In bladder cancer patients, prevalent gut dysbiosis and impaired intestinal barrier function are considered to constitute the pathological basis of a disrupted gut-bladder axis (He et al., 2020; Qin et al., 2022). This disruption of intestinal barrier integrity, often termed “leaky gut,” allows bacterial lipopolysaccharide and other pathogen-associated molecular patterns to translocate into systemic circulation. This process triggers chronic, low-grade systemic inflammation, which may potentially accelerate bladder cancer progression (Wang et al., 2022). FMT is proposed as a direct approach to rectifying this defect by introducing a complete, healthy microbial community. A key proposed mechanism involves restoring beneficial bacteria that produce short-chain fatty acids, particularly butyrate. As a crucial energy source for colonic epithelial cells, butyrate significantly upregulates the expression of tight junction proteins such as ZO-1 and Occludin, thereby directly strengthening and repairing the intestinal physical barrier (Hays et al., 2024; He et al., 2018). Simultaneously, the reconstructed microbial ecology could help maintain gut immune homeostasis, mitigating the persistent damage to the barrier caused by local inflammation. As intestinal barrier function is restored, the levels of systemic pro-inflammatory cytokines (e.g., IL-1β, IL-6) are effectively reduced (He et al., 2018). These cytokines are well-established tumor promoters that activate key signaling pathways, such as NF-κB and AP-1, thereby driving tumor cell proliferation, invasion, and anti-apoptosis (Xia et al., 2018). Given that chronic systemic inflammation is closely linked to local urinary tract inflammation, which plays a critical role in bladder cancer pathogenesis, FMT could potentially hold promise for curbing the pro-carcinogenic inflammatory environment at its source. Theoretically, by serving as a “firewall” and “anti-inflammatory agent,” it may indirectly suppress inflammation-driven malignant progression in the bladder. However, while the “leaky gut” model and its link to systemic inflammation provide a compelling mechanistic rationale, the hypothesis that FMT can suppress bladder cancer progression by specifically restoring intestinal barrier integrity awaits direct experimental and clinical validation in the context of this disease.

Epigenetic modifications, specifically disruptions in DNA methylation and regulation by non-coding RNAs, are key drivers of malignant progression and chemoresistance in bladder cancer (Li et al., 2025). By remodeling the gut microbiota, FMT could remotely and systemically intervene in these two parallel mechanisms, thereby reprogramming the host’s gene expression profile (Zhang et al., 2025). At the DNA methylation level, bladder cancer is characterized by the hypermethylation-induced silencing of tumor suppressor genes and the hypomethylation-driven activation of oncogenes. These alterations are closely associated with tumor proliferation, invasion, and cisplatin resistance (Li et al., 2025; Maesaka et al., 2022; Ma et al., 2024; Li et al., 2023). The microbiota introduced by FMT metabolically generate key molecules such as short-chain fatty acids, folate, and S-adenosylmethionine. These compounds can act as methyl donors or directly modulate DNA methyltransferase activity, thereby systemically correcting aberrant DNA methylation patterns. Clinical studies have observed the remodeling of the host DNA methylome by FMT in other diseases, providing a proof-of-principle for its potential application in bladder cancer (Zhang et al., 2025; Stols-Gonçalves et al., 2023; Zhang et al., 2023). At the non-coding RNA level, various miRNAs such as miR-320a-3p, long non-coding RNAs such as LINC00665, and circular RNAs such as Hsa_circ_0001583, are dysregulated in bladder cancer and mediate key malignant behaviors (Liu et al., 2024; Li et al., 2023; Lv et al., 2024; Zou et al., 2024). For instance, the downregulation of miR-320a-3p leads to overexpression of its target IGF2BP3, which in turn stabilizes HMGB1 mRNA and promotes tumor progression through the IGF2BP3-HMGB1 axis (Lv et al., 2024). Similarly, the long non-coding RNA DLX6-AS1 is upregulated and functions as a competing endogenous RNA (ceRNA)for miR-195-5p, thereby activating the VEGFA/Ras/Raf/MEK/ERK signaling cascade to drive proliferation and metastasis (Wang et al., 2020). Another example is LINC00858, which promotes invasion by sequestering miR-3064-5p and upregulating CTGF (cellular communication network factor 2) (Huang et al., 2021). Taken together, given that FMT may indirectly modulate the expression of such non-coding RNAs by altering specific gut microbial populations, it is hypothesized to remotely reprogram the epigenetic landscape of bladder cancer through these coordinated mechanisms, thereby reshaping downstream target gene networks and influencing cancer progression (Zhu et al., 2020; Ma et al., 2025). It is critical to distinguish, however, between the well-established role of epigenetic dysregulation in bladder cancer and the proposed ability of FMT to reverse it. While preclinical evidence and parallels from other diseases are supportive, direct clinical evidence validating FMT’s epigenetic efficacy in bladder cancer is awaited.

Beyond the systemic and epigenetic influences outlined earlier, the gut bladder axis may also contribute to shaping the local tumor microenvironment of the bladder by modulating the urinary microbiota. Once considered largely sterile, the urinary tract is now known to host a unique microbial community, and its composition can interact with both the gut microbiota and the host immune system (Stone, 2023). Multiple studies have revealed significant differences in the urinary microbiota between bladder cancer patients and healthy individuals. For example, Veillonella has been found to be enriched in the urine of bladder cancer patients in several studies, and it appears particularly prominent in patients with recurrence after surgery for both muscle invasive and non- muscle-invasive bladder cancer, suggesting a potential link to disease progression and recurrence (Hrbáček et al., 2023; Hussein et al., 2023; Hussein et al., 2021). Importantly, a case report of Veillonella bacteremia in a bladder cancer patient provides supporting evidence that this bacterium may originate from the gut and spread through the bloodstream to various sites, including the urinary system (Cobo et al., 2020). Furthermore, other studies have identified additional bacterial genera that are relatively enriched in the urine of bladder cancer patients, such as Fusobacterium, Achromobacter, and Brucella (Hussein et al., 2021; Bučević Popović et al., 2018). While the specific mechanisms through which the urinary microbiota influences the development and progression of bladder cancer are not yet fully understood, existing evidence strongly underscores its significance as a valuable area of research.

It is important to note that the gut is likely a major source of microorganisms for the urinary tract (Magruder et al., 2019). In addition to hematogenous spread, the anatomical proximity of the anus and urethra suggests possible ascending colonization pathways, enabling certain gut bacteria to establish residence in the urogenital tract (Curtis et al., 2025). Concurrently, metabolites produced by the gut microbiota can influence the colonization landscape of the urogenital tract by modulating systemic immune status or altering urinary physicochemical properties, such as pH (Colella et al., 2023). Dysbiosis of the urinary microbiota may further disrupt the local bladder microenvironment. Current perspectives propose that uropathogenic microbes may participate in bladder carcinogenesis through multiple pathways, including cellular microenvironment modulation by the microbiome, bacterial-induced inflammation, direct DNA damage caused by bacterial toxins, and modulation of intracellular signaling pathways that exert either pro tumor or anti-tumor effects (Butt and De Biase, 2025). For instance, the bladder urothelium is coated with glycosaminoglycans, components of the extracellular matrix, which help separate it from urine. Some microorganisms can secrete matrix metalloproteinases (MMPs), collagenases, and other enzymes that degrade the structure of glycosaminoglycans, leading to abnormal breakdown or remodeling of the extracellular matrix. This promotes bacterial dissemination and compromises the epithelial barrier (Alfano et al., 2016; De Gregorio et al., 2022). Simultaneously, this process may trigger an inflammatory response, which can, in turn, interfere with intracellular signaling pathways, particularly the STAT3 pathway. This pathway has been shown to play a key role in the initiation and proliferation of bladder cancer (Sadhukhan et al., 2024). Therefore, FMT, as an approach to reshape the gut microbiota, may indirectly influence the urinary microbiota and subsequently affect the progression of bladder cancer. Although evidence in this field is still accumulating, the urinary microbiota is increasingly recognized as a critical link between gut ecology and local bladder pathology. Its research value is growing, and it holds promise as a potential target for novel adjuvant therapeutic strategies.

In summary, the potential mechanisms by which FMT influences bladder cancer through gut microbiota modulation may rely on a complete “gut-bladder axis” signaling pathway. The initiating step of this pathway is likely the production of key signaling molecules by gut microbiota, such as tryptophan derivatives, short-chain fatty acids, and bile acids. These molecules depend on an intact intestinal mucosal barrier for absorption into the bloodstream through the intestinal epithelium and subsequently enter the liver via the portal vein for potential metabolic transformation (Schiweck et al., 2022). Following this, they enter systemic circulation and may be further delivered to the bladder through the bloodstream (Yang et al., 2025). Within the bladder, these circulating metabolites may, on one hand, directly act on tumor cells. On the other hand, they may indirectly influence the composition and function of the urinary microbiota by altering urine physicochemical properties and the state of the bladder epithelium. This process could form a cascade-amplifying regulatory network, ultimately reshaping the bladder tumor microenvironment. The potential mechanisms of FMT are summarized in Figure 1.

FMT is an emerging strategy to remodel the tumor immune microenvironment and has shown significant potential in enhancing the efficacy of tumor immunotherapy. The effectiveness of immune checkpoint inhibitors (ICIs) depends on an “immune-inflamed” tumor microenvironment. However, most bladder cancers present as either an “immune-desert” or “immune-excluded” phenotype, lacking infiltration of cytotoxic T cells, which represents a core bottleneck underlying primary resistance to treatment (Bellone and Elia, 2017; Kandalaft et al., 2022; Yu et al., 2023). This bottleneck may be overcome through the systemic immunomodulatory functions of gut microbiota. As a key “remote regulator,” gut microbiota can systemically shape antitumor immune responses by modulating macrophages, T/B cells, and cytokines (Ma et al., 2025). Hence, the value of FMT becomes evident: by transplanting a complete healthy microbial community, it can rapidly remodel the patient’s gut ecosystem, thereby precisely introducing and enriching key bacterial taxa with immune-activating functions (Yang et al., 2024).

Emerging research evidence is progressively validating the feasibility of this approach. Furthermore, preclinical studies have demonstrated that FMT can effectively reverse the host’s state of immune inertia (Xu et al., 2025). For instance, a high abundance of Blautia coccoides can promote the infiltration of CD8⁺ T cells into tumor sites through its metabolites, thereby enhancing the efficacy of bladder cancer immunotherapy. More importantly, combining FMT from healthy donors or specific beneficial bacteria such as Parabacteroides distasonis with anti-PD-1 therapy has been shown to synergistically increase the accumulation of intratumoral CD4⁺ and CD8⁺ T cells and significantly suppress bladder tumor growth (Wang et al., 2024; Wang et al., 2024). Notably, antibiotic-induced gut dysbiosis can significantly compromise the efficacy of ICIs. A study revealed that in urothelial carcinoma patients receiving ICI therapy, antibiotic exposure was strongly associated with markedly shortened overall survival and progression-free survival (Febriyanto et al., 2024).

The potential of FMT to reverse immune dysregulation has also been validated in clinical practice. A case report demonstrated that a bladder cancer patient who developed severe colitis following ICI treatment achieved steroid-free complete remission within one week after receiving FMT. Post-FMT stool analysis confirmed successful engraftment of donor-derived Bacteroidetes and Akkermansia species (Wang et al., 2018). This observation aligns with preclinical findings, collectively suggesting that precise modulation of the gut microbiota via FMT may transform immune-unresponsive “cold” bladder tumors into “hot” tumors, thereby offering novel strategies for managing immune-related adverse events.

Beyond its applications in immunotherapy, FMT also demonstrates potential in modulating chemotherapy efficacy. Although cisplatin-based neoadjuvant chemotherapy (NAC) remains the standard treatment for MIBC and provides a 5–9% recurrence-free survival benefit, its overall response rate remains suboptimal (Rouprêt et al., 2011; Park et al., 2025). This challenge underscores the importance of understanding host factors that influence chemotherapy sensitivity, with the gut microbiota emerging as a key mediator of interindividual variability in treatment response (Alexander et al., 2017). FMT influences chemotherapy response through two primary mechanisms: systemic immunomodulation and direct microbial metabolism of drugs (Böhm et al., 2025). Evidence indicates that gut microbiota-encoded enzymatic systems can directly modify chemotherapeutic agents such as cisplatin, thereby altering their pharmacokinetics and therapeutic efficacy (Zimmermann et al., 2019; Li et al., 2024). Moreover, specific gut microbiota compositions are closely associated with chemotherapy responses. A multicenter prospective study confirmed that bladder cancer patients with a high baseline abundance of Bacteroides exhibited poorer responses to NAC (Bukavina et al., 2024). This suggests that FMT may counteract such negative predictive factors by establishing a “favorable” microbial community, thereby optimizing the baseline therapeutic profile.

On the other hand, chemotherapy itself could induce gut microbiota dysbiosis. For instance, treatment with gemcitabine (administered alone or in combination with cisplatin) has been shown to significantly reduce microbial diversity (Miyake et al., 2023). This treatment-induced secondary dysbiosis consequently creates a therapeutic window for FMT intervention. Preclinical studies provide proof-of-concept for this approach, demonstrating that probiotic supplementation can enhance the antitumor efficacy of gemcitabine against bladder cancer through modulation of the gut-immune axis (Miyake et al., 2023). This suggests that FMT, as a more comprehensive and potent microbial restructuring strategy, possesses greater pre-sensitization potential. Consequently, FMT offers a potential novel approach to pre-emptively shape the gut microbiome into a state that supports rather than hinders chemotherapy efficacy, thereby providing new directions for overcoming the current chemotherapeutic bottlenecks in bladder cancer treatment.

Pelvic radiotherapy serves as an important alternative curative treatment for MIBC, particularly for patient ineligible for radical cystectomy. However, its widespread adoption is constrained by two major factors: intrinsic tumor radioresistance and radiation-induced damage to normal tissues, especially the intestinal tract (Efstathiou et al., 2009). This condition could lead to radiation-induced enteritis, triggering a range of clinical complications such as diarrhea, perforation, and obstruction, thereby significantly constraining both treatment implementation and patients’ quality of life (Tirado et al., 2021; Murthy et al., 2025). The core pathophysiology primarily involves radiation-induced disruption of the intestinal multiple protective barriers, encompassing the physical, chemical, and immune components (Xin et al., 2022).

Encouragingly, gut microbiota and their metabolites have been found to possess dual potential, offering both radiosensitizing and radioprotective properties (Xin et al., 2022; Xie et al., 2024). FMT, as a potent approach for microbiota remodeling, holds promise for delivering synergistic effects in this field. In terms of radiosensitization, specific microbial community structures can enhance tumor response to radiation (Eaton et al., 2022). For instance, preclinical studies have confirmed that high dietary fiber intervention significantly delays tumor growth in tumor-bearing mice, with this radiosensitizing effect being closely associated with increased abundance of Bacteroidetes and elevated levels of the metabolite isoferulic acid (Then et al., 2024). In terms of radioprotection, FMT facilitates the restoration of damaged intestinal barriers, mitigates oxidative stress, and modulates local immune responses through the introduction of healthy microbiota, thereby alleviating radiation-induced enteritis. Specifically, higher abundance of probiotics such as Lactobacillus and Akkermansia is associated with improved survival outcomes, whereas enrichment of harmful bacteria like Fusobacterium exacerbates radiation-induced damage (Xie et al., 2024; Yi et al., 2023). Notably, the restoration of SCFA levels has been identified as a pivotal mechanism through which FMT mitigates radiation-induced toxicities (Then et al., 2024).

Thus, FMT holds promise as a novel dual-effect adjuvant that, when combined with radiotherapy, could enhance tumoricidal efficacy against bladder cancer while providing systemic protection for normal tissues, thereby broadening the therapeutic window of radiation.