Comparative analysis of gut microbiome-derived short-chain fatty acids in patients with severe mental disorder: Insights from schizophrenia and bipolar disorder.

Both schizophrenia (SZ) and bipolar disorder (BD) are associated with disruptions in the gut microbiome. Short-chain fatty acids (SCFAs), such as acetate, propionate and butyrate, are key metabolites produced by gut bacteria that influence brain function, immune responses and behaviour. We conducted a cross-sectional observational study with 123 patients (86 with SZ and 37 with BD). We analysed faecal samples for SCFA and examined associations with clinical (psychopathology and cognition), metabolic and lifestyle factors. We performed analysis of covariance to find differences in SCFA levels between diagnostic groups, adjusting for covariates. Faecal SCFA levels were numerically higher in the SZ group than in the BD group. However, after adjusting for covariates, a significant sex-by-diagnosis interaction was observed only for acetate levels. Body mass index emerged as a key predictor of SCFA levels but we observed no significant associations with other metabolic or lifestyle variables, including diet, physical activity and blood inflammatory biomarkers. Additionally, SCFA levels showed no correlation with symptom severity or cognitive performance in either group. This study is the first to compare SCFA profiles between SZ and BD, highlighting potential differences in gut microbiota-derived metabolites between these disorders. These findings suggest greater disruption of the gut-brain axis in SZ, potentially reflecting distinct pathophysiological mechanisms involving metabolic and sex-related factors. Further research, including blood SCFA measurements, could better explain the role of SCFAs and explore microbiota-targeted therapeutic strategies for SZ and BD.