Enriched environment inhibits melanoma by reshaping gut microbiota and enriching Parabacteroides distasonis

The role of psychological factors in the holistic regulation of cancer has garnered significant attention. Psychological eustress induced by an enriched environment (EE) inhibits various cancers including melanoma, but underlying mechanisms remain largely unknown. The brain-gut axis may play a key role in modulating psychological factors and cancer progression. This study investigates the role of gut microbiota in EE-induced anti-melanoma effects.

C57BL/6 mice were housed in EE or standard environment (SE). Longitudinal fecal samples from EE and SE mice underwent 16S rRNA gene sequencing. SE melanoma-bearing mice received fecal microbiota transplantation (FMT) from EE or SE donors to assess the microbiota's causal role in EE's anti-tumor effects. Bacterial species upregulated by EE in tumor-bearing mice were identified;Parabacteroides distasonis (Pd) was selected for therapeutic administration. Immune cells in spleen and tumor were quantified by flow cytometry. Natural killer (NK) cell function was tested using anti-NK1.1 depletion.

EE increased the alpha diversity of the gut microbiota and alleviated the dysbiosis caused by melanoma. FMT from EE mice to SE mice inhibited melanoma growth, suggesting that the gut microbiota contributes to EE's anti-tumor effects. EE upregulated seven bacterial species in tumor-bearing mice, including Pd. Oral administration of Pd inhibited melanoma growth and increased intratumoral NK/NKT cell proportions and NK cell granzyme B expression. NK cell depletion abrogated Pd's anti-tumor effect.

This study underscores the interconnectedness of psychological eustress, gut microbiota, and cancer, providing preclinical insights into holistic cancer treatments. Leveraging the brain-gut-cancer axis, targeting psychological factors and gut microbiota could offer a potential adjunctive strategy for melanoma management.