Relationship between fecal short-chain fatty acids (SCFAs) and microbial SCFA pathways with depressive symptoms in Dutch adults

Short-chain fatty acids (SCFAs), including acetate, butyrate and propionate, have been linked to depression. It remains unclear whether fecal SCFA levels or predicted SCFA synthesis and degradation are associated with depressive symptoms. We explored these relationships in a Dutch, non-clinical adult sample, considering systolic blood pressure (SBP) as a potential moderator. We studied 200 adults (<50 years old) from the HELIUS cohort with high or low SBP, matched on age, sex and BMI. Fecal SCFA concentrations were quantified by HPLC. SCFA synthesis and degradation pathways were inferred from 16S rRNA gene sequencing using PICRUSt and mapped to gut-brain modules. Depressive symptoms were assessed using the Patient Health Questionnaire-9. Negative binomial regression was used to explore associations between depressive symptoms and SCFA measures, adjusting for demographic, lifestyle, and clinical covariates, with SBP as a potential moderator. In the high SBP group, higher depressive symptom severity was associated with lower acetate concentrations, but this association did not survive multiple-testing (IRR = 0.82, 95% CI [0.69–0.96], p = 0.016, p-adjusted = 0.063). No significant associations were observed in the low SBP group, and similarly no association was found in either group for other fecal SCFA ratios or predicted SCFA pathways. Our exploratory analyses do not provide conclusive evidence for associations between fecal SCFA concentrations or ratios, or SCFA pathways, and depressive symptoms in this non-clinical subsample, although the acetate finding suggests a potential signal influenced by metabolic status. Future research in clinical populations is needed to inform gut-targeted interventions in depression.