Gut microbe alleviates stress-related cancer metastasis by oleic acid degradation

Background Chronic stress is a known risk factor for cancer metastasis. However, the underlying mechanisms, particularly those involving the gut microbiota and their metabolites, remain unclear. Objective To investigate whether gut microbiota dysbiosis and metabolic alterations mediate the sustained pro-metastatic effects of chronic stress, even after normalisation of stress hormone levels. Design Multiple metastatic models were performed after stress cessation. Shotgun metagenomics and metabolomics were performed to assess changes in microbiota and metabolites. The effects of Bifidobacterium animalis and oleic acid (OA) on metastasis were evaluated in vivo and in vitro . Moreover, we explored how B. animalis degraded OA. Mechanistically, we discovered the interaction between corticosteroids and gut bacteria through guanine metabolism assays. Human samples were collected from patients with colorectal cancer (CRC) with varying perceived stress scores and metastatic status for validation. Results Mice that underwent chronic stress exhibited increased metastasis even after hormone levels recovered. The gut microenvironment was altered, with a significant reduction in B. animalis and an increase in OA. B. animalis administration reduced OA levels and suppressed metastasis, while OA supplementation had the opposite effect. B. animalis expresses oleate hydratase, an enzyme that degrades OA. Stress hormones inhibited B. animalis by altering guanine metabolism in the intestinal epithelium. In patients, high stress was associated with more OA, lower B. animalis levels and increased metastasis. Conclusions Chronic stress promotes metastasis by altering microbiota and increasing OA. Targeting B. animalis and OA may help prevent stress-related tumour progression.