This study provides genetic causal inference evidence supporting a close association between gut microbiota and prostate cancer risk, and identifies multiple key signature genes (RASSF3, CROCC, UBE4B, SMOC2, ACACA) implicated in immune microenvironment regulation and tumor progression, though further functional studies are required.
Two-sample Mendelian randomization identified five gut microbial taxa causally associated with prostate cancer (PRAD) risk: four positively and one inversely.
Integrating MR-derived SNP-mapped genes with GEO datasets yielded 21 differentially expressed associated genes, five of which were designated key signature genes.
Immune infiltration analysis linked specific genes to particular immune cell types.
Among the machine learning models built, the random forest classifier performed best in predicting PRAD.
Single-cell RNA sequencing and spatial transcriptomics showed cell-type-associated expression patterns of ACACA, SMOC2, and UBE4B.
qRT-PCR in prostate cancer cells validated differential expression of the candidate genes.
This study asked whether the bacteria living in the gut might play a causal role in prostate cancer. The researchers used a genetic approach called Mendelian randomization, which uses natural genetic variation as a kind of built-in experiment to reduce confounding. They found that four bacterial groups (Brevibacillaceae, Brevibacillales, CAG-110, and Pararhizobium) were associated with higher genetic risk of prostate cancer, while one (Lawsonibacter sp000492175) was associated with lower risk. The team then linked the genetic variants to specific genes and compared gene activity in prostate cancer data. They highlighted five genes (RASSF3, CROCC, UBE4B, SMOC2, and ACACA) and found links to immune cells such as regulatory T cells and neutrophils. A random forest machine learning model using these genes distinguished cancer in a validation group with an AUC of 0.853. Single-cell and spatial analyses showed the genes are active in different cell populations within tumors, and lab tests in prostate cancer cells confirmed differences in their expression.</br></br>This research suggests a genetic link between gut microbiota and prostate cancer risk and points to candidate molecular signatures worth studying further. However, the authors stress these are associations, and more functional experiments are needed to determine whether these genes directly mediate microbiota effects on prostate cancer. The findings do not yet show that changing gut bacteria would alter cancer risk.
Qiu C, Zhang H, Du Z, Gao Y, Dai L. (2026). Integrating Mendelian randomization with single-cell and spatial transcriptomics to investigate gut microbiota-associated genetic signals and molecular characteristics in prostate cancer.. Frontiers in cellular and infection microbiology. https://doi.org/10.3389/fcimb.2026.1899354