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

Abstract

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. 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. Multiple metastatic models were performed after stress cessation. Shotgun metagenomics and metabolomics were performed to assess changes in microbiota and metabolites. The effects of <i>Bifidobacterium animalis</i> and oleic acid (OA) on metastasis were evaluated <i>in vivo</i> and <i>in vitro</i>. Moreover, we explored how <i>B. animalis</i> 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. Mice that underwent chronic stress exhibited increased metastasis even after hormone levels recovered. The gut microenvironment was altered, with a significant reduction in <i>B. animalis</i> and an increase in OA. <i>B. animalis</i> administration reduced OA levels and suppressed metastasis, while OA supplementation had the opposite effect. <i>B. animalis</i> expresses oleate hydratase, an enzyme that degrades OA. Stress hormones inhibited <i>B. animalis</i> by altering guanine metabolism in the intestinal epithelium. In patients, high stress was associated with more OA, lower <i>B. animalis</i> levels and increased metastasis. Chronic stress promotes metastasis by altering microbiota and increasing OA. Targeting <i>B. animalis</i> and OA may help prevent stress-related tumour progression.