Altered gut metabolome contributes to depression-like behaviors in rats exposed to chronic unpredictable mild stress

Li Jianguo,Qin Xuemei,Jia Xueyang,Wang Cui,Wu Changxin

doi:10.1038/s41398-019-0391-z

Li Jianguo, Qin Xuemei + Show 3 more

Open Access

https://doi.org/10.1038/s41398-019-0391-z

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Abstract

The gut microbiota has been increasingly correlated with depressive disorder. It was recently shown that the transplantation of the gut microbiota from depressed patients to animals can produce depressive-like behaviors, suggesting that the gut microbiota plays a causal role in the development of depression. In addition, metabolic disorder, which is strongly associated with depression, is exacerbated by changes in the composition of the gut microbiota and is alleviated by treatment with antidepressants. However, the key players and pathways that link the gut microbiota to the pathogenesis of depression remain largely unknown. To evaluate the relationships between depression and metabolic disorders in feces and plasma, we monitored changes in fecal and plasma metabolomes during the development of depressive-like behaviors in rats exposed to chronic unpredictable mild stress (CUMS). In these animals, the fecal metabolome was altered first and subjected to changes in the plasma metabolome. Changes in the abundance of fecal metabolites were associated with depressive-like behaviors and with altered levels of neurotransmitters in the hippocampus. Furthermore, the analysis of the fecal metabolome and the fecal microbiota in CUMS rats demonstrated consistent changes in the levels of several amino acids, including L-threonine, isoleucine, alanine, serine, tyrosine, and oxidized proline. Finally, we observed significant correlations between these amino acids and the altered fecal microbiota. The results of this study suggest that changes in amino acid metabolism by the gut microbiota contribute to changes in circulating amino acids and are associated with the behavior indices of depression.

Highlights

Major depressive disorder (MDD) is a widespread mood disorder that has significant adverse effects on personal health and results in staggering medical costs[1]
While much attention has been paid to the terminal state of chronic unpredictable mild stress (CUMS), comparatively little is known about the timing of symptom origin[28,36,37,38,39]
We did not observe significant changes in sucrose preference rate (Fig. 1b), grooming time (Fig. 1e) or crossing counts (Fig. 1g) of open-field tests (OFTs) until the last week of CUMS modeling, an isolated notable change was evident in grooming time (Fig. 1e) at the 1st week

Summary

Introduction

Major depressive disorder (MDD) is a widespread mood disorder that has significant adverse effects on personal health and results in staggering medical costs[1]. Despite a battery of psychological and pharmacological treatments for depression, only 74% of patients with MDD show improvement[2]. There is an urgent need to develop more efficacious therapies and to identify the additional causal factors of depression[3,4]. MDD is primarily a psychological condition, the overall physiology of depression is embedded in the central nervous system[5]. The symptoms of depression are far-reaching, including weight loss[6], sleeping difficulties[7], and psychomotor agitation[8]. A more comprehensive understanding of the pathophysiology of depression will, require a multifaceted investigation of the physiological factors that contribute to depression[9,10]

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