Background: Cancer patients often face psychological distress. Cancer metastasis is critical for prognosis. Recent research highlights the link between chronic stress and metastasis. However, the underlying mechanisms is far from known. Methods: Animal models of cancer metastasis were used to explore the effect of chronic stress in promoting tumor metastasis. A combination of antibiotic cocktail treatment, fecal microbiota transplantation and germ-free mice were carried out to confirm whether the pro-metastatic ability of chronic stress was dependent on gut microbiota. 16S rDNA sequencing and liquid chromatography mass spectrometry were parallelly performed on mice stools to investigate alterations in microbiota and metabolites. Additionally, we assessed hormone changes post-stress and demonstrated the correlation between glucocorticoid elevation and gut microbiota through in vivo and in vitro experiments. Finally, we validated our hypothesis using a prospective colorectal cancer cohort. Results: Mice undergone chronic stress had significantly increased cancer metastasis compared with stress-free control mice. Gut microbial dysbiosis was observed in mice undergone chronic stress, with Bifidobacterium being significantly depleted. Stress hormone, corticosterone could alter intestinal epithelium metabolism, and thus inhibit the growth of Bifidobacterium. Metabolomic analysis showed increased Oleic Acid (OA) in the colonic contents from chronic stress-treated mice, and the pro-metastatic role of OA were examined in vitro and in vivo experiments. Supplement of Bifidobacterium animalis (isolated from feces of the stress-free control mice) could decrease the level of OA and inhibit pro-metastasis effect of stress in mice. OhyA which encoded oleate hydratase was identified in Bifidobacterium animalis by whole genome sequencing. Heterogeneous expression of OhyA in Escherichia coli BL21 showed that supplement of OhyA could decrease the level of OA and abrogate the pro-metastatic effect of chronic stress. We found that glucocorticoid secretion increases during chronic stress, promoting the nuclear translocation of glucocorticoid receptors in epithelial cells and activating the transcription of downstream target genes. Through integrated metabolomic analysis, we demonstrated that glucocorticoids degrade guanine, reducing its concentration in the intestine and thereby inhibiting the growth of Bifidobacterium. Furthermore, our investigation into clinical cohorts revealed that patients with higher stress scores are more prone to tumor metastasis, accompanied by a decrease in the abundance of Bifidobacterium in the gut and an increase in serum and fecal oleic acid levels. Conclusions: Chronic phycological stress promotes cancer metastasis by inhibiting the growth of probiotic microbe Bifidobacterium through modulating epithelium purine metabolism and increasing the level of OA.