Plasma short-chain fatty acid concentrations in social anxiety disorder and changes after cognitive behavioral therapy

Abstract Emerging evidence indicates that the gut microbiota are linked to variation in social behavior and anxiety, with short-chain fatty acids (SCFAs) proposed as key microbial metabolites that may mediate microbiota-brain communication. Cognitive behavioral therapy (CBT) is an effective treatment for social anxiety disorder (SAD), but it remains unclear whether gut microbiota changes following treatment. In this longitudinal study, 46 individuals with SAD underwent nine weeks of internet-delivered CBT. Plasma concentrations of nine SCFAs were measured using liquid chromatography-mass spectrometry: twice at pre-treatment, once at post-treatment and once at a 36-month follow-up in patients, with > 80% data completeness. Healthy controls ( n = 42) underwent two SCFA assessments 11 weeks apart. Generalized additive mixed models were used to assess longitudinal changes with CBT, linear mixed models for patient-control differences, and intraclass correlation coefficients for test-retest reliability. CBT led to significant reductions in social anxiety symptoms, and effects were sustained at 36 months follow-up. Plasma concentrations of butyric, isobutyric, propionic, and valeric acids increased after CBT, with trajectories predominantly explained by time rather than individual variability. Before CBT, isobutyric acid was statistically significantly lower in SAD patients, relative to healthy controls. These findings provide initial evidence that sustained therapeutic benefits of CBT may be linked to alterations in circulating microbial metabolites, as indexed by lower isobutyric acid in SAD patients at pre-treatment, and increases in isobutyric, butyric, propionic and valeric acids after therapy. Lifestyle factors were not assessed but may have contributed to the observed long-term metabolic changes.