Cai_2025_J.Affect.Disord_381_131

BACKGROUND: Intestinal dysbacteriosis is frequently implicated in generalized anxiety disorder (GAD). However, the molecular mechanisms and functional changes of the gut-brain axis in GAD remain largely unexplored. METHODS: We investigated anxiety-like behaviors, gut microbiota changes, brain region-specific endocannabinoid (eCB) system alterations, including the expression of cannabinoid type 1 (CB1R), monoacylglycerol lipase (MAGL), and fatty acid amide hydrolase (FAAH) in the hippocampus (Hip), prefrontal cortex (PFC), and amygdala (Amy), as well as plasma medium- and long-chain fatty acids (MLCFAs) in a mouse model of chronic restraint stress (CRS) and antibiotic-treated mice receiving fecal microbiota transplantation from GAD patients (FMT-GAD). Additionally, we assessed the impact of FMT-GAD on anxiety-like behavior in systemic CB1R/FAAH/MAGL knockout mice. RESULTS: CRS induced anxiety-like behaviors, suppressed eCB signaling in the brain, and altered the gut microbiota and plasma MLCFA composition in mice. FMT-GAD-treated mice exhibited anxiety-like behaviors, increased FAAH expression in the Hip and Amy, and MAGL expression in the Hip, while reducing CB1R expression in the Hip. FMT-GAD was associated with decreased plasma polyunsaturated fatty acids (PUFAs) and reduced microbiome function for fatty acid biosynthesis. Notably, FMT-GAD intensified anxiety-like behaviors in CB1R-KO mice but failed to induce anxiety-like behaviors in MAGL-KO and FAAH-KO mice. CONCLUSIONS: This study demonstrates that the interplay between the gut microbiota and the eCB system modulates GAD-related anxiety-like behaviors.