Links Between Gut Dysbiosis and Neurotransmitter Disturbance in Chronic Restraint Stress-Induced Depressive Behaviours: the Role of Inflammation.

ABSTRACT

Accumulating evidence has shown that inflammation, the gut microbiota, and neurotransmitters are closely associated with the pathophysiology of depression. However, the links between the gut microbiota and neurotransmitter metabolism remain poorly understood. The present study aimed to investigate the neuroinflammatory reactions in chronic restraint stress (CRS)-induced depression and to delineate the potential links between the gut microbiota and neurotransmitter metabolism. C57BL/6 mice were subjected to chronic restraint stress for 5 weeks, followed by behavioural tests (the sucrose preference test, forced swim test, open field test, and elevated plus maze) and analysis. The results showed that CRS significantly increased interleukin-1 beta (IL-1ß), interleukin-2 (IL-2), interleukin-6 (IL-6), and tumour necrosis factor α (TNFα) levels and decreased brain-derived neurotrophic factor (BDNF) expression, accompanied by the activation of IkappaB-alpha-phosphorylation-nuclear factor kappa-B (IκBα-p-NF-κB) signalling in the mouse hippocampus. In addition, the neurotransmitter metabolomics results showed that CRS resulted in decreased levels of plasma 5-hydroxytryptamine (5-HT), dopamine (DA), and noradrenaline (NE) and their corresponding metabolites, and gut microbiota faecal metabolites with the 16S rRNA gene sequencing indicated that CRS caused marked microbiota dysbiosis in mice, with a significant increase in Helicobacter, Lactobacillus, and Oscillibacter and a decrease in Parabacteroides, Ruminococcus, and Prevotella. Notably, CRS-induced depressive behaviours and the disturbance of neurotransmitter metabolism and microbiota dysbiosis can be substantially restored by dexamethasone (DXMS) administration. Furthermore, a Pearson heatmap focusing on correlations between the microbiota, behaviours, and neurotransmitters showed that Helicobacter, Lactobacillus, and Oscillibacter were positively correlated with depressive behaviours but were negatively correlated with neurotransmitter metabolism, and Parabacteroides and Ruminococcus were negatively correlated with depressive behaviours but were positively correlated with neurotransmitter metabolism. Taken together, the results suggest that inflammation is involved in microbiota dysbiosis and the disturbance of neurotransmitter metabolism in CRS-induced depressive changes, and the delineation of the potential links between the microbiota and neurotransmitter metabolism will provide novel strategies for depression treatment.