Microbiota-immune crosstalk underlying cancer-induced depression in patients with breast cancer.

[BACKGROUND] Cancer-induced depression (CID) is frequent in breast cancer (BC), yet its biological basis is poorly understood. We examined CID-related gut microbiota changes and their associations with immune and mood alterations.

[METHODS] A total of 49 female BC patients were enrolled, of whom 17 developed CID during treatment. Prior to the onset of depressive symptoms at baseline, gut microbiota composition, diversity, and functional potential were analyzed, while serum cytokines and changes in depressive symptoms (ΔBDI) before and after intervention were measured, and their interrelationships were explored.

[RESULTS] CID patients showed increased baseline immune activation, with higher IFN-α, IL-12p70, and IFN-γ levels. They also exhibited significantly reduced gut microbial α-diversity. In addition, six differential genera were identified, including Lawsonella, Holdemania, Lachnospiraceae UCG010, Actinomyces, Negativibacillus and Scardovia, which showed significant differences between the CID and BC groups. Functional analysis indicated reduced glycosphingolipid biosynthesis and increased N-glycan biosynthesis, with these pathway changes corresponding to specific differential genera such as Actinomyces and Lachnospiraceae UCG010. Notably, at baseline, Lawsonella abundance was positively correlated with both IFN-α levels and ΔBDI, and mediation analysis revealed a statistically significant association between Lawsonella and ΔBDI through IFN-α, with the estimated indirect effect (ACME = 0.128, p < 0.05) accounting for approximately 19.3% of the total association.

[CONCLUSION] CID patients showed marked gut microbiota dysbiosis and functional pathway alterations at baseline. The Lawsonella-IFN-α-mood axis may be associated with subsequent mood changes, providing a theoretical basis for exploring CID mechanisms and early identification.