Gut microbe Terrisporobacter promotes papillary thyroid carcinoma progression by upregulating the NTRK1 oncogene and fostering an immunosuppressive tumor microenvironment

Growing evidence suggests a link between the gut microbiome and papillary thyroid carcinoma (PTC), but the causal relationships and the impact on the tumor immune microenvironment (TME) are poorly understood. This study aimed to elucidate the causal role of specific gut microbes in PTC and uncover the underlying immunological and molecular mechanisms. We employed a multi-stage design, beginning with a two-sample Mendelian randomization (MR) analysis using large-scale GWAS data to infer causality. Findings were then validated in 450 PTC patients from The Cancer Genome Atlas (TCGA) by analyzing correlations between microbial abundance, gene expression, immune cell infiltration, and survival. Finally, the core mechanism was confirmed through extensive in vitro experiments with PTC cell lines. Our MR analysis identified a causal association between a genetically predicted higher abundance of the genus Terrisporobacter and an increased risk of PTC (Odds Ratio OR = 2.06, 95% Confidence Interval CI: 1.34-3.16). In the TCGA cohort, higher intratumoral signals of Terrisporobacter was significantly correlated with an immunosuppressive TME, characterized by increased infiltration of M2 macrophages (ρ = 0.25, p 0.001) and decreased CD8+ T cells (ρ = -0.19, p = 0.008). Mechanistically, Terrisporobacter abundance was also strongly associated with the upregulation of the oncogene NTRK1 (ρ = 0.35, p 0.001), which independently predicted poorer overall survival (Hazard Ratio HR = 2.15, p = 0.004). In vitro experiments confirmed that supernatant from Terrisporobacter culture not only upregulated NTRK1 expression and promoted PTC cell proliferation but also enhanced invasion and induced cell de-differentiation. Importantly, pharmacological inhibition of TRK signaling reversed the bacteria-induced aggressive phenotype. Our integrated analysis provides robust, multi-layered evidence for a causal role of Terrisporobacter in promoting PTC progression. We define a novel gut-thyroid axis where Terrisporobacter contributes to PTC development by upregulating the NTRK1 oncogene and shaping a pro-tumorigenic, immunosuppressive microenvironment. These findings reveal a new dimension of host-microbe interaction in thyroid cancer and highlight the TME as a key downstream target of microbial influence.