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Page 6 of 17 Peng et al. Microbiome Res Rep 2024;3:5 https://dx.doi.org/10.20517/mrr.2023.47

The inconsistent evidence [Table 2] did not suggest potential microbial biomarkers associated with bladder
cancer progression. As mentioned before, 16S rRNA sequencing of the urinary microbiota is not precise
enough to identify species, which may ignore changes in the abundance of specific bacteria in the urine. The
intratumoral and urinary microbiota are not completely equivalent, but urinary microbial signatures
associated with bladder cancer progression appear to have more clinical potential because urine, rather than
bladder cancer tissue, is an easily accessible specimen clinically.

Interactions between microbiota and tumor microenvironment
The crosstalk among different components of a tumor is intricate. Emerging evidence suggests microbiota is
an unexpected participant in the tumor microenvironment (TME), even in some types of tumors that appear
to be “germ-free”. In 7 kinds of solid tumors, such as breast cancer and brain tumor, microbes were
detected inside tumor cells and immune cells and presented to be in a cell wall-deficient state similar to
[51]
L-form bacteria . Intratumoral microbial communities are located in microniches that are less vascularized
[52]
and more immunosuppressive , suggesting that the distribution of microbes in tumor tissue is not random
but rather prefers a compatible niche in ECM or inside cells. In a word, intratumoral microbes located in
different microniches may have various active states and functional responses. Considering the evidence
that there exists microbiota inside bladder cancer tissue, we hope to recapitulate the possible function of
microbiota in the TME and put forward potential mechanisms [Figure 2].

Commensals living in bladder mucosa may interact with the tumor immune microenvironment and
promote bladder cancer progression. Innate immunity, including pathogen-associated molecular pattern
(PAMP) and innate immune cells, probably contributes to bladder cancer development. Uropathogenic
[40]
Escherichia coli (UPEC) is the most common microbe in urinary tract infection , and UPEC infection
upregulates the expression of cytokines such as IL-6 and IL-8 in urothelial cells through the TLR-4
[60]
pathway . IL-6 induces antimicrobial peptide expression to promote the clearance of UPEC, and IL-8
promotes neutrophil chemotaxis towards the site of infection to engulf UPEC . Of note, IL-6 promotes the
[61]
survival and proliferation of tumor cells and attenuates the antitumor ability of tumor-infiltrating immune
cells through the IL-6/JAK/STAT3 signaling pathway in the TME . Elevated expression of STAT3 is also
[62]
linked to proliferation and invasion of bladder cancer . Similarly, IL-8 can enhance tumor proliferation
[63]
through the CXCR1/2 receptor on the tumor cell, thus recruiting myeloid-derived suppressor cells (MDSC)
and neutrophils to TME, where an immunosuppressive microenvironment is formed . Furthermore,
[64]
microbiota may induce commensal-specific memory T cells that cross-react with tumor-associated
antigens , thus influencing the outcome of cancer. So, this forms a possible potential mechanism of the
[65]
microbiota-immune-tumor axis in the TME parallel with opposing responses of tumor-promoting
inflammation and antitumor immunity induced by tumor cells. Analogous mechanisms through the
microbiota-immune-tumor axis have been revealed in other cancers, for instance, the microbiota is able to
promote cancer development via γδT cells in lung cancer . Hence, whether the microbiota-mediated
[66]
inflammatory or immune response plays a pivotal role in the progression of bladder cancer remains unclear
and further investigations should evaluate the validity of this hypothesis.

Microbial metabolites, especially those produced by gut microbiota, have been extensively investigated and
provided insights into the relationship between gut microbiota and the progression of extraintestinal
cancers. The gut microbiota-produced microbial metabolites, including tryptophan-derived microbial
metabolites, bile acid, trimethylamine N-oxide (TMAO), short-chain fatty acids (SCFAs), etc. are identified
to regulate various components in the TME. Many compounds produced by tryptophan metabolism play a