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Page 12 of 17 Peng et al. Microbiome Res Rep 2024;3:5 https://dx.doi.org/10.20517/mrr.2023.47

[105]
or chemical cystitis, contracted bladder, fever, and general malaise . Hence, it is necessary and promising
to develop novel antitumor drugs that are instilled into the bladder and probiotics seem a reasonable choice.
Intravesical instillation of Ty21a (a vaccine against typhoid fever) was demonstrated to control bladder
cancer through a dendritic cell and T cell-dependent manner in mice model and a relevant phase I trial is
underway(NCT 03421236: IVES Ty21a) . Systemic metabolites produced by gut microbiota are capable of
[106]
modulating treatment efficacy in multiple kinds of cancers, based on preclinical experiments where oral
gavage with microbiota or precursors of microbial metabolites controls tumor growth, suggesting oral
probiotics or relevant microbial metabolites are promising in cancer therapy [55,56,74] , but this hypothesis needs
verification through clinical trials. There is growing evidence indicating that the microbiota has a synergistic
effect [98,99,101,102] with immunotherapy on immunomodulation of the TME, and this might be applied to
anti-PD-1 therapy in metastatic bladder cancer, addressing its limited efficacy in advanced patients’
outcomes.

In conclusion, both intratumoral microbiota and gut microbiota could be a potential therapeutic target for
cancer. Special treatment strategies to manipulate microbiota composition in bladder cancer (such as
intravesical instillation or drugs metabolized through the kidney) deserve attention.

CONCLUSION
After the discovery that urine is no longer sterile, numerous studies aimed to characterize the microbiota
have observed high variability in urine and bladder cancer tissue between different individuals, which brings
greater challenges to the investigation of microbes in pathological conditions. Furthermore, the concept of
“asymptomatic bacteriuria” seems to be partly explained due to the progressive understanding of urinary
microbiota. Different studies suggest some genera, such as Anaerococcus, under the phylum Firmicutes and
Acinetobacter, may be responsible for the development of bladder cancer, but further preclinical studies are
needed to verify. The bacteria that are not detected precisely enough to distinguish spices may be attributed
to the insufficient accuracy of 16S rRNA sequencing technology, which makes it challenging to elucidate the
potential role of specific microbiota in bladder cancer. Urinary microbes may serve as potential biological
predictors to assess the chances of bladder cancer recurrence and the effectiveness of treatment, but
confirmation of their clinical application value requires further study.

Microbiota has been proved to be related to tumorigenesis and progression in different types of tumors.
Currently, only chronic cystitis caused by Schistosoma infection has a causality relationship with bladder
squamous cell carcinoma, suggesting that chronic inflammation plays an important part in the malignant
transformation of urothelial cells. There are few studies directly revealing how a certain type of microbe
influences the biological behaviors of bladder cancer, hindering our comprehension of the role of
microbiota in this disease. The tumor microenvironment is closely related to tumor cell proliferation,
invasion, metastasis, and other biological behaviors . Increasing pieces of evidence elucidate that
[107]
microbiota is also identified to be one of the key components of the tumor microenvironment, and it can
exist in different microniches of the tumor microenvironment and perform different functions. The balance
between pro-tumor inflammation and antitumor immunity plays an important role in tumor
progression , and some special microbes may interact with the host through innate immune response to
[108]
skew this balance. Therefore, the immune or inflammatory response acts like a bridge in the study of the
effect of microbiota on bladder cancer. The application of BCG in the treatment of bladder cancer
represents an example of microbe-mediated antitumor immunity, although the mechanism has not been
fully elucidated. The gut microbiota can extensively influence the efficacy of immune checkpoint inhibitors
in intestinal and extraintestinal cancer, suggesting a systemic change induced by gut microbiota
metabolism. The intratumoral microbiota has been identified to influence multiple components of the