Microbiota-Derived SCFAs Mediate the Synergistic Antidepressant Effects of Dajianzhong Decoction and Ketamine via FFAR2-NLRP3-IL-1β Signaling

Background: Ketamine is a rapid-acting antidepressant for major depressive disorder; however, its effects are short-lasting and associated with neurotoxic side effects. Thus, identifying strategies to prolong its antidepressant effects is of critical importance. It has been shown that Dajianzhong Decoction (DJZT) prolongs the antidepressant effects of ketamine through modulation of the gut microbiota, but the underlying mechanisms remain unclear. Method: Fecal microbiota transplantation, metabolomic profiling, pharmacological interventions, and behavioral approaches were employed together with a chronic unpredictable mild stress (CUMS) mouse model to investigate how microbiota-derived signals mediate the combined effects of DJZT and ketamine. Results: Microbiota from CUMS mice induced depressive-like behaviors in recipient mice, accompanied by reduced levels of short-chain fatty acids (SCFAs), decreased FFAR2 expression in the medial prefrontal cortex, and increased neuroinflammation and synaptic deficits. These alterations were reversed by microbiota from DJZT-plus-ketamine-treated donors. Notably, acetic acid and isobutyric acid were identified as key SCFAs restored by the combined treatment and were significantly associated with behavioral outcomes. Moreover, SCFA supplementation recapitulated these effects by activating FFAR2 and suppressing NLRP3–IL-1β signaling. Importantly, pharmacological inhibition of FFAR2 using GLPG0974 abolished the antidepressant-like, anti-inflammatory, and synaptic protective effects of the microbiota from DJZT-plus-ketamine-treated donors. Conclusions: These findings demonstrate that microbiota-derived SCFAs mediate the synergistic antidepressant effects of DJZT and ketamine via a central FFAR2-dependent mechanism involving suppression of neuroinflammation. This work highlights a potential role of the SCFA–FFAR2–NLRP3– IL-1β axis in influencing ketamine efficacy and points to microbiota-modulating strategies as a possible avenue for improving antidepressant therapy.