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Page 2 of 17 Peng et al. Microbiome Res Rep 2024;3:5 https://dx.doi.org/10.20517/mrr.2023.47

In the last decade, advancements in urine culture protocols, like the enhanced quantitative urine culture
[4]
(EQUC) , and 16S rRNA gene sequencing technology, have revealed the presence of microbiota in urine,
[5,6]
challenging the long-held belief that urine is sterile . These findings suggest that the urinary system may
have a microbial ecosystem similar to the gut microbiota. It is acknowledged that microbiota plays a vital
role in cancer and powerful molecular evidence suggests microbiota exists within tumor tissue across at
least 33 types of tumors, including bladder urothelial carcinoma . The microbiota inside tumor tissue is
[7]
demonstrated to be tumor type-specific and may directly modulate tumorigenesis, progression, and
response to cancer treatment by various mechanisms [8-12] . Based on observational studies, alterations in the
urinary microbiota have been linked to neurogenic bladder dysfunction, urge urinary incontinence, bladder
cancer, and some other urinary system diseases [6,13] , but how the microbiota correlates with the initiation
and progression of bladder cancer remains unclear.

Here, we summarize research about bladder cancer-associated microbiota, and put forward the possible
underlying mechanisms that may elucidate the interaction between microbiota and bladder cancer. At last,
we hypothesize the potential clinical applications of microbiota in the diagnosis, prognosis, and treatment of
bladder cancer.

MICROBIOTA AND TUMORIGENESIS OF BLADDER CANCER
The signature of urinary and tissue microbiota in patients with bladder cancer
To investigate the relevance of microbiota in the tumorigenesis of bladder cancer, a comparison of
microbiota composition between healthy individuals and bladder cancer patients is a reasonable approach
[Table 1].

Up to now, there are some studies concentrating on the possible relevance between urinary microbiota and
bladder cancer. Urinary microbiota in bladder cancer patients was demonstrated to be distinguished from
that of healthy controls, characterized by a decreased diversity, evenness, and richness . Xu et al. pointed
[14]
out that the abundance of Streptococcus increased in urine from cancer patients through a small-sample
[15]
study involving 8 urothelial cancer patients and 6 healthy controls . Bučević Popović et al. found that the
urinary microbiota of both 12 male patients with bladder cancer and 11 healthy controls showed
[16]
enrichment in Firmicutes, Actinobacteria, Bacteroidetes, and Proteobacteria . Meanwhile, there was no
difference in microbial diversity and overall composition between the two groups, but the abundance of
Fusobacterium, Actinobaculum, Facklamia, and Campylobacter in the urinary microbiota of the cancer
group was significantly elevated. Wu et al. demonstrated the abundance of Acinetobacter, Anaerococcus,
Rubrobacter, Sphingobacterium, Atopostipes, and Geobacillus presented a higher level in urine from bladder
[17]
cancer patients, along with significantly increased microbiota richness in the cancer group . These
publications are inconsistent, which may be attributed to clinical demographic characteristics. For instance,
sex is a key factor and it was reported that urinary microbiota showed different enrichment species between
male and female patients with bladder cancer . In addition, insufficient quantity of samples, varying urine
[18]
sample collection methods, and contamination could account for the discrepancy. The heterogeneity of the
urinary microbiota in different healthy individuals indicates that identifying bladder cancer-associated
[6]
microbiota solely through a statistical approach is difficult, so pinpointing the role of certain microbes in
tumorigenesis is still a great challenge.

The ability of urine microbiota to reflect tumor tissue microbiota is an ongoing controversial topic [18,19] .
Therefore, it is essential to examine intratumoral microbiota in bladder cancer due to emerging evidence