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Peng et al. Microbiome Res Rep 2024;3:5 https://dx.doi.org/10.20517/mrr.2023.47 Page 9 of 17

Intracellular microbiota in the TME has an impact on the progression of bladder cancer in unique ways.
Prior research in other cancers revealed complex functions of the intracellular microbiota. Intracellular
bacteria can affect cancer cell invasion, metastasis, and repair of DNA damage based on a study of oral
[59]
[52]
squamous cell carcinoma and colorectal cancer cells . Some types of cancers, such as melanoma cells ,
can present intracellular bacterial peptides through HLA molecules, shaping the tumor immune
microenvironment and influencing T cell reactivity. Intracellular bacteria are emphasized to infect the
urothelial layer and the tumor cells, and this could be a prominent target for humoral immunity, linking
[79]
immune memory cells to response to non-microbial tumor antigens , but the mechanisms are poorly
understood. The formation of intracellular bacterial communities in chronic infectious urothelial epithelial
cells implies that the intracellular microbiota in bladder cancer might disturb the intracellular signaling
pathways, or relevant microbial antigens could be present at the surface of the cell membrane of bladder
cancer and interact with the immune compartment of TME, although there is no evidence about the
existence and functional activity of intracellular bacteria of bladder cancer so far.

MICROBIOTA AND TREATMENT OF BLADDER CANCER
The discovery of intratumoral microbiota is the milestone of a comprehensive understanding of the tumor
microenvironment, and it has been proved that microbiota plays a potential role in mediating tumor
resistance to drugs .
[80]

Relationship between microbiota and recurrence of bladder cancer
The standard treatment option for patients with NMIBC is transurethral resection, and whether the
subsequent intravesical instillation treatment is necessary depends on the assessment of pathohistological
slides and other risk factors, with 5-year recurrence rate ranging from 20% to more than 50% according to
different risk groups to which the patients belong . The recurrence mechanisms of urothelial cancer can be
[81]
recapitulated into five points, including undetected cancer at cystoscopy, local residual disease after TURBT,
tumor reimplantation, drop metastasis from upper tract urothelial carcinoma, and field change
[82]
cancerization effect . As a urine storage organ, the bladder is exposed to the urine with the accumulation
of carcinogens such as cigarette metabolites and chemicals, which induces multiple independent lesions
with precancerous genetic changes, leading to multiple tumors or recurrence. This prompts us to consider
whether the potential presence of microbes in urine or bladder mucosa also has this field-change effect. To
investigate this, we have compiled and summarized observational studies to explore whether part of the
microbiota is linked to the recurrence of bladder cancer [Table 3].

In the early 1990s, a clinical study found that oral administration of Lactobacillus casei preparation had a
protective effect on the recurrence of bladder cancer after surgery [83,84] . Although the mechanism of
Lactobacillus casei intervention in the recurrence of bladder cancer was unclarified then, this study showed
the prospect of microbial application in the treatment of bladder cancer. Patients with asymptomatic
bacteriuria (defined as the presence of bacterial growth on clinical standard urine culture but no symptoms
of infection) in low-grade papillary NMIBC have a significantly lower recurrence rate than those without
[85]
infection , which may be related to innate immunity activated by bacteria and suggests the potential of the
urinary microbiota for predicting tumor recurrence in clinical practice. However, this observational study
did not identify the composition of the urinary microbiota. Further investigation of urinary microbial
species showed that patients with NMIBC had an elevated risk of recurrence with a higher bacterial richness
in urine samples; Herbaspirillum, Gemella, Bacteroides, Porphyrobacter, Faecalibacterium, and Aeromonas
may be potential predictive biomarkers . Inconsistently, Zeng et al. found that the abundance of 9 species
[17]
a
o f b a c t e r i a , i n c l u d i n g Anoxybacillus, Massilia, Thermomonas, Brachybacterium, Micrococcus, n d
Nocardioides, was significantly increased in the NMIBC patients with recurrence . A study concentrating
[86]