IDDF2024-ABS-0223 Chronic stress promotes cancer metastasis through glucocorticoid-driven bifidobacterium depletion and oleic acid accumulation

<h3>Background</h3> Recent research has indicated that chronic psychological stress can lead to alterations in the gut microbial community. While the involvement of gut microbiota in regulating numerous aspects of human health is well-established, their potential role in promoting cancer metastasis under chronic psychological stress and the relationship between psychological stress and microbiota remains largely unexplored. <h3>Methods</h3> Firstly, we discovered the correlation between chronic stress and metastasis from our colorectal cancer (CRC) cohorts. We used the breast cancer (BC) metastasis model (spontaneous metastasis) and colorectal cancer metastasis model (tail-vain injection) to prove that chronic stress promoted metastasis. Additionally, germ-free animal and fecal microbiota transplantation (FMT) experiments demonstrated the involvement of microbiota. Key bacteria were then screened through 16S rRNA gene sequencing. Hormone screening and mass spectrometry were employed to clarify hormone-epithelial interplay, identifying key metabolites leading to microbiota alterations. Metabolome, whole-genome sequencing and gene editing were conducted to identify key metabolites affecting metastasis and explore mechanisms by which these bacteria resist tumor metastasis. <h3>Results</h3> CRC patients with chronic stress exhibited enhanced metastasis compared to those without chronic stress, accompanied by altered gut microbiota, particularly a decrease in <i>Bifidobacterium</i>. In both CRC and BC metastasis models, mice that underwent chronic stress showed enhanced metastasis, concomitant with reduced abundance of <i>Bifidobacterium</i>. In germ-free mice, this promotion disappeared. However, after FMT of stress-related microbiota, mice exhibited increased metastasis. Replenishing <i>Bifidobacterium</i> effectively counteracted the pro-metastatic effects. Glucocorticoids notably increase post-stress, and intraperitoneal injection of glucocorticoids significantly decreases the abundance of <i>Bifidobacterium</i>. The metabolome of intestinal epithelial cells showed decreased guanine concentration under chronic stress, which caused the reduction of <i>Bifidobacterium</i>. Furthermore, analysis of the fecal metabolome of stressed mice revealed increased oleic acid, which could be degraded by oleate hydratase encoded by<i> Bifidobacterium. Bifidobacterium</i> or BL21 carrying oleate hydratase effectively countered tumor metastasis. Finally, our clinical data established a significantly decreased <i>Bifidobacterium</i> and increased oleic acid level in metastasis CRC patients. <h3>Conclusions</h3> Chronic stress elevates glucocorticoids, reduces luminal guanine, and inhibits the growth of <i>Bifidobacterium</i>. This diminished capacity of <i>Bifidobacterium</i> to degrade oleic acid results in increased serum oleic acid levels, promoting tumor metastasis.