Akkermansia muciniphila-Driven ceRNA Networks Regulate Immune Modulation and Breast Cancer Progression.

Abstract

Background: Microbiota-derived metabolites are increasingly recognized as modulators of systemic immunity and cancer biology. This study investigates how a structurally distinct lipid from Akkermansia muciniphila influences immune transcriptional programs and their connection to breast cancer (BRCA)-associated pathways.

Methods: Donor-adjusted reanalysis of PBMC RNA-seq data was performed to identify lipid-responsive transcriptional changes while minimizing interindividual variability. Differential expression was assessed across time points, followed by pathway enrichment and immune gene filtering. Immune cell composition was inferred using deconvolution analysis. Integration with The Cancer Genome Atlas (TCGA)-BRCA datasets enabled tumor immune infiltration profiling and network-based identification of hub genes. ceRNA interactions were refined using correlation-supported datasets and prognostic relevance was evaluated in TCGA and METABRIC cohorts.

Results: Transcriptional variation was primarily driven by the treatment and exposure duration rather than donor effects. A biphasic immune response (IR) was observed, with early suppression followed by progressive activation. Lipid-responsive genes significantly overlapped with BRCA immune signatures and were enriched in metabolic and stress-related pathways. Immune deconvolution revealed shifts in macrophage polarization and cytotoxic cell populations. Network analysis identified key regulators, including ADIPOR1, KLF4, MYC, CXCL10, and ALDH1A1, linked to distinct immune infiltration patterns. ceRNA networks highlighted oncogenic and tumor-suppressive miRNA interactions. A five-gene signature demonstrated moderate prognostic value across cohorts.

Conclusion: Microbial lipid signaling induces dynamic immune reprogramming that converges on tumor-relevant pathways, suggesting a systemic immune-mediated link between microbiota and BRCA progression, with potential implications for immune-targeted therapeutic strategies.