Gut blautia coccoides-derived 5Z-dodecenoic acid attenuates chronic psychological stress-induced gastric cancer progression.

[BACKGROUND] Chronic psychological stress is a critical oncogenic factor of gastric cancer (GC). However, the mechanisms underlying stress-induced malignant progression remain largely unknown. Gut microbiota dysregulation is tightly associated with cancer development and metabolism.

[MATERIALS AND METHODS] Chronic unpredictable mild stress (CUMS) modeling was used to prepare mice suffering from chronic psychological stress. 16s rRNA sequencing and Q300 targeted metabolite quantification were jointly conducted to depict landscapes of gut microbiome and metabolomics of CUMS mice. Fecal microbiota transplantation was employed to investigate the functions of gut microbial communities in regulating CUMS-mediated GC growth. Drug affinity responsive target stability, surface plasmon resonance and molecular docking assays were performed to screen direct target proteins of 5Z-dodecenoic acid. The interactions between RIOK2 and BYSL were verified with co-immunoprecipitation and GST pull-down and fluorescent co-localization analysis. A series of experiments for malignant behaviors and glycolysis and subcutaneous tumor transplantation were employed to detect alterations of GC cell phenotypes ex vivo and in vivo, respectively.

[RESULTS] Microbiome and metabolomics collectively demonstrated disrupted gut microbial communities and metabolic patterns. Particularly, Blautia coccoides-derived 5Z-dodecenoic acid was predominately declined by CUMS. Supplementation with Blautia coccoides or 5Z-dodecenoic acid effectively mitigated the negative effects of CUMS on glycolysis and malignancy. Mechanistically, 5Z-dodecenoic acid directly inhibits the functions of RIOK2, which maintained ectopic glycolysis and malignant behaviors. RIOK2 further interacted with BYSL and maintained its properties of potentiation of GC progression and metabolism.

[CONCLUSION] Our findings advance the insights of Blautia coccoides-derived 5Z-dodecenoic acid implicated in chronic psychological stress-induced GC progression and provide novel strategies for dampening GC progression.