Microbiota alterations associated with metastatic progression in Renal Cell Carcinoma: Evidence from urine and paired tumor tissues
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Background Renal cell carcinoma (RCC) is characterized by pronounced biological heterogeneity, which limits the prognostic value of traditional clinical parameters. Emerging evidence suggests that the host-associated microbiome modulates the tumor microenvironment (TME). This study aims to characterize microbiome alterations across different sample types to identify microbial signatures associated with metastatic progression. Methods 16S rRNA sequencing was performed on two distinct sets of samples. We analyzed independent urine samples from 48 RCC patients and 37 healthy controls, as well as 29 paired FFPE renal tissue samples (comprising tumor and adjacent non-tumoral tissue) from metastatic (M1) and non-metastatic (M0) patients. Alpha diversity, beta diversity, and differential abundance taxon (DAT) analyses were performed. Results The urinary microbiota of the RCC patients showed a significant reduction in the Shannon diversity index (p = 0.0083) and distinct community structure shifts (Weighted UniFrac, p < 0.001). The Lactobacillus genus was identified as significantly enriched in patients compared to controls. In contrast, analysis of paired tissue samples revealed that metastatic (M1) patients exhibited significantly higher alpha diversity within the tumor tissue compared with adjacent non-tumoral tissue (Shannon, p = 0.012; Observed features, p = 0.022). Furthermore, M1 tumors showed distinct microbial community membership (Unweighted UniFrac, p = 0.0187), whereas M0 tissue remained relatively conserved. Notably, the genus Treponema was identified as significantly enriched exclusively in metastatic tumor tissue after multiple-testing correction (q = 0.017). Conclusion Microbiota alterations in RCC follow a compartment- and progression-dependent pattern. Significant microbial differences and dysbiosis are primarily localized within the tumor microenvironment (TME) of metastatic patients rather than being robustly reflected in the urine. The enrichment of Treponema in advanced tumors supports its potential as a novel biomarker for disease aggressiveness and metastatic potential.
