Abstract
Major depressive disorder is caused by gene–environment interactions and the gut microbiota plays a pivotal role in the development of depression. However, the underlying mechanisms remain elusive. Herein, the differentially expressed hippocampal long non-coding RNAs (lncRNAs), messenger RNAs (mRNAs), and microRNAs (miRNAs) between mice inoculated with gut microbiota from major depressive disorder patients or healthy controls were detected, to identify the effects of gut microbiota-dysbiosis on gene regulation patterns at the transcriptome level, and in further to explore the microbial-regulated pathological mechanisms of depression. As a result, 200 mRNAs, 358 lncRNAs, and 4 miRNAs were differentially expressed between the two groups. Functional analysis of these differential mRNAs indicated dysregulated inflammatory response to be the primary pathological change. Intersecting these differential mRNAs with targets of differentially expressed miRNAs identified 47 intersected mRNAs, which were mainly related to neurodevelopment. Additionally, a microbial-regulated lncRNA–miRNA–mRNA network based on RNA–RNA interactions was constructed. Subsequently, according to the competitive endogenous RNAs (ceRNA) hypothesis and the biological functions of these intersected genes, two neurodevelopmental ceRNA sub-networks implicating in depression were identified, one including two lncRNAs (4930417H01Rik and AI480526), one miRNA (mmu-miR-883b-3p) and two mRNAs (Adcy1 and Nr4a2), and the other including six lncRNAs (5930412G12Rik, 6430628N08Rik, A530013C23Rik, A930007I19Rik, Gm15489, and Gm16251), one miRNA (mmu-miR-377-3p) and three mRNAs (Six4, Stx16, and Ube3a), and these molecules could be recognized as potential genetic and epigenetic biomarkers in microbial-associated depression. This study provides new understanding of the pathogenesis of depression induced by gut microbiota-dysbiosis and may act as a theoretical basis for the development of gut microbiota-based antidepressants.
Highlights
Major depressive disorder (MDD) is a heterogeneous and multifactorial psychiatric disorder
Microarray-based analysis of hippocampal tissues from gut microbiota-dysbiosis mice identified the levels of Long non-coding RNAs (lncRNAs), mRNAs, and miRNAs
Two neurodevelopmental-associated lncRNA– miRNA–mRNA competitive endogenous RNAs (ceRNAs) regulatory network were constructed in gut microbiota-dysbiosis-induced depression, one including two lncRNAs (4930417H01Rik and AI480526), one miRNA and two mRNAs (Adcy1 and Nr4a2), and the other including six lncRNAs (5930412G12Rik, 6430628N08Rik, A530013C23Rik, A930007I19Rik, Gm15489, and Gm16251), one miRNA and three mRNAs (Six4, Stx16, and Ube3a), and these molecules could be recognized as potential genetic and epigenetic biomarkers in microbial-associated depression
Summary
Major depressive disorder (MDD) is a heterogeneous and multifactorial psychiatric disorder. More than 350 million people suffer from depression and the lifetime prevalence of MDD is 6.8% (GBD 2017 Disease and Injury Incidence and Prevalence Collaborators, 2018). Gene–environment interaction plays a crucial role in the etiology of MDD (Assary et al, 2018). The gut microbiota, a community of microorganisms in the gastrointestinal tract, is a pivotal environmental factor that is recognized to play an important role in regulating human health and disease through microbiota–host bidirectional communication (Lynch and Pedersen, 2016). The gut microbiota may interact with genetic factors to co-regulate the host’s disease symptoms. A “pathogenic” microbiota may be sufficient to trigger a psychiatric condition, such as depression, even without a genetic risk
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