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Page 4 of 17 Peng et al. Microbiome Res Rep 2024;3:5 https://dx.doi.org/10.20517/mrr.2023.47

species’ biological function in the urothelial local environment. Therefore, mapping specific microbes may
be necessary to establish a precise link between urinary microbiota dysbiosis and tumors, similar to gut
microbiota and colorectal cancer.

Possible mechanisms that microbiota promotes tumorigenesis of bladder cancer
In the past, researchers rarely identified directly carcinogenic microbes, such as Helicobacter pylori, but
increasing evidence indicates a type of “complicit microbes” that promote tumorigenesis without directly
causing cancer . This reminds us that microbe-meditated tumorigenesis may be related to dysbiosis of the
[20]
microbiota and an inappropriate host response, rather than simply be attributed to a single specific
pathologic microbe [26,27] . The microbiota in the urinary tract provides us with new insights about the
carcinogenesis of the bladder; whether some “special” microbes in the urinary tract are highly related to the
occurrence of bladder cancer in carcinogenic or protective mechanisms requires further study.

The mechanisms of how microbiota promotes tumorigenesis can be concluded as epithelium barrier
destruction, inflammation, induction of gene mutations, influence of intracellular signaling transduction
pathways for pro- or antitumor effects, etc., based on advances in different cancers [12,26] .

Extracellular matrix (ECM) is a key component supporting cells to behave well biologically, and it is
considered to play a crucial role in carcinogenesis, progression, and metastasis in cancer [28,29] . Normally, in
[30]
the bladder, the umbrella cell layer covered by a glycosaminoglycan (also the component of ECM) barrier
touches the urine and commensals directly, which means the epithelium is separated from microbes and
hemostasis is maintained if there are no invasive pathogens. Some bacteria produce virulence factors,
including collagenases, hyaluronidases, elastase, etc., to cause ECM degradation , including the
[31]
glycosaminoglycan barrier and conjunction of cells, promoting bacteria spread and eventually leading to
epithelium destruction and exfoliation. This process may cause severe inflammation response and obvious
symptoms such as hematuria and lower urinary tract symptoms, thus prompting people to medical
antibiotics treatment (the concept “urinary tract infection”). However, when the immune system fails to
completely clear the infection, for instance, due to the formation of intracellular quiescent bacteria
communities , the unresolved and chronic inflammation attributed to a bacteria infection is characterized
[32]
by induction of inflammatory pathways, various inflammatory mediators (cytokines, chemokines) and
recruiting of immune cells, and this chronic stimulation is identified as a risk factor of bladder cancer [33,34] .
Observations of reduced expression of Toll-like receptors (TLRs) in bladder cancer imply a possible role of
microbiota in this immune-deficient situation . Persistent damage from microbiota, disruption induced by
[35]
inflammation, and continuous regeneration of bladder epithelial cells cause genomic instability and increase
the possibility of gene mutation . Additionally, the inflammatory environment disrupts the intracellular
[36]
signaling pathway, especially STAT3 signaling, which is demonstrated to play a crucial role in the
occurrence and proliferation of bladder cancer [37-39] . Multiple hits and steps induced by microbiota may
contribute to the initiation of bladder cancer [Figure 1].

Currently, a pathogen with a clear carcinogenic effect in the bladder is Schistosoma, which is not a microbe
but a parasite. Chronic bladder schistosomiasis induces local inflammation, fibrosis, and granulomas
histologically. And the chemical products of Schistosoma (such as catechol-estrogen-like metabolites) can
damage DNA directly, or indirectly through oxidative stress, leading to the accumulation of mutations in
genes including RAS, TP53 and others, and eventually inducing a malignant transformation of bladder
epithelial cells . Bacteroides and Enterococcus were highly abundant in bladder cancer tissue [19,22] . Previous
[42]
studies demonstrated that enterotoxigenic Bacteroides fragilis in the gut cleaves E-cadherin on the surface of
colonic epithelial cells by B. fragilis toxin, which causes proliferation and cancerous transformation of