Microbiota-Derived SCFAs Mediate the Synergistic Antidepressant Effects of Dajianzhong Decoction and Ketamine via FFAR2-NLRP3-IL-1β Signaling.
Pharmaceuticals (Basel, Switzerland) May 31, 2026 Wenting Zhang, Xin Guo, Jiping Zhang et al.
Combining the herbal formula Dajianzhong Decoction (DJZT) with ketamine produces synergistic antidepressant effects in a mouse model of depression. The combination restores levels of short-chain fatty acids (SCFAs), particularly acetic acid and isobutyric acid, in the gut. These SCFAs activate the FFAR2 receptor in the brain's medial prefrontal cortex, which suppresses NLRP3-IL-1β-driven neuroinflammation and reverses synaptic deficits. Blocking FFAR2 with the inhibitor GLPG0974 eliminates these benefits. The findings suggest that the SCFA-FFAR2-NLRP3-IL-1β axis mediates the prolonged antidepressant action of the combined treatment, pointing to microbiota-modulating strategies for improving ketamine therapy.