Metabolomics changes in brain-gut axis after unpredictable chronic mild stress

Abstract

Background: Major depressive disorder is a leading cause of disability worldwide, affecting up to 17 % of the general population. The neural mechanisms of depression, however, are yet to be uncovered. Recently, attention has been drawn to the effects of dysfunctional brain-gut axis on depression, and many substances have been suggested to be involved in the communication between the gut and brain, such as ghrelin.

Methods: We herein systematically examined the changes of metabolomics after unpredictable chronic mild stress (UCMS)-induced depression-like behaviors in rats and compared the altered metabolites in the hippocampus and jejunum samples.

Results: Our results show that many metabolites significantly changed with UCMS both in the hippocampus and jejunum, such as L-glutamine, L-tyrosine, hydroxylamine, and 3-phosphoglyceric acid. Further studies suggested that these changes are the reasons for anxiety-like behaviors and depression-like behaviors in UCMS rats and also are the reasons for hippocampal neural plasticity.

Conclusions: Coexistence of brain and gut metabolic changes in UCMS-induced depressive behavior in rats suggests a possible role of brain-gut axis in depression. This study provides insights into the neurobiology of depression.

Keywords: Brain-gut axis; MDD; Major depressive disorders; Metabolomics; UCMS.

Fig. 1

Behavior tests and physiological changes after UCMS. A Scores for sucrose preference test; B forced swim test; C open field test (distance); D open field test (grooming bouts). Sucrose preference test represents sugar water preference rates, which were calculated with the equation: SPT, sucrose consumption/(sucrose consumption + water consumption); E body weight changes during the UCMS training; F corticosterone (cort) levels in the blood (n = 12)

Fig. 2

GC-MS total ion chromatograms (TIC) of hippocampus samples and jejunum samples. A The detected metabolites in the hippocampal samples can be called the typical total ion chromatogram (TIC) of the hippocampus (n = 8). In hippocampus samples, 144 endogenous metabolites were identified as changed significantly, including amino acids, glucose, amides, pyrimidines, and fatty acids. B In jejunum samples, 190 endogenous metabolites were identified as changed significantly, including amino acids, amino alcohol derivatives, fatty acid, and pyrimidines

Fig. 3

PCA scores scatter plot of hippocampus and jejunum metabolites. A Principal component analysis (PCA) score scatter plot demonstrated a good separation among UCMS group and control, indicating that UCMS significantly decreased some endogenous metabolites levels in hippocampus (n = 8). B PCA scatter plot of the metabolites changed in the jejunum of the UCMS rats (n = 8)

Fig. 4

Heatmap of identified differential metabolites with hippocampus (A) and jejunum (B) metabolomics profile. Each cell in the heatmap represents the fold change of a particular metabolite. C A Venn diagram generated based on the proportion of the changed substances (n = 8)

Fig. 5

Scatter plots of significantly changed metabolites normalized peak intensity in rat hippocampus (A) and jejunum samples (B). The x-axis shows the specific metabolite’s normalized peak intensity, and each scatter represents a corresponding sample of the rat. represents hippocampus samples of control, represents hippocampus samples of UCMS, represents jejunum samples of control, represents jejunum samples of UCMS, the scatter plots show the mean and SD of the metabolites. *p<0.05, **p<0.01, vs. control (n = 8)

Fig. 6

LTP results from the hippocampus. A LTP decreases in the hippocampus from UCMS mice (n = 4). B The record of the experiment operation. C The statistical analysis of the fEPSPs (field excitatory postsynaptic potentials). Unpaired t-test revealed that LTP was significantly decreased in hippocampal slices of UCMS rats. Data are presented as the mean ± SEM. *** p < 0.01, (n = 4)

Fig. 7

Schematic diagram of metabolite distribution. Metabolites derived from the amino acid difference in the hippocampus. Metabolites derived from the different metabolites of sugar in the jejunum. Different metabolites coexisting in the hippocampus and jejunum

Fig. 8

The pathways closely associated with the depression effects. Bold blue metabolites were potential biomarkers of the hippocampus from depression model; bold black metabolites were potential biomarkers of the jejunum from depression model. Bold red metabolites were potential biomarkers of the hippocampus and jejunum from depression model