Focusing on the serotonergic system—the foundation of the monoamine hypothesis of depression—we observed a significant reduction in 5-HT levels in the PFC following FMT, along with H3K27me3-mediated transcriptional repression of key genes including Tph2, Htr1d, Htr2a, Htr3a, Htr6, and Htr7. Here, HTR1D is linked to depressive disorder.