In summary, this study reveals a novel gut microbiota-brain pathway underlying depression: the depletion of specific microbial taxa (f_Lachnospiraceae, f_Oscillospiraceae and f_Erysipelotrichaceae) leads to reduced inosine levels, attenuating A2aR-PKA-CREB-HDAC3 signaling, increasing H3K9ac, and promoting EZH2 transcription. Here, ADORA2A is linked to major depressive disorder.