Circulating Short-Chain Fatty Acid (SCFA) Profiles as a Biomarker of Gut-Brain Axis Dysfunction: A Meta-Analysis for the SCFA Signature in Major Depression

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    Blood SCFA concentrations are reduced in patients with depression, especially in clinically diagnosed patients.
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    SCFA supplementation may improve depressive-like behaviors in animal models.
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    SCFA deficiency may contribute to depression, supporting SCFAs as potential biomarkers and therapeutic targets.

Abstract

Background

Major Depressive Disorder (MDD) is increasingly viewed through the lens of the neuroinflammatory hypothesis and gut-brain axis dysfunction. Short-Chain Fatty Acids (SCFAs), the primary metabolites produced by the gut microbiota, are vital signaling molecules that maintain intestinal barrier integrity, modulate peripheral immunity, and influence microglial function. While individual studies suggest altered SCFAs levels in MDD, a definitive, quantitative synthesis establishing a robust biomarker signature is currently lacking. This meta-analysis aimed to precisely characterize the signature of SCFAs (acetic, propionic, butyric, and isobutyric acid) in MDD patients compared to healthy controls.

Methods

We systematically searched major databases across PubMed, Embase, and Web of Science databases for studies quantifying SCFAs levels up to September 15, 2025. Studies examining SCFAs levels in depressed patients and depressive-like murine models, as well as studies investigating SCFAs interventions for depressive-like behavior, were selected for synthesis. Risk of bias was evaluated using the Newcastle–Ottawa Scale. The effect sizes were synthesized using a random-effects model and presented as standardized mean differences.

Results

Eight human and 52 murine studies were included in the meta-analyses. Depressed patients showed significantly lower concentrations in blood (plasma and serum) of propionic (SMD = -0.60, p-value = 0.007), butyric (SMD = -0.50, p-value = 0.006), isobutyric (SMD = -0.72, p-value = 0.020), valeric (SMD = -0.43, p-value = 0.040) and isovaleric acids (SMD = -0.75, p-value = 0.002). Secondary analysis of MDD patients confirmed consistent reductions. High heterogeneity was observed. In murine models, SCFAs depletion was frequently observed, while supplementation improved depressive-like behaviors.

Conclusion

MDD is characterized by a significant, quantifiable deficit in the circulating SCFAs metabolome, which provides strong empirical validation for the gut-brain axis hypothesis in depression. We advocate for the investigation of SCFAs as novel, measurable peripheral biomarkers and targeted therapeutic agents (e.g., butyrate supplementation) for precision nutritional psychiatry.

Read full article for free (open access):
https://www.sciencedirect.com/science/article/pii/S2319417026000247


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