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Huang C, Lin J, Chen L, Sun W, Xia J, Wu M. Upregulation of C1QC as a Mediator of Blood-Brain Barrier Damage in Type 2 Diabetes Mellitus. Mol Neurobiol 2025; 62:5234-5251. [PMID: 39531193 DOI: 10.1007/s12035-024-04615-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/18/2024] [Accepted: 11/05/2024] [Indexed: 11/16/2024]
Abstract
The blood-brain barrier (BBB) is a neurovascular structure that safeguards the brain by inhibiting the passage of harmful substances. In individuals with type 2 diabetes mellitus (T2DM), the heightened blood glucose may cause damage to endothelial cells and neurons, increase collagen protein content, and elevate BBB permeability. Although the impact of blood glucose regulation on the structure and function of BBB has been documented, the exact mechanism remains incompletely elucidated. The primary aim of this investigation was to uncover the pivotal dysregulation of specific genes observed within the cerebral microvascular endothelial cells of diabetic patients, with a particular focus on understanding its biological implications in the disruption of the BBB. By integrating bioinformatics analysis, we identified C1QC as a potential upregulated marker. The expression level of C1QC was subsequently verified in both in vivo and in vitro models. Our experiments have discovered that, under diabetic conditions, suppressing C1QC leads to the mitigation of BBB damage. The presence of a high level of C1QC, through its binding to discoidin domain receptor 2 (DDR2), may trigger the activation of its downstream MMP9, a calcium-dependent enzyme that is capable of degrading protein components in the extracellular matrix, consequently leading to the structural and functional disruption of BBB. In summary, the findings of this study indicate that the aberrantly upregulated expression of C1QC may exert deleterious effects on the BBB under diabetes. To alleviate neurological impairments in individuals with T2DM, C1QC may emerge as a promising therapeutic target worthy of further investigation.
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Affiliation(s)
- Cheng Huang
- Department of Neurology, The Second Affiliated Hospital (Xinqiao Hospital), Army Medical University (Third Military Medical University), Chongqing, China
| | - Jiaxing Lin
- Department of Neurology, The Second Affiliated Hospital, Guangzhou Medical University, Guangzhou, China
| | - Lan Chen
- Taylor's University, Subang Jaya, Malaysia
| | - Wenzhe Sun
- Department of Neurology, The Second Affiliated Hospital (Xinqiao Hospital), Army Medical University (Third Military Medical University), Chongqing, China
| | - Jinjun Xia
- Department of Clinical Laboratory, Wuxi 9th People's Hospital Affiliated to Soochow University, Wuxi, China
| | - Min Wu
- Department of Neurosurgery, Guizhou Provincial People's Hospital, Guiyang, China.
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2
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Zhang Y, Liu C, Zhu Q, Wu H, Liu Z, Zeng L. Relationship Between Depression and Epigallocatechin Gallate from the Perspective of Gut Microbiota: A Systematic Review. Nutrients 2025; 17:259. [PMID: 39861389 PMCID: PMC11767295 DOI: 10.3390/nu17020259] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/06/2024] [Revised: 01/07/2025] [Accepted: 01/10/2025] [Indexed: 01/27/2025] Open
Abstract
Depression, a serious mental illness, is characterized by high risk, high incidence, persistence, and tendency to relapse, posing a significant burden on global health. The connection between depression and gut microbiota is an emerging field of study in psychiatry and neuroscience. Understanding the gut-brain axis is pivotal for understanding the pathogenesis and treatment of depression. Gut microbes influence depression-like behaviors by impacting the hypothalamic-pituitary-adrenal axis (HPA), monoamine neurotransmitters, immune responses, cell signaling, and metabolic pathways. Tea, widely used in clinical practice to improve neuropsychiatric disorders, contains Epigallocatechin gallate (EGCG), a major ingredient of green tea, which effectively regulates intestinal flora. This review examined the risks and causes of depression, the complications associated with intestinal flora, their role in the development and treatment of depression, and how EGCG may alleviate depression through interactions with gut microbiota and other mechanisms.
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Affiliation(s)
- Yangbo Zhang
- School of Pharmacy, Shaoyang University, Shaoyang 422000, China; (Y.Z.); (Q.Z.); (H.W.)
- Key Laboratory of Tea Science of Ministry of Education, Hunan Agricultural University, Changsha 410128, China;
| | - Changwei Liu
- Key Laboratory of Tea Science of Ministry of Education, Hunan Agricultural University, Changsha 410128, China;
- School of Life and Health Sciences, Hunan University of Science and Technology, Xiangtan 411201, China
| | - Qi Zhu
- School of Pharmacy, Shaoyang University, Shaoyang 422000, China; (Y.Z.); (Q.Z.); (H.W.)
| | - Hui Wu
- School of Pharmacy, Shaoyang University, Shaoyang 422000, China; (Y.Z.); (Q.Z.); (H.W.)
| | - Zhonghua Liu
- Key Laboratory of Tea Science of Ministry of Education, Hunan Agricultural University, Changsha 410128, China;
- National Research Center of Engineering and Technology for Utilization of Botanical Functional Ingredients, Hunan Agricultural University, Changsha 410128, China
- Co-Innovation Center of Education Ministry for Utilization of Botanical Functional Ingredients, Hunan Agricultural University, Changsha 410128, China
| | - Li Zeng
- School of Pharmacy, Shaoyang University, Shaoyang 422000, China; (Y.Z.); (Q.Z.); (H.W.)
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3
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Huang C, Liu Y, Wang S, Xia J, Hu D, Xu R. From Genes to Metabolites: HSP90B1's Role in Alzheimer's Disease and Potential for Therapeutic Intervention. Neuromolecular Med 2025; 27:6. [PMID: 39760808 DOI: 10.1007/s12017-024-08822-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/07/2024] [Accepted: 12/06/2024] [Indexed: 01/07/2025]
Abstract
Alzheimer's disease (AD) is a prototypical neurodegenerative disorder, predominantly affecting individuals in the presenile and elderly populations, with an etiology that remains elusive. This investigation aimed to elucidate the alterations in anoikis-related genes (ARGs) in the AD brain, thereby expanding the repertoire of biomarkers for the disease. Using publically available gene expression data for the hippocampus from both healthy and AD subjects, differentially expressed genes (DEGs) were identified. Subsequent intersection with a comprehensive list of 575 ARGs yielded a subset for enrichment analysis. Machine learning algorithms were employed to identify potential biomarker, which was validated in an AD animal model. Additionally, gene set enrichment analysis was conducted on the biomarker and its interacting genes and microRNAs were predicted through online databases. To assess its biological functions, the expression of the marker was suppressed in an in vitro model to examine cell viability and inflammation-related indicators. Furthermore, following treatment with the inhibitor, the dysregulated metabolites in the hippocampus of the model mice were evaluated. Forty-seven ARGs were ultimately identified, with HSP90B1 emerging as a central marker. HSP90B1 was found to be significantly up-regulated in AD hippocampal samples and its inhibition conferred increased cell viability and reduced levels of inflammatory factors in amyloid β-protein (Aβ)-treated cells. A total of 24 differentially expressed metabolites were confidently identified between model mice and those with low HSP90B1 expression, with bioinformatics analysis shedding light on the molecular underpinnings of HSP90B1's involvement in AD. Collectively, these findings may inform novel insights into the pathogenesis, mechanisms, or therapeutic strategies for AD.
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Affiliation(s)
- Cheng Huang
- Department of Neurology, Second Affiliated Hospital of Army Medical University (Xinqiao Hospital), Chongqing, China
| | - Ying Liu
- Department of Geriatrics, Chongqing General Hospital, Chongqing University, Chongqing, China
| | - Shuxin Wang
- Department of Neurology, Second Affiliated Hospital of Army Medical University (Xinqiao Hospital), Chongqing, China
| | - Jinjun Xia
- Department of Clinical Laboratory, Wuxi 9th People's Hospital Affiliated to Soochow University, No. 999 Liang Xi Road, Binhu District, Wuxi, 214000, Jiangsu, China
| | - Di Hu
- Department of Neurology, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, China
| | - Rui Xu
- Department of Neurology, Second Affiliated Hospital of Army Medical University (Xinqiao Hospital), Chongqing, China.
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Iglesias Pastrana C, Navas González FJ, Macri M, Martínez Martínez MDA, Ciani E, Delgado Bermejo JV. Identification of novel genetic loci related to dromedary camel (Camelus dromedarius) morphometrics, biomechanics, and behavior by genome-wide association studies. BMC Vet Res 2024; 20:418. [PMID: 39294626 PMCID: PMC11409489 DOI: 10.1186/s12917-024-04263-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/24/2024] [Accepted: 09/03/2024] [Indexed: 09/21/2024] Open
Abstract
In the realm of animal breeding for sustainability, domestic camels have traditionally been valued for their milk and meat production. However, key aspects such as zoometrics, biomechanics, and behavior have often been overlooked in terms of their genetic foundations. Recognizing this gap, the present study perfomed genome-wide association analyses to identify genetic markers associated with zoometrics-, biomechanics-, and behavior-related traits in dromedary camels (Camelus dromedarius). 16 and 108 genetic markers were significantly associated (q < 0.05) at genome and chromosome-wide levels of significance, respectively, with zoometrics- (width, length, and perimeter/girth), biomechanics- (acceleration, displacement, spatial position, and velocity), and behavior-related traits (general cognition, intelligence, and Intelligence Quotient (IQ)) in dromedaries. In most association loci, the nearest protein-coding genes are linkedto neurodevelopmental and sensory disorders. This suggests that genetic variations related to neural development and sensory perception play crucial roles in shaping a dromedary camel's physical characteristics and behavior. In summary, this research advances our understanding of the genomic basis of essential traits in dromedary camels. Identifying specific genetic markers associated with zoometrics, biomechanics, and behavior provides valuable insights into camel domestication. Moreover, the links between these traits and genes related to neurodevelopmental and sensory disorders highlight the broader implications of domestication and modern selection on the health and welfare of dromedary camels. This knowledge could guide future breeding strategies, fostering a more holistic approach to camel husbandry and ensuring the sustainability of these animals in diverse agricultural contexts.
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Affiliation(s)
| | | | - Martina Macri
- Department of Genetics, Faculty of Veterinary Sciences, University of Córdoba, Córdoba, Spain
- Animal Breeding Consulting S.L, Parque Científico Tecnológico de Córdoba, Córdoba, Spain
| | | | - Elena Ciani
- Department of Biosciences, Biotechnologies and Environment, Faculty of Veterinary Sciences, University of Bari 'Aldo Moro', Bari, Italy
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Chen CY, Wang YF, Lei L, Zhang Y. Impacts of microbiota and its metabolites through gut-brain axis on pathophysiology of major depressive disorder. Life Sci 2024; 351:122815. [PMID: 38866215 DOI: 10.1016/j.lfs.2024.122815] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/03/2024] [Revised: 05/21/2024] [Accepted: 06/04/2024] [Indexed: 06/14/2024]
Abstract
Major depressive disorder (MDD) is characterized by a high rate of recurrence and disability, which seriously affects the quality of life of patients. That's why a deeper understanding of the mechanisms of MDD pathology is an urgent task, and some studies have found that intestinal symptoms accompany people with MDD. The microbiota-gut-brain axis is the bidirectional communication between the gut microbiota and the central nervous system, which was found to have a strong association with the pathogenesis of MDD. Previous studies have focused more on the communication between the gut and the brain through neuroendocrine, neuroimmune and autonomic pathways, and the role of gut microbes and their metabolites in depression is unclear. Metabolites of intestinal microorganisms (e.g., tryptophan, kynurenic acid, indole, and lipopolysaccharide) can participate in the pathogenesis of MDD through immune and inflammatory pathways or by altering the permeability of the gut and blood-brain barrier. In addition, intestinal microbes can communicate with intestinal neurons and glial cells to affect the integrity and function of intestinal nerves. However, the specific role of gut microbes and their metabolites in the pathogenesis of MDD is not well understood. Hence, the present review summarizes how gut microbes and their metabolites are directly or indirectly involved in the pathogenesis of MDD.
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Affiliation(s)
- Cong-Ya Chen
- Department of Anatomy, School of Chinese Medicine, Beijing University of Chinese Medicine, Beijing 102488, China
| | - Yu-Fei Wang
- Department of Anatomy, School of Chinese Medicine, Beijing University of Chinese Medicine, Beijing 102488, China
| | - Lan Lei
- Department of Anatomy, School of Chinese Medicine, Beijing University of Chinese Medicine, Beijing 102488, China
| | - Yi Zhang
- Department of Anatomy, School of Chinese Medicine, Beijing University of Chinese Medicine, Beijing 102488, China.
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Wang Q, Gu Y, Chen J, Liu X, Xie C, Wang X. Bioinformatics gene analysis for potential biomarkers and therapeutic targets of Parkinson's disease based on neutrophil extracellular traps. Front Aging Neurosci 2024; 16:1388226. [PMID: 38882525 PMCID: PMC11178047 DOI: 10.3389/fnagi.2024.1388226] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/19/2024] [Accepted: 04/30/2024] [Indexed: 06/18/2024] Open
Abstract
Introduction Neutrophil extracellular traps (NETs) provide key innate immune mechanisms, and studies have shown innate immunity and adaptive immunity are directly linked to Parkinson's disease (PD) pathology. However, limited research has been conducted on NETs in the context of PD. Methods A differential analysis was implemented to acquire differentially expressed genes (DEGs) between PD and control as well as between high- and low-score groups determined by a gene set variation analysis (GSVA). Then, the genes within the critical module, obtained through a weighted gene co-expression network analysis (WGCNA), were intersected with the DEGs to identify the overlapping genes. Then, five kinds of algorithms in the protein-protein interaction (PPI) were performed to identify potential biomarkers. Subsequently, a nomogram for forecasting PD probability was created. An enrichment analysis and an immune infiltration analysis were performed on the identified biomarkers. qRT-PCR was performed to validate the expression trends of three biomarkers. Results We revealed 798 DEGs between PD and control groups as well as 168 DEGs between high- and low-score groups obtained by differential analyses. The pink module containing 926 genes was identified as the critical module. According to the intersection of these gene sets, a total of 43 overlapping genes were screened out. Furthermore, GPR78, CADM3, and CACNA1E were confirmed as biomarkers. Moreover, we found that biomarkers mainly participated in pathways, such as the 'hydrogen peroxide catabolic process', and 'cell cycle'; five kinds of differential immune cells between PD and control groups were identified. Finally, the qRT-PCR analysis demonstrated the up-regulation of GPR78, CADM3, and CACNA1E in the PD group. Discussion Our study authenticated GPR78, CADM3, and CACNA1E as the biomarkers associated with PD. These findings provide an original reference for the diagnosis and treatment of PD.
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Affiliation(s)
- Qiang Wang
- Department of Neurology, The First Hospital of Lanzhou University, Lanzhou, China
| | - Youquan Gu
- Department of Neurology, The First Hospital of Lanzhou University, Lanzhou, China
| | - Jun Chen
- Department of Neurology, The First Hospital of Lanzhou University, Lanzhou, China
| | - Xiaoyan Liu
- Chengdu shi Longquanyi qu Diyi Renmin Yiyuan: The First People's Hospital of Longquanyi District, Longquanyi District, Chengdu, China
| | - Chen Xie
- Department of Neurology, The First Hospital of Lanzhou University, Lanzhou, China
| | - Xueping Wang
- Department of Neurology, The First Hospital of Lanzhou University, Lanzhou, China
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Feng H, Hu X, Lin Y, Xiao J, Dai C, Hu Z, Feng H, Qin J, Chen L. Dexmedetomidine attenuates acute stress-impaired learning and memory in mice by maintaining the homeostasis of intestinal flora. Eur J Med Res 2024; 29:271. [PMID: 38711117 DOI: 10.1186/s40001-024-01832-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/07/2024] [Accepted: 04/05/2024] [Indexed: 05/08/2024] Open
Abstract
Dexmedetomidine (Dex) has been used in surgery to improve patients' postoperative cognitive function. However, the role of Dex in stress-induced anxiety-like behaviors and cognitive impairment is still unclear. In this study, we tested the role of Dex in anxiety-like behavior and cognitive impairment induced by acute restrictive stress and analyzed the alterations of the intestinal flora to explore the possible mechanism. Behavioral and cognitive tests, including open field test, elevated plus-maze test, novel object recognition test, and Barnes maze test, were performed. Intestinal gut Microbe 16S rRNA sequencing was analyzed. We found that intraperitoneal injection of Dex significantly improved acute restrictive stress-induced anxiety-like behavior, recognition, and memory impairment. After habituation in the environment, mice (male, 8 weeks, 18-23 g) were randomly divided into a control group (control, N = 10), dexmedetomidine group (Dex, N = 10), AS with normal saline group (AS + NS, N = 10) and AS with dexmedetomidine group (AS + Dex, N = 10). By the analysis of intestinal flora, we found that acute stress caused intestinal flora disorder in mice. Dex intervention changed the composition of the intestinal flora of acute stress mice, stabilized the ecology of the intestinal flora, and significantly increased the levels of Blautia (A genus of anaerobic bacteria) and Coprobacillus. These findings suggest that Dex attenuates acute stress-impaired learning and memory in mice by maintaining the homeostasis of intestinal flora.
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Affiliation(s)
- Hao Feng
- Department of Dermatology, Hunan Provincial People's Hospital (The First Affiliated Hospital of Hunan Normal University), Changsha, Hunan, 410000, People's Republic of China
| | - Xing Hu
- Department of Dermatology, Hunan Provincial People's Hospital (The First Affiliated Hospital of Hunan Normal University), Changsha, Hunan, 410000, People's Republic of China
| | - Yizi Lin
- Department of Radiology, The Third Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, 325200, People's Republic of China
| | - Jingni Xiao
- Department of Nephrology, Hengyang Medical School, University of South China Affiliated Changsha Central Hospital, No. 161 Shaoshan South Road, Changsha, Hunan, 410004, People's Republic of China
| | - Chao Dai
- Department of Nephrology, Hengyang Medical School, University of South China Affiliated Changsha Central Hospital, No. 161 Shaoshan South Road, Changsha, Hunan, 410004, People's Republic of China
| | - Zhaolan Hu
- Department of Anesthesiology, The Second Xiangya Hospital, Central South University, 139 Ren-Min Central Road, Changsha City, Hunan, 410011, People's Republic of China
| | - Hao Feng
- State Key Laboratory of Developmental Biology of Freshwater Fish, College of Life Science, Hunan Normal University, Changsha, 410081, People's Republic of China
| | - Jiao Qin
- Department of Nephrology, Hengyang Medical School, University of South China Affiliated Changsha Central Hospital, No. 161 Shaoshan South Road, Changsha, Hunan, 410004, People's Republic of China.
| | - Li Chen
- Department of Anesthesiology, The Third Affiliated Hospital of Wenzhou Medical University, No.108 Wansong Road, Wenzhou, Zhejiang, 325200, People's Republic of China.
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8
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Chang M, Chang KT, Chang F. Just a gut feeling: Faecal microbiota transplant for treatment of depression - A mini-review. J Psychopharmacol 2024; 38:353-361. [PMID: 38532577 DOI: 10.1177/02698811241240308] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 03/28/2024]
Abstract
BACKGROUND The microbiota-gut-brain axis (MGBA) allows bidirectional crosstalk between the brain and gut microbiota (GM) and is believed to contribute to regulating mood/cognition/behaviour/metabolism/health and homeostasis. Manipulation of GM through faecal microbiota transplant (FMT) is a new, exciting and promising treatment for major depressive disorder (MDD). AIMS This mini-review examines current research into GM and FMT as a therapy for depression. METHODS Original research articles published in Medline/Cochrane Library/PubMed/EMBASE/PsycINFO databases/National Institute of Health website Clinicaltrials.gov/controlled-trials.com were searched. Full articles included in reference lists were evaluated. We summarise current data on GM and depression and discuss communication through the MGBA and the interaction of antidepressants and GM through this. We review compositions of dysbiosis in depressed cohorts, focusing on future directions in the treatment of MDD. RESULTS Studies have demonstrated significant gut dysbiosis in depressed patients compared to healthy cohorts, with overgrowth of pro-inflammatory microbiota, reduction in anti-inflammatory species and reduced overall stability and taxonomic richness. FMT allows the introduction of healthy microbiota into the gastrointestinal tract, facilitating the restoration of eubiosis. CONCLUSION The GM plays an integral role in human health and disease through its communication with the rest of the body via the MGBA. FMT may provide a means to transfer the healthy phenotype into the recipient and this concept in humans is attracting enormous attention as a prospective treatment for psychopathologies, such as MDD, in the future. It may be possible to manipulate the GM in a number of ways, but further research is needed to determine the exact likelihood and profiles involved in the development and amelioration of MDD in humans, as well as the long-term effects and potential risks of this procedure.
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Affiliation(s)
- Minna Chang
- Epsom and St Helier Hospital University and Hospital Trust, Sutton, Carshalton, UK
| | | | - Fuju Chang
- King's College London, Gastrointestinal Research Group, School of Cancer and Pharmaceutical Sciences, Strand, London, UK
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Han S, Li Z, Shi Y, Cui Y, Huang J, Frost DC, Rey FE, Liu R, Li L. 11-Plex DiLeu Isobaric Labeling Enables Quantitative Assessment of Brain Region Protein Association Networks Impacted by the Gut Microbiome. Anal Chem 2024; 96:3870-3878. [PMID: 38373348 PMCID: PMC11757003 DOI: 10.1021/acs.analchem.3c05327] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/21/2024]
Abstract
Gut microbiota can regulate host brain functions and influence various physiological and pathological processes through the brain-gut axis. To systematically elucidate the intervention of different gut environments on different brain regions, we implemented an integrated approach that combines 11-plex DiLeu isobaric tags with a "BRIDGE" normalization strategy to comparatively analyze the proteome of six brain regions in germ-free (GF)- and conventionally raised (ConvR)-mice. A total of 5945 proteins were identified and 5656 were quantifiable, while 1906 of them were significantly changed between GF- and ConvR-mice; 281 proteins were filtered with FC greater than 1.2 in at least one brain region, of which heatmap analysis showed clear protein profile disparities, both between brain regions and gut microbiome conditions. Gut microbiome impact is most overt in the hypothalamus and the least in the thalamus region. Collectively, this approach allows an in-depth investigation of the induced protein changes by multiple gut microbiome environments in a brain region-specific manner. This comprehensive proteomic work improves the understanding of the brain region protein association networks impacted by the gut microbiome and highlights the critical roles of the brain-gut axis.
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Affiliation(s)
- Shuying Han
- Jiangsu Collaborative Innovation Center of Chinese Medicinal Resources Industrialization, and National and Local Collaborative Engineering Center of Chinese Medicinal Resources Industrialization and Formulae Innovative Medicine, Nanjing 210023, PR China
- School of Pharmacy, University of Wisconsin-Madison, Madison, Wisconsin 53705, United States
- School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing 210023, PR China
| | - Zihui Li
- Department of Chemistry, University of Wisconsin-Madison, Madison, Wisconsin 53706, United States
| | - Yatao Shi
- School of Pharmacy, University of Wisconsin-Madison, Madison, Wisconsin 53705, United States
| | - Yusi Cui
- Department of Chemistry, University of Wisconsin-Madison, Madison, Wisconsin 53706, United States
| | - Junfeng Huang
- School of Pharmacy, University of Wisconsin-Madison, Madison, Wisconsin 53705, United States
| | - Dustin C. Frost
- School of Pharmacy, University of Wisconsin-Madison, Madison, Wisconsin 53705, United States
| | - Federico E. Rey
- Department of Bacteriology, University of Wisconsin-Madison, Madison, Wisconsin 53705, United States
| | - Rui Liu
- Jiangsu Collaborative Innovation Center of Chinese Medicinal Resources Industrialization, and National and Local Collaborative Engineering Center of Chinese Medicinal Resources Industrialization and Formulae Innovative Medicine, Nanjing 210023, PR China
- School of Pharmacy, University of Wisconsin-Madison, Madison, Wisconsin 53705, United States
- School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing 210023, PR China
- Animal-Derived Chinese Medicine and Functional Peptides International Collaboration Joint Laboratory, Nanjing 210023, PR China
| | - Lingjun Li
- School of Pharmacy, University of Wisconsin-Madison, Madison, Wisconsin 53705, United States
- Department of Chemistry, University of Wisconsin-Madison, Madison, Wisconsin 53706, United States
- Lachman Institute for Pharmaceutical Development, School of Pharmacy, University of Wisconsin-Madison, Madison, WI 53705, United States
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10
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McGuinness AJ, Loughman A, Foster JA, Jacka F. Mood Disorders: The Gut Bacteriome and Beyond. Biol Psychiatry 2024; 95:319-328. [PMID: 37661007 DOI: 10.1016/j.biopsych.2023.08.020] [Citation(s) in RCA: 6] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/18/2023] [Revised: 08/09/2023] [Accepted: 08/29/2023] [Indexed: 09/05/2023]
Abstract
Knowledge of the microbiome-gut-brain axis has revolutionized the field of psychiatry. It is now well recognized that the gut bacteriome is associated with, and likely influences, the pathogenesis of mental disorders, including major depressive disorder and bipolar disorder. However, while substantial advances in the field of microbiome science have been made, we have likely only scratched the surface in our understanding of how these ecosystems might contribute to mental disorder pathophysiology. Beyond the gut bacteriome, research into lesser explored components of the gut microbiome, including the gut virome, mycobiome, archaeome, and parasitome, is increasingly suggesting relevance in psychiatry. The contribution of microbiomes beyond the gut, including the oral, lung, and small intestinal microbiomes, to human health and pathology should not be overlooked. Increasing both our awareness and understanding of these less traversed fields of research are critical to improving the therapeutic benefits of treatments targeting the gut microbiome, including fecal microbiome transplantation, postbiotics and biogenics, and dietary intervention. Interdisciplinary collaborations integrating systems biology approaches are required to fully elucidate how these different microbial components and distinct microbial niches interact with each other and their human hosts. Excitingly, we may be at the start of the next microbiome revolution and thus one step closer to informing the field of precision psychiatry to improve outcomes for those living with mental illness.
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Affiliation(s)
- Amelia J McGuinness
- Food and Mood Centre, Institute for Mental and Physical Health and Clinical Translation, School of Medicine, Deakin University, Geelong, Australia.
| | - Amy Loughman
- Food and Mood Centre, Institute for Mental and Physical Health and Clinical Translation, School of Medicine, Deakin University, Geelong, Australia
| | - Jane A Foster
- Center for Depression Research and Clinical Care, Department of Psychiatry, UT Southwestern Medical Center, Dallas, Texas
| | - Felice Jacka
- Food and Mood Centre, Institute for Mental and Physical Health and Clinical Translation, School of Medicine, Deakin University, Geelong, Australia; Centre for Adolescent Health, Murdoch Children's Research Institute, Melbourne, Victoria, Australia; College of Public Health, Medical and Veterinary Sciences, James Cook University, Townsville, Queensland, Australia
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11
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Cui L, Li S, Wang S, Wu X, Liu Y, Yu W, Wang Y, Tang Y, Xia M, Li B. Major depressive disorder: hypothesis, mechanism, prevention and treatment. Signal Transduct Target Ther 2024; 9:30. [PMID: 38331979 PMCID: PMC10853571 DOI: 10.1038/s41392-024-01738-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/20/2023] [Revised: 12/24/2023] [Accepted: 12/28/2023] [Indexed: 02/10/2024] Open
Abstract
Worldwide, the incidence of major depressive disorder (MDD) is increasing annually, resulting in greater economic and social burdens. Moreover, the pathological mechanisms of MDD and the mechanisms underlying the effects of pharmacological treatments for MDD are complex and unclear, and additional diagnostic and therapeutic strategies for MDD still are needed. The currently widely accepted theories of MDD pathogenesis include the neurotransmitter and receptor hypothesis, hypothalamic-pituitary-adrenal (HPA) axis hypothesis, cytokine hypothesis, neuroplasticity hypothesis and systemic influence hypothesis, but these hypothesis cannot completely explain the pathological mechanism of MDD. Even it is still hard to adopt only one hypothesis to completely reveal the pathogenesis of MDD, thus in recent years, great progress has been made in elucidating the roles of multiple organ interactions in the pathogenesis MDD and identifying novel therapeutic approaches and multitarget modulatory strategies, further revealing the disease features of MDD. Furthermore, some newly discovered potential pharmacological targets and newly studied antidepressants have attracted widespread attention, some reagents have even been approved for clinical treatment and some novel therapeutic methods such as phototherapy and acupuncture have been discovered to have effective improvement for the depressive symptoms. In this work, we comprehensively summarize the latest research on the pathogenesis and diagnosis of MDD, preventive approaches and therapeutic medicines, as well as the related clinical trials.
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Affiliation(s)
- Lulu Cui
- Department of Forensic Analytical Toxicology, School of Forensic Medicine, China Medical University, Shenyang, China
- Liaoning Province Key Laboratory of Forensic Bio-evidence Sciences, Shenyang, China
- China Medical University Centre of Forensic Investigation, Shenyang, China
| | - Shu Li
- Department of Forensic Analytical Toxicology, School of Forensic Medicine, China Medical University, Shenyang, China
- Liaoning Province Key Laboratory of Forensic Bio-evidence Sciences, Shenyang, China
- China Medical University Centre of Forensic Investigation, Shenyang, China
| | - Siman Wang
- Department of Forensic Analytical Toxicology, School of Forensic Medicine, China Medical University, Shenyang, China
- Liaoning Province Key Laboratory of Forensic Bio-evidence Sciences, Shenyang, China
- China Medical University Centre of Forensic Investigation, Shenyang, China
| | - Xiafang Wu
- Department of Forensic Analytical Toxicology, School of Forensic Medicine, China Medical University, Shenyang, China
- Liaoning Province Key Laboratory of Forensic Bio-evidence Sciences, Shenyang, China
- China Medical University Centre of Forensic Investigation, Shenyang, China
| | - Yingyu Liu
- Department of Forensic Analytical Toxicology, School of Forensic Medicine, China Medical University, Shenyang, China
- Liaoning Province Key Laboratory of Forensic Bio-evidence Sciences, Shenyang, China
- China Medical University Centre of Forensic Investigation, Shenyang, China
| | - Weiyang Yu
- Department of Forensic Analytical Toxicology, School of Forensic Medicine, China Medical University, Shenyang, China
- Liaoning Province Key Laboratory of Forensic Bio-evidence Sciences, Shenyang, China
- China Medical University Centre of Forensic Investigation, Shenyang, China
| | - Yijun Wang
- Department of Forensic Analytical Toxicology, School of Forensic Medicine, China Medical University, Shenyang, China
- Liaoning Province Key Laboratory of Forensic Bio-evidence Sciences, Shenyang, China
- China Medical University Centre of Forensic Investigation, Shenyang, China
| | - Yong Tang
- International Joint Research Centre on Purinergic Signalling/Key Laboratory of Acupuncture for Senile Disease (Chengdu University of TCM), Ministry of Education/School of Health and Rehabilitation, Chengdu University of Traditional Chinese Medicine/Acupuncture and Chronobiology Key Laboratory of Sichuan Province, Chengdu, China
| | - Maosheng Xia
- Department of Orthopaedics, The First Hospital, China Medical University, Shenyang, China.
| | - Baoman Li
- Department of Forensic Analytical Toxicology, School of Forensic Medicine, China Medical University, Shenyang, China.
- Liaoning Province Key Laboratory of Forensic Bio-evidence Sciences, Shenyang, China.
- China Medical University Centre of Forensic Investigation, Shenyang, China.
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12
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Nohesara S, Abdolmaleky HM, Zhou JR, Thiagalingam S. Microbiota-Induced Epigenetic Alterations in Depressive Disorders Are Targets for Nutritional and Probiotic Therapies. Genes (Basel) 2023; 14:2217. [PMID: 38137038 PMCID: PMC10742434 DOI: 10.3390/genes14122217] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/15/2023] [Revised: 12/08/2023] [Accepted: 12/11/2023] [Indexed: 12/24/2023] Open
Abstract
Major depressive disorder (MDD) is a complex disorder and a leading cause of disability in 280 million people worldwide. Many environmental factors, such as microbes, drugs, and diet, are involved in the pathogenesis of depressive disorders. However, the underlying mechanisms of depression are complex and include the interaction of genetics with epigenetics and the host immune system. Modifications of the gut microbiome and its metabolites influence stress-related responses and social behavior in patients with depressive disorders by modulating the maturation of immune cells and neurogenesis in the brain mediated by epigenetic modifications. Here, we discuss the potential roles of a leaky gut in the development of depressive disorders via changes in gut microbiota-derived metabolites with epigenetic effects. Next, we will deliberate how altering the gut microbiome composition contributes to the development of depressive disorders via epigenetic alterations. In particular, we focus on how microbiota-derived metabolites such as butyrate as an epigenetic modifier, probiotics, maternal diet, polyphenols, drugs (e.g., antipsychotics, antidepressants, and antibiotics), and fecal microbiota transplantation could positively alleviate depressive-like behaviors by modulating the epigenetic landscape. Finally, we will discuss challenges associated with recent therapeutic approaches for depressive disorders via microbiome-related epigenetic shifts, as well as opportunities to tackle such problems.
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Affiliation(s)
- Shabnam Nohesara
- Department of Medicine (Biomedical Genetics), Boston University Chobanian & Avedisian School of Medicine, Boston, MA 02118, USA;
| | - Hamid Mostafavi Abdolmaleky
- Nutrition/Metabolism Laboratory, Department of Surgery, Beth Israel Deaconess Medical Center, Harvard Medical School, Boson, MA 02215, USA;
| | - Jin-Rong Zhou
- Nutrition/Metabolism Laboratory, Department of Surgery, Beth Israel Deaconess Medical Center, Harvard Medical School, Boson, MA 02215, USA;
| | - Sam Thiagalingam
- Department of Medicine (Biomedical Genetics), Boston University Chobanian & Avedisian School of Medicine, Boston, MA 02118, USA;
- Department of Pathology & Laboratory Medicine, Boston University Chobanian & Avedisian School of Medicine, Boston, MA 02118, USA
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13
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Lv H, Gao Z, Wang Y, Chen S, Liu P, Xie Y, Guan M, Cong J, Xu Y. Metformin Improves Comorbid Depressive Symptoms in Mice with Allergic Rhinitis by Reducing Olfactory Bulb Damage. Neurochem Res 2023; 48:3639-3651. [PMID: 37574530 DOI: 10.1007/s11064-023-04012-9] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/14/2023] [Revised: 08/06/2023] [Accepted: 08/08/2023] [Indexed: 08/15/2023]
Abstract
Allergic rhinitis (AR) is a widespread disease that is frequently comorbid with depression. However, the mechanisms and treatments for depression in AR remain underexplored. Metformin, a widely used antidiabetic drug, has shown antidepressant effects. The aim of this study was to explore the effects and potential mechanisms of metformin on depression-like behaviors in an AR mouse model. In the present study, mice were sensitized and challenged with ovalbumin (OVA) to induce AR. Results showed that mice with AR exhibited significant depression-like behavior which was attenuated by metformin. In addition, the levels of expression of synaptic plasticity markers (anti-microtubule-associated protein 2, synaptophysin, postsynaptic density protein 95), neurogenesis markers (doublecortin and Ki-67), and brain-derived neurotrophic factor were decreased in the olfactory bulb (OB) of mice with AR, while metformin ameliorated all these alterations and reduced apoptosis in the OB of these mice. Furthermore, it enhanced the phosphorylation of AMP-activated kinase (AMPK) and the levels of ten-eleven translocation 2 (TET2) and 5-hydroxymethylcytosine in the OB. In conclusion, our findings suggest that metformin might be a viable strategy for treating AR-related depression, possibly by modulating neuroplasticity, neurogenesis, apoptosis, and BDNF signaling in the OB via the AMPK/TET2 pathway.
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Affiliation(s)
- Hao Lv
- Department of Otolaryngology-Head and Neck Surgery, Renmin Hospital of Wuhan University, 238 Jiefang Rd, Wuhan, Hubei, 430060, China
- Department of Rhinology and Allergy, Renmin Hospital of Wuhan University, 238 Jiefang Rd, Wuhan, Hubei, 430060, China
| | - Ziang Gao
- Department of Otolaryngology-Head and Neck Surgery, Renmin Hospital of Wuhan University, 238 Jiefang Rd, Wuhan, Hubei, 430060, China
- Department of Rhinology and Allergy, Renmin Hospital of Wuhan University, 238 Jiefang Rd, Wuhan, Hubei, 430060, China
- Research Institute of Otolaryngology-Head and Neck Surgery, Renmin Hospital of Wuhan University, 238 Jiefang Rd, Wuhan, Hubei, 430060, China
| | - Yunfei Wang
- Department of Otolaryngology-Head and Neck Surgery, Renmin Hospital of Wuhan University, 238 Jiefang Rd, Wuhan, Hubei, 430060, China
- Department of Rhinology and Allergy, Renmin Hospital of Wuhan University, 238 Jiefang Rd, Wuhan, Hubei, 430060, China
| | - Siyuan Chen
- Department of Otolaryngology-Head and Neck Surgery, Renmin Hospital of Wuhan University, 238 Jiefang Rd, Wuhan, Hubei, 430060, China
- Department of Rhinology and Allergy, Renmin Hospital of Wuhan University, 238 Jiefang Rd, Wuhan, Hubei, 430060, China
| | - Peiqiang Liu
- Department of Otolaryngology-Head and Neck Surgery, Renmin Hospital of Wuhan University, 238 Jiefang Rd, Wuhan, Hubei, 430060, China
- Department of Rhinology and Allergy, Renmin Hospital of Wuhan University, 238 Jiefang Rd, Wuhan, Hubei, 430060, China
- Research Institute of Otolaryngology-Head and Neck Surgery, Renmin Hospital of Wuhan University, 238 Jiefang Rd, Wuhan, Hubei, 430060, China
| | - Yulie Xie
- Department of Otolaryngology-Head and Neck Surgery, Renmin Hospital of Wuhan University, 238 Jiefang Rd, Wuhan, Hubei, 430060, China
- Department of Rhinology and Allergy, Renmin Hospital of Wuhan University, 238 Jiefang Rd, Wuhan, Hubei, 430060, China
| | - Mengting Guan
- Department of Otolaryngology-Head and Neck Surgery, Renmin Hospital of Wuhan University, 238 Jiefang Rd, Wuhan, Hubei, 430060, China
- Department of Rhinology and Allergy, Renmin Hospital of Wuhan University, 238 Jiefang Rd, Wuhan, Hubei, 430060, China
| | - Jianchao Cong
- Department of Otolaryngology-Head and Neck Surgery, Renmin Hospital of Wuhan University, 238 Jiefang Rd, Wuhan, Hubei, 430060, China
- Department of Rhinology and Allergy, Renmin Hospital of Wuhan University, 238 Jiefang Rd, Wuhan, Hubei, 430060, China
| | - Yu Xu
- Department of Otolaryngology-Head and Neck Surgery, Renmin Hospital of Wuhan University, 238 Jiefang Rd, Wuhan, Hubei, 430060, China.
- Department of Rhinology and Allergy, Renmin Hospital of Wuhan University, 238 Jiefang Rd, Wuhan, Hubei, 430060, China.
- Research Institute of Otolaryngology-Head and Neck Surgery, Renmin Hospital of Wuhan University, 238 Jiefang Rd, Wuhan, Hubei, 430060, China.
- Hubei Province Key Laboratory of Allergy and Immunology, Wuhan, Hubei, 430060, China.
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14
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Liu L, Wang H, Chen X, Xie P. Gut microbiota: a new insight into neurological diseases. Chin Med J (Engl) 2023; 136:1261-1277. [PMID: 35830286 PMCID: PMC10309523 DOI: 10.1097/cm9.0000000000002212] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/23/2022] [Indexed: 12/13/2022] Open
Abstract
ABSTRACT In the last decade, it has become increasingly recognized that a balanced gut microbiota plays an important role in maintaining the health of the host. Numerous clinical and preclinical studies have shown that changes in gut microbiota composition are associated with a variety of neurological diseases, e.g., Parkinson's disease, Alzheimer's disease, and myasthenia gravis. However, the underlying molecular mechanisms are complex and remain unclear. Behavioral phenotypes can be transmitted from humans to animals through gut microbiota transplantation, indicating that the gut microbiota may be an important regulator of neurological diseases. However, further research is required to determine whether animal-based findings can be extended to humans and to elucidate the relevant potential mechanisms by which the gut microbiota regulates neurological diseases. Such investigations may aid in the development of new microbiota-based strategies for diagnosis and treatment and improve the clinical management of neurological disorders. In this review, we describe the dysbiosis of gut microbiota and the corresponding mechanisms in common neurological diseases, and discuss the potential roles that the intestinal microbiome may play in the diagnosis and treatment of neurological disorders.
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Affiliation(s)
- Lanxiang Liu
- Department of Neurology, Yongchuan Hospital of Chongqing Medical University, Chongqing 402160, China
- National Health Commission Key Laboratory of Diagnosis and Treatment on Brain Functional Diseases, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, China
| | - Haiyang Wang
- National Health Commission Key Laboratory of Diagnosis and Treatment on Brain Functional Diseases, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, China
| | - Xueyi Chen
- National Health Commission Key Laboratory of Diagnosis and Treatment on Brain Functional Diseases, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, China
| | - Peng Xie
- Department of Neurology, Yongchuan Hospital of Chongqing Medical University, Chongqing 402160, China
- National Health Commission Key Laboratory of Diagnosis and Treatment on Brain Functional Diseases, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, China
- Department of Neurology, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, China
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15
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Green JE, Berk M, Mohebbi M, Loughman A, McGuinness AJ, Castle D, Chatterton ML, Perez J, Strandwitz P, Athan E, Hair C, Nierenberg AA, Cryan JF, Jacka F. Feasibility, Acceptability, and Safety of Faecal Microbiota Transplantation in the Treatment of Major Depressive Disorder: A Pilot Randomized Controlled Trial. CANADIAN JOURNAL OF PSYCHIATRY. REVUE CANADIENNE DE PSYCHIATRIE 2023; 68:315-326. [PMID: 36637229 PMCID: PMC10192831 DOI: 10.1177/07067437221150508] [Citation(s) in RCA: 14] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/14/2023]
Abstract
OBJECTIVES Perturbations of the intestinal microbiota have been associated with mental health disorders, including major depressive disorder (MDD). Therefore, faecal microbiota transplantation (FMT) holds promise as a microbiota-modulating treatment for MDD. Yet, to date, there are no published controlled studies evaluating the use of FMT for MDD. This study aimed to address this gap by evaluating the feasibility, acceptability, and safety of FMT for MDD. METHODS The study was an 8-week, double-blind, 2:1 parallel group, randomized controlled pilot trial (n = 15) of enema-delivered FMT (n = 10) compared with a placebo enema (n = 5) in adults with moderate-to-severe MDD. RESULTS Recruitment was completed within 2 months, with 0% attrition and 100% attendance at key study appointments. There were no major protocol deviations. The placebo and blinding strategies were considered successful; nurses and participants correctly guessing their treatment allocation at a rate similar to that anticipated by chance. No serious or severe adverse events were reported in either group, and there were no significant differences in mild-to-moderate adverse events between groups (median of 2 adverse events per participant reported in both groups). Furthermore, the 12/15 participants who completed the Week 2 participant satisfaction survey agreed or strongly agreed that the enema delivery was tolerable and that they would have the treatment again if required. Whilst the study was not designed to measure clinical outcomes, exploratory data also suggested that the active FMT treatment may lead to improvements in gastrointestinal symptoms and quality of life in this population, noting that irritable bowel syndrome is commonly comorbid with MDD. CONCLUSIONS All feasibility targets were met or exceeded. This study found that enema-delivered FMT is feasible, acceptable, well-tolerated, and safe in patients with MDD. The findings of this study support further research to evaluate clinical efficacy, and the use of this protocol is supported.
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Affiliation(s)
- Jessica Emily Green
- Deakin University, Food & Mood Centre, IMPACT (the Institute for Mental and Physical Health and Clinical Translation, Geelong, Victoria, Australia
- Monash Alfred Psychiatry Research Centre (MAPrc), Central Clinical School, Faculty of Medicine Nursing and Health Sciences, Monash University, Melbourne, Australia
- Department of Psychiatry, Peninsula Health, Frankston, Australia
| | - Michael Berk
- Deakin University, Food & Mood Centre, IMPACT (the Institute for Mental and Physical Health and Clinical Translation, Geelong, Victoria, Australia
- Department of Psychiatry, University of Melbourne, Parkville, Australia
| | - Mohammadreza Mohebbi
- Deakin University, Food & Mood Centre, IMPACT (the Institute for Mental and Physical Health and Clinical Translation, Geelong, Victoria, Australia
- Faculty of Health, Biostatistics Unit, Deakin University, Geelong, Australia
| | - Amy Loughman
- Deakin University, Food & Mood Centre, IMPACT (the Institute for Mental and Physical Health and Clinical Translation, Geelong, Victoria, Australia
| | - Amelia J. McGuinness
- Deakin University, Food & Mood Centre, IMPACT (the Institute for Mental and Physical Health and Clinical Translation, Geelong, Victoria, Australia
| | - David Castle
- Centre for Addiction and Mental Health and Department of Psychiatry, University of Toronto, Parkville, Australia
| | - Mary Lou Chatterton
- School of Public Health and Preventive Medicine, Monash University, Melbourne, Australia
- Institute for Health Transformation, Deakin University, Geelong, Australia
| | - Joahna Perez
- School of Public Health and Preventive Medicine, Monash University, Melbourne, Australia
| | | | - Eugene Athan
- Deakin University, Food & Mood Centre, IMPACT (the Institute for Mental and Physical Health and Clinical Translation, Geelong, Victoria, Australia
- School of Medicine, Barwon Health, Geelong, Australia
- School of Medicine, Deakin University, Geelong, Australia
| | | | - Andrew A. Nierenberg
- Dauten Family Center for Bipolar Treatment Innovation, Department of Psychiatry, Massachusetts General Hospital, Boston, MA, USA
- Harvard Medical School, Boston, MA, USA
| | - John F. Cryan
- Department of Anatomy and Neuroscience, University College Cork and APC Microbiome, County Cork, Ireland
| | - Felice Jacka
- Deakin University, Food & Mood Centre, IMPACT (the Institute for Mental and Physical Health and Clinical Translation, Geelong, Victoria, Australia
- Centre for Adolescent Health, Murdoch Children's Research Institute, Royal Children's Hospital, Parkville, Australia
- College of Public Health, Medical & Veterinary Sciences, James Cook University, Townsville, Australia
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16
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Gao Y, Xu S, Cui X, Xu H, Qiu Y, Wei Y, Dong Y, Zhu B, Peng C, Liu S, Zhang XC, Sun J, Huang Z, Zhao Y. Molecular insights into the gating mechanisms of voltage-gated calcium channel Ca V2.3. Nat Commun 2023; 14:516. [PMID: 36720859 PMCID: PMC9889812 DOI: 10.1038/s41467-023-36260-2] [Citation(s) in RCA: 11] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/20/2022] [Accepted: 01/23/2023] [Indexed: 02/02/2023] Open
Abstract
High-voltage-activated R-type CaV2.3 channel plays pivotal roles in many physiological activities and is implicated in epilepsy, convulsions, and other neurodevelopmental impairments. Here, we determine the high-resolution cryo-electron microscopy (cryo-EM) structure of human CaV2.3 in complex with the α2δ1 and β1 subunits. The VSDII is stabilized in the resting state. Electrophysiological experiments elucidate that the VSDII is not required for channel activation, whereas the other VSDs are essential for channel opening. The intracellular gate is blocked by the W-helix. A pre-W-helix adjacent to the W-helix can significantly regulate closed-state inactivation (CSI) by modulating the association and dissociation of the W-helix with the gate. Electrostatic interactions formed between the negatively charged domain on S6II, which is exclusively conserved in the CaV2 family, and nearby regions at the alpha-interacting domain (AID) and S4-S5II helix are identified. Further functional analyses indicate that these interactions are critical for the open-state inactivation (OSI) of CaV2 channels.
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Affiliation(s)
- Yiwei Gao
- National Laboratory of Biomacromolecules, CAS Center for Excellence in Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing, China.,State Key Laboratory of Brain and Cognitive Science, Institute of Biophysics, Chinese Academy of Sciences, 15 Datun Road, Beijing, China.,College of Life Sciences, University of Chinese Academy of Sciences, Beijing, China
| | - Shuai Xu
- State Key Laboratory of Natural and Biomimetic Drugs, Department of Molecular and Cellular Pharmacology, School of Pharmaceutical Sciences, Peking University Health Science Center, Beijing, China
| | - Xiaoli Cui
- State Key Laboratory of Brain and Cognitive Science, Institute of Biophysics, Chinese Academy of Sciences, 15 Datun Road, Beijing, China.,College of Life Sciences, University of Chinese Academy of Sciences, Beijing, China.,Chinese Institute for Brain Research, Beijing, China
| | - Hao Xu
- National Laboratory of Biomacromolecules, CAS Center for Excellence in Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing, China.,Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China
| | - Yunlong Qiu
- National Laboratory of Biomacromolecules, CAS Center for Excellence in Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing, China.,State Key Laboratory of Brain and Cognitive Science, Institute of Biophysics, Chinese Academy of Sciences, 15 Datun Road, Beijing, China.,College of Life Sciences, University of Chinese Academy of Sciences, Beijing, China
| | - Yiqing Wei
- National Laboratory of Biomacromolecules, CAS Center for Excellence in Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing, China.,State Key Laboratory of Brain and Cognitive Science, Institute of Biophysics, Chinese Academy of Sciences, 15 Datun Road, Beijing, China.,College of Life Sciences, University of Chinese Academy of Sciences, Beijing, China
| | - Yanli Dong
- National Laboratory of Biomacromolecules, CAS Center for Excellence in Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing, China.,State Key Laboratory of Brain and Cognitive Science, Institute of Biophysics, Chinese Academy of Sciences, 15 Datun Road, Beijing, China.,College of Life Sciences, University of Chinese Academy of Sciences, Beijing, China
| | - Boling Zhu
- Center for Biological Imaging, Institute of Biophysics, Chinese Academy of Sciences, Beijing, China
| | - Chao Peng
- State Key Laboratory of Natural and Biomimetic Drugs, Department of Molecular and Cellular Pharmacology, School of Pharmaceutical Sciences, Peking University Health Science Center, Beijing, China
| | - Shiqi Liu
- State Key Laboratory of Natural and Biomimetic Drugs, Department of Molecular and Cellular Pharmacology, School of Pharmaceutical Sciences, Peking University Health Science Center, Beijing, China
| | - Xuejun Cai Zhang
- National Laboratory of Biomacromolecules, CAS Center for Excellence in Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing, China.,State Key Laboratory of Brain and Cognitive Science, Institute of Biophysics, Chinese Academy of Sciences, 15 Datun Road, Beijing, China.,College of Life Sciences, University of Chinese Academy of Sciences, Beijing, China
| | - Jianyuan Sun
- State Key Laboratory of Brain and Cognitive Science, Institute of Biophysics, Chinese Academy of Sciences, 15 Datun Road, Beijing, China.,College of Life Sciences, University of Chinese Academy of Sciences, Beijing, China.,Sino-Danish College, University of Chinese Academy of Sciences, Beijing, China.,The Brain Cognition and Brain Disease Institute, Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences (CAS), Shenzhen-Hong Kong Institute of Brain Science-Shenzhen Fundamental Research Institutions, Shenzhen, China
| | - Zhuo Huang
- State Key Laboratory of Natural and Biomimetic Drugs, Department of Molecular and Cellular Pharmacology, School of Pharmaceutical Sciences, Peking University Health Science Center, Beijing, China. .,IDG/McGovern Institute for Brain Research, Peking University, Beijing, China.
| | - Yan Zhao
- National Laboratory of Biomacromolecules, CAS Center for Excellence in Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing, China. .,State Key Laboratory of Brain and Cognitive Science, Institute of Biophysics, Chinese Academy of Sciences, 15 Datun Road, Beijing, China. .,College of Life Sciences, University of Chinese Academy of Sciences, Beijing, China.
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17
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Xia J, Zhang L, Gu T, Liu Q, Wang Q. Identification of ferroptosis related markers by integrated bioinformatics analysis and In vitro model experiments in rheumatoid arthritis. BMC Med Genomics 2023; 16:18. [PMID: 36717858 PMCID: PMC9887825 DOI: 10.1186/s12920-023-01445-7] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/05/2022] [Accepted: 01/25/2023] [Indexed: 01/31/2023] Open
Abstract
BACKGROUND Rheumatoid arthritis (RA) is an autoimmune disease characterized by destructive and symmetrical joint diseases and synovitis. This research attempted to explore the mechanisms involving ferroptosis in RA, and find the biological markers by integrated analysis. METHODS Gene expression data (GSE55235 and GSE55457) of synovial tissues from healthy and RA individuals were downloaded. By filtering the differentially expressed genes (DEGs) and intersecting them with the 484 ferroptosis-related genes (FRGs), the overlapping genes were identified. After the enrichment analysis, the machine learning-based approaches were introduced to screen the potential biomarkers, which were further validated in other two datasets (GSE77298 and GSE93272) and cell samples. Besides, we also analyze the infiltrating immune cells in RA and their correlation with the biomarkers. RESULTS With the criteria, 635 DEGs in RA were included, and 29 of them overlapped in the reported 484 FRGs. The enrichments of the 29 differentially expressed ferroptosis-related genes indicated that they may involve in the FoxO signaling pathway and inherited metabolic disorder. RRM2, validating by the external datasets and western blot, were identified as the biomarker with the high diagnostic value, whose associated immune cells, such as Neutrophils and Macrophages M1, were also further evaluated. CONCLUSION We preliminary explored the mechanisms between ferroptosis and RA. These results may help us better comprehend the pathophysiological changes of RA in basic research, and provide new evidences for the clinical transformation.
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Affiliation(s)
- Jinjun Xia
- grid.263761.70000 0001 0198 0694Department of Clinical Laboratory, Wuxi 9Th People’s Hospital Affiliated to Soochow University, No. 999 Liang Xi Road, Binhu District, Wuxi, 214000 Jiangsu China
| | - Lulu Zhang
- grid.263761.70000 0001 0198 0694Department of Clinical Laboratory, Wuxi 9Th People’s Hospital Affiliated to Soochow University, No. 999 Liang Xi Road, Binhu District, Wuxi, 214000 Jiangsu China
| | - Tao Gu
- grid.263761.70000 0001 0198 0694Department of Clinical Laboratory, Wuxi 9Th People’s Hospital Affiliated to Soochow University, No. 999 Liang Xi Road, Binhu District, Wuxi, 214000 Jiangsu China
| | - Qingyang Liu
- grid.263761.70000 0001 0198 0694Department of Clinical Laboratory, Wuxi 9Th People’s Hospital Affiliated to Soochow University, No. 999 Liang Xi Road, Binhu District, Wuxi, 214000 Jiangsu China
| | - Qiubo Wang
- grid.263761.70000 0001 0198 0694Department of Clinical Laboratory, Wuxi 9Th People’s Hospital Affiliated to Soochow University, No. 999 Liang Xi Road, Binhu District, Wuxi, 214000 Jiangsu China
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18
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Green JE, McGuinness AJ, Berk M, Castle D, Athan E, Hair C, Strandwitz P, Loughman A, Nierenberg AA, Cryan JF, Mohebbi M, Jacka F. Safety and feasibility of faecal microbiota transplant for major depressive disorder: study protocol for a pilot randomised controlled trial. Pilot Feasibility Stud 2023; 9:5. [PMID: 36624505 PMCID: PMC9827014 DOI: 10.1186/s40814-023-01235-z] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/29/2022] [Accepted: 01/02/2023] [Indexed: 01/11/2023] Open
Abstract
BACKGROUND Mental disorders, including major depressive disorder (MDD), are a leading cause of non-fatal burden of disease globally. Current conventional treatments for depression have significant limitations, and there have been few new treatments in decades. The microbiota-gut-brain-axis is now recognised as playing a role in mental and brain health, and promising preclinical and clinical data suggest Faecal Microbiota Transplants (FMT) may be efficacious for treating a range of mental illnesses. However, there are no existing published studies in humans evaluating the efficacy of FMT for MDD. METHODS AND DESIGN This protocol describes an 8-week, triple-blind, 2:1 parallel group, randomised controlled pilot trial (n = 15), of enema-delivered FMT treatment (n = 10) compared with a placebo enema (n = 5) in adults with moderate-to-severe MDD. There will be a further 26-week follow-up to monitor longer-term safety. Participants will receive four FMT or placebo enemas over four consecutive days. The primary aims of the study are to evaluate feasibility and safety of FMT as an adjunctive treatment for MDD in adults. Changes in gut microbiota will be assessed as a secondary outcome. Other data will be collected, including changes in depression and anxiety symptoms, and safety parameters. DISCUSSION Modification of the microbiota-gut-brain axis via FMT is a promising potential treatment for MDD, but there are no published rigorous clinical trials evaluating its use. If this study finds that our FMT strategy is safe and feasible, a larger fully powered RCT is planned. Further high-quality research in this field is urgently needed to address unmet need. TRIAL REGISTRATION Australian and New Zealand Clinical Trials Registry: ACTRN12621000932864.
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Affiliation(s)
- Jessica E. Green
- grid.414257.10000 0004 0540 0062Deakin University, Food & Mood Centre, IMPACT-the Institute for Mental and Physical Health and Clinical Translation, School of Medicine, Barwon Health, Geelong, Australia ,grid.1002.30000 0004 1936 7857Monash Alfred Psychiatry Research Centre (MAPrc), Central Clinical School, Faculty of Medicine Nursing and Health Sciences, Monash University, Melbourne, Australia ,grid.466993.70000 0004 0436 2893Department of Psychiatry, Peninsula Health, Frankston, Australia
| | - Amelia J. McGuinness
- grid.414257.10000 0004 0540 0062Deakin University, Food & Mood Centre, IMPACT-the Institute for Mental and Physical Health and Clinical Translation, School of Medicine, Barwon Health, Geelong, Australia
| | - Michael Berk
- grid.414257.10000 0004 0540 0062Deakin University, Food & Mood Centre, IMPACT-the Institute for Mental and Physical Health and Clinical Translation, School of Medicine, Barwon Health, Geelong, Australia ,grid.1008.90000 0001 2179 088XDepartment of Psychiatry, University of Melbourne, Parkville, Australia ,grid.488596.e0000 0004 0408 1792Orygen Youth Health Research Centre and the Centre of Youth Mental Health, Melbourne, Australia ,grid.418025.a0000 0004 0606 5526The Florey Institute for Neuroscience and Mental Health, Parkville, Australia ,grid.414257.10000 0004 0540 0062Barwon Health, Geelong, Australia
| | - David Castle
- grid.17063.330000 0001 2157 2938Centre for Addiction and Mental Health and Department of Psychiatry, University of Toronto, Toronto, Canada
| | - Eugene Athan
- grid.414257.10000 0004 0540 0062Deakin University, Food & Mood Centre, IMPACT-the Institute for Mental and Physical Health and Clinical Translation, School of Medicine, Barwon Health, Geelong, Australia ,grid.414257.10000 0004 0540 0062Barwon Health, Geelong, Australia ,grid.1021.20000 0001 0526 7079School of Medicine, Deakin University, Geelong, Australia
| | - Christopher Hair
- grid.414257.10000 0004 0540 0062Barwon Health, Geelong, Australia
| | | | - Amy Loughman
- grid.414257.10000 0004 0540 0062Deakin University, Food & Mood Centre, IMPACT-the Institute for Mental and Physical Health and Clinical Translation, School of Medicine, Barwon Health, Geelong, Australia
| | - Andrew A. Nierenberg
- grid.32224.350000 0004 0386 9924Dauten Family Center for Bipolar Treatment Innovation, Department of Psychiatry, Massachusetts General Hospital, Boston, MA USA ,grid.38142.3c000000041936754XHarvard Medical School, Boston, MA USA
| | - John F. Cryan
- grid.7872.a0000000123318773Department of Anatomy and Neuroscience, University College Cork and APC Microbiome, Cork, Ireland
| | - Mohammadreza Mohebbi
- grid.414257.10000 0004 0540 0062Deakin University, Food & Mood Centre, IMPACT-the Institute for Mental and Physical Health and Clinical Translation, School of Medicine, Barwon Health, Geelong, Australia
| | - Felice Jacka
- grid.414257.10000 0004 0540 0062Deakin University, Food & Mood Centre, IMPACT-the Institute for Mental and Physical Health and Clinical Translation, School of Medicine, Barwon Health, Geelong, Australia ,grid.416107.50000 0004 0614 0346Centre for Adolescent Health, Murdoch Children’s Research Institute, Royal Children’s Hospital, Parkville, Australia ,grid.418393.40000 0001 0640 7766Black Dog Institute, Melbourne, Australia ,grid.1011.10000 0004 0474 1797James Cook University, Townsville, Australia
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Liang D, Chen C, Huang S, Liu S, Fu L, Niu Y. Alterations of Lysine Acetylation Profile in Murine Skeletal Muscles Upon Exercise. Front Aging Neurosci 2022; 14:859313. [PMID: 35592697 PMCID: PMC9110802 DOI: 10.3389/fnagi.2022.859313] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/21/2022] [Accepted: 04/04/2022] [Indexed: 11/16/2022] Open
Abstract
Objective Regular exercise is a powerful tool that enhances skeletal muscle mass and strength. Lysine acetylation is an important post-translational modification (PTM) involved in a broad array of cellular functions. Skeletal muscle protein contains a considerable number of lysine-acetylated (Kac) sites, so we aimed to investigate the effects of exercise-induced lysine acetylation on skeletal muscle proteins. Methods We randomly divided 20 male C57BL/6 mice into exercise and control groups. After 6 weeks of treadmill exercise, a lysine acetylation proteomics analysis of the gastrocnemius muscles of mice was performed. Results A total of 2,254 lysine acetylation sites in 693 protein groups were identified, among which 1,916 sites in 528 proteins were quantified. The enrichment analysis suggested that protein acetylation could influence both structural and functional muscle protein properties. Moreover, molecular docking revealed that mimicking protein deacetylation primarily influenced the interaction between substrates and enzymes. Conclusion Exercise-induced lysine acetylation appears to be a crucial contributor to the alteration of skeletal muscle protein binding free energy, suggesting that its modulation is a potential approach for improving exercise performance.
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Affiliation(s)
- Dehuan Liang
- Department of Rehabilitation, School of Medical Technology, Tianjin Medical University, Tianjin, China
| | - Cheng Chen
- Department of Rehabilitation, School of Medical Technology, Tianjin Medical University, Tianjin, China
| | - Song Huang
- Department of Rehabilitation, School of Medical Technology, Tianjin Medical University, Tianjin, China
| | - Sujuan Liu
- Department of Anatomy and Histology, School of Basic Medical Science, Tianjin Medical University, Tianjin, China
| | - Li Fu
- Department of Rehabilitation, School of Medical Technology, Tianjin Medical University, Tianjin, China
| | - Yanmei Niu
- Department of Rehabilitation, School of Medical Technology, Tianjin Medical University, Tianjin, China
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20
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Mamieva Z, Poluektova E, Svistushkin V, Sobolev V, Shifrin O, Guarner F, Ivashkin V. Antibiotics, gut microbiota, and irritable bowel syndrome: What are the relations? World J Gastroenterol 2022; 28:1204-1219. [PMID: 35431513 PMCID: PMC8968486 DOI: 10.3748/wjg.v28.i12.1204] [Citation(s) in RCA: 31] [Impact Index Per Article: 10.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/24/2021] [Revised: 12/01/2021] [Accepted: 02/23/2022] [Indexed: 02/06/2023] Open
Abstract
Irritable bowel syndrome (IBS) is a functional gastrointestinal disorder in which recurrent abdominal pain is associated with defecation or a change in bowel habits (constipation, diarrhea, or both), and it is often accompanied by symptoms of abdominal bloating and distension. IBS is an important health care issue because it negatively affects the quality of life of patients and places a considerable financial burden on health care systems. Despite extensive research, the etiology and underlying pathophysiology of IBS remain incompletely understood. Proposed mechanisms involved in its pathogenesis include increased intestinal permeability, changes in the immune system, visceral hypersensitivity, impaired gut motility, and emotional disorders. Recently, accumulating evidence has highlighted the important role of the gut microbiota in the development of IBS. Microbial dysbiosis within the gut is thought to contribute to all aspects of its multifactorial pathogenesis. The last few decades have also seen an increasing interest in the impact of antibiotics on the gut microbiota. Moreover, antibiotics have been suggested to play a role in the development of IBS. Extensive research has established that antibacterial therapy induces remarkable shifts in the bacterial community composition that are quite similar to those observed in IBS. This suggestion is further supported by data from cohort and case-control studies, indicating that antibiotic treatment is associated with an increased risk of IBS. This paper summarizes the main findings on this issue and contributes to a deeper understanding of the link between antibiotic use and the development of IBS.
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Affiliation(s)
- Zarina Mamieva
- Department of Internal Disease Propaedeutics, N.V. Sklifosovsky Institute of Clinical Medicine, I.M. Sechenov First Moscow State Medical University (Sechenov University), Moscow 119991, Russia
| | - Elena Poluektova
- Department of Internal Disease Propaedeutics, N.V. Sklifosovsky Institute of Clinical Medicine, I.M. Sechenov First Moscow State Medical University (Sechenov University), Moscow 119991, Russia
| | - Valery Svistushkin
- Department of Ear, Throat and Nose Diseases, N.V. Sklifosovsky Institute of Clinical Medicine, I.M. Sechenov First Moscow State Medical University (Sechenov University), Moscow 119991, Russia
| | - Vasily Sobolev
- Department of Ear, Throat and Nose Diseases, N.V. Sklifosovsky Institute of Clinical Medicine, I.M. Sechenov First Moscow State Medical University (Sechenov University), Moscow 119991, Russia
| | - Oleg Shifrin
- Department of Internal Disease Propaedeutics, N.V. Sklifosovsky Institute of Clinical Medicine, I.M. Sechenov First Moscow State Medical University (Sechenov University), Moscow 119991, Russia
| | - Francisco Guarner
- Digestive System Research Unit, Vall d’Hebron Research Institute, Barcelona 08035, Spain
| | - Vladimir Ivashkin
- Department of Internal Disease Propaedeutics, N.V. Sklifosovsky Institute of Clinical Medicine, I.M. Sechenov First Moscow State Medical University (Sechenov University), Moscow 119991, Russia
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21
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Linking Diabetes Mellitus with Alzheimer's Disease: Bioinformatics Analysis for the Potential Pathways and Characteristic Genes. Biochem Genet 2021; 60:1049-1075. [PMID: 34779951 DOI: 10.1007/s10528-021-10154-8] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/16/2021] [Accepted: 11/03/2021] [Indexed: 01/22/2023]
Abstract
As the surging epidemics with significant disability, Alzheimer's disease (AD) and type II diabetes mellitus (T2DM) with microvascular complications are widely prevalent, sharing considerable similarities in putative pathomechanism. Despite a spurt of researches on the biology, knowledge about their interactive mechanisms is still rudimentary. Applying bioinformatics ways to explore the differentially co-expressed genes contributes to achieve our objectives to find new therapeutic targets. In this study, we firstly integrated gene expression omnibus datasets (GSE28146 and GSE43950) to identify differentially expressed genes. The enrichment analysis of pivotal genes, like gene ontology and pathway signaling proceeded subsequently. Besides, the related protein-protein interaction (PPI) network was then constructed. To further explain the inner connections, we ended up unearthing the biological significance of valuable targets. As a result, a set of 712, 630, 487, and 997 genes were differentially identified in T2DM with microvascular complications and AD at incipient, moderate, and severe, respectively. The enrichment analysis involving both diseases implicated the dominance of immune system, especially the noteworthy chemokine signaling. Multiple comparisons confirmed that CACNA2D3, NUMB, and IER3 were simultaneously participate in these two conditions, whose respective associations with neurological and endocrine diseases, and regulators including interacting chemicals, transcription factors, and miRNAs were analyzed. Bioinformatics analysis eventually concluded that immune-related biological functions and pathways closely link AD and T2DM with microvascular complications. Further exploration of the regulatory factors about CACNA2D3, NUMB, and IER3 in neuroendocrine field may provide us a promising direction to discover potential strategies for the comorbidity status.
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22
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Liu Y, Wang H, Gui S, Zeng B, Pu J, Zheng P, Zeng L, Luo Y, Wu Y, Zhou C, Song J, Ji P, Wei H, Xie P. Proteomics analysis of the gut-brain axis in a gut microbiota-dysbiosis model of depression. Transl Psychiatry 2021; 11:568. [PMID: 34744165 PMCID: PMC8572885 DOI: 10.1038/s41398-021-01689-w] [Citation(s) in RCA: 41] [Impact Index Per Article: 10.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/27/2021] [Revised: 10/17/2021] [Accepted: 10/20/2021] [Indexed: 12/21/2022] Open
Abstract
Major depressive disorder (MDD) is a serious mental illness. Increasing evidence from both animal and human studies suggested that the gut microbiota might be involved in the onset of depression via the gut-brain axis. However, the mechanism in depression remains unclear. To explore the protein changes of the gut-brain axis modulated by gut microbiota, germ-free mice were transplanted with gut microbiota from MDD patients to induce depression-like behaviors. Behavioral tests were performed following fecal microbiota transplantation. A quantitative proteomics approach was used to examine changes in protein expression in the prefrontal cortex (PFC), liver, cecum, and serum. Then differential protein analysis and weighted gene coexpression network analysis were used to identify microbiota-related protein modules. Our results suggested that gut microbiota induced the alteration of protein expression levels in multiple tissues of the gut-brain axis in mice with depression-like phenotype, and these changes of the PFC and liver were model specific compared to chronic stress models. Gene ontology enrichment analysis revealed that the protein changes of the gut-brain axis were involved in a variety of biological functions, including metabolic process and inflammatory response, in which energy metabolism is the core change of the protein network. Our data provide clues for future studies in the gut-brain axis on protein level and deepen the understanding of how gut microbiota cause depression-like behaviors.
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Affiliation(s)
- Yiyun Liu
- grid.452206.70000 0004 1758 417XNHC Key Laboratory of Diagnosis and Treatment on Brain Functional Diseases, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Haiyang Wang
- grid.452206.70000 0004 1758 417XNHC Key Laboratory of Diagnosis and Treatment on Brain Functional Diseases, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Siwen Gui
- grid.452206.70000 0004 1758 417XNHC Key Laboratory of Diagnosis and Treatment on Brain Functional Diseases, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Benhua Zeng
- grid.410570.70000 0004 1760 6682Department of Laboratory Animal Science, College of Basic Medical Sciences, Third Military Medical University, Chongqing, China
| | - Juncai Pu
- grid.452206.70000 0004 1758 417XNHC Key Laboratory of Diagnosis and Treatment on Brain Functional Diseases, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Peng Zheng
- grid.452206.70000 0004 1758 417XNHC Key Laboratory of Diagnosis and Treatment on Brain Functional Diseases, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Li Zeng
- grid.452206.70000 0004 1758 417XNHC Key Laboratory of Diagnosis and Treatment on Brain Functional Diseases, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Yuanyuan Luo
- grid.452206.70000 0004 1758 417XNHC Key Laboratory of Diagnosis and Treatment on Brain Functional Diseases, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - You Wu
- grid.452206.70000 0004 1758 417XNHC Key Laboratory of Diagnosis and Treatment on Brain Functional Diseases, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Chanjuan Zhou
- grid.452206.70000 0004 1758 417XNHC Key Laboratory of Diagnosis and Treatment on Brain Functional Diseases, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Jinlin Song
- grid.203458.80000 0000 8653 0555College of Stomatology, Chongqing Medical University, Chongqing, China
| | - Ping Ji
- grid.203458.80000 0000 8653 0555College of Stomatology, Chongqing Medical University, Chongqing, China
| | - Hong Wei
- Department of Laboratory Animal Science, College of Basic Medical Sciences, Third Military Medical University, Chongqing, China.
| | - Peng Xie
- NHC Key Laboratory of Diagnosis and Treatment on Brain Functional Diseases, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China.
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23
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Kronsten VT, Shawcross DL. Hepatic encephalopathy and depression in chronic liver disease: is the common link systemic inflammation? Anal Biochem 2021; 636:114437. [PMID: 34715068 DOI: 10.1016/j.ab.2021.114437] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/27/2021] [Revised: 09/26/2021] [Accepted: 10/22/2021] [Indexed: 02/08/2023]
Abstract
Hepatic encephalopathy and depression share a number of clinical features, such as cognitive impairment and psychomotor retardation, and are highly prevalent in patients with chronic liver disease. Both conditions signify a poor prognosis, carry an increased mortality and are major determinants of reduced health related quality of life. The pathophysiology of hepatic encephalopathy is complex. Whilst cerebral accumulation of ammonia is well-recognised as being central to the development of hepatic encephalopathy, systemic inflammation, which acts in synergy with hyperammonaemia, is emerging as a key driver in its development. The pro-inflammatory state is also widely documented in depression, and peripheral to brain communication occurs resulting in central inflammation, behavioural changes and depressive symptoms. Gut dysbiosis, with a similar reduction in beneficial bacteria, increase in pathogens and decreased bacterial diversity, has been observed in both hepatic encephalopathy and depression, and it may be that the resultant increased bacterial translocation causes their shared inflammatory pathophysiology. Whilst the literature on a positive association between hepatic encephalopathy and depression in cirrhosis remains to be substantiated, there is evolving evidence that treatment with psychobiotics may be of dual benefit, improving cognition and mood in cirrhosis.
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Affiliation(s)
- Victoria Tatiana Kronsten
- Institute of Liver Studies, School of Immunology and Microbial Sciences, Faculty of Life Sciences and Medicine, King's College London, UK.
| | - Debbie Lindsay Shawcross
- Institute of Liver Studies, School of Immunology and Microbial Sciences, Faculty of Life Sciences and Medicine, King's College London, UK
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24
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The role of microbiota-gut-brain axis in neuropsychiatric and neurological disorders. Pharmacol Res 2021; 172:105840. [PMID: 34450312 DOI: 10.1016/j.phrs.2021.105840] [Citation(s) in RCA: 322] [Impact Index Per Article: 80.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/15/2021] [Revised: 08/14/2021] [Accepted: 08/17/2021] [Indexed: 12/12/2022]
Abstract
Emerging evidence indicates that the gut microbiota play a crucial role in the bidirectional communication between the gut and the brain suggesting that the gut microbes may shape neural development, modulate neurotransmission and affect behavior, and thereby contribute to the pathogenesis and/or progression of many neurodevelopmental, neuropsychiatric, and neurological conditions. This review summarizes recent data on the role of microbiota-gut-brain axis in the pathophysiology of neuropsychiatric and neurological disorders including depression, anxiety, schizophrenia, autism spectrum disorders, Parkinson's disease, migraine, and epilepsy. Also, the involvement of microbiota in gut disorders co-existing with neuropsychiatric conditions is highlighted. We discuss data from both in vivo preclinical experiments and clinical reports including: (1) studies in germ-free animals, (2) studies exploring the gut microbiota composition in animal models of diseases or in humans, (3) studies evaluating the effects of probiotic, prebiotic or antibiotic treatment as well as (4) the effects of fecal microbiota transplantation.
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25
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Genome-wide DNA methylation profiling and gut flora analysis in intestinal polyps patients. Eur J Gastroenterol Hepatol 2021; 33:1071-1081. [PMID: 34213504 DOI: 10.1097/meg.0000000000002181] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
BACKGROUND The intestinal polyp is the precancerous lesion of colorectal cancer. DNA methylation and intestinal microbiota may play an important role in the development of intestinal polyp. MATERIALS AND METHODS In this study, we included 10 patients with intestinal polyps who received the colonoscopy examination. We applied the Illumina Human Methylation 850K array to investigate the epigenome-wide DNA methylation patterns. Then, we filtered out the hub genes in the protein-protein interaction networks using functional epigenetic modules analysis. We also analyzed the colonizing bacteria on the surface of polyps compared with those in normal colonic mucosal epithelium with 16S ribosomal DNA sequencing. RESULTS We identified 323 hypermethylated sites and 7992 hypomethylated sites between intestinal polyps and normal samples. Five hub genes, including CREB1, LPA, SVIL and KRT18, were identified in five modules. Hypomethylation of CREB1 is a candidate marker of colorectal adenoma. Gut microbiota analysis showed that Butyricicoccus was significantly decreased in the intestinal polyp groups. CONCLUSION In conclusion, we identified DNA methylation disparities in intestinal polyps compared with normal tissue, of which methylation of CREB1 may hold clinical significance in colorectal cancer progress. Colonizing bacteria in the colonic epithelium might be related to the formation of intestinal polyps.
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26
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Fan L, Yang L, Li X, Teng T, Xiang Y, Liu X, Jiang Y, Zhu Y, Zhou X, Xie P. Proteomic and metabolomic characterization of amygdala in chronic social defeat stress rats. Behav Brain Res 2021; 412:113407. [PMID: 34111472 DOI: 10.1016/j.bbr.2021.113407] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/24/2021] [Revised: 06/04/2021] [Accepted: 06/04/2021] [Indexed: 12/24/2022]
Abstract
BACKGROUND Depression is a leading cause of disability worldwide. There is increasing evidence showing that depression is associated with the pathophysiology in amygdala; however, the underlying mechanism remains poorly understood. METHOD We established a rat model of chronic social defeat stress (CSDS) and conducted a series of behavior tests to observe behavioral changes. Then liquid chromatography mass spectrometry (LC-MS)-based metabolomics and isobaric tags for relative and absolute quantitation (iTRAQ)-based proteomics were employed to detect metabolomes and proteomes in the amygdala, respectively. Ingenuity pathway analysis (IPA) and other bioinformatic analyses were used to analyze differentially expressed metabolites and proteins. RESULTS The significantly lower sucrose preference index in the sucrose preference test and longer immobile time in the forced swim test were observed in the CSDS rats compared with control rats. In the multi-omics analysis, thirty-seven significantly differentially expressed metabolites and 123 significant proteins were identified. Integrated analysis of differentially expressed metabolites and proteins by IPA revealed molecular changes mainly associated with synaptic plasticity, phospholipase c signaling, and glutamine degradation I. We compared the metabolites in the amygdala with those in the hippocampus and prefrontal cortex from our previous studies and found two common metabolites: arachidonic acid and N-acetyl-l-aspartic acid among these three brain regions. CONCLUSION Our study revealed the presence of depressive-like behaviors and molecular changes of amygdala in the CSDS rat model, which may provide further insights into the pathogenesis of depression, and help to identify potential targets for antidepressants.
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Affiliation(s)
- Li Fan
- Department of Neurology, The First Affiliated Hospital of Chongqing Medical University, Chongqing, 400016, China; NHC Key Laboratory of Diagnosis and Treatment on Brain Functional Diseases, The First Affiliated Hospital of Chongqing Medical University, Chongqing, 400016, China
| | - Lining Yang
- Department of Rehabilitation Medicine, The First Affiliated Hospital of Chongqing Medical University, Chongqing, 400016, China
| | - Xuemei Li
- Department of Neurology, The First Affiliated Hospital of Chongqing Medical University, Chongqing, 400016, China; NHC Key Laboratory of Diagnosis and Treatment on Brain Functional Diseases, The First Affiliated Hospital of Chongqing Medical University, Chongqing, 400016, China
| | - Teng Teng
- Department of Neurology, The First Affiliated Hospital of Chongqing Medical University, Chongqing, 400016, China; NHC Key Laboratory of Diagnosis and Treatment on Brain Functional Diseases, The First Affiliated Hospital of Chongqing Medical University, Chongqing, 400016, China
| | - Yajie Xiang
- Department of Neurology, The First Affiliated Hospital of Chongqing Medical University, Chongqing, 400016, China; NHC Key Laboratory of Diagnosis and Treatment on Brain Functional Diseases, The First Affiliated Hospital of Chongqing Medical University, Chongqing, 400016, China
| | - Xueer Liu
- Department of Neurology, The First Affiliated Hospital of Chongqing Medical University, Chongqing, 400016, China; NHC Key Laboratory of Diagnosis and Treatment on Brain Functional Diseases, The First Affiliated Hospital of Chongqing Medical University, Chongqing, 400016, China
| | - Yuanliang Jiang
- NHC Key Laboratory of Diagnosis and Treatment on Brain Functional Diseases, The First Affiliated Hospital of Chongqing Medical University, Chongqing, 400016, China; Department of Psychiatry, The First Affiliated Hospital of Chongqing Medical University, Chongqing, 400016, China
| | - Yinglin Zhu
- School of Osteopathic Medicine, Kansas City University of Medicine and Biosciences, Joplin, MO, 64801, United States
| | - Xinyu Zhou
- NHC Key Laboratory of Diagnosis and Treatment on Brain Functional Diseases, The First Affiliated Hospital of Chongqing Medical University, Chongqing, 400016, China; Department of Psychiatry, The First Affiliated Hospital of Chongqing Medical University, Chongqing, 400016, China.
| | - Peng Xie
- Department of Neurology, The First Affiliated Hospital of Chongqing Medical University, Chongqing, 400016, China; NHC Key Laboratory of Diagnosis and Treatment on Brain Functional Diseases, The First Affiliated Hospital of Chongqing Medical University, Chongqing, 400016, China.
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27
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Yu Y, Wang H, Rao X, Liu L, Zheng P, Li W, Zhou W, Chai T, Ji P, Song J, Wei H, Xie P. Proteomic Profiling of Lysine Acetylation Indicates Mitochondrial Dysfunction in the Hippocampus of Gut Microbiota-Absent Mice. Front Mol Neurosci 2021; 14:594332. [PMID: 33776647 PMCID: PMC7991600 DOI: 10.3389/fnmol.2021.594332] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/27/2020] [Accepted: 02/17/2021] [Indexed: 12/21/2022] Open
Abstract
Major depressive disorder (MDD) is a leading cause of disability around the world and contributes greatly to the global burden of disease. Mounting evidence suggests that gut microbiota dysbiosis may be involved in the pathophysiology of MDD through the microbiota–gut–brain axis. Recent research suggests that epigenetic modifications might relate to depression. However, our knowledge of the role of epigenetics in host–microbe interactions remains limited. In the present study, we used a combination of affinity enrichment and high-resolution liquid chromatography tandem mass spectrometry analysis to identify hippocampal acetylated proteins in germ-free and specific pathogen-free mice. In total, 986 lysine acetylation sites in 543 proteins were identified, of which 747 sites in 427 proteins were quantified. Motif analysis identified several conserved sequences surrounding the acetylation sites, including D∗Kac, DKac, KacY, KacD, and D∗∗Kac. Gene ontology annotations revealed that these differentially expressed acetylated proteins were involved in multiple biological functions and were mainly located in mitochondria. In addition, pathway enrichment analysis demonstrated that oxidative phosphorylation and the tricarboxylic acid cycle II (eukaryotic), both of which are exclusively localized to the mitochondria, were the primarily disturbed functions. Taken together, this study indicates that lysine acetylation alterations may play a pivotal role in mitochondrial dysfunction and may be a mechanism by which gut microbiota regulate brain function and behavioral phenotypes.
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Affiliation(s)
- Ying Yu
- The Ministry of Education, Key Laboratory of Laboratory Medical Diagnostics, The College of Laboratory Medicine, Chongqing Medical University, Chongqing, China.,National Health Commission, Key Laboratory of Diagnosis and Treatment on Brain Functional Diseases, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Haiyang Wang
- National Health Commission, Key Laboratory of Diagnosis and Treatment on Brain Functional Diseases, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China.,College of Stomatology and Affiliated Stomatological Hospital of Chongqing Medical University, Chongqing, China
| | - Xuechen Rao
- National Health Commission, Key Laboratory of Diagnosis and Treatment on Brain Functional Diseases, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China.,College of Biomedical Engineering, Chongqing Medical University, Chongqing, China
| | - Lanxiang Liu
- National Health Commission, Key Laboratory of Diagnosis and Treatment on Brain Functional Diseases, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China.,Department of Neurology, Yongchuan Hospital of Chongqing Medical University, Chongqing, China.,Department of Neurology, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Peng Zheng
- National Health Commission, Key Laboratory of Diagnosis and Treatment on Brain Functional Diseases, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China.,Department of Neurology, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Wenxia Li
- National Health Commission, Key Laboratory of Diagnosis and Treatment on Brain Functional Diseases, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Wei Zhou
- National Health Commission, Key Laboratory of Diagnosis and Treatment on Brain Functional Diseases, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Tingjia Chai
- National Health Commission, Key Laboratory of Diagnosis and Treatment on Brain Functional Diseases, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Ping Ji
- College of Stomatology and Affiliated Stomatological Hospital of Chongqing Medical University, Chongqing, China
| | - Jinlin Song
- College of Stomatology and Affiliated Stomatological Hospital of Chongqing Medical University, Chongqing, China
| | - Hong Wei
- Department of Laboratory Animal Science, College of Basic Medical Sciences, Third Military Medical University, Chongqing, China
| | - Peng Xie
- The Ministry of Education, Key Laboratory of Laboratory Medical Diagnostics, The College of Laboratory Medicine, Chongqing Medical University, Chongqing, China.,National Health Commission, Key Laboratory of Diagnosis and Treatment on Brain Functional Diseases, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China.,Department of Neurology, Yongchuan Hospital of Chongqing Medical University, Chongqing, China.,Department of Neurology, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China
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28
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Wilmes L, Collins JM, O'Riordan KJ, O'Mahony SM, Cryan JF, Clarke G. Of bowels, brain and behavior: A role for the gut microbiota in psychiatric comorbidities in irritable bowel syndrome. Neurogastroenterol Motil 2021; 33:e14095. [PMID: 33580895 DOI: 10.1111/nmo.14095] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/19/2021] [Accepted: 01/21/2021] [Indexed: 12/16/2022]
Abstract
BACKGROUND The gastrointestinal microbiota has emerged as a key regulator of gut-brain axis signalling with important implications for neurogastroenterology. There is continuous bidirectional communication between the gut and the brain facilitated by neuronal, endocrine, metabolic, and immune pathways. The microbiota influences these signalling pathways via several mechanisms. Studies have shown compositional and functional alterations in the gut microbiota in stress-related psychiatric disorders. Gut microbiota reconfigurations are also a feature of irritable bowel syndrome (IBS), a gut-brain axis disorder sharing high levels of psychiatric comorbidity including both anxiety and depression. It remains unclear how the gut microbiota alterations in IBS align with both core symptoms and these psychiatric comorbidities. METHODS In this review, we highlight common and disparate features of these microbial signatures as well as the associated gut-brain axis signalling pathways. Studies suggest that patients with either IBS, depression or anxiety, alone or comorbid, present with alterations in gut microbiota composition and harbor immune, endocrine, and serotonergic system alterations relevant to the common pathophysiology of these comorbid conditions. KEY RESULTS Research has illustrated the utility of fecal microbiota transplantation in animal models, expanding the evidence base for a potential causal role of disorder-specific gut microbiota compositions in symptom set expression. Moreover, an exciting study by Constante and colleagues in this issue highlights the possibility of counteracting this microbiota-associated aberrant behavioral phenotype with a probiotic yeast, Saccharomyces boulardii CNCM I-745. CONCLUSIONS AND INFERENCES Such data highlights the potential for therapeutic targeting of the gut microbiota as a valuable strategy for the management of comorbid psychiatric symptoms in IBS.
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Affiliation(s)
- Lars Wilmes
- APC Microbiome Ireland, University College Cork, Cork, Ireland.,Department of Anatomy and Neuroscience, University College Cork, Cork, Ireland.,Department of Psychiatry and Behavioural Science, University College Cork, Cork, Ireland
| | - James M Collins
- APC Microbiome Ireland, University College Cork, Cork, Ireland.,Department of Anatomy and Neuroscience, University College Cork, Cork, Ireland
| | | | - Siobhain M O'Mahony
- APC Microbiome Ireland, University College Cork, Cork, Ireland.,Department of Anatomy and Neuroscience, University College Cork, Cork, Ireland
| | - John F Cryan
- APC Microbiome Ireland, University College Cork, Cork, Ireland.,Department of Anatomy and Neuroscience, University College Cork, Cork, Ireland
| | - Gerard Clarke
- APC Microbiome Ireland, University College Cork, Cork, Ireland.,Department of Psychiatry and Behavioural Science, University College Cork, Cork, Ireland
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Rao X, Liu L, Wang H, Yu Y, Li W, Chai T, Zhou W, Ji P, Song J, Wei H, Xie P. Regulation of Gut Microbiota Disrupts the Glucocorticoid Receptor Pathway and Inflammation-related Pathways in the Mouse Hippocampus. Exp Neurobiol 2021; 30:59-72. [PMID: 33462159 PMCID: PMC7926043 DOI: 10.5607/en20055] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/26/2020] [Revised: 12/28/2020] [Accepted: 01/04/2021] [Indexed: 11/19/2022] Open
Abstract
An increasing number of studies have recently indicated the important effects of gut microbes on various functions of the central nervous system. However, the underlying mechanisms by which gut microbiota regulate brain functions and behavioral phenotypes remain largely unknown. We therefore used isobaric tags for relative and absolute quantitation (iTRAQ)-based quantitative proteomic analysis to obtain proteomic profiles of the hippocampus in germ-free (GF), colonized GF, and specific pathogen-free (SPF) mice. We then integrated the resulting proteomic data with previously reported mRNA microarray data, to further explore the effects of gut microbes on host brain functions. We identified that 61 proteins were upregulated and 242 proteins were downregulated in GF mice compared with SPF mice. Of these, 124 proteins were significantly restored following gut microbiota colonization. Bioinformatic analysis of these significant proteins indicated that the glucocorticoid receptor signaling pathway and inflammation-related pathways were the most enriched disrupted pathways. This study provides new insights into the pathological mechanisms of gut microbiota-regulated diseases.
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Affiliation(s)
- Xuechen Rao
- College of Biomedical Engineering, Chongqing Medical University, Chongqing 400016, China.,NHC Key Laboratory of Diagnosis and Treatment on Brain Functional Diseases, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, China
| | - Lanxiang Liu
- NHC Key Laboratory of Diagnosis and Treatment on Brain Functional Diseases, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, China.,Department of Neurology, Yongchuan Hospital of Chongqing Medical University, Chongqing 402160, China
| | - Haiyang Wang
- NHC Key Laboratory of Diagnosis and Treatment on Brain Functional Diseases, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, China.,College of Stomatology and Affiliated Stomatological Hospital of Chongqing Medical University, Chongqing 401147, China
| | - Ying Yu
- NHC Key Laboratory of Diagnosis and Treatment on Brain Functional Diseases, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, China
| | - Wenxia Li
- NHC Key Laboratory of Diagnosis and Treatment on Brain Functional Diseases, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, China
| | - Tingjia Chai
- NHC Key Laboratory of Diagnosis and Treatment on Brain Functional Diseases, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, China
| | - Wei Zhou
- NHC Key Laboratory of Diagnosis and Treatment on Brain Functional Diseases, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, China
| | - Ping Ji
- College of Stomatology and Affiliated Stomatological Hospital of Chongqing Medical University, Chongqing 401147, China
| | - Jinlin Song
- College of Stomatology and Affiliated Stomatological Hospital of Chongqing Medical University, Chongqing 401147, China
| | - Hong Wei
- Department of Laboratory Animal Science, College of Basic Medical Sciences, Third Military Medical University, Chongqing 400038, China
| | - Peng Xie
- NHC Key Laboratory of Diagnosis and Treatment on Brain Functional Diseases, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, China.,Department of Neurology, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, China
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30
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Liu L, Wang H, Rao X, Yu Y, Li W, Zheng P, Zhao L, Zhou C, Pu J, Yang D, Fang L, Ji P, Song J, Wei H, Xie P. Comprehensive analysis of the lysine acetylome and succinylome in the hippocampus of gut microbiota-dysbiosis mice. J Adv Res 2020; 30:27-38. [PMID: 34026284 PMCID: PMC8132208 DOI: 10.1016/j.jare.2020.12.002] [Citation(s) in RCA: 30] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/08/2020] [Revised: 11/12/2020] [Accepted: 12/03/2020] [Indexed: 12/26/2022] Open
Abstract
Introduction Major depressive disorder is caused by gene–environment interactions, and the host microbiome has been recognized as an important environmental factor. However, the underlying mechanisms of the host–microbiota interactions that lead to depression are complex and remain poorly understood. Objectives The present study aimed to explore the possible mechanisms underlying gut microbiota dysbiosis-induced depressive-like behaviors. Methods We used high-performance liquid chromatography-tandem mass spectrometry to analyze alterations in the hippocampal lysine acetylome and succinylome in male mice that had received gut microbiota from fecal samples of either patients with major depressive disorder or healthy controls. This was followed by bioinformatic analyses. Results A total of 315 acetylation sites on 223 proteins and 624 succinylation sites on 494 proteins were differentially expressed in the gut microbiota-dysbiosis mice. The significantly acetylated proteins were primarily associated with carbon metabolism disruption and gene transcription suppression, while the synaptic vesicle cycle and protein translation were the most significantly altered functions for succinylated proteins. Additionally, our findings suggest that gut microbiota dysbiosis disturbs mitochondria-mediated biological processes and the MAPK signaling pathway through crosstalk between acetylation and succinylation on relevant proteins. Conclusions This is the first study to demonstrate modifications in acetylation and succinylation in gut microbiota-dysbiosis mice. Our findings provide new avenues for exploring the pathogenesis of gut microbiota dysbiosis-related depression, and highlight potential targets for depression treatment.
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Affiliation(s)
- Lanxiang Liu
- Department of Neurology, Yongchuan Hospital of Chongqing Medical University, Chongqing 402160, China.,NHC Key Laboratory of Diagnosis and Treatment on Brain Functional Diseases, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, China.,Department of Neurology, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, China
| | - Haiyang Wang
- College of Stomatology and Affiliated Stomatological Hospital of Chongqing Medical University, 401147, China.,NHC Key Laboratory of Diagnosis and Treatment on Brain Functional Diseases, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, China
| | - Xuechen Rao
- NHC Key Laboratory of Diagnosis and Treatment on Brain Functional Diseases, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, China.,College of Biomedical Engineering, Chongqing Medical University, Chongqing 400016, China
| | - Ying Yu
- NHC Key Laboratory of Diagnosis and Treatment on Brain Functional Diseases, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, China
| | - Wenxia Li
- NHC Key Laboratory of Diagnosis and Treatment on Brain Functional Diseases, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, China
| | - Peng Zheng
- NHC Key Laboratory of Diagnosis and Treatment on Brain Functional Diseases, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, China.,Department of Neurology, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, China
| | - Libo Zhao
- Department of Neurology, Yongchuan Hospital of Chongqing Medical University, Chongqing 402160, China
| | - Chanjuan Zhou
- NHC Key Laboratory of Diagnosis and Treatment on Brain Functional Diseases, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, China
| | - Juncai Pu
- NHC Key Laboratory of Diagnosis and Treatment on Brain Functional Diseases, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, China.,Department of Neurology, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, China
| | - Deyu Yang
- Department of Neurology, Yongchuan Hospital of Chongqing Medical University, Chongqing 402160, China
| | - Liang Fang
- Department of Neurology, Yongchuan Hospital of Chongqing Medical University, Chongqing 402160, China
| | - Ping Ji
- College of Stomatology and Affiliated Stomatological Hospital of Chongqing Medical University, 401147, China.,Chongqing Key Laboratory for Oral Diseases and Biomedical Sciences, Chongqing 401147, China
| | - Jinlin Song
- College of Stomatology and Affiliated Stomatological Hospital of Chongqing Medical University, 401147, China.,Chongqing Key Laboratory for Oral Diseases and Biomedical Sciences, Chongqing 401147, China
| | - Hong Wei
- Department of Laboratory Animal Science, College of Basic Medical Sciences, Third Military Medical University, Chongqing 400038, China
| | - Peng Xie
- Department of Neurology, Yongchuan Hospital of Chongqing Medical University, Chongqing 402160, China.,College of Stomatology and Affiliated Stomatological Hospital of Chongqing Medical University, 401147, China.,NHC Key Laboratory of Diagnosis and Treatment on Brain Functional Diseases, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, China.,Department of Neurology, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, China
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Wang H, Liu L, Rao X, Zeng B, Yu Y, Zhou C, Zeng L, Zheng P, Pu J, Xu S, Cheng K, Zhang H, Ji P, Wei H, Xie P. Integrated phosphoproteomic and metabolomic profiling reveals perturbed pathways in the hippocampus of gut microbiota dysbiosis mice. Transl Psychiatry 2020; 10:346. [PMID: 33051451 PMCID: PMC7553953 DOI: 10.1038/s41398-020-01024-9] [Citation(s) in RCA: 26] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/12/2019] [Revised: 08/27/2020] [Accepted: 09/22/2020] [Indexed: 12/12/2022] Open
Abstract
The dysbiosis of gut microbiota is an important environmental factor that can induce mental disorders, such as depression, through the microbiota-gut-brain axis. However, the underlying pathogenic mechanisms are complex and not completely understood. Here we utilized mass spectrometry to identify the global phosphorylation dynamics in hippocampus tissue in germ-free mice and specific pathogen-free mice (GF vs SPF), fecal microbiota transplantation (FMT) model ("depression microbiota" and the "healthy microbiota" recipient mice). As a result, 327 phosphosites of 237 proteins in GF vs SPF, and 478 phosphosites of 334 proteins in "depression microbiota" vs "healthy microbiota" recipient mice were identified as significant. These phosphorylation dysregulations were consistently associated with glutamatergic neurotransmitter system disturbances. The FMT mice exhibited disturbances in lipid metabolism and amino acid metabolism in both the periphery and brain through integrating phosphoproteomic and metabolomic analysis. Moreover, CAMKII-CREB signaling pathway, in response to these disturbances, was the primary common perturbed cellular process. In addition, we demonstrated that the spliceosome, never directly implicated in mental disorders previously, was a substantially neuronal function disrupted by gut microbiota dysbiosis, and the NCBP1 phosphorylation was identified as a novel pathogenic target. These results present a new perspective to study the pathologic mechanisms of gut microbiota dysbiosis related depression and highlight potential gut-mediated therapies for depression.
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Affiliation(s)
- Haiyang Wang
- grid.459985.cChongqing Key Laboratory of Oral Diseases and Biomedical Sciences, Stomatological Hospital of Chongqing Medical University, 401147 Chongqing, China ,grid.203458.80000 0000 8653 0555College of Biomedical Engineering, Chongqing Medical University, 400016 Chongqing, China ,grid.452206.7NHC Key Laboratory of Diagnosis and Treatment on Brain Functional Diseases, The First Affiliated Hospital of Chongqing Medical University, 400016 Chongqing, China
| | - Lanxiang Liu
- grid.452206.7NHC Key Laboratory of Diagnosis and Treatment on Brain Functional Diseases, The First Affiliated Hospital of Chongqing Medical University, 400016 Chongqing, China ,grid.203458.80000 0000 8653 0555Department of Neurology, Yongchuan Hospital of Chongqing Medical University, 402460 Chongqing, China
| | - Xuechen Rao
- grid.203458.80000 0000 8653 0555College of Biomedical Engineering, Chongqing Medical University, 400016 Chongqing, China ,grid.452206.7NHC Key Laboratory of Diagnosis and Treatment on Brain Functional Diseases, The First Affiliated Hospital of Chongqing Medical University, 400016 Chongqing, China
| | - Benhua Zeng
- grid.410570.70000 0004 1760 6682Department of Laboratory Animal Science, College of Basic Medical Sciences, Third Military Medical University, 400038 Chongqing, China
| | - Ying Yu
- grid.452206.7NHC Key Laboratory of Diagnosis and Treatment on Brain Functional Diseases, The First Affiliated Hospital of Chongqing Medical University, 400016 Chongqing, China
| | - Chanjuan Zhou
- grid.452206.7NHC Key Laboratory of Diagnosis and Treatment on Brain Functional Diseases, The First Affiliated Hospital of Chongqing Medical University, 400016 Chongqing, China
| | - Li Zeng
- grid.452206.7NHC Key Laboratory of Diagnosis and Treatment on Brain Functional Diseases, The First Affiliated Hospital of Chongqing Medical University, 400016 Chongqing, China ,grid.412461.4Department of Nephrology, The Second Affiliated Hospital of Chongqing Medical University, 400010 Chongqing, China
| | - Peng Zheng
- grid.452206.7NHC Key Laboratory of Diagnosis and Treatment on Brain Functional Diseases, The First Affiliated Hospital of Chongqing Medical University, 400016 Chongqing, China ,grid.452206.7Department of Neurology, The First Affiliated Hospital of Chongqing Medical University, 400016 Chongqing, China
| | - Juncai Pu
- grid.452206.7NHC Key Laboratory of Diagnosis and Treatment on Brain Functional Diseases, The First Affiliated Hospital of Chongqing Medical University, 400016 Chongqing, China ,grid.452206.7Department of Neurology, The First Affiliated Hospital of Chongqing Medical University, 400016 Chongqing, China
| | - Shaohua Xu
- grid.452206.7NHC Key Laboratory of Diagnosis and Treatment on Brain Functional Diseases, The First Affiliated Hospital of Chongqing Medical University, 400016 Chongqing, China
| | - Ke Cheng
- grid.452206.7NHC Key Laboratory of Diagnosis and Treatment on Brain Functional Diseases, The First Affiliated Hospital of Chongqing Medical University, 400016 Chongqing, China ,grid.452206.7Department of Neurology, The First Affiliated Hospital of Chongqing Medical University, 400016 Chongqing, China
| | - Hanping Zhang
- grid.452206.7NHC Key Laboratory of Diagnosis and Treatment on Brain Functional Diseases, The First Affiliated Hospital of Chongqing Medical University, 400016 Chongqing, China ,grid.452206.7Department of Neurology, The First Affiliated Hospital of Chongqing Medical University, 400016 Chongqing, China
| | - Ping Ji
- grid.459985.cChongqing Key Laboratory of Oral Diseases and Biomedical Sciences, Stomatological Hospital of Chongqing Medical University, 401147 Chongqing, China
| | - Hong Wei
- Department of Laboratory Animal Science, College of Basic Medical Sciences, Third Military Medical University, 400038, Chongqing, China.
| | - Peng Xie
- Chongqing Key Laboratory of Oral Diseases and Biomedical Sciences, Stomatological Hospital of Chongqing Medical University, 401147, Chongqing, China. .,NHC Key Laboratory of Diagnosis and Treatment on Brain Functional Diseases, The First Affiliated Hospital of Chongqing Medical University, 400016, Chongqing, China. .,Department of Neurology, The First Affiliated Hospital of Chongqing Medical University, 400016, Chongqing, China.
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Liu L, Wang H, Yu Y, Zeng B, Rao X, Chen J, Zhou C, Zheng P, Pu J, Yang L, Zhang H, Wei H, Xie P. Microbial regulation of a lincRNA-miRNA-mRNA network in the mouse hippocampus. Epigenomics 2020; 12:1377-1387. [PMID: 32878473 DOI: 10.2217/epi-2019-0307] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/26/2022] Open
Abstract
Aim: To comprehensively understand microbiota-regulated lincRNA-miRNA-mRNA networks in psychiatric disorders. Materials & methods: Integrated analyses of lincRNAs, mRNAs and miRNAs, obtained by microarray analysis of hippocampus from specific pathogen-free, germ-free and colonized germ-free mice, were performed. Results: Expression of 139 mRNAs, seven miRNAs and one lincRNA was restored following colonization. The restored transcripts were mainly involved in CREB and Ras/MAPK signaling pathways. RNA transcription and post-transcriptional regulation were the primary perturbed functions. Finally, 12 lincRNAs, six miRNAs and 47 mRNAs were included in a lincRNA-miRNA-mRNA network, and lincRNA0926-miR-190a-5p-Celf4 interactions may play a pivotal role in this regulatory network. Conclusion: This study provides clues for understanding the molecular basis of gut microbiota-brain interactions in depressive- and anxiety-like behaviors.
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Affiliation(s)
- Lanxiang Liu
- Department of Neurology, Yongchuan Hospital of Chongqing Medical University, Chongqing 402160, China.,NHC Key Laboratory of Diagnosis & Treatment on Brain Functional Diseases, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, China.,Department of Neurology, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, China
| | - Haiyang Wang
- College of Stomatology and Affiliated Stomatological Hospital of Chongqing Medical University, 401147, China.,NHC Key Laboratory of Diagnosis & Treatment on Brain Functional Diseases, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, China
| | - Ying Yu
- NHC Key Laboratory of Diagnosis & Treatment on Brain Functional Diseases, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, China
| | - Benhua Zeng
- Department of Laboratory Animal Science, College of Basic Medical Sciences, Third Military Medical University, Chongqing 400038, China
| | - Xuechen Rao
- NHC Key Laboratory of Diagnosis & Treatment on Brain Functional Diseases, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, China.,College of Biomedical Engineering, Chongqing Medical University, Chongqing 400016, China
| | - Jianjun Chen
- Institute of Life Sciences, Chongqing Medical University, Chongqing 400016, China
| | - Chanjuan Zhou
- NHC Key Laboratory of Diagnosis & Treatment on Brain Functional Diseases, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, China
| | - Peng Zheng
- NHC Key Laboratory of Diagnosis & Treatment on Brain Functional Diseases, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, China.,Department of Neurology, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, China
| | - Juncai Pu
- NHC Key Laboratory of Diagnosis & Treatment on Brain Functional Diseases, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, China.,Department of Neurology, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, China
| | - Lining Yang
- NHC Key Laboratory of Diagnosis & Treatment on Brain Functional Diseases, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, China
| | - Hanping Zhang
- NHC Key Laboratory of Diagnosis & Treatment on Brain Functional Diseases, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, China.,Department of Neurology, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, China
| | - Hong Wei
- Department of Laboratory Animal Science, College of Basic Medical Sciences, Third Military Medical University, Chongqing 400038, China
| | - Peng Xie
- Department of Neurology, Yongchuan Hospital of Chongqing Medical University, Chongqing 402160, China.,College of Stomatology and Affiliated Stomatological Hospital of Chongqing Medical University, 401147, China.,NHC Key Laboratory of Diagnosis & Treatment on Brain Functional Diseases, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, China.,Department of Neurology, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, China
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Chinna Meyyappan A, Forth E, Wallace CJK, Milev R. Effect of fecal microbiota transplant on symptoms of psychiatric disorders: a systematic review. BMC Psychiatry 2020; 20:299. [PMID: 32539741 PMCID: PMC7294648 DOI: 10.1186/s12888-020-02654-5] [Citation(s) in RCA: 126] [Impact Index Per Article: 25.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/27/2020] [Accepted: 05/04/2020] [Indexed: 02/08/2023] Open
Abstract
BACKGROUND The Gut-Brain-Axis is a bidirectional signaling pathway between the gastrointestinal (GI) tract and the brain. The hundreds of trillions of microorganisms populating the gastrointestinal tract are thought to modulate this connection, and have far reaching effects on the immune system, central and autonomic nervous systems, and GI functioning. These interactions Diagnostic and statistical manual of mental disorders have also been linked to various psychiatric illnesses such as depression, anxiety, substance abuse, autism spectrum disorder, and eating disorders. It is hypothesized that techniques aimed at strengthening and repopulating the gut microbiome, such as Fecal Microbiota Transplant (FMT), may be useful in the prevention and treatment of psychiatric illnesses. METHODS A systematic search of five databases was conducted using key terms related to FMT and psychiatric illnesses. All results were then evaluated based on specific eligibility criteria. RESULTS Twenty-one studies met the eligibility criteria and were analysed for reported changes in mood and behavioural measures indicative of psychiatric wellbeing. The studies included were either entirely clinical (n = 8), preclinical with human donors (n = 9), or entirely preclinical (n = 11). All studies found a decrease in depressive and anxiety-like symptoms and behaviours resulting from the transplantation of healthy microbiota. The inverse was also found, with the transmission of depressive and anxiety-like symptoms and behaviours resulting from the transplantation of microbiota from psychiatrically ill donors to healthy recipients. CONCLUSION There appears to be strong evidence for the treatment and transmission of psychiatric illnesses through FMT. Further research with larger sample sizes and stronger scientific design is warranted in order to fully determine the efficacy and safety of this potential treatment. Registered on PROSPERO, IRD: CRD42019126795.
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Affiliation(s)
- Arthi Chinna Meyyappan
- Department of Psychiatry, Queen's University, 752 King St. West, Kingston, ON, K7L 4X3, Canada. .,Providence Care Hospital, 752 King St. West, Kingston, ON, K7L 4X3, Canada. .,Centre for Neuroscience Studies, Queen's University, 18 Stuart St., Kingston, ON, K7L 3N6, Canada.
| | - Evan Forth
- grid.410356.50000 0004 1936 8331Department of Psychiatry, Queen’s University, 752 King St. West, Kingston, ON K7L 4X3 Canada ,Providence Care Hospital, 752 King St. West, Kingston, ON K7L 4X3 Canada ,grid.410356.50000 0004 1936 8331Centre for Neuroscience Studies, Queen’s University, 18 Stuart St., Kingston, ON K7L 3N6 Canada
| | - Caroline J. K. Wallace
- grid.410356.50000 0004 1936 8331Department of Psychiatry, Queen’s University, 752 King St. West, Kingston, ON K7L 4X3 Canada ,Providence Care Hospital, 752 King St. West, Kingston, ON K7L 4X3 Canada ,grid.410356.50000 0004 1936 8331Centre for Neuroscience Studies, Queen’s University, 18 Stuart St., Kingston, ON K7L 3N6 Canada
| | - Roumen Milev
- grid.410356.50000 0004 1936 8331Department of Psychiatry, Queen’s University, 752 King St. West, Kingston, ON K7L 4X3 Canada ,Providence Care Hospital, 752 King St. West, Kingston, ON K7L 4X3 Canada ,grid.410356.50000 0004 1936 8331Centre for Neuroscience Studies, Queen’s University, 18 Stuart St., Kingston, ON K7L 3N6 Canada ,grid.410356.50000 0004 1936 8331Department of Psychology, Queen’s University, 62 Arch St., Kingston, K7L 3L3 ON Canada
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He Y, Wang Y, Wu Z, Lan T, Tian Y, Chen X, Li Y, Dang R, Bai M, Cheng K, Xie P. Metabolomic abnormalities of purine and lipids implicated olfactory bulb dysfunction of CUMS depressive rats. Metab Brain Dis 2020; 35:649-659. [PMID: 32152797 DOI: 10.1007/s11011-020-00557-8] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/29/2019] [Accepted: 02/24/2020] [Indexed: 12/27/2022]
Abstract
Major depressive disorder (MDD) is a serious mood disorder and leads to a high suicide rate as well as financial burden. The volume and function (the sensitivity and neurogenesis) of the olfactory bulb (OB) were reported to be altered among the MDD patients and rodent models of depression. In addition, the olfactory epithelium was newly reported to decrease its volume and function under chronic unpredictable mild stress (CUMS) treatment. However, the underlying molecular mechanism still remains unclear. Herein, we conducted the non-targeted metabolomics method based on gas chromatography-mass spectrometry (GC-MS) coupled with multivariate statistical analysis to characterize the differential metabolites in OB of CUMS rats. Our results showed that 19 metabolites were categorized into two perturbed pathways: purine metabolism and lipid metabolism, which were regarded as the vital pathways concerned with dysfunction of OB. These findings indicated that the turbulence of metabolic pathways may be partly responsible for the dysfunction of OB in MDD.
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Affiliation(s)
- Yong He
- Chongqing Key Laboratory of Neurobiology, Chongqing, 400016, China
- Institute of Neuroscience and the Collaborative Innovation Center for Brain Science, Chongqing Medical University, Chongqing, 400016, China
| | - Yue Wang
- Chongqing Key Laboratory of Neurobiology, Chongqing, 400016, China
- Institute of Neuroscience and the Collaborative Innovation Center for Brain Science, Chongqing Medical University, Chongqing, 400016, China
- Institute of Neuroscience, Basic Medical College, Chongqing Medical University, Chongqing, 400016, China
| | - Zhonghao Wu
- Chongqing Key Laboratory of Neurobiology, Chongqing, 400016, China
- Institute of Neuroscience and the Collaborative Innovation Center for Brain Science, Chongqing Medical University, Chongqing, 400016, China
- College of Biomedical Engineering, Chongqing Medical University, Chongqing, 400016, China
| | - Tianlan Lan
- Chongqing Key Laboratory of Neurobiology, Chongqing, 400016, China
- Institute of Neuroscience and the Collaborative Innovation Center for Brain Science, Chongqing Medical University, Chongqing, 400016, China
- College of Biomedical Engineering, Chongqing Medical University, Chongqing, 400016, China
| | - Yu Tian
- Chongqing Key Laboratory of Neurobiology, Chongqing, 400016, China
- Institute of Neuroscience and the Collaborative Innovation Center for Brain Science, Chongqing Medical University, Chongqing, 400016, China
- Department of Neurology, The First Affiliated Hospital of Chongqing Medical University, Chongqing, 400016, China
| | - Xi Chen
- Chongqing Key Laboratory of Neurobiology, Chongqing, 400016, China
- Institute of Neuroscience and the Collaborative Innovation Center for Brain Science, Chongqing Medical University, Chongqing, 400016, China
- Department of Neurology, Yongchuan Hospital of Chongqing Medical University, Chongqing, 402460, China
| | - Yan Li
- Chongqing Key Laboratory of Neurobiology, Chongqing, 400016, China
- Institute of Neuroscience and the Collaborative Innovation Center for Brain Science, Chongqing Medical University, Chongqing, 400016, China
- Department of Neurology, The First Affiliated Hospital of Chongqing Medical University, Chongqing, 400016, China
| | - Ruozhi Dang
- Chongqing Key Laboratory of Neurobiology, Chongqing, 400016, China
- Institute of Neuroscience and the Collaborative Innovation Center for Brain Science, Chongqing Medical University, Chongqing, 400016, China
- Department of Neurology, The First Affiliated Hospital of Chongqing Medical University, Chongqing, 400016, China
| | - Mengge Bai
- Chongqing Key Laboratory of Neurobiology, Chongqing, 400016, China
- Institute of Neuroscience and the Collaborative Innovation Center for Brain Science, Chongqing Medical University, Chongqing, 400016, China
- Key Laboratory of Laboratory Medical Diagnostics of Education, Department of Laboratory Medicine, Chongqing Medical University, Chongqing, 400016, China
| | - Ke Cheng
- Chongqing Key Laboratory of Neurobiology, Chongqing, 400016, China.
- Institute of Neuroscience and the Collaborative Innovation Center for Brain Science, Chongqing Medical University, Chongqing, 400016, China.
- Department of Neurology, The First Affiliated Hospital of Chongqing Medical University, Chongqing, 400016, China.
| | - Peng Xie
- Chongqing Key Laboratory of Neurobiology, Chongqing, 400016, China.
- Institute of Neuroscience and the Collaborative Innovation Center for Brain Science, Chongqing Medical University, Chongqing, 400016, China.
- Department of Neurology, The First Affiliated Hospital of Chongqing Medical University, Chongqing, 400016, China.
- Department of Neurology, Yongchuan Hospital of Chongqing Medical University, Chongqing, 402460, China.
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Kim YG, Woo J, Park J, Kim S, Lee YS, Kim Y, Kim SJ. Quantitative Proteomics Reveals Distinct Molecular Signatures of Different Cerebellum-Dependent Learning Paradigms. J Proteome Res 2020; 19:2011-2025. [PMID: 32181667 DOI: 10.1021/acs.jproteome.9b00826] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/24/2023]
Abstract
The cerebellum improves motor performance by adjusting motor gain appropriately. As de novo protein synthesis is essential for the formation and retention of memories, we hypothesized that motor learning in the opposite direction would induce a distinct pattern of protein expression in the cerebellum. We conducted quantitative proteomic profiling to compare the level of protein expression in the cerebellum at 1 and 24 h after training from mice that underwent different paradigms of cerebellum-dependent oculomotor learning from specific directional changes in motor gain. We quantified a total of 43 proteins that were significantly regulated in each of the three learning paradigms in the cerebellum at 1 and 24 h after learning. In addition, functional enrichment analysis identified protein groups that were differentially enriched or depleted in the cerebellum at 24 h after the three oculomotor learnings, suggesting that distinct biological pathways may be engaged in the formation of three oculomotor memories. Weighted correlation network analysis discovered groups of proteins significantly correlated with oculomotor memory. Finally, four proteins (Snca, Sncb, Cttn, and Stmn1) from the protein group correlated with the learning amount after oculomotor training were validated by Western blot. This study provides a comprehensive and unbiased list of proteins related to three cerebellum-dependent motor learning paradigms, suggesting the distinct nature of protein expression in the cerebellum for each learning paradigm. The proteomics data have been deposited to the ProteomeXchange Consortium with identifiers <PXD008433>.
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Affiliation(s)
- Yong Gyu Kim
- Department of Biomedical Sciences, Seoul National University College of Medicine, Seoul 03080, Korea.,Department of Physiology, Seoul National University College of Medicine, Seoul 03080, Korea
| | - Jongmin Woo
- Department of Biomedical Sciences, Seoul National University College of Medicine, Seoul 03080, Korea.,Environmental Molecular Sciences Laboratory, Pacific Northwest National Laboratory, Richland, Washington 99354, United States
| | - Joonho Park
- Interdisciplinary Program in Bioengineering, College of Engineering, Seoul National University, 1 Gwanak-ro, Seoul 151-742, Korea
| | - Sooyong Kim
- Department of Biomedical Sciences, Seoul National University College of Medicine, Seoul 03080, Korea.,Department of Physiology, Seoul National University College of Medicine, Seoul 03080, Korea
| | - Yong-Seok Lee
- Department of Biomedical Sciences, Seoul National University College of Medicine, Seoul 03080, Korea.,Department of Physiology, Seoul National University College of Medicine, Seoul 03080, Korea.,Neuroscience Research Institute, Seoul National University College of Medicine, Seoul 03080, Korea
| | - Youngsoo Kim
- Department of Biomedical Sciences, Seoul National University College of Medicine, Seoul 03080, Korea.,Interdisciplinary Program in Bioengineering, College of Engineering, Seoul National University, 1 Gwanak-ro, Seoul 151-742, Korea
| | - Sang Jeong Kim
- Department of Biomedical Sciences, Seoul National University College of Medicine, Seoul 03080, Korea.,Department of Physiology, Seoul National University College of Medicine, Seoul 03080, Korea.,Neuroscience Research Institute, Seoul National University College of Medicine, Seoul 03080, Korea
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36
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Wang H, Liu L, Rao X, Chai T, Zeng B, Zhang X, Yu Y, Zhou C, Pu J, Zhou W, Li W, Zhang H, Wei H, Xie P. Commensal Microbiota Regulation of Metabolic Networks During Olfactory Dysfunction in Mice. Neuropsychiatr Dis Treat 2020; 16:761-769. [PMID: 32256072 PMCID: PMC7090175 DOI: 10.2147/ndt.s236541] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/30/2019] [Accepted: 03/01/2020] [Indexed: 12/26/2022] Open
Abstract
INTRODUCTION Recently, an increasing number of studies have focused on commensal microbiota. These microorganisms have been suggested to impact human health and disease. However, only a small amount of data exists to support the assessment of the influences that commensal microbiota exert on olfactory function. METHODS We used a buried food pellet test (BFPT) to investigate and compare olfactory functions in adult, male, germ-free (GF) and specific-pathogen-free (SPF) mice, then examined and compared the metabolomic profiles for olfactory bulbs (OBs) isolated from GF and SPF mice to uncover the mechanisms associated with olfactory dysfunction. RESULTS We found that the absence of commensal microbiota was able to influence olfactory function and the metabolic signatures of OBs, with 38 metabolites presenting significant differences between the two groups. These metabolites were primarily associated with disturbances in glycolysis, the tricarboxylic acid (TCA) cycle, amino acid metabolism, and purine catabolism. Finally, the commensal microbiota regulation of metabolic networks during olfactory dysfunction was identified, based on an integrated analysis of metabolite, protein, and mRNA levels. CONCLUSION This study demonstrated that the absence of commensal microbiota may impair olfactory function and disrupt metabolic networks. These findings provide a new entry-point for understanding olfactory-associated disorders and their potential underlying mechanisms.
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Affiliation(s)
- Haiyang Wang
- NHC Key Laboratory of Diagnosis and Treatment on Brain Functional Diseases, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, People's Republic of China.,College of Biomedical Engineering, Chongqing Medical University, Chongqing 400016, People's Republic of China
| | - Lanxiang Liu
- NHC Key Laboratory of Diagnosis and Treatment on Brain Functional Diseases, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, People's Republic of China.,Department of Neurology, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, People's Republic of China
| | - Xuechen Rao
- NHC Key Laboratory of Diagnosis and Treatment on Brain Functional Diseases, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, People's Republic of China.,College of Biomedical Engineering, Chongqing Medical University, Chongqing 400016, People's Republic of China
| | - Tingjia Chai
- NHC Key Laboratory of Diagnosis and Treatment on Brain Functional Diseases, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, People's Republic of China
| | - Benhua Zeng
- Department of Laboratory Animal Science, College of Basic Medical Sciences, Third Military Medical University, Chongqing 400038, People's Republic of China
| | - Xiaotong Zhang
- NHC Key Laboratory of Diagnosis and Treatment on Brain Functional Diseases, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, People's Republic of China
| | - Ying Yu
- NHC Key Laboratory of Diagnosis and Treatment on Brain Functional Diseases, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, People's Republic of China
| | - Chanjuan Zhou
- NHC Key Laboratory of Diagnosis and Treatment on Brain Functional Diseases, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, People's Republic of China
| | - Juncai Pu
- NHC Key Laboratory of Diagnosis and Treatment on Brain Functional Diseases, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, People's Republic of China.,Department of Neurology, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, People's Republic of China
| | - Wei Zhou
- NHC Key Laboratory of Diagnosis and Treatment on Brain Functional Diseases, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, People's Republic of China
| | - Wenxia Li
- Department of Laboratory Animal Science, College of Basic Medical Sciences, Third Military Medical University, Chongqing 400038, People's Republic of China
| | - Hanping Zhang
- NHC Key Laboratory of Diagnosis and Treatment on Brain Functional Diseases, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, People's Republic of China.,Department of Neurology, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, People's Republic of China
| | - Hong Wei
- Department of Laboratory Animal Science, College of Basic Medical Sciences, Third Military Medical University, Chongqing 400038, People's Republic of China
| | - Peng Xie
- NHC Key Laboratory of Diagnosis and Treatment on Brain Functional Diseases, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, People's Republic of China.,College of Biomedical Engineering, Chongqing Medical University, Chongqing 400016, People's Republic of China.,Department of Neurology, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, People's Republic of China
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Wang Y, Arthur EW, Liu N, Li X, Xiang W, Maxwell A, Li Z, Zhou Z. iTRAQ-Based Quantitative Proteomics Analysis of HeLa Cells Infected With Chlamydia muridarum TC0668 Mutant and Wild-Type Strains. Front Microbiol 2019; 10:2553. [PMID: 31787950 PMCID: PMC6854023 DOI: 10.3389/fmicb.2019.02553] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/20/2019] [Accepted: 10/22/2019] [Indexed: 12/15/2022] Open
Abstract
Chlamydia muridarum, an obligate intracellular pathogen, was used to establish a murine model of female upper genital tract infection by Chlamydia trachomatis. TC0668 in C. muridarum is a hypothetical chromosomal virulence protein that is involved in upper genital tract pathogenesis. The infection of mice with the C. muridarum TC0668-mutant (G216*) strain results in less pathological damage in the upper genital tract. In this study, an isobaric tags for relative and absolute quantitation (iTRAQ)-based quantitative proteomics analysis was performed to identify differentially expressed proteins between TC0668 wild-type (TC0668wt) and TC0668 mutant (TC0668mut) strains at 6, 12, 18, and 24 h post-infection (p.i.). Of the 550 proteins differentially expressed at 18 h p.i., 222 and 328 were up-regulated and down-regulated, respectively, inTC0668mut-infected cells. The expression of seven up-regulated proteins (encoded by SRPRB, JAK1, PMM1, HLA-DQB1, THBS1, ITPR1, and BCAP31) and three down-regulated proteins (encoded by MAPKAPK2, TRAFD1, and IFI16) from the iTRAQ analysis were validated using quantitative real-time (qRT)-PCR. The qRT-PCR results were consistent with those of iTRAQ. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses revealed that the differentially expressed proteins primarily participated in inflammatory responses, fibrosis, metabolic processes, and complement coagulation cascades, and were mainly enriched in the phosphatidylinositol 3′-kinase (PI3K)/Akt, nuclear factor kappa-B (NF-κB), and other signaling pathways. Using western-blotting and immunofluorescence detection, significant differences in activation of the PI3K/Akt and NF-κB signaling pathways were observed between the TC0668wt- and TC0668mut-infected cells. Differentially expressed proteins linked with inflammation and fibrosis were used in a protein-protein interaction network analysis. The results suggest that TC0668 may play a pivotal role in C. muridarum-induced genital pathology by inducing inflammatory responses and fibrosis, which may involve the activation of the PI3K/Akt and NF-κB signaling pathways.
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Affiliation(s)
- Yingzi Wang
- Institute of Pathogenic Biology, Hengyang Medical College, University of South China, Hengyang, China.,Hunan Provincial Key Laboratory for Special Pathogens Prevention and Control, Pathogenic Biology Institute, University of South China, Hengyang, China
| | - Emmanuel Wirekoh Arthur
- Institute of Pathogenic Biology, Hengyang Medical College, University of South China, Hengyang, China.,Hunan Provincial Key Laboratory for Special Pathogens Prevention and Control, Pathogenic Biology Institute, University of South China, Hengyang, China
| | - Na Liu
- Institute of Pathogenic Biology, Hengyang Medical College, University of South China, Hengyang, China.,Hunan Provincial Key Laboratory for Special Pathogens Prevention and Control, Pathogenic Biology Institute, University of South China, Hengyang, China
| | - Xiaofang Li
- Institute of Pathogenic Biology, Hengyang Medical College, University of South China, Hengyang, China.,Hunan Provincial Key Laboratory for Special Pathogens Prevention and Control, Pathogenic Biology Institute, University of South China, Hengyang, China
| | - Wenjing Xiang
- Institute of Pathogenic Biology, Hengyang Medical College, University of South China, Hengyang, China.,Hunan Provincial Key Laboratory for Special Pathogens Prevention and Control, Pathogenic Biology Institute, University of South China, Hengyang, China
| | - Asamoah Maxwell
- Institute of Pathogenic Biology, Hengyang Medical College, University of South China, Hengyang, China.,Hunan Provincial Key Laboratory for Special Pathogens Prevention and Control, Pathogenic Biology Institute, University of South China, Hengyang, China
| | - Zhongyu Li
- Institute of Pathogenic Biology, Hengyang Medical College, University of South China, Hengyang, China.,Hunan Provincial Key Laboratory for Special Pathogens Prevention and Control, Pathogenic Biology Institute, University of South China, Hengyang, China
| | - Zhou Zhou
- Institute of Pathogenic Biology, Hengyang Medical College, University of South China, Hengyang, China.,Hunan Provincial Key Laboratory for Special Pathogens Prevention and Control, Pathogenic Biology Institute, University of South China, Hengyang, China
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Hippocampus-specific regulation of long non-coding RNA and mRNA expression in germ-free mice. Funct Integr Genomics 2019; 20:355-365. [PMID: 31677064 DOI: 10.1007/s10142-019-00716-w] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/16/2019] [Revised: 09/16/2019] [Accepted: 09/20/2019] [Indexed: 12/13/2022]
Abstract
Gut microbiota can affect multiple brain functions and cause behavioral alterations through the microbiota-gut-brain axis. In our previous study, we found that the absence of gut microbiota can influence the expression of microRNAs and mRNAs in the hippocampal region of the germ-free (GF) mice. Long non-coding RNAs (lncRNAs) are increasingly being recognized as an important functional transcriptional regulator in the brain. In the present study, we aim to identify possible biological pathways and functional networks for lncRNA-associated transcript of the gut microbiota in relation to the brain function. The profiles of lncRNA and mRNA from specific pathogen-free (SPF), colonized GF (CGF), and GF mice were generated using the Agilent Mouse LncRNA Array v2.0. Differentially expressed (DE) lncRNAs and mRNAs were identified, and lncRNA target genes were also predicted. Ingenuity pathway analysis (IPA) was performed to analyze related signaling pathways and biological functions associated with these dysregulated mRNAs and target genes. Validation with quantitative real-time PCR was performed on several key genes. Compared with SPF mice a total of 2230 DE lncRNAs were found in GF mice. Among these, 1355 were upregulated and 875 were downregulated. After comparing the target genes of DE lncRNAs with mRNA datasets, 669 overlapping genes were identified. IPA core analyses revealed that most of these genes were highly associated with cardiac hypertrophy, nuclear factors of activated T cells (NFAT) gonadotropin-releasing hormone (GnRH), calcium, and cAMP-response element-binding protein (CREB) signaling pathways. Additionally, mRNA expression levels of APP, CASP9, IGFBP2, PTGDS, and TGFBR2 genes that are involved in central nervous system functions were significantly changed in the GF mouse hippocampus. Through this study, for the first time, we describe the effect of gut microbiota on the hippocampal lncRNA regulation. This will help in enhancing the overall knowledge about microbiota-gut-brain axis.
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Xie W, Meng X, Zhai Y, Ye T, Zhou P, Nan F, Sun G, Sun X. Antidepressant-like effects of the Guanxin Danshen formula via mediation of the CaMK II-CREB-BDNF signalling pathway in chronic unpredictable mild stress-induced depressive rats. ANNALS OF TRANSLATIONAL MEDICINE 2019; 7:564. [PMID: 31807545 DOI: 10.21037/atm.2019.09.39] [Citation(s) in RCA: 35] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
Background Depression is a chronic and recurrent syndrome of mood disorder causing immense social and economic burden; thus, treatment should be improved. Guanxin Danshen formula (GXDSF), a natural botanical drug composition prescription, has significant cardiovascular protective effects and is widely used in the clinical treatment of myocardial ischaemic diseases. However, it is still unclear and seldom studied whether GXDSF has neuroprotective effects against depressive disorders. This study explored whether GXDSF has antidepressant-like effects in rats exposed to chronic unpredictable mild stress (CUMS) and analysed the possible underlying neurotrophic expression and psychotropic mechanisms. Methods The present study was designed to investigate the antidepressant effects of GXDSF treatment in a CUMS-induced rat model. Based on the clinical doses, the drug-treated group was intragastrically administered GXDSF for 30 days, and rats were simultaneously exposed to CUMS stimulation for 30 days. After induction and drug administration, the depression-like behaviours were determined via the sucrose preference test (SPT), the open field test (OFT), the tail suspension test (TST), and the forced swim test (FST). ELISA kits were used to examine the monoaminergic neurotransmitters, monoamine oxidase (MAO) and Ca2+ levels in the hippocampus. Moreover, we measured and analysed the brain-derived neurotrophic factor (BDNF) and nerve growth factor (NGF) levels and the upstream regulation and signal pathways of BDNF and NGF to explore their related mechanisms in this animal model of depression, including calcium-calmodulin dependent protein kinase-II (CaMKII) and cAMP response element-binding (CREB). Results The results revealed that GXDSF may possess significant antidepressant-like effects via improving body weight, raising the sucrose preference in the SPT, increasing the total distance, the number of upright stands, and the residence time of the central zone in the open field test (OPF) and reducing the immobility time in the TST and FST. In addition, GXDSF significantly upregulated the relative levels of neurotransmitters, including dopamine (DA), norepinephrine (NE), and serotonin (5-HT), in a dose-dependent manner and inhibited MAO activities in the hippocampus. Moreover, GXDSF reversed the decline in intracellular CREB and p-CREB expression induced by CUMS, downregulated the phosphorylation levels of intracellular CaMKII and its two subunits CaMKIIα and CaMKIIβ in the hippocampus, and thus, clearly upregulated the downstream effector protein expression levels of BDNF, NGF, and synitaxine-1 in the hippocampus. These data suggest that the antidepressant effects of GXDSF have a potential relationship with regulating changes in the CaMKII-CREB-BDNF pathway. Conclusions Despite several limitations of this study, the results have suggested that GXDSF administration possesses antidepressant-like effects in CUMS-treated rats and provide the first in vivo demonstration of a possible mechanism of GXDSF via regulating changes in the CaMKII-CREB-BDNF signalling pathway. These findings provide a novel potential substrate by which herbal antidepressants may exert therapeutic effects in the treatment of depression.
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Affiliation(s)
- Weijie Xie
- Beijing Key Laboratory of Innovative Drug Discovery of Traditional Chinese Medicine (Natural Medicine) and Translational Medicine, Institute of Medicinal Plant Development, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing 100193, China.,Key Laboratory of Bioactive Substances and Resource Utilization of Chinese Herbal Medicine, Ministry of Education, Beijing 100193, China.,Key Laboratory of Efficacy Evaluation of Chinese Medicine against Glycolipid Metabolic Disorders, State Administration of Traditional Chinese Medicine, Beijing 100193, China.,Zhongguancun Open Laboratory of the Research and Development of Natural Medicine and Health Products, Beijing 100193, China
| | - Xiangbao Meng
- Beijing Key Laboratory of Innovative Drug Discovery of Traditional Chinese Medicine (Natural Medicine) and Translational Medicine, Institute of Medicinal Plant Development, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing 100193, China.,Key Laboratory of Bioactive Substances and Resource Utilization of Chinese Herbal Medicine, Ministry of Education, Beijing 100193, China.,Key Laboratory of Efficacy Evaluation of Chinese Medicine against Glycolipid Metabolic Disorders, State Administration of Traditional Chinese Medicine, Beijing 100193, China.,Zhongguancun Open Laboratory of the Research and Development of Natural Medicine and Health Products, Beijing 100193, China
| | - Yadong Zhai
- Beijing Key Laboratory of Innovative Drug Discovery of Traditional Chinese Medicine (Natural Medicine) and Translational Medicine, Institute of Medicinal Plant Development, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing 100193, China.,Key Laboratory of Bioactive Substances and Resource Utilization of Chinese Herbal Medicine, Ministry of Education, Beijing 100193, China.,Key Laboratory of Efficacy Evaluation of Chinese Medicine against Glycolipid Metabolic Disorders, State Administration of Traditional Chinese Medicine, Beijing 100193, China.,Zhongguancun Open Laboratory of the Research and Development of Natural Medicine and Health Products, Beijing 100193, China
| | - Tianyuan Ye
- Beijing Key Laboratory of Innovative Drug Discovery of Traditional Chinese Medicine (Natural Medicine) and Translational Medicine, Institute of Medicinal Plant Development, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing 100193, China.,Key Laboratory of Bioactive Substances and Resource Utilization of Chinese Herbal Medicine, Ministry of Education, Beijing 100193, China.,Key Laboratory of Efficacy Evaluation of Chinese Medicine against Glycolipid Metabolic Disorders, State Administration of Traditional Chinese Medicine, Beijing 100193, China.,Zhongguancun Open Laboratory of the Research and Development of Natural Medicine and Health Products, Beijing 100193, China
| | - Ping Zhou
- Beijing Key Laboratory of Innovative Drug Discovery of Traditional Chinese Medicine (Natural Medicine) and Translational Medicine, Institute of Medicinal Plant Development, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing 100193, China.,Key Laboratory of Bioactive Substances and Resource Utilization of Chinese Herbal Medicine, Ministry of Education, Beijing 100193, China.,Key Laboratory of Efficacy Evaluation of Chinese Medicine against Glycolipid Metabolic Disorders, State Administration of Traditional Chinese Medicine, Beijing 100193, China.,Zhongguancun Open Laboratory of the Research and Development of Natural Medicine and Health Products, Beijing 100193, China
| | - Fengwei Nan
- Beijing Key Laboratory of Innovative Drug Discovery of Traditional Chinese Medicine (Natural Medicine) and Translational Medicine, Institute of Medicinal Plant Development, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing 100193, China.,Key Laboratory of Bioactive Substances and Resource Utilization of Chinese Herbal Medicine, Ministry of Education, Beijing 100193, China.,Key Laboratory of Efficacy Evaluation of Chinese Medicine against Glycolipid Metabolic Disorders, State Administration of Traditional Chinese Medicine, Beijing 100193, China.,Zhongguancun Open Laboratory of the Research and Development of Natural Medicine and Health Products, Beijing 100193, China
| | - Guibo Sun
- Beijing Key Laboratory of Innovative Drug Discovery of Traditional Chinese Medicine (Natural Medicine) and Translational Medicine, Institute of Medicinal Plant Development, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing 100193, China.,Key Laboratory of Bioactive Substances and Resource Utilization of Chinese Herbal Medicine, Ministry of Education, Beijing 100193, China.,Key Laboratory of Efficacy Evaluation of Chinese Medicine against Glycolipid Metabolic Disorders, State Administration of Traditional Chinese Medicine, Beijing 100193, China.,Zhongguancun Open Laboratory of the Research and Development of Natural Medicine and Health Products, Beijing 100193, China
| | - Xiaobo Sun
- Beijing Key Laboratory of Innovative Drug Discovery of Traditional Chinese Medicine (Natural Medicine) and Translational Medicine, Institute of Medicinal Plant Development, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing 100193, China.,Key Laboratory of Bioactive Substances and Resource Utilization of Chinese Herbal Medicine, Ministry of Education, Beijing 100193, China.,Key Laboratory of Efficacy Evaluation of Chinese Medicine against Glycolipid Metabolic Disorders, State Administration of Traditional Chinese Medicine, Beijing 100193, China.,Zhongguancun Open Laboratory of the Research and Development of Natural Medicine and Health Products, Beijing 100193, China
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Dempsey JL, Little M, Cui JY. Gut microbiome: An intermediary to neurotoxicity. Neurotoxicology 2019; 75:41-69. [PMID: 31454513 DOI: 10.1016/j.neuro.2019.08.005] [Citation(s) in RCA: 31] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/26/2019] [Revised: 08/04/2019] [Accepted: 08/16/2019] [Indexed: 12/12/2022]
Abstract
There is growing recognition that the gut microbiome is an important regulator for neurological functions. This review provides a summary on the role of gut microbiota in various neurological disorders including neurotoxicity induced by environmental stressors such as drugs, environmental contaminants, and dietary factors. We propose that the gut microbiome remotely senses and regulates CNS signaling through the following mechanisms: 1) intestinal bacteria-mediated biotransformation of neurotoxicants that alters the neuro-reactivity of the parent compounds; 2) altered production of neuro-reactive microbial metabolites following exposure to certain environmental stressors; 3) bi-directional communication within the gut-brain axis to alter the intestinal barrier integrity; and 4) regulation of mucosal immune function. Distinct microbial metabolites may enter systemic circulation and epigenetically reprogram the expression of host genes in the CNS, regulating neuroinflammation, cell survival, or cell death. We will also review the current tools for the study of the gut-brain axis and provide some suggestions to move this field forward in the future.
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Affiliation(s)
- Joseph L Dempsey
- Department of Environmental and Occupational Health Sciences, University of Washington, United States
| | - Mallory Little
- Department of Environmental and Occupational Health Sciences, University of Washington, United States
| | - Julia Yue Cui
- Department of Environmental and Occupational Health Sciences, University of Washington, United States.
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