DataSheet_1_Associations Between Disordered Microbial Metabolites and Changes of Neurotransmitters in Depressed Mice.docx

BackgroundsMany pieces of evidence demonstrated that there were close relationships between gut microbiota and depression. However, the specific molecular mechanisms were still unknown. Here, using targeted metabolomics, this study was conducted to explore the relationships between microbial metabolites in feces and neurotransmitters in prefrontal cortex of depressed mice.
MethodsChronic unpredictable mild stress (CUMS) model of depression was built in this study. Targeted liquid chromatography–mass spectrometry analysis was used to detect the microbial metabolites in feces and neurotransmitters in prefrontal cortex of mice. Both univariate and multivariate statistical analyses were applied to identify the differential microbial metabolites and neurotransmitters and explore relationships between them.
ResultsNinety-eight differential microbial metabolites (mainly belonged to amino acids, fatty acids, and bile acids) and 11 differential neurotransmitters (belonged to tryptophan pathway, GABAergic pathway, and catecholaminergic pathway) were identified. Five affected amino acid–related metabolic pathways were found in depressed mice. The 19 differential microbial metabolites and 10 differential neurotransmitters were found to be significantly correlated with depressive-like behaviors. The two differential neurotransmitters (tyrosine and glutamate) and differential microbial metabolites belonged to amino acids had greater contributions to the overall correlations between microbial metabolites and neurotransmitters. In addition, the significantly decreased L-tyrosine as microbial metabolites and tyrosine as neurotransmitter had the significantly positive correlation (r = 0.681, p = 0.0009).
ConclusionsThese results indicated that CUMS-induced disturbances of microbial metabolites (especially amino acids) might affect the levels of neurotransmitters in prefrontal cortex and then caused the onset of depression. Our findings could broaden the understanding of how gut microbiota was involved in the onset of depression.

研究背景：已有多项研究证据表明，肠道菌群（gut microbiota）与抑郁症存在紧密关联，但具体的分子机制仍未明确。本研究采用靶向代谢组学（targeted metabolomics）技术，探究抑郁模型小鼠粪便中的微生物代谢物与前额叶皮层（prefrontal cortex）神经递质之间的关联。
研究方法：本研究构建了慢性不可预见性温和应激（chronic unpredictable mild stress, CUMS）抑郁症小鼠模型。采用靶向液相色谱-质谱联用（liquid chromatography–mass spectrometry）技术检测小鼠粪便中的微生物代谢物与前额叶皮层神经递质水平。通过单变量统计分析与多变量统计分析相结合的方法，筛选差异微生物代谢物与差异神经递质，并探究二者之间的关联。
研究结果：本研究共筛选得到98种差异微生物代谢物，主要涵盖氨基酸、脂肪酸与胆汁酸类；同时鉴定出11种差异神经递质，分别隶属于色氨酸通路（tryptophan pathway）、γ-氨基丁酸能通路（GABAergic pathway）与儿茶酚胺能通路（catecholaminergic pathway）。在抑郁模型小鼠中，共发现5条受扰动的氨基酸相关代谢通路。另有19种差异微生物代谢物与10种差异神经递质与小鼠抑郁样行为呈显著相关。其中，酪氨酸（tyrosine）、谷氨酸（glutamate）两类差异神经递质，以及氨基酸类差异微生物代谢物，对微生物代谢物与神经递质间的整体关联贡献度最高。此外，作为微生物代谢物的L-酪氨酸（L-tyrosine）水平显著降低，其与作为神经递质的酪氨酸呈显著正相关（r=0.681，p=0.0009）。
研究结论：本研究结果表明，慢性不可预见性温和应激（CUMS）诱导的微生物代谢物紊乱（尤其是氨基酸类代谢物紊乱）可能通过影响前额叶皮层神经递质水平，进而引发抑郁症。本研究发现有助于加深对肠道菌群参与抑郁症发病机制的理解。