Gut microbiota remodeling contributes to nicotine-associated behavioral improvement and restoration of serotonin-related metabolism in CUMS mice

Abstract Major depressive disorder is a heterogeneous neuropsychiatric disorder in which serotonin-related pathways remain important pharmacological targets. Nicotine has been reported to exert antidepressant-like effects, yet whether the gut microbiota contributes to these effects remains unclear. Here, we found that sustained-release nicotine (0.2 mg/kg/d) improved depression-like behavioral measures in a chronic unpredictable mild stress (CUMS) mouse model. Nicotine treatment was also associated with improved intestinal barrier integrity, reduced colonic inflammation, partially restored short-chain fatty acid levels, and changes in central and peripheral serotonin metabolism. Several of these behavioral and metabolic improvements were substantially attenuated by antibiotic-induced microbiota depletion, supporting a functional contribution of the gut microbiota under the present experimental conditions. Metagenomic profiling revealed the enrichment of Akkermansia muciniphila following nicotine treatment. Notably, fecal microbiota transplantation from nicotine-treated donors or direct A. muciniphila supplementation reproduced selected improvements in behavioral, inflammatory and serotonin-related metabolic outcomes in CUMS recipients. Collectively, these findings support a microbiota-associated contribution to the behavioral and metabolic effects of nicotine in CUMS mice and implicate A. muciniphila as a microbial contributor to serotonin-related metabolic regulation.