[Advances in neurobiological mechanisms of comorbid depression and gastrointestinal disease].

Depression is a common mood disorder, which is harmful to public health critically. Gastrointestinal diseases are a series of diseases with both dynamic changes and organic disease, including functional gastrointestinal disease, gastroesophageal reflux disease, gastritis, and gastric ulcer. In recent years, the phenomena of comorbid depression and gastrointestinal disease have become common, however, most patients were diagnosed as unilateral depression or gastrointestinal disease in the clinical treatment process, resulting in delayed treatment or even invalid. The present review focuses on some of the clinical symptoms of comorbid depression and gastrointestinal disease, and begins to explore the possible pathogenesis, so as to find out the potential neurobiological pathways of comorbidity. Consequently, the more attention on comorbid depression and gastrointestinal disease will be paid, and the clinical and basic research of comorbidity and the drug development will be provided.

Novel targets for ameliorating energy metabolism disorders in depression through stable isotope-resolved metabolomics.

The severe harm of depression to human health and life has attracted global attention, but the exact mechanism is not yet known due to the complicated pathogenesis. The existing antidepressants are far from ideal, indicating it is urgently needed to seek safe and effective drugs from a unique perspective. Based on the hypothesis of "mitochondrial dysfunction" proposed recently, we attempt to focus on the substrates supply of energy metabolism. We applied stable isotope-resolved metabolomics, and revealed that significantly decreased TCA cycle and abnormally increased gluconeogenesis pathway in CUMS rats. Pyruvate dehydrogenase (PDH) and pyruvate carboxylase (PC) maybe the key metabolic enzymes. This metabolic reprogramming was confirmed through ELISA assays and Western blot analysis. To explore the causes of substrates supply disorder in depression, we conducted the mitochondrial structure-function evaluation. Interestingly, the levels of the mitochondrial pyruvate carrier (MPC) decreased significantly, which is essential for the entry of pyruvic acid into the TCA cycle. Together, MPC, PDH and PC are expected to become potential novel therapeutic targets for treating depressive disorders. This research provides a unique insight for re-cognizing the pathological mechanisms of depression, the novel targets for development of ideal antidepressants, as well as a paradigm for deciphering abnormal metabolic pathways in other metabolic diseases.

Metabolomic analysis of the hippocampus in a rat model of chronic mild unpredictable stress-induced depression based on a pathway crosstalk and network module approach.

BACKGROUND: The molecular alterations underlying the pathogenesis of depression have not been systematically defined. Increasing evidence suggests that hippocampus metabolism is strongly involved in the pathogenesis of chronic mild unpredictable stress (CUMS)-induced depression. The principal objective of this study was to reveal important information concerning the pathogenesis of depression through a comprehensive analysis of metabolites in the hippocampus in a CUMS rat model. METHODS: Metabolites related to metabolic changes in the hippocampus in the CUMS model were collected from a depression-specific database and published literature. Potential metabolite pathways were identified by the Omicsolution tool. Then, crosstalk analysis was carried out to investigate the relationship between different important pathways. In addition, MetaboAnalyst was used to analyze potential metabolites for drug-related metabolite enrichment analysis, which was used to study hippocampus metabolite-related drug pathways in a CUMS model. Then, a metabolite-protein interaction (MPI) network was constructed and analyzed to identify important metabolites and proteins. The functional modules were extracted using the CNM network decomposition algorithm. Finally, neurotransmitters in the hippocampus of rats with CUMS depression were detected to verify the important pathways. RESULTS: In the current study, 53 significantly enriched pathways related to the 107 identified metabolites were selected, and the top ranked enriched pathways included arginine and proline metabolism, neuroactive ligand-receptor interaction, phenylalanine metabolism, bile secretion, and glutathione metabolism. Pathway crosstalk analysis showed that the significantly enriched pathways were divided into two interrelated modules, which were mainly involved in metabolism, signal transduction, neurotransmitters, and the endocrine system. Enrichment analysis of drug-related metabolic KEGG pathways identified the antibiotic pathways as the most important pathways. In the MPI network, the hub metabolites were phosphate, arachidonic acid, oxoglutaric acid, l-glutamic acid, and glutathione, and the hub proteins were Got1, Got2, Tat, Ccbl1, Ccbl2, Il4i1. A total of 16 functional modules were extracted from the MPI network by using the CNM algorithm. Finally, metabolites related to serotonergic synapses, dopaminergic synapses, and glutamatergic synapses were found to be involved in the pathology of depression. CONCLUSION: We found that neurotransmitter pathways (serotonergic synapses, dopaminergic synapses and glutamatergic synapses) in the hippocampus play a crucial role in the underlying molecular mechanism of depression, which provides useful clues for identifying the detailed depression-associated metabolic profiles.

A unique insight for energy metabolism disorders in depression based on chronic unpredictable mild stress rats using stable isotope-resolved metabolomics.

Depression is currently the main disease which endangers human health and emotion. However, the existing antidepressants have the disadvantages of slowly taking effect and high recurrence rate. Numerous studies have shown that depression causes disorders in energy metabolism, but the specific metabolic pathways remain unclear. The stable isotope-resolved metabolomics (SIRM) can clarify the specific metabolic pathways of energy metabolism disorders in depression and provide a strong basis for the pathogenesis of depression and new targets for the development of new antidepressants. We applied this method to the chronic unpredictable mild stress (CUMS) model, and the metabolites related to energy metabolism were comprehensively analyzed on HILIC and T3 columns through LC-MS. Conventional untargeted metabolomics found 50 differential metabolites, and most of them were focused on the energy metabolism pathway. SIRM exhibited that 78 metabolites related to energy metabolism were labeled, and 28 of them were observed significantly changed in the model group compared with control. Our results revealed depression inhibited TCA cycle and activated gluconeogenesis pathway, and abnormally increased pyruvic acid may participate in pyrimidine biosynthesis, phospholipid synthesis, and amino acid metabolism pathways. Pyruvate carboxylase (PC), pyruvate dehydrogenase (PDH), aspartate aminotransferase (AST) and phosphoenolpyruvate carboxykinase (PEPC) may be the new targets for depression. We established a SIRM method at animal level. To the best of our knowledge, it is the first time to apply the method for the study of depression. The method is of great significance and value for further explaining the pathogenesis of depression and the development of antidepressants.