Abstract
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.
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Research reported in this publication is funded by the Centre for Urban Mental Health, a research priority area of the University of Amsterdam, the Netherlands. The Centre for Urban Mental Health had no role in conducting the research and preparation of the article. The Academic Medical Center (AMC) of Amsterdam and the Public Health Service of Amsterdam (GGD Amsterdam) provided core financial support for HELIUS. The HELIUS study is also funded by research grants of the Dutch Heart Foundation (Hartstichting; grant no. 2010T084), the Netherlands Organization for Health Research and Development (ZonMw; grant no. 200500003), the European Integration Fund (EIF; grant no. 2013EIF013) and the European Union (Seventh Framework Programme, FP-7; grant no. 278901). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
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MN is a founder and scientific advisory board member of Caelus Pharmaceuticals and Advanced Microbiome Interventions, the Netherlands. He is also on the board of directors of Diabeter Netherlands BV. SB is chair of the curatorium of DSM-Firmenich’s professor by special appointment on behalf of the Bèta Plus foundation of the University of Amsterdam (Industrial Molecular Microbiology). None of the former bear direct relevance to the content of the current manuscript. All other authors declare no competing of interests.
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Korenblik, V., Bastiaanssen, T.F.S., de Haas, I.M. et al. Relationship between fecal short-chain fatty acids (SCFAs) and microbial SCFA pathways with depressive symptoms in Dutch adults. Transl Psychiatry (2026). https://doi.org/10.1038/s41398-026-04296-9
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DOI: https://doi.org/10.1038/s41398-026-04296-9
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