Urinary Microbiome Dysbiosis and Immune Dysregulations as Potential Diagnostic Indicators of Bladder Cancer

Simple Summary Current means of bladder cancer diagnosis are invasive or lack sensitivity. Dysbiosis of the urinary microbiome has been implicated in the development of bladder cancer, though its potential as a diagnostic tool is unknown. This study attempts to characterize bladder cancer-specific dysbiosis of the urinary microbiome to explore its diagnostic potential. Numerous species were observed to be differentially abundant between the urine samples of patients with bladder cancer and healthy individuals. Specific immune modulations were observed with respect to these species, as was the enrichment of select pathways known to be implicated in the progression of bladder cancer. The study suggests that the urinary microbiome may reflect dysregulations of the tumor microenvironment. Further investigation may reveal the potential of the identified species as urinary biomarkers of this disease. In this way, the urinary microbiome may allow for the noninvasive and earlier detection of bladder cancer, regardless of stage or subtype.Abstract There are a total of 82,290 new cases and 16,710 deaths estimated for bladder cancer in the United States in 2023. Currently, urine cytology tests are widely used for bladder cancer diagnosis, though they suffer from variable sensitivity, ranging from 45 to 97%. More recently, the microbiome has become increasingly recognized for its role in human diseases, including cancers. This study attempts to characterize urinary microbiome bladder cancer-specific dysbiosis to explore its diagnostic potential. RNA-sequencing data of urine samples from patients with bladder cancer (n = 18) and matched controls (n = 12) were mapped to bacterial sequences to yield species-level abundance approximations. Urine samples were analyzed at both the population and species level to reveal dysbiosis associated with bladder cancer. A panel of 35 differentially abundant species was discovered, which may be useful as urinary biomarkers for this disease. We further assessed whether these species were of similar significance in a validation dataset (n = 81), revealing that the genera Escherichia, Acinetobacter, and Enterobacter were consistently differentially abundant. We discovered distinct patterns of microbial-associated immune modulation in these samples. Several immune pathways were found to be significantly enriched with respect to the abundance of these species, including antigen processing and presentation, cytosolic DNA sensing, and leukocyte transendothelial migration. Differential cytokine activity was similarly observed, suggesting the urinary microbiome's correlation to immune modulation. The adherens junction and WNT signaling pathways, both implicated in the development and progression of bladder cancer, were also enriched with these species. Our findings indicate that the urinary microbiome may reflect both microbial and immune dysregulations of the tumor microenvironment in bladder cancer. Given the potential biomarker species identified, the urinary microbiome may provide a non-invasive, more sensitive, and more specific diagnostic tool, allowing for the earlier diagnosis of patients with bladder cancer.