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Peng et al. Microbiome Res Rep 2024;3:5 https://dx.doi.org/10.20517/mrr.2023.47 Page 7 of 17

Table 2. Urinary or intratumoral microbiota in different tumor staging of bladder cancer
Research Sample Microbiota related to staging Ref.
Chipollini et al. 2018 Urine samples from 38 UC and 10 HC MIBC group: [14]
Bacteroides ↑
Faecalibacterium ↑
Wu et al. 2018 Urine samples from 29 BC and 18 HC Low-grade tumor: [17]
Enterococcus ↑
Mansour et al. 2020 10 BC urine samples and 14 BC tissue samples No difference between NMIBC and MIBC [19]
Parra-Grande et al. 2022 32 BC tissue samples and 26 adjacent controls High risk of progression group: [22]
Herbaspirillum ↑
Porphyrobacter ↑
Bacteroides ↑
Marmoricola ↑
Oresta et al. 2021 / With the progression of BC: [50]
Veillonella ↑
Corynebacterium ↑

BC: Bladder cancer; HC: healthy controls; MIBC: muscle invasive bladder cancer; NMIBC: non-muscle invasive bladder cancer; UC: urothelium
carcinoma.

[67]
significant role in inflammation and immune response . Indole-3-acetic acid, a tryptophan metabolite
produced by gut microbiota, was reported to activate tumor-associated macrophage to suppress the CD8+ T
cell-mediated antitumor immunity in a pancreatic tumor model , while another one, indole-3-aldehyde,
[55]
can activate CD8+ T cells to proliferate and release IFN-γ to enhance antitumor immunity in a melanoma
model . Lactobacillus reuteri administration suppresses colorectal tumorigenesis via the tryptophan
[56]
catabolite-indole-3-lactic acid (ILA), which exerts antitumorigenic effects by downregulating the IL-17
signaling pathway . In addition, indoleamine 2,3-dioxygenase 1, a key enzyme of tryptophan metabolism,
[68]
was demonstrated to promote antitumor immunity and inhibit angiogenesis in bladder cancer . A study
[69]
revealed that plasma tryptophan level was significantly decreased in bladder cancer patients . So, whether
[70]
systemic tryptophan-derived microbial metabolites have an impact on TME of bladder cancer needs to be
further explored. Bile acids that are metabolized by gut microbiota and the liver (this forms enterohepatic
circulation of bile acid) play a pivotal role in maintaining healthy gut microbiota and innate immunity, and
are linked with carcinogenesis of colorectal cancer and hepatocellular carcinoma [57,58] . However, bile acids,
including chenodeoxycholic acid (CDCA), Glycoursodeoxycholic acid (GUDCA), and
glycochenodeoxycholic acid (GCDCA), were detected to be upregulated in urine samples of bladder cancer
patients compared to healthy controls . Furthermore, farnesoid X receptor (a nuclear receptor that can be
[71]
activated by binding with bile acids) was reported to inhibit the migration, invasion, and angiogenesis of
bladder cancer in vitro through various mechanisms [72,73] . This reminds us that the bile acids in circulation or
urine may partly influence the progression of bladder cancer. TMAO is broadly studied in cardiovascular
diseases such as atherosclerosis and heart failure. However, recent publications revealed that the
microbiota-derived metabolite TMAO also activates CD8+ T cells and promotes antitumor immunity in
breast cancer and pancreatic cancer . In addition, microbial SCFAs enhance the antitumor activity of
[75]
[74]
cytotoxic T lymphocytes (CTLs) and chimeric antigen receptor (CAR) T cells in syngeneic murine
melanoma and pancreatic cancer models by increasing the production of effector molecules such as CD25,
IFN-γ and TNF-α , indicating complicated crosstalk between microbial metabolites and cytokines. Until
[76]
now, no evidence showed a connection between microbial metabolites, including TMAO and SCFAs, and
the progression of bladder cancer. Although the progression of bladder cancer has not been demonstrated
to be linked with systemic change of microbial metabolites in circulation or accumulation of microbial
metabolites in urine, more and more evidence implies that gut microbiota may exert a remote effect to
influence the TME of bladder cancer.