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

IF 6.3 3区医学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY

Biomedical Journal Pub Date : 2026-06-01 Epub Date: 2026-03-20 DOI:10.1016/j.bj.2026.100968

Quang Le Do , Ikbal Andrian Malau , Hoan Thi Nguyen , Jiaming Liu , Jane Pei-Chen Chang , Kuan-Pin Su

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引用次数: 0

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.

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循环短链脂肪酸（SCFA）谱作为肠-脑轴功能障碍的生物标志物：重度抑郁症中SCFA特征的荟萃分析

背景：重度抑郁障碍（MDD）越来越多地通过神经炎症假说和肠-脑轴功能障碍来看待。短链脂肪酸（SCFAs）是肠道微生物群产生的主要代谢物，是维持肠道屏障完整性、调节外周免疫和影响小胶质细胞功能的重要信号分子。虽然个别研究表明MDD患者的SCFAs水平发生了改变，但目前还缺乏一种确定的、定量的合成方法来建立强有力的生物标志物特征。本荟萃分析旨在与健康对照者相比，准确表征重度抑郁症患者的scfa（乙酸、丙酸、丁酸和异丁酸）特征。方法：我们系统地检索了PubMed、Embase和Web of Science数据库中截至2025年9月15日量化SCFAs水平的主要数据库。在抑郁症患者和抑郁样小鼠模型中检测SCFAs水平的研究，以及研究SCFAs干预抑郁样行为的研究，被选择用于综合。偏倚风险采用纽卡斯尔-渥太华量表进行评估。效应量采用随机效应模型合成，并以标准化平均差异表示。结果：8项人类研究和52项小鼠研究被纳入meta分析。抑郁症患者血液（血浆和血清）中丙酸（SMD = -0.60， p值= 0.007）、丁酸（SMD = -0.50， p值= 0.006）、异丁酸（SMD = -0.72， p值= 0.020）、戊酸（SMD = -0.43， p值= 0.040）和异戊酸（SMD = -0.75， p值= 0.002）浓度显著降低。对重度抑郁症患者的二次分析证实了持续的降低。观察到高度异质性。在小鼠模型中，经常观察到SCFAs消耗，而补充可改善抑郁样行为。结论：重度抑郁症的特点是循环SCFAs代谢组存在显著的、可量化的缺陷，这为抑郁症的肠脑轴假说提供了强有力的经验验证。我们提倡将SCFAs作为一种新型的、可测量的外周生物标志物和靶向治疗药物（如丁酸盐补充剂）用于精确营养精神病学的研究。

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来源期刊

Biomedical Journal Medicine-General Medicine

CiteScore

11.60

自引率

1.80%

发文量

128

审稿时长

42 days

期刊介绍： Biomedical Journal publishes 6 peer-reviewed issues per year in all fields of clinical and biomedical sciences for an internationally diverse authorship. Unlike most open access journals, which are free to readers but not authors, Biomedical Journal does not charge for subscription, submission, processing or publication of manuscripts, nor for color reproduction of photographs. Clinical studies, accounts of clinical trials, biomarker studies, and characterization of human pathogens are within the scope of the journal, as well as basic studies in model species such as Escherichia coli, Caenorhabditis elegans, Drosophila melanogaster, and Mus musculus revealing the function of molecules, cells, and tissues relevant for human health. However, articles on other species can be published if they contribute to our understanding of basic mechanisms of biology. A highly-cited international editorial board assures timely publication of manuscripts. Reviews on recent progress in biomedical sciences are commissioned by the editors.