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Peng et al. Microbiome Res Rep 2024;3:5 https://dx.doi.org/10.20517/mrr.2023.47 Page 5 of 17

Figure 1. Possible mechanisms that microbiota promotes initiation of bladder cancer. Lesion starts with invasion of microbiota, which
usually damages epithelial barrier through multiple virulence factors [31,40] and increases the chance that microbiota interacts with
bladder cells. Formation of intracellular bacteria and incomplete clearance [41] from innate immune cells leads to chronic infection with
an inflammatory environment characterized by various inflammatory mediators and immune cells. Chronic barrier destruction leads to
more interactions between microbes and host, and persistent damage-repair loop (an inappropriate host response) of bladder
epithelium plus inflammation environment increases the possibility of gene mutation and disrupts the intracellular signaling
[36]
pathways . Overall, multiple microbiota-mediated hits may contribute to the carcinogenesis of bladder cancer and further research
needs to evaluate this relevance.

colonic epithelial cells through the β-catenin signaling pathway . In addition, enterotoxigenic Bacteroides
[43]
fragilis triggers IL-17R, NF-κB, and STAT3 inflammatory pathways that play key roles in colon
[44]
carcinogenesis . Similarly, Enterococcus faecalis in the gut induces M1 polarization of macrophages and
activates the Wnt/β-catenin pathway, leading to reprogramming and dedifferentiating colonic epithelial
cells and driving the initiation of colorectal cancer . The Wnt/β-catenin signaling pathway plays an
[45]
important role in the initiation, invasion, metastasis, and epithelial-mesenchymal transition of bladder
cancer, confirmed by numerous researches [46-48] . In vitro and animal experiments have also found that
silencing STAT3 has an inhibitory effect on bladder cancer . So, whether chronic bladder transitional
[49]
epithelium infection by these bacteria leads to malignant transformation of epithelial cells through a similar
cancer-promoting molecular mechanism deserves further study.

MICROBIOTA AND PROGRESSION OF BLADDER CANCER
The composition of microbiota in different tumor staging
Tumor grading and staging are the basis of the clinical treatment of cancer. Tumor grading, a histology
concept, depends on histopathologic slides, while the staging is more of a clinical application and is relevant
to the outcome of cancer.

Bladder cancer can be classified as non-muscle invasive bladder cancer (NMIBC) and muscle invasive
bladder cancer (MIBC), and it is reported that no striking difference was validated when comparing the
composition of urinary microbiota between NMIBC and MIBC . Contradictorily, Chipollini et al. detected
[19]
significant enrichment of Bacteroides and Faecalibacterium in MIBC group compared to NMIBC group .
[14]
Wu et al. found that different risk levels stratified by EORTC (European Organization for Research and
Treatment of Cancer) were related to different spectrums of urinary microbiota . An overrepresentation of
[17]
Herbaspirillum, Porphyrobacter, and Bacteroides was detected in bladder cancer patients with a high risk of
recurrence and progression, suggesting that these genera could be utilized for risk stratification and
prediction of cancer prognosis. Oresta et al. discovered that with the progression of bladder cancer, the
[50]
abundance of Veillonella and Corynebacterium in the urine increased significantly . Parra-Grande et al.
pointed out that the abundance of Enterococcus in low-grade bladder cancer tissue was significantly higher
[22]
than that in high-grade cancer tissue .