Repeated ketamine administration (20 mg/kg) induces conditioned place preference (CPP) in mice, a model of addiction, and significantly alters gut microbiota diversity and composition. Compared to controls, ketamine exposure increased the relative abundance of four microbial families (Lachnospiraceae, Ruminococcaceae, Desulfovibrionaceae, Family-XIII) and decreased one (Prevotellaceae). At the genus level, five genera increased and one decreased. Ketamine dependence reduced levels of tight junction proteins, GABA, and GABRA1, while increasing BDNF and 5-HT. However, an oral antibiotic cocktail that created pseudo-germ-free mice did not enhance ketamine-induced addictive behavior, suggesting the gut microbiota mediates ketamine-induced CPP.
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.