IC/PBS, using state-of-the-art resources in microbial community profiling. In contrast to prior studies that have attempted to characterize the urinary microbiome, this project will be one of the first large-scale determinations of urinary microflora from both IC/PBS and healthy controls using specimens obtained by bladder catheterization, which will minimize the potential contamination from vaginal flora. We will also identify disease-associated variations in blood and urine proteins diagnostic of IC/PBS through the application of deep proteomics. We will take advantage of recent advances the core technologies for proteomics research to achieve a more rapid and sensitive discovery process than has been possible in prior studies. This approach will allow the discovery of clinically useful disease markers, which may also promote a more comprehensive understanding of IC/PBS pathogenesis, and will identify their associations with variations in both "healthy" and pathologic microorganisms. In addition, the identification of novel biomarkers of disease and the identification of pathogenic microbes in IC/PBS could allow for the development of new therapeutic targets and novel disease prevention strategies. Positive results from
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Aug 07, 2017
- Source ID
- W81XWH1710433
Entities
People
- A. Lenore Ackerman
Organizations
- Cedars-Sinai Medical Center
- United States Army