Systematic impacts of chronic unpredictable mild stress on metabolomics in rats

Abstract

Depression is the most common disabling psychiatric disease, with a high prevalence and mortality. Chronic unpredictable mild stress (CUMS) is a well-accepted method used to mimic clinical depression. Recent evidence has consistently suggested that the cumulative effects of CUMS could lead to allostatic overload in the body, thereby inducing systemic disorders; however, there are no previous systematic metabonomics studies on the main stress-targeted tissues associated with depression. A non-targeted gas chromatography-mass spectrometry (GC-MS) approach was used to identify metabolic biomarkers in the main stress-targeted tissues (serum, heart, liver, brain, and kidney) in a CUMS model of depression. Male Sprague-Dawley rats were randomly allocated to the CUMS group (n = 8) or a control group (n = 8). Multivariate analysis was performed to identify the metabolites that were differentially expressed between the two groups. There were 10, 10, 9, 4, and 7 differentially expressed metabolites in the serum, heart, liver, brain and kidney tissues, respectively, between the control and CUMS groups. These were linked to nine different pathways related to the metabolism of amino acids, lipids, and energy. In summary, we provided a comprehensive understanding of metabolic alterations in the main stress-targeted tissues, helping to understand the potential mechanisms underlying depression. An increasing body of evidence has revealed that the cumulative effect of stress can trigger allostatic overload 1-3. "Allostatic load" refers to the effects of prolonged continuous or intermittent activation of effectors involved in allostasis 4-6. Allostatic load has been associated with many diseases, such as cardiovascular disease, diabetes, stroke, chronic kidney disease, abdominal obesity, and depression 7,8. These all involve the whole body. Thus, the stress-induced allostatic overload involved in depression is focused on in our study. Depression is a seriously debilitating psychiatric disease, characterized by high mortality and morbidity. The chronic unpredictable mild stress (CUMS) model, a well-accepted animal model of depression, is used to explore the mechanisms underlying depression 9-11. One proposed mechanism involves allostatic load, a multidimensional biologic construct that involves biomarkers across the physiologic domains of neuroendocrine, autonomic, immune, and metabolic function 7. Allostatic overload resulting from CUMS in animal models causes atrophy of neurons in the hippocampus and prefrontal cortex 4,5 , myocardial ischemia 9 , abnormal hepatic metabolism 12 , and poor kidney outcomes 8,13. Thus, the impact of stress involves the whole body and depression is linked to multiple diseases such as cardiovascular disease 9. However, there are no previous systematic metabonomics studies focusing on the main stress-targeted tissues. Thus, the aim of the present study was to provide a panoramic and systematic view of metabolic alterations in stress-targeted tissues (serum, heart, liver, brain, and kidney) in the conte...

Alterations in Metabolome and Microbiome Associated with an Early Stress Stage in Male Wistar Rats: A Multi-Omics Approach

“…Additionally, pyruvic acid and 3-hydroxibutiric acid in plasma metabolomics and N,N-dimethylglycine and taurine in urine metabolomics match as candidate biomarkers in two different statistical methodologies (Figure 7). Globally, considering the results of the present 3d CUMS study and previous CUMS studies, we have observed that energy metabolism has a greater impact together with fatty acids, while in CUMS, energy metabolism does not have much impact while there is greater alteration of amino acids associated with the monitoring of depression [31,52].…”

“…Related to the energy metabolism, pyruvic acid, which is increased in the 3 CUMS group, is the end-product of glycolysis, a major substrate for oxidative metabolism and a branching point for glucose, lactate, fatty acid and amino acid synthesis [30]. In previous CUMS studies, pyruvic acid was disturbed without being significant, and for this reason, we suggest that the increased pyruvic acid is related to the early response to stress instead of depression when pyruvic acid returns to its normal levels, leading to other metabolic changes [31]. The slightly plasmatic increase in 3-hydroxybutiric acid, a known ketone body, reflects an increase in energy production through fatty acid oxidation, supporting the idea that the disruption of carbohydrate and energy metabolism might be disrupted in the 3d CUMS group.…”

“…Related to the energy metabolism, pyruvic acid, which is increased in the 3 CUMS group, is the end-product of glycolysis, a major substrate for oxidative metabolism and a branching point for glucose, lactate, fatty acid and amino acid synthesis [ 30 ]. In previous CUMS studies, pyruvic acid was disturbed without being significant, and for this reason, we suggest that the increased pyruvic acid is related to the early response to stress instead of depression when pyruvic acid returns to its normal levels, leading to other metabolic changes [ 31 ].…”

Transthyretin as a Biomarker to Predict and Monitor Major Depressive Disorder Identified by Whole-Genome Transcriptomic Analysis in Mouse Models

“…Accumulated evidence has revealed the link between CMS and alteration of metabolism. For example, stressed animals demonstrate decreased food intake and preference, as well as decreased appetite hormone homeostasis and systematic metabolome changes [ 31 , 32 ]. Upon deeper examination, we found significant changes in gene families related to electron transfer in the mitochondria complexes of stressed mice, suggesting that energy consumption may be affected by CMS ( Figure 4 d,e).…”

Neurobiological effects of a probiotic-supplemented diet in chronically stressed male Long-Evans rats: Evidence of enhanced resilience

“…Whereas acute stress is often investigated in preclinical rodent studies, the extended duration of the chronic unpredictable stress paradigm in this study provided an opportunity to investigate the effects of PB supplements in chronically challenged animals. Since past research suggests that the effects of PB-supplemented diets are most influential in stressful conditions ( Papalini et al, 2018 ), the animals in this study were exposed to chronic unpredictable stress ( Kent et al, 2018 ), as this is a preclinical model with putative translational value for human stress-related illnesses including depression ( Geng et al, 2020 , Hariri and Holmes, 2015 , Nikolova et al, 2018 ).…”