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Zhang L, Wei J, Liu X, Li D, Pang X, Chen F, Cao H, Lei P. Gut microbiota-astrocyte axis: new insights into age-related cognitive decline. Neural Regen Res 2025; 20:990-1008. [PMID: 38989933 PMCID: PMC11438350 DOI: 10.4103/nrr.nrr-d-23-01776] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/03/2023] [Accepted: 03/04/2024] [Indexed: 07/12/2024] Open
Abstract
With the rapidly aging human population, age-related cognitive decline and dementia are becoming increasingly prevalent worldwide. Aging is considered the main risk factor for cognitive decline and acts through alterations in the composition of the gut microbiota, microbial metabolites, and the functions of astrocytes. The microbiota-gut-brain axis has been the focus of multiple studies and is closely associated with cognitive function. This article provides a comprehensive review of the specific changes that occur in the composition of the gut microbiota and microbial metabolites in older individuals and discusses how the aging of astrocytes and reactive astrocytosis are closely related to age-related cognitive decline and neurodegenerative diseases. This article also summarizes the gut microbiota components that affect astrocyte function, mainly through the vagus nerve, immune responses, circadian rhythms, and microbial metabolites. Finally, this article summarizes the mechanism by which the gut microbiota-astrocyte axis plays a role in Alzheimer's and Parkinson's diseases. Our findings have revealed the critical role of the microbiota-astrocyte axis in age-related cognitive decline, aiding in a deeper understanding of potential gut microbiome-based adjuvant therapy strategies for this condition.
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Affiliation(s)
- Lan Zhang
- Haihe Laboratory of Cell Ecosystem, Department of Geriatrics, Tianjin Medical University General Hospital, Tianjin, China
- Tianjin Geriatrics Institute, Tianjin Medical University General Hospital, Tianjin, China
| | - Jingge Wei
- Department of Gastroenterology and Hepatology, Tianjin Medical University General Hospital, National Key Clinical Specialty, Tianjin Institute of Digestive Diseases, Tianjin Key Laboratory of Digestive Diseases, Tianjin, China
| | - Xilei Liu
- Department of Urology, Tianjin Medical University General Hospital, Tianjin, China
| | - Dai Li
- Haihe Laboratory of Cell Ecosystem, Department of Geriatrics, Tianjin Medical University General Hospital, Tianjin, China
- Tianjin Geriatrics Institute, Tianjin Medical University General Hospital, Tianjin, China
| | - Xiaoqi Pang
- Department of Gastroenterology and Hepatology, Tianjin Medical University General Hospital, National Key Clinical Specialty, Tianjin Institute of Digestive Diseases, Tianjin Key Laboratory of Digestive Diseases, Tianjin, China
| | - Fanglian Chen
- Tianjin Neurological Institution, Tianjin Medical University General Hospital, Tianjin, China
| | - Hailong Cao
- Department of Gastroenterology and Hepatology, Tianjin Medical University General Hospital, National Key Clinical Specialty, Tianjin Institute of Digestive Diseases, Tianjin Key Laboratory of Digestive Diseases, Tianjin, China
| | - Ping Lei
- Haihe Laboratory of Cell Ecosystem, Department of Geriatrics, Tianjin Medical University General Hospital, Tianjin, China
- Tianjin Geriatrics Institute, Tianjin Medical University General Hospital, Tianjin, China
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Ren C, Cha L, Huang SY, Bai GH, Li JH, Xiong X, Feng YX, Feng DP, Gao L, Li JY. Dysregulation of bile acid signal transduction causes neurological dysfunction in cirrhosis rats. World J Hepatol 2025; 17:101340. [DOI: 10.4254/wjh.v17.i3.101340] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/12/2024] [Revised: 01/19/2025] [Accepted: 02/21/2025] [Indexed: 03/26/2025] Open
Abstract
BACKGROUND The pathogenesis of hepatic encephalopathy (HE) remains unclear, and the classical theory of ammonia toxicity lacks sufficient justification.
AIM To investigate the potential of bile acids as intervention targets for HE.
METHODS This study employed 42 wild-type male SD rats weighing 200 ± 20 g. Using a random number table method, two rats were randomly selected to undergo common bile duct ligation (BDL). The remaining 40 rats were randomly assigned to four groups serving as controls: The vehicle + control diet (VC) group, the thioacetamide (TAA) group, the TAA + total bile acids (TAAT) group, and the TAA + cholestyramine (TAAC) group. Except for the VC group, all rats were intraperitoneally injected with 100 mg/kg TAA solution once daily for ten consecutive days to establish a HE model. Simultaneously, the TAAT and TAAC groups were administered a diet containing 0.3% bile acids (derived from BDL rats) and 2% cholestyramine, respectively, by gavage for ten days. For the BDL rat model group, the common BDL procedure was performed following the aforementioned protocol. After four weeks, laparotomy revealed swollen bile ducts at the ligation site, and bile was collected. Following successful modeling, behavioral tests, including the elevated plus maze and open field test, were conducted to assess the HE status of the rats. Peripheral blood, liver, and cerebral cortex tissue samples were collected, and the total bile acid content in the serum and cerebral cortex was measured using an enzyme cycling method. The levels of inflammatory factors in the serum and cerebral cortex were analyzed using enzyme-linked immunosorbent assay. Liver histological examination was performed using the hematoxylin-eosin double-labeling method. Reverse transcription polymerase chain reaction, western blot, immunohistochemistry, and other techniques were employed to observe the expression of microglial activation marker ionized calcium-binding adaptor molecule-1 and Takeda G protein-coupled receptor 5 (TGR5) protein.
RESULTS Compared to the VC group, the TAA group exhibited an exacerbation of HE in rats. The total bile acid content, pro-inflammatory factors [interleukin-1β (IL-1β), IL-6], and the anti-inflammatory factor IL-10 in both the serum and cerebral cortex were significantly elevated. Similarly, the expression of the TGR5 receptor in the cerebral cortex was upregulated. To investigate the impact of total bile acids on HE in rats, comparisons were made with the TAA group. In the TAAT group, the severity of HE was further aggravated, accompanied by increased total bile acid content in the serum and cerebral cortex, elevated pro-inflammatory factors (IL-1β, IL-6), reduced levels of the anti-inflammatory factor IL-10, and decreased expression of the TGR5 receptor in the cerebral cortex. In the TAAC group, the severity of HE was alleviated. This group showed reductions in total bile acid content in the serum and cerebral cortex, decreased pro-inflammatory factors (IL-1β, IL-6), increased levels of the anti-inflammatory factor IL-10, and enhanced expression of the TGR5 receptor in the cerebral cortex.
CONCLUSION This study demonstrated that the total bile acid content in the serum and cerebral cortex of TAA-induced liver cirrhosis rats was elevated. Furthermore, total bile acids exacerbate the progression of HE in rats. This effect may be attributed to bile acids’ involvement in the development of neurological dysfunction by mediating TGR5 expression and regulating neuroinflammation.
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Affiliation(s)
- Chao Ren
- College of Medical Imaging, Shanxi Medical University, Taiyuan 030001, Shanxi Province, China
| | - Li Cha
- College of Medical Imaging, Shanxi Medical University, Taiyuan 030001, Shanxi Province, China
| | - Shu-Yue Huang
- Department of Ultrasound, Qingdao Central Hospital, University of Health and Rehabilitation, Qingdao 266000, Shandong Province, China
| | - Guo-Hui Bai
- College of Medical Imaging, Shanxi Medical University, Taiyuan 030001, Shanxi Province, China
| | - Jin-Hui Li
- College of Medical Imaging, Shanxi Medical University, Taiyuan 030001, Shanxi Province, China
| | - Xin Xiong
- Academy of Medical Sciences, Shanxi Medical University, Taiyuan 030001, Shanxi Province, China
| | - Yu-Xing Feng
- Department of Occupational Health, School of Public Health, Shanxi Medical University, Taiyuan 030001, Shanxi Province, China
| | - Dui-Ping Feng
- Department of Oncological and Vascular Intervention, First Hospital of Shanxi Medical University, Taiyuan 030001, Shanxi Province, China
| | - Long Gao
- Department of Oncological and Vascular Intervention, First Hospital of Shanxi Medical University, Taiyuan 030001, Shanxi Province, China
| | - Jin-Yu Li
- Department of Oncological and Vascular Intervention, First Hospital of Shanxi Medical University, Taiyuan 030001, Shanxi Province, China
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Zorumski CF, Covey DF, Izumi Y, Evers AS, Maguire JL, Mennerick SJ. New directions in neurosteroid therapeutics in neuropsychiatry. Neurosci Biobehav Rev 2025; 172:106119. [PMID: 40127877 DOI: 10.1016/j.neubiorev.2025.106119] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/02/2024] [Revised: 02/22/2025] [Accepted: 03/17/2025] [Indexed: 03/26/2025]
Abstract
In recent years three neuroactive steroids (NAS), brexanolone (allopregnanolone, AlloP), ganaxolone and zuranolone, have been approved for the treatment of neuropsychiatric illnesses including postpartum depression and seizures in a neurodevelopmental syndrome. The approved agents are pregnane steroids and strong positive allosteric modulators (PAMs) of gamma-aminobutyric acid type A receptors (GABAARs). Broad effects on GABAARs play important roles in therapeutic benefits. However, these NAS also have actions on non-GABAR targets that could be important for clinical outcomes. Thus, understanding the broader effects of NAS is potentially important for expanding the therapeutic landscape of these important modulators. The approved NAS as well as other structurally distinct NAS and oxysterols have effects on non-GABAAR receptors and ion channels, along with intracellular actions that could have therapeutic importance, including modulation of cellular stress mechanisms, neuroinflammation, mitochondrial function and autophagy, among others. In this review, we explore GABAergic and other cellular effects of pregnane steroids including novel molecules that have potential therapeutic importance. This work discusses the complex chemical nature of NAS and what is being learned at cellular, molecular, synaptic and brain network levels about key sites of action including GABAARs and other targets.
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Affiliation(s)
- Charles F Zorumski
- Departments of Psychiatry, Washington University School of Medicine, St. Louis, MO, USA; Taylor Family Institute for Innovative Psychiatric Research, Washington University School of Medicine, St. Louis, MO, USA.
| | - Douglas F Covey
- Departments of Psychiatry, Washington University School of Medicine, St. Louis, MO, USA; Developmental Biology, Washington University School of Medicine, St. Louis, MO, USA; Anesthesiology, Washington University School of Medicine, St. Louis, MO, USA; Taylor Family Institute for Innovative Psychiatric Research, Washington University School of Medicine, St. Louis, MO, USA
| | - Yukitoshi Izumi
- Departments of Psychiatry, Washington University School of Medicine, St. Louis, MO, USA; Taylor Family Institute for Innovative Psychiatric Research, Washington University School of Medicine, St. Louis, MO, USA
| | - Alex S Evers
- Developmental Biology, Washington University School of Medicine, St. Louis, MO, USA; Anesthesiology, Washington University School of Medicine, St. Louis, MO, USA; Taylor Family Institute for Innovative Psychiatric Research, Washington University School of Medicine, St. Louis, MO, USA
| | - Jamie L Maguire
- Department of Neuroscience, Tufts University School of Medicine, Boston, MA, USA
| | - Steven J Mennerick
- Taylor Family Institute for Innovative Psychiatric Research, Washington University School of Medicine, St. Louis, MO, USA
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Zhang Z, Zhang Y, Peng H, Yu Q, Kang X, Liu Y, Zheng Y, Cheng F, Wang X, Li F. Decoding TGR5: A comprehensive review of its impact on cerebral diseases. Pharmacol Res 2025; 213:107671. [PMID: 39988005 DOI: 10.1016/j.phrs.2025.107671] [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] [Received: 01/02/2025] [Revised: 02/18/2025] [Accepted: 02/20/2025] [Indexed: 02/25/2025]
Abstract
Currently, unraveling the enigmatic realm of drug targets for cerebral disorders poses a formidable challenge. Takeda G protein-coupled receptor 5 (TGR5), also known as G protein-coupled bile acid receptor 1, is a specific bile acid receptor. Widely distributed across various tissues, TGR5 orchestrates a myriad of biological functions encompassing inflammation, energy metabolism, fatty acid metabolism, immune responses, cellular proliferation, apoptosis, and beyond. Alongside its well-documented implications in liver diseases, obesity, type 2 diabetes, tumors, and cardiovascular diseases, a growing body of evidence accentuates the pivotal role of TGR5 in cerebral diseases. Thus, this comprehensive review aimed to scrutinize the current insights into the pathological mechanisms involving TGR5 in cerebral diseases, while contemplating its potential as a promising therapeutic target for cerebral diseases.
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Affiliation(s)
- Zehan Zhang
- Beijing University of Chinese Medicine, The northeast corner of the intersection of Sunshine South Street and Baiyang East Road, Beijing 102488, China.
| | - Yifei Zhang
- Beijing University of Chinese Medicine, The northeast corner of the intersection of Sunshine South Street and Baiyang East Road, Beijing 102488, China.
| | - Hongye Peng
- Beijing University of Chinese Medicine, The northeast corner of the intersection of Sunshine South Street and Baiyang East Road, Beijing 102488, China.
| | - Qingqian Yu
- Beijing University of Chinese Medicine, The northeast corner of the intersection of Sunshine South Street and Baiyang East Road, Beijing 102488, China.
| | - Xiangdong Kang
- Beijing University of Chinese Medicine, The northeast corner of the intersection of Sunshine South Street and Baiyang East Road, Beijing 102488, China.
| | - Ying Liu
- Beijing University of Chinese Medicine, The northeast corner of the intersection of Sunshine South Street and Baiyang East Road, Beijing 102488, China.
| | - Yuxiao Zheng
- Beijing University of Chinese Medicine, The northeast corner of the intersection of Sunshine South Street and Baiyang East Road, Beijing 102488, China.
| | - Fafeng Cheng
- Beijing University of Chinese Medicine, The northeast corner of the intersection of Sunshine South Street and Baiyang East Road, Beijing 102488, China.
| | - Xueqian Wang
- Beijing University of Chinese Medicine, The northeast corner of the intersection of Sunshine South Street and Baiyang East Road, Beijing 102488, China.
| | - Feng Li
- Beijing University of Chinese Medicine, The northeast corner of the intersection of Sunshine South Street and Baiyang East Road, Beijing 102488, China.
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Tang Y, Zhang Y, Chen C, Cao Y, Wang Q, Tang C. Gut microbiota: A new window for the prevention and treatment of neuropsychiatric disease. J Cent Nerv Syst Dis 2025; 17:11795735251322450. [PMID: 39989718 PMCID: PMC11846125 DOI: 10.1177/11795735251322450] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/17/2024] [Revised: 12/11/2024] [Accepted: 01/27/2025] [Indexed: 02/25/2025] Open
Abstract
Under normal physiological conditions, gut microbiota and host mutually coexist. They play key roles in maintaining intestinal barrier integrity, absorption, and metabolism, as well as promoting the development of the central nervous system (CNS) and emotional regulation. The dysregulation of gut microbiota homeostasis has attracted significant research interest, specifically in its impact on neurological and psychiatric disorders. Recent studies have highlighted the important role of the gut- brain axis in conditions including Alzheimer's Disease (AD), Parkinson's Disease (PD), and depression. This review aims to elucidate the regulatory mechanisms by which gut microbiota affect the progression of CNS disorders via the gut-brain axis. Additionally, we discuss the current research landscape, identify gaps, and propose future directions for microbial interventions against these diseases. Finally, we provide a theoretical reference for clinical treatment strategies and drug development for AD, PD, and depression.
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Affiliation(s)
- Yali Tang
- Department of Pharmacy, Taihe Hospital, Hubei University of Medicine, Shiyan, China
| | - Yizhu Zhang
- State Key Laboratory on Technologies for Chinese Medicine Pharmaceutical Process Control and Intelligent Manufacture, Nanjing University of Chinese Medicine, Nanjing, People’s Republic of China
| | - Chen Chen
- Department of Pharmacy, Taihe Hospital, Hubei University of Medicine, Shiyan, China
| | - Ying Cao
- School of Food Science and Pharmaceutical Engineering, Nanjing Normal University, Nanjing, People’s Republic of China
| | - Qiaona Wang
- School of Ecology and Applied Meteorology, Nanjing University of Information Science & Technology, Nanjing, People’s Republic of China
| | - Chuanfeng Tang
- State Key Laboratory on Technologies for Chinese Medicine Pharmaceutical Process Control and Intelligent Manufacture, Nanjing University of Chinese Medicine, Nanjing, People’s Republic of China
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Toivonen E, Sikkinen J, Salonen A, Kärkkäinen O, Koistinen V, Klåvus A, Meuronen T, Heini T, Maltseva A, Niku M, Jääskeläinen T, Laivuori H. Metabolic profiles of meconium in preeclamptic and normotensive pregnancies. Metabolomics 2025; 21:21. [PMID: 39863780 PMCID: PMC11762436 DOI: 10.1007/s11306-025-02224-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/29/2024] [Accepted: 01/16/2025] [Indexed: 01/27/2025]
Abstract
INTRODUCTION Preeclampsia (PE) is a common vascular pregnancy disorder affecting maternal and fetal metabolism with severe immediate and long-term consequences in mothers and infants. During pregnancy, metabolites in the maternal circulation pass through the placenta to the fetus. Meconium, a first stool of the neonate, offers a view to maternal and fetoplacental unit metabolism and could add to knowledge on the effects of PE on the fetus and newborn. OBJECTIVES To compare meconium metabolome of infants from PE and normotensive pregnancies. METHODS A cohort of preeclamptic parturients and normotensive controls were recruited in Tampere University Hospital during 2019-2022. Meconium was sampled and its metabolome analyzed using liquid chromatography- mass spectrometry in 48 subjects in each group. RESULTS Differences in abundances of 1263 compounds, of which 19 could be annotated, were detected between the two groups. Several acylcarnitines, androsterone sulfate, three bile acids, amino acid derivatives (phenylacetylglutamine, epsilon-(gamma-glutamyl)lysine and N-(phenylacetyl)glutamic acid), as well as caffeine and paraxanthine were lower in the PE group compared to the control group. Urea and progesterone were higher in the PE group. CONCLUSION PE is associated with alterations in the meconium metabolome of infants. The differing abundances of several metabolites show alterations in the interaction between the fetoplacental unit and mother in PE, but whether they are a cause or an effect of the disorder remains to be further investigated.
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Affiliation(s)
- Elli Toivonen
- Center for Child, Adolescent and Maternal Health Research, Faculty of Medicine and Health Technology, Tampere University, Tampere, Finland.
- Department of Obstetrics and Gynecology, Tampere University Hospital, The Wellbeing Services County of Pirkanmaa, Tampere, Finland.
| | - Jutta Sikkinen
- Center for Child, Adolescent and Maternal Health Research, Faculty of Medicine and Health Technology, Tampere University, Tampere, Finland
| | - Anne Salonen
- Human Microbiome Research Program, Faculty of Medicine, University of Helsinki, Helsinki, Finland
| | - Olli Kärkkäinen
- Afekta Technologies Ltd., Kuopio, Finland
- School of Pharmacy, University of Eastern Finland, Kuopio, Finland
| | | | | | | | - Tuomas Heini
- Human Microbiome Research Program, Faculty of Medicine, University of Helsinki, Helsinki, Finland
| | - Arina Maltseva
- Department of Veterinary Biosciences, University of Helsinki, Helsinki, Finland
| | - Mikael Niku
- Department of Veterinary Biosciences, University of Helsinki, Helsinki, Finland
| | - Tiina Jääskeläinen
- Medical and Clinical Genetics, University of Helsinki and Helsinki University Hospital, Helsinki, Finland
- Department of Food and Nutrition, University of Helsinki, Helsinki, Finland
| | - Hannele Laivuori
- Center for Child, Adolescent and Maternal Health Research, Faculty of Medicine and Health Technology, Tampere University, Tampere, Finland
- Department of Obstetrics and Gynecology, Tampere University Hospital, The Wellbeing Services County of Pirkanmaa, Tampere, Finland
- Medical and Clinical Genetics, University of Helsinki and Helsinki University Hospital, Helsinki, Finland
- Institute for Molecular Medicine Finland, Helsinki Institute of Life Science, Helsinki, Finland
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Ghannadzadeh Kermani Pour R, Kamali Zounouzi S, Farshbafnadi M, Rezaei N. The interplay between gut microbiota composition and dementia. Rev Neurosci 2025:revneuro-2024-0113. [PMID: 39829047 DOI: 10.1515/revneuro-2024-0113] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/20/2024] [Accepted: 01/03/2025] [Indexed: 01/22/2025]
Abstract
Recently, researchers have been interested in the potential connection between gut microbiota composition and various neuropsychological disorders. Dementia significantly affects the socioeconomics of families. Gut microbiota is considered as a probable factor in its pathogenesis. Multiple bacterial metabolites such as short-chain fatty acids, lipopolysaccharides, and various neurotransmitters that are responsible for the incidence and progression of dementia can be produced by gut microbiota. Various bacterial species such as Bifidobacterium breve, Akkermansia muciniphila, Streptococcus thermophilus, Escherichia coli, Blautia hydrogenotrophica, etc. are implicated in the pathogenesis of dementia. Gut microbiota can be a great target for imitating or inhibiting their metabolites as an adjunctive therapy based on their role in its pathogenesis. Therefore, some diets can prevent or decelerate dementia by altering the gut microbiota composition. Moreover, probiotics can modulate gut microbiota composition by increasing beneficial bacteria and reducing detrimental species. These therapeutic modalities are considered novel methods that are probably safe and effective. They can enhance the efficacy of traditional medications and improve cognitive function.
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Affiliation(s)
| | - Sara Kamali Zounouzi
- School of Medicine, 48439 Tehran University of Medical Sciences , Tehran, 1416634793, Iran
| | - Melina Farshbafnadi
- School of Medicine, 48439 Tehran University of Medical Sciences , Tehran, 1416634793, Iran
- Universal Scientific Education and Research Network (USERN), Tehran, 1416634793, Iran
| | - Nima Rezaei
- Universal Scientific Education and Research Network (USERN), Tehran, 1416634793, Iran
- Research Center for Immunodeficiencies, Children's Medical Center, 48439 Tehran University of Medical Sciences , Tehran, 1416634793, Iran
- Department of Immunology, School of Medicine, 48439 Tehran University of Medical Sciences , Tehran, 1416634793, Iran
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K M M, Ghosh P, Nagappan K, Palaniswamy DS, Begum R, Islam MR, Tagde P, Shaikh NK, Farahim F, Mondal TK. From Gut Microbiomes to Infectious Pathogens: Neurological Disease Game Changers. Mol Neurobiol 2025; 62:1184-1204. [PMID: 38967904 DOI: 10.1007/s12035-024-04323-0] [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: 04/02/2024] [Accepted: 06/19/2024] [Indexed: 07/06/2024]
Abstract
Gut microbiota and infectious diseases affect neurological disorders, brain development, and function. Compounds generated in the gastrointestinal system by gut microbiota and infectious pathogens may mediate gut-brain interactions, which may circulate throughout the body and spread to numerous organs, including the brain. Studies shown that gut bacteria and disease-causing organisms may pass molecular signals to the brain, affecting neurological function, neurodevelopment, and neurodegenerative diseases. This article discusses microorganism-producing metabolites with neuromodulator activity, signaling routes from microbial flora to the brain, and the potential direct effects of gut bacteria and infectious pathogens on brain cells. The review also considered the neurological aspects of infectious diseases. The infectious diseases affecting neurological functions and the disease modifications have been discussed thoroughly. Recent discoveries and unique insights in this perspective need further validation. Research on the complex molecular interactions between gut bacteria, infectious pathogens, and the CNS provides valuable insights into the pathogenesis of neurodegenerative, behavioral, and psychiatric illnesses. This study may provide insights into advanced drug discovery processes for neurological disorders by considering the influence of microbial communities inside the human body.
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Affiliation(s)
- Muhasina K M
- Department of Pharmacognosy, JSS College of Pharmacy, Ooty, Tamil Nadu, 643001, India.
| | - Puja Ghosh
- Department of Pharmacognosy, JSS College of Pharmacy, Ooty, Tamil Nadu, 643001, India
| | - Krishnaveni Nagappan
- Department of Pharmaceutical Analysis, JSS College of Pharmacy, Ooty, Tamil Nadu, 643001, India
| | | | - Rahima Begum
- Department of Microbiology, Gono Bishwabidyalay, Dhaka, Bangladesh
| | - Md Rabiul Islam
- Tennessee State University Chemistry department 3500 John A Merritt Blvd, Nashville, TN, 37209, USA
| | - Priti Tagde
- PRISAL(Pharmaceutical Royal International Society), Branch Office Bhopal, Bhopal, Madhya Pradesh, 462042, India
| | - Nusrat K Shaikh
- Department of Quality Assurance, Smt. N. M, Padalia Pharmacy College, Navapura, Ahmedabad, 382 210, Gujarat, India
| | - Farha Farahim
- Department of Nursing, King Khalid University, Abha, 61413, Kingdom of Saudi Arabia
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9
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Monteiro-Cardoso VF, Yeo XY, Bae HG, Mayan DC, Wehbe M, Lee S, Krishna-K K, Baek SH, Palomera LF, Wu LH, Pakkiri LS, Shanmugam S, Sem KP, Yew MG, Parsons MP, Hayden MR, Yeo LLL, Sharma VK, Drum C, Liehn EA, Sajikumar S, Davanger S, Jo DG, Chan MYY, Tan BYQ, Jung S, Singaraja RR. The bile acid chenodeoxycholic acid associates with reduced stroke in humans and mice. J Lipid Res 2025; 66:100712. [PMID: 39577772 PMCID: PMC11721534 DOI: 10.1016/j.jlr.2024.100712] [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: 06/26/2024] [Revised: 11/07/2024] [Accepted: 11/18/2024] [Indexed: 11/24/2024] Open
Abstract
Bile acids are liver-derived signaling molecules that can be found in the brain, but their role there remains largely unknown. We found increased brain chenodeoxycholic acid (CDCA) in mice with absent 12α-hydroxylase (Cyp8b1), a bile acid synthesis enzyme. In these Cyp8b1-/-, and in Wt mice administered CDCA, stroke infarct area was reduced. Elevated glutamate-induced excitotoxicity mediated by aberrant N-methyl-D-aspartate receptor (NMDAR) overactivation contributes to neuronal death in ischemic stroke. We found reduced glutamate-induced excitotoxicity in neurons from Cyp8b1-/- and CDCA-treated Wt mice. CDCA decreased NMDAR-mediated excitatory post-synaptic currents by reducing over-activation of NMDAR subunit GluN2B in Wt brains. Synaptic NMDAR activity was also decreased in Cyp8b1-/- brains. Expression and synaptic distribution of GluN2B were unaltered in Cyp8b1-/- mice, suggesting CDCA may directly antagonize GluN2B-containing NMDARs. Supporting our findings, in a case-control cohort of acute ischemic stroke patients, we found lower circulatory CDCA. Together, our data suggest that CDCA, acting in the liver-brain axis, decreases GluN2B-containing NMDAR overactivation, contributing to neuroprotection in stroke.
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Affiliation(s)
- Vera F Monteiro-Cardoso
- Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore; Translational Laboratories in Genetic Medicine, Agency for Science, Technology and Research, Singapore, Singapore
| | - Xin Yi Yeo
- Institute for Molecular and Cellular Biology, Agency for Science, Technology and Research, Singapore, Singapore; Department of Psychological Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore; Department of Medical Science, College of Medicine, CHA University, Pocheon, Republic of Korea
| | - Han-Gyu Bae
- Institute for Molecular and Cellular Biology, Agency for Science, Technology and Research, Singapore, Singapore; Department of Life Sciences, Yeungnam University, Gyeongsan, South Korea
| | - David Castano Mayan
- Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore; Translational Laboratories in Genetic Medicine, Agency for Science, Technology and Research, Singapore, Singapore; Cardiovascular Research Institute, National University Health System, Singapore, Singapore
| | - Mariam Wehbe
- Institute of Basic Medical Sciences, University of Oslo, Oslo, Norway
| | - Sejin Lee
- Institute for Molecular and Cellular Biology, Agency for Science, Technology and Research, Singapore, Singapore
| | - Kumar Krishna-K
- Department of Physiology and Healthy Longevity Translational Research Program, Yong Loo Lin School of Medicine, National University Singapore, Singapore, Singapore
| | - Seung Hyun Baek
- School of Pharmacy, Sungkyunkwan University, Suwon, Republic of Korea
| | - Leon F Palomera
- School of Pharmacy, Sungkyunkwan University, Suwon, Republic of Korea
| | - Lik Hang Wu
- Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
| | - Leroy S Pakkiri
- Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
| | - Sangeetha Shanmugam
- Translational Laboratories in Genetic Medicine, Agency for Science, Technology and Research, Singapore, Singapore
| | - Kai Ping Sem
- Translational Laboratories in Genetic Medicine, Agency for Science, Technology and Research, Singapore, Singapore
| | - Mun Geok Yew
- Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
| | - Matthew P Parsons
- Division of BioMedical Sciences, Faculty of Medicine, Memorial University of Newfoundland, St. John's, Newfoundland, Canada
| | - Michael R Hayden
- Department of Medical Genetics, Centre for Molecular Medicine and Therapeutics, The University of British Columbia, Vancouver, British Columbia, Canada
| | - Leonard L L Yeo
- Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore; Division of Neurology, Department of Medicine, National University Hospital, Singapore, Singapore
| | - Vijay K Sharma
- Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore; Division of Neurology, Department of Medicine, National University Hospital, Singapore, Singapore
| | - Chester Drum
- Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
| | - Elisa A Liehn
- Institute for Innovation and eHealth, University of Medicine and Pharmacy Carol Davila, Bucharest, Romania; The Heart Center, Singapore, Singapore
| | - Sreedharan Sajikumar
- Department of Physiology and Healthy Longevity Translational Research Program, Yong Loo Lin School of Medicine, National University Singapore, Singapore, Singapore
| | - Svend Davanger
- Institute of Basic Medical Sciences, University of Oslo, Oslo, Norway
| | - Dong-Gyu Jo
- School of Pharmacy, Sungkyunkwan University, Suwon, Republic of Korea
| | - Mark Y Y Chan
- Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
| | - Benjamin Y Q Tan
- Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore; Division of Neurology, Department of Medicine, National University Hospital, Singapore, Singapore
| | - Sangyong Jung
- Institute for Molecular and Cellular Biology, Agency for Science, Technology and Research, Singapore, Singapore; Department of Medical Science, College of Medicine, CHA University, Pocheon, Republic of Korea; Department of Physiology and Healthy Longevity Translational Research Program, Yong Loo Lin School of Medicine, National University Singapore, Singapore, Singapore.
| | - Roshni R Singaraja
- Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore; Translational Laboratories in Genetic Medicine, Agency for Science, Technology and Research, Singapore, Singapore; Cardiovascular Research Institute, National University Health System, Singapore, Singapore.
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10
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Darmanto AG, Yen TL, Jan JS, Linh TTD, Taliyan R, Yang CH, Sheu JR. Beyond metabolic messengers: Bile acids and TGR5 as pharmacotherapeutic intervention for psychiatric disorders. Pharmacol Res 2025; 211:107564. [PMID: 39733841 DOI: 10.1016/j.phrs.2024.107564] [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] [Received: 10/11/2024] [Revised: 12/05/2024] [Accepted: 12/23/2024] [Indexed: 12/31/2024]
Abstract
Psychiatric disorders pose a significant global health challenge, exacerbated by the COVID-19 pandemic and insufficiently addressed by the current treatments. This review explores the emerging role of bile acids and the TGR5 receptor in the pathophysiology of psychiatric conditions, emphasizing their signaling within the gut-brain axis. We detail the synthesis and systemic functions of bile acids, their transformation by gut microbiota, and their impact across various neuropsychiatric disorders, including major depressive disorder, general anxiety disorder, schizophrenia, autism spectrum disorder, and bipolar disorder. The review highlights how dysbiosis and altered bile acid metabolism contribute to the development and exacerbation of these neuropsychiatric disorders through mechanisms involving inflammation, oxidative stress, and neurotransmitter dysregulation. Importantly, we detail both pharmacological and non-pharmacological interventions that modulate TGR5 signaling, offering potential breakthroughs in treatment strategies. These include dietary adjustments to enhance beneficial bile acids production and the use of specific TGR5 agonists that have shown promise in preclinical and clinical settings for their regulatory effects on critical pathways such as cAMP-PKA, NRF2-mediated antioxidant responses, and neuroinflammation. By integrating findings from the dynamics of gut microbiota, bile acids metabolism, and TGR5 receptor related signaling events, this review underscores cutting-edge therapeutic approaches poised to revolutionize the management and treatment of psychiatric disorders.
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Affiliation(s)
- Arief Gunawan Darmanto
- Department of Pharmacology, School of Medicine, College of Medicine, Taipei Medical University, No. 250, Wu Hsing St., Taipei 110, Taiwan, ROC; School of Medicine, Universitas Ciputra, Surabaya 60219, Indonesia
| | - Ting-Lin Yen
- Department of Pharmacology, School of Medicine, College of Medicine, Taipei Medical University, No. 250, Wu Hsing St., Taipei 110, Taiwan, ROC; Department of Medical Research, Cathay General Hospital, Taipei 22174, Taiwan, ROC
| | - Jing-Shiun Jan
- Department of Pharmacology, School of Medicine, College of Medicine, Taipei Medical University, No. 250, Wu Hsing St., Taipei 110, Taiwan, ROC
| | - Tran Thanh Duy Linh
- Family Medicine Training Center, University of Medicine and Pharmacy at Ho Chi Minh City, Ho Chi Minh City 700000, Viet Nam
| | - Rajeev Taliyan
- Neuropsychopharmacology Division, Department of Pharmacy, Birla Institute of Technology and Science-Pilani, Pilani Campus, Pilani, Rajasthan, India
| | - Chih-Hao Yang
- Department of Pharmacology, School of Medicine, College of Medicine, Taipei Medical University, No. 250, Wu Hsing St., Taipei 110, Taiwan, ROC; Research Center for Neuroscience, Taipei Medical University, Taipei, Taiwan, ROC.
| | - Joen-Rong Sheu
- Department of Pharmacology, School of Medicine, College of Medicine, Taipei Medical University, No. 250, Wu Hsing St., Taipei 110, Taiwan, ROC; Research Center for Neuroscience, Taipei Medical University, Taipei, Taiwan, ROC; Graduate Institute of Medical Sciences, College of Medicine, Taipei Medical University, Taipei 110, Taiwan, ROC.
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11
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Qiao L, Yang G, Wang P, Xu C. The potential role of mitochondria in the microbiota-gut-brain axis: Implications for brain health. Pharmacol Res 2024; 209:107434. [PMID: 39332752 DOI: 10.1016/j.phrs.2024.107434] [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] [Received: 07/04/2024] [Revised: 09/02/2024] [Accepted: 09/23/2024] [Indexed: 09/29/2024]
Abstract
Mitochondria are crucial organelles that regulate cellular energy metabolism, calcium homeostasis, and oxidative stress responses, playing pivotal roles in brain development and neurodegeneration. Concurrently, the gut microbiota has emerged as a key modulator of brain physiology and pathology through the microbiota-gut-brain axis. Recent evidence suggests an intricate crosstalk between the gut microbiota and mitochondrial function, mediated by microbial metabolites that can influence mitochondrial activities in the brain. This review aims to provide a comprehensive overview of the emerging role of mitochondria as critical mediators in the microbiota-gut-brain axis, shaping brain health and neurological disease pathogenesis. We discuss how gut microbial metabolites such as short-chain fatty acids, secondary bile acids, tryptophan metabolites, and trimethylamine N-oxide can traverse the blood-brain barrier and modulate mitochondrial processes including energy production, calcium regulation, mitophagy, and oxidative stress in neurons and glial cells. Additionally, we proposed targeting the mitochondria through diet, prebiotics, probiotics, or microbial metabolites as a promising potential therapeutic approach to maintain brain health by optimizing mitochondrial fitness. Overall, further investigations into how the gut microbiota and its metabolites regulate mitochondrial bioenergetics, dynamics, and stress responses will provide valuable insights into the microbiota-gut-brain axis in both health and disease states.
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Affiliation(s)
- Lei Qiao
- School of Life Sciences, Northwestern Polytechnical University, Xi'an, Shaanxi 710072, China; Key Laboratory of Molecular Animal Nutrition of the Ministry of Education, College of Animal Sciences, Zhejiang University, Hangzhou, Zhejiang 310058, China
| | - Ge Yang
- School of Life Sciences, Northwestern Polytechnical University, Xi'an, Shaanxi 710072, China
| | - Peng Wang
- School of Life Sciences, Northwestern Polytechnical University, Xi'an, Shaanxi 710072, China; Department of Psychiatry, The Affiliated Xi'an Central Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi 710000, China
| | - Chunlan Xu
- School of Life Sciences, Northwestern Polytechnical University, Xi'an, Shaanxi 710072, China.
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12
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Shi WG, Yao Y, Liang YJ, Lei J, Feng SY, Zhang ZX, Tian Y, Cai J, Xing GG, Fu KY. Activation of TGR5 in the injured nerve site according to a prevention protocol mitigates partial sciatic nerve ligation-induced neuropathic pain by alleviating neuroinflammation. Pain 2024:00006396-990000000-00753. [PMID: 39450924 DOI: 10.1097/j.pain.0000000000003460] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/09/2024] [Accepted: 09/22/2024] [Indexed: 10/26/2024]
Abstract
ABSTRACT Neuropathic pain is a pervasive medical challenge currently lacking effective treatment options. Molecular changes at the site of peripheral nerve injury contribute to both peripheral and central sensitization, critical components of neuropathic pain. This study explores the role of the G-protein-coupled bile acid receptor (GPBAR1 or TGR5) in the peripheral mechanisms underlying neuropathic pain induced by partial sciatic nerve ligation in male mice. TGR5 was upregulated in the injured nerve site and predominantly colocalized with macrophages. Perisciatic nerve administration of the TGR5 agonist, INT-777 according to a prevention protocol (50 μg/μL daily from postoperative day [POD] 0 to POD6) provided sustained relief from mechanical allodynia and spontaneous pain, whereas the TGR5 antagonist, SBI-115 worsened neuropathic pain. Transcriptome sequencing linked the pain relief induced by TGR5 activation to reduced neuroinflammation, which was further evidenced by a decrease in myeloid cells and pro-inflammatory mediators (eg, CCL3, CXCL9, interleukin [IL]-6, and tumor necrosis factor [TNF] α) and an increase in CD86-CD206+ anti-inflammatory macrophages at POD7. Besides, myeloid-cell-specific TGR5 knockdown in the injured nerve site exacerbated both neuropathic pain and neuroinflammation, which was substantiated by bulk RNA-sequencing and upregulated expression levels of inflammatory mediators (including CCL3, CCL2, IL-6, TNF α, and IL-1β) and the increased number of monocytes/macrophages at POD7. Furthermore, the activation of microglia in the spinal cord on POD7 and POD14 was altered when TGR5 in the sciatic nerve was manipulated. Collectively, TGR5 activation in the injured nerve site mitigates neuropathic pain by reducing neuroinflammation, while TGR5 knockdown in myeloid cells worsens pain by enhancing neuroinflammation.
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Affiliation(s)
- Wen-Ge Shi
- Center for TMD and Orofacial Pain, Peking University School and Hospital of Stomatology, Beijing, China
- National Center for Stomatology & National Clinical Research Center for Oral Diseases, Beijing, China
| | - Yao Yao
- Department of General Dentistry and Integrated Emergency Dental Care, Beijing Stomatological Hospital, Capital Medical University, Beijing, China
| | - Ya-Jing Liang
- Department of General Dentistry and Integrated Emergency Dental Care, Beijing Stomatological Hospital, Capital Medical University, Beijing, China
| | - Jie Lei
- Center for TMD and Orofacial Pain, Peking University School and Hospital of Stomatology, Beijing, China
- National Center for Stomatology & National Clinical Research Center for Oral Diseases, Beijing, China
| | - Shi-Yang Feng
- Center for TMD and Orofacial Pain, Peking University School and Hospital of Stomatology, Beijing, China
- National Center for Stomatology & National Clinical Research Center for Oral Diseases, Beijing, China
| | - Zi-Xian Zhang
- Neuroscience Research Institute, Peking University, Department of Neurobiology, School of Basic Medical Sciences, Peking University Health Science Center, Key Laboratory for Neuroscience, Ministry of Education of China & National Health, Beijing, China
| | - Yue Tian
- Neuroscience Research Institute, Peking University, Department of Neurobiology, School of Basic Medical Sciences, Peking University Health Science Center, Key Laboratory for Neuroscience, Ministry of Education of China & National Health, Beijing, China
| | - Jie Cai
- Neuroscience Research Institute, Peking University, Department of Neurobiology, School of Basic Medical Sciences, Peking University Health Science Center, Key Laboratory for Neuroscience, Ministry of Education of China & National Health, Beijing, China
| | - Guo-Gang Xing
- Neuroscience Research Institute, Peking University, Department of Neurobiology, School of Basic Medical Sciences, Peking University Health Science Center, Key Laboratory for Neuroscience, Ministry of Education of China & National Health, Beijing, China
| | - Kai-Yuan Fu
- Center for TMD and Orofacial Pain, Peking University School and Hospital of Stomatology, Beijing, China
- National Center for Stomatology & National Clinical Research Center for Oral Diseases, Beijing, China
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13
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Zhao Y, Ma S, Liang L, Cao S, Fan Z, He D, Shi X, Zhang Y, Liu B, Zhai M, Wu S, Kuang F, Zhang H. Gut Microbiota-Metabolite-Brain Axis Reconstitution Reverses Sevoflurane-Induced Social and Synaptic Deficits in Neonatal Mice. RESEARCH (WASHINGTON, D.C.) 2024; 7:0482. [PMID: 39301264 PMCID: PMC11411162 DOI: 10.34133/research.0482] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 07/12/2024] [Revised: 08/21/2024] [Accepted: 09/04/2024] [Indexed: 09/22/2024]
Abstract
Background: The mechanisms underlying social dysfunction caused by repeated sevoflurane in early life remain unclear. Whether the gut microbiota-metabolite-brain axis is involved in the mechanism of sevoflurane developmental neurotoxicity still lacks report. Methods: Mice received 3% sevoflurane at postnatal day (PND) 6, 7, and 8 for 2 h per day. Metagenomic sequencing and untargeted metabolomic analysis were applied to investigate the effects of sevoflurane on gut microbiota and metabolism. The animal social behavior and the synaptic development were analyzed during PND 35. Subsequently, fecal microbiota transplantation (FMT) from the control group and bile acid administration were performed to see the expected rescuing effect on socially related behaviors that were impaired by repeated sevoflurane exposure in the mice. Results: In the 3-chamber test, sevoflurane-exposed mice spent less time with stranger mice compared with the control group. The density of both the apical and basal spine decreased in mice exposed to sevoflurane. In addition, repeated sevoflurane exposure led to a notable alteration in the gut microbiota and metabolite synthesis, particularly bile acid. FMT reduced the production of intestinal bile acid and attenuated the effect of sevoflurane exposure on social function and synaptic development. Cholestyramine treatment mimics the protective effects of FMT. Conclusions: The gut microbiota-metabolite-brain axis underlies social dysfunction caused by sevoflurane exposure in early age, and bile acid regulation may be a promising intervention to this impairment.
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Affiliation(s)
- Youyi Zhao
- State Key Laboratory of Oral & Maxillofacial Reconstruction and Regeneration, National Clinical Research Center for Oral Diseases, Shaanxi Engineering Research Center for Dental Materials and Advanced Manufacture, Department of Anesthesiology, School of Stomatology, Fourth Military Medical University, Xi'an, Shaanxi 710032, P. R. China
- Department of Neurobiology and Institute of Neurosciences, School of Basic Medicine, Fourth Military Medical University, Xi'an, Shaanxi 710032, P. R. China
| | - Sanxing Ma
- State Key Laboratory of Oral & Maxillofacial Reconstruction and Regeneration, National Clinical Research Center for Oral Diseases, Shaanxi Engineering Research Center for Dental Materials and Advanced Manufacture, Department of Anesthesiology, School of Stomatology, Fourth Military Medical University, Xi'an, Shaanxi 710032, P. R. China
| | - Lirong Liang
- State Key Laboratory of Oral & Maxillofacial Reconstruction and Regeneration, National Clinical Research Center for Oral Diseases, Shaanxi Engineering Research Center for Dental Materials and Advanced Manufacture, Department of Anesthesiology, School of Stomatology, Fourth Military Medical University, Xi'an, Shaanxi 710032, P. R. China
| | - Shuhui Cao
- State Key Laboratory of Oral & Maxillofacial Reconstruction and Regeneration, National Clinical Research Center for Oral Diseases, Shaanxi Engineering Research Center for Dental Materials and Advanced Manufacture, Department of Anesthesiology, School of Stomatology, Fourth Military Medical University, Xi'an, Shaanxi 710032, P. R. China
| | - Ze Fan
- State Key Laboratory of Oral & Maxillofacial Reconstruction and Regeneration, National Clinical Research Center for Oral Diseases, Shaanxi Engineering Research Center for Dental Materials and Advanced Manufacture, Department of Anesthesiology, School of Stomatology, Fourth Military Medical University, Xi'an, Shaanxi 710032, P. R. China
| | - Danyi He
- State Key Laboratory of Oral & Maxillofacial Reconstruction and Regeneration, National Clinical Research Center for Oral Diseases, Shaanxi Engineering Research Center for Dental Materials and Advanced Manufacture, Department of Anesthesiology, School of Stomatology, Fourth Military Medical University, Xi'an, Shaanxi 710032, P. R. China
| | - Xiaotong Shi
- State Key Laboratory of Oral & Maxillofacial Reconstruction and Regeneration, National Clinical Research Center for Oral Diseases, Shaanxi Engineering Research Center for Dental Materials and Advanced Manufacture, Department of Anesthesiology, School of Stomatology, Fourth Military Medical University, Xi'an, Shaanxi 710032, P. R. China
| | - Yao Zhang
- State Key Laboratory of Oral & Maxillofacial Reconstruction and Regeneration, National Clinical Research Center for Oral Diseases, Shaanxi Engineering Research Center for Dental Materials and Advanced Manufacture, Department of Anesthesiology, School of Stomatology, Fourth Military Medical University, Xi'an, Shaanxi 710032, P. R. China
| | - Bing Liu
- State Key Laboratory of Oral & Maxillofacial Reconstruction and Regeneration, National Clinical Research Center for Oral Diseases, Shaanxi Engineering Research Center for Dental Materials and Advanced Manufacture, Department of Anesthesiology, School of Stomatology, Fourth Military Medical University, Xi'an, Shaanxi 710032, P. R. China
| | - Meiting Zhai
- State Key Laboratory of Oral & Maxillofacial Reconstruction and Regeneration, National Clinical Research Center for Oral Diseases, Shaanxi Engineering Research Center for Dental Materials and Advanced Manufacture, Department of Anesthesiology, School of Stomatology, Fourth Military Medical University, Xi'an, Shaanxi 710032, P. R. China
| | - Shengxi Wu
- Department of Neurobiology and Institute of Neurosciences, School of Basic Medicine, Fourth Military Medical University, Xi'an, Shaanxi 710032, P. R. China
| | - Fang Kuang
- Department of Neurobiology and Institute of Neurosciences, School of Basic Medicine, Fourth Military Medical University, Xi'an, Shaanxi 710032, P. R. China
| | - Hui Zhang
- State Key Laboratory of Oral & Maxillofacial Reconstruction and Regeneration, National Clinical Research Center for Oral Diseases, Shaanxi Engineering Research Center for Dental Materials and Advanced Manufacture, Department of Anesthesiology, School of Stomatology, Fourth Military Medical University, Xi'an, Shaanxi 710032, P. R. China
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14
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Romero-Ramírez L, Mey J. Emerging Roles of Bile Acids and TGR5 in the Central Nervous System: Molecular Functions and Therapeutic Implications. Int J Mol Sci 2024; 25:9279. [PMID: 39273226 PMCID: PMC11395147 DOI: 10.3390/ijms25179279] [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: 07/31/2024] [Revised: 08/15/2024] [Accepted: 08/17/2024] [Indexed: 09/15/2024] Open
Abstract
Bile acids (BAs) are cholesterol derivatives synthesized in the liver and released into the digestive tract to facilitate lipid uptake during the digestion process. Most of these BAs are reabsorbed and recycled back to the liver. Some of these BAs progress to other tissues through the bloodstream. The presence of BAs in the central nervous system (CNS) has been related to their capacity to cross the blood-brain barrier (BBB) from the systemic circulation. However, the expression of enzymes and receptors involved in their synthesis and signaling, respectively, support the hypothesis that there is an endogenous source of BAs with a specific function in the CNS. Over the last decades, BAs have been tested as treatments for many CNS pathologies, with beneficial effects. Although they were initially reported as neuroprotective substances, they are also known to reduce inflammatory processes. Most of these effects have been related to the activation of the Takeda G protein-coupled receptor 5 (TGR5). This review addresses the new challenges that face BA research for neuroscience, focusing on their molecular functions. We discuss their endogenous and exogenous sources in the CNS, their signaling through the TGR5 receptor, and their mechanisms of action as potential therapeutics for neuropathologies.
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Affiliation(s)
- Lorenzo Romero-Ramírez
- Laboratorio de Regeneración Neuronal, Hospital Nacional de Parapléjicos, Servicio de Salud de Castilla-La Mancha, 45071 Toledo, Spain
| | - Jörg Mey
- Laboratorio de Regeneración Neuronal, Hospital Nacional de Parapléjicos, Servicio de Salud de Castilla-La Mancha, 45071 Toledo, Spain
- EURON Graduate School of Neuroscience, Maastricht University, 6229 ER Maastricht, The Netherlands;
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15
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Liu A, Li Y, Li L, Chen K, Tan M, Zou F, Zhang X, Meng X. Bile acid metabolism is altered in learning and memory impairment induced by chronic lead exposure. JOURNAL OF HAZARDOUS MATERIALS 2024; 471:134360. [PMID: 38663295 DOI: 10.1016/j.jhazmat.2024.134360] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/12/2024] [Revised: 04/07/2024] [Accepted: 04/18/2024] [Indexed: 05/12/2024]
Abstract
Lead is a neurotoxic contaminant that exists widely in the environment. Although lead neurotoxicity has been found to be tightly linked to gut microbiota disturbance, the effect of host metabolic disorders caused by gut microbiota disturbance on lead neurotoxicity has not been investigated. In this work, the results of new object recognition tests and Morris water maze tests showed that chronic low-dose lead exposure caused learning and memory dysfunction in mice. The results of 16 S rRNA sequencing of cecal contents and fecal microbiota transplantation showed that the neurotoxicity of lead could be transmitted through gut microbiota. The results of untargeted metabolomics and bile acid targeted metabolism analysis showed that the serum bile acid metabolism profile of lead-exposed mice was significantly changed. In addition, supplementation with TUDCA or INT-777 significantly alleviated chronic lead exposure-induced learning and memory impairment, primarily through inhibition of the NLRP3 inflammasome in the hippocampus to relieve neuroinflammation. In conclusion, our findings suggested that dysregulation of host bile acid metabolism may be one of the mechanisms of lead-induced neurotoxicity, and supplementation of specific bile acids may be a possible therapeutic strategy for lead-induced neurotoxicity.
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Affiliation(s)
- Anfei Liu
- Department of Occupational Health and Occupational Medicine, Guangdong Provincial Key Laboratory of Tropical Disease Research, School of Public Health, Southern Medical University, Guangzhou 510515, China
| | - Yunting Li
- Department of Occupational Health and Occupational Medicine, Guangdong Provincial Key Laboratory of Tropical Disease Research, School of Public Health, Southern Medical University, Guangzhou 510515, China
| | - Lifan Li
- Department of Occupational Health and Occupational Medicine, Guangdong Provincial Key Laboratory of Tropical Disease Research, School of Public Health, Southern Medical University, Guangzhou 510515, China
| | - Kaiju Chen
- Department of Occupational Health and Occupational Medicine, Guangdong Provincial Key Laboratory of Tropical Disease Research, School of Public Health, Southern Medical University, Guangzhou 510515, China
| | - Meitao Tan
- Department of Occupational Health and Occupational Medicine, Guangdong Provincial Key Laboratory of Tropical Disease Research, School of Public Health, Southern Medical University, Guangzhou 510515, China
| | - Fei Zou
- Department of Occupational Health and Occupational Medicine, Guangdong Provincial Key Laboratory of Tropical Disease Research, School of Public Health, Southern Medical University, Guangzhou 510515, China
| | - Xingmei Zhang
- Department of Neurobiology, School of Basic Medical Sciences, Southern Medical University, Guangzhou 510515, China
| | - Xiaojing Meng
- Department of Occupational Health and Occupational Medicine, Guangdong Provincial Key Laboratory of Tropical Disease Research, School of Public Health, Southern Medical University, Guangzhou 510515, China.
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16
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Li XY, Zhang SY, Hong YZ, Chen ZG, Long Y, Yuan DH, Zhao JJ, Tang SS, Wang H, Hong H. TGR5-mediated lateral hypothalamus-dCA3-dorsolateral septum circuit regulates depressive-like behavior in male mice. Neuron 2024; 112:1795-1814.e10. [PMID: 38518778 DOI: 10.1016/j.neuron.2024.02.019] [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: 07/17/2023] [Revised: 01/30/2024] [Accepted: 02/28/2024] [Indexed: 03/24/2024]
Abstract
Although bile acids play a notable role in depression, the pathological significance of the bile acid TGR5 membrane-type receptor in this disorder remains elusive. Using depression models of chronic social defeat stress and chronic restraint stress in male mice, we found that TGR5 in the lateral hypothalamic area (LHA) predominantly decreased in GABAergic neurons, the excitability of which increased in depressive-like mice. Upregulation of TGR5 or inhibition of GABAergic excitability in LHA markedly alleviated depressive-like behavior, whereas down-regulation of TGR5 or enhancement of GABAergic excitability facilitated stress-induced depressive-like behavior. TGR5 also bidirectionally regulated excitability of LHA GABAergic neurons via extracellular regulated protein kinases-dependent Kv4.2 channels. Notably, LHA GABAergic neurons specifically innervated dorsal CA3 (dCA3) CaMKIIα neurons for mediation of depressive-like behavior. LHA GABAergic TGR5 exerted antidepressant-like effects by disinhibiting dCA3 CaMKIIα neurons projecting to the dorsolateral septum (DLS). These findings advance our understanding of TGR5 and the LHAGABA→dCA3CaMKIIα→DLSGABA circuit for the development of potential therapeutic strategies in depression.
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Affiliation(s)
- Xu-Yi Li
- College of Pharmacy, China Pharmaceutical University, Nanjing 210009, China
| | - Shi-Ya Zhang
- College of Pharmacy, China Pharmaceutical University, Nanjing 210009, China
| | - Yi-Zhou Hong
- Research Center of Biostatistics and Computational Pharmacy, China Pharmaceutical University, Nanjing 210009, China
| | - Zhi-Gang Chen
- College of Pharmacy, China Pharmaceutical University, Nanjing 210009, China
| | - Yan Long
- College of Pharmacy, China Pharmaceutical University, Nanjing 210009, China
| | - Dan-Hua Yuan
- College of Pharmacy, China Pharmaceutical University, Nanjing 210009, China
| | - Jia-Jia Zhao
- College of Pharmacy, China Pharmaceutical University, Nanjing 210009, China
| | - Su-Su Tang
- College of Pharmacy, China Pharmaceutical University, Nanjing 210009, China.
| | - Hao Wang
- Affiliated Mental Health Center and Hangzhou Seventh People's Hospital, Zhejiang University School of Medicine/Nanhu Brain-Computer Interface Institute, Hangzhou 310013, China.
| | - Hao Hong
- College of Pharmacy, China Pharmaceutical University, Nanjing 210009, China.
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17
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Bäckström T, Doverskog M, Blackburn TP, Scharschmidt BF, Felipo V. Allopregnanolone and its antagonist modulate neuroinflammation and neurological impairment. Neurosci Biobehav Rev 2024; 161:105668. [PMID: 38608826 DOI: 10.1016/j.neubiorev.2024.105668] [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: 10/19/2023] [Revised: 03/18/2024] [Accepted: 04/07/2024] [Indexed: 04/14/2024]
Abstract
Neuroinflammation accompanies several brain disorders, either as a secondary consequence or as a primary cause and may contribute importantly to disease pathogenesis. Neurosteroids which act as Positive Steroid Allosteric GABA-A receptor Modulators (Steroid-PAM) appear to modulate neuroinflammation and their levels in the brain may vary because of increased or decreased local production or import from the systemic circulation. The increased synthesis of steroid-PAMs is possibly due to increased expression of the mitochondrial cholesterol transporting protein (TSPO) in neuroinflammatory tissue, and reduced production may be due to changes in the enzymatic activity. Microglia and astrocytes play an important role in neuroinflammation, and their production of inflammatory mediators can be both activated and inhibited by steroid-PAMs and GABA. What is surprising is the finding that both allopregnanolone, a steroid-PAM, and golexanolone, a novel GABA-A receptor modulating steroid antagonist (GAMSA), can inhibit microglia and astrocyte activation and normalize their function. This review focuses on the role of steroid-PAMs in neuroinflammation and their importance in new therapeutic approaches to CNS and liver disease.
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Affiliation(s)
| | | | | | | | - Vicente Felipo
- Laboratory of Neurobiology, Centro de Investigación Príncipe Felipe, Valencia, Spain
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18
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Ren Z, Zhao L, Zhao M, Bao T, Chen T, Zhao A, Zheng X, Gu X, Sun T, Guo Y, Tang Y, Xie G, Jia W. Increased intestinal bile acid absorption contributes to age-related cognitive impairment. Cell Rep Med 2024; 5:101543. [PMID: 38697101 PMCID: PMC11148718 DOI: 10.1016/j.xcrm.2024.101543] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/14/2023] [Revised: 12/27/2023] [Accepted: 04/09/2024] [Indexed: 05/04/2024]
Abstract
Cognitive impairment in the elderly is associated with alterations in bile acid (BA) metabolism. In this study, we observe elevated levels of serum conjugated primary bile acids (CPBAs) and ammonia in elderly individuals, mild cognitive impairment, Alzheimer's disease, and aging rodents, with a more pronounced change in females. These changes are correlated with increased expression of the ileal apical sodium-bile acid transporter (ASBT), hippocampal synapse loss, and elevated brain CPBA and ammonia levels in rodents. In vitro experiments confirm that a CPBA, taurocholic acid, and ammonia induced synaptic loss. Manipulating intestinal BA transport using ASBT activators or inhibitors demonstrates the impact on brain CPBA and ammonia levels as well as cognitive decline in rodents. Additionally, administration of an intestinal BA sequestrant, cholestyramine, alleviates cognitive impairment, normalizing CPBAs and ammonia in aging mice. These findings highlight the potential of targeting intestinal BA absorption as a therapeutic strategy for age-related cognitive impairment.
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Affiliation(s)
- Zhenxing Ren
- Center for Translational Medicine and Shanghai Key Laboratory of Diabetes Mellitus, Shanghai Sixth People's Hospital Affiliated with Shanghai Jiaotong University School of Medicine, Shanghai 200233, China
| | - Ling Zhao
- School of Integrative Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China
| | - Mingliang Zhao
- Center for Translational Medicine and Shanghai Key Laboratory of Diabetes Mellitus, Shanghai Sixth People's Hospital Affiliated with Shanghai Jiaotong University School of Medicine, Shanghai 200233, China
| | - Tianhao Bao
- The Affiliated Mental Health Center of Kunming Medical University, Kunming, Yunnan 650224, China
| | - Tianlu Chen
- Center for Translational Medicine and Shanghai Key Laboratory of Diabetes Mellitus, Shanghai Sixth People's Hospital Affiliated with Shanghai Jiaotong University School of Medicine, Shanghai 200233, China
| | - Aihua Zhao
- Center for Translational Medicine and Shanghai Key Laboratory of Diabetes Mellitus, Shanghai Sixth People's Hospital Affiliated with Shanghai Jiaotong University School of Medicine, Shanghai 200233, China
| | - Xiaojiao Zheng
- Center for Translational Medicine and Shanghai Key Laboratory of Diabetes Mellitus, Shanghai Sixth People's Hospital Affiliated with Shanghai Jiaotong University School of Medicine, Shanghai 200233, China
| | - Xinru Gu
- Center for Translational Medicine and Shanghai Key Laboratory of Diabetes Mellitus, Shanghai Sixth People's Hospital Affiliated with Shanghai Jiaotong University School of Medicine, Shanghai 200233, China
| | - Tao Sun
- Center for Translational Medicine and Shanghai Key Laboratory of Diabetes Mellitus, Shanghai Sixth People's Hospital Affiliated with Shanghai Jiaotong University School of Medicine, Shanghai 200233, China
| | - Yuhuai Guo
- School of Kinesiology, Shanghai University of Sport, Shanghai 200438, China
| | - Yajun Tang
- Center for Translational Medicine and Shanghai Key Laboratory of Diabetes Mellitus, Shanghai Sixth People's Hospital Affiliated with Shanghai Jiaotong University School of Medicine, Shanghai 200233, China
| | - Guoxiang Xie
- Human Metabolomics Institute, Inc., Shenzhen, Guangdong 518109, China
| | - Wei Jia
- Center for Translational Medicine and Shanghai Key Laboratory of Diabetes Mellitus, Shanghai Sixth People's Hospital Affiliated with Shanghai Jiaotong University School of Medicine, Shanghai 200233, China; Department of Pharmacology and Pharmacy, University of Hong Kong, Hong Kong, China.
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Munawar Cheema M, Macakova Kotrbova Z, Hrcka Krausova B, Adla SK, Slavikova B, Chodounska H, Kratochvil M, Vondrasek J, Sedlak D, Balastik M, Kudova E. 5β-reduced neuroactive steroids as modulators of growth and viability of postnatal neurons and glia. J Steroid Biochem Mol Biol 2024; 239:106464. [PMID: 38246201 DOI: 10.1016/j.jsbmb.2024.106464] [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] [Received: 09/29/2023] [Revised: 01/11/2024] [Accepted: 01/17/2024] [Indexed: 01/23/2024]
Abstract
Endogenous neurosteroids (NS) and their synthetic analogs, neuroactive steroids (NAS), are potentially useful drug-like compounds affecting the pathophysiology of miscellaneous central nervous system disorders (e.g. Alzheimer´s disease, epilepsy, depression, etc.). Additionally, NS have been shown to promote neuron viability and neurite outgrowth upon injury. The molecular, structural and physicochemical basis of the NS effect on neurons is so far not fully understood, and the development of new, biologically relevant assays is essential for their comparative analysis and for assessment of their mechanism of action. Here, we report the development of a novel, plate-based, high-content in vitro assay for screening of NS and newly synthesized, 5β-reduced NAS for the promotion of postnatal neuron survival and neurite growth using fluorescent, postnatal mixed cortical neuron cultures isolated from thy1-YFP transgenic mice. The screen allows a detailed time course analysis of different parameters, such as the number of neurons or neurite lengths of 7-day, in vitro neuron cultures. Using the screen, we identify a new NAS, compound 42, that promotes the survival and growth of postnatal neurons significantly better than several endogenous NS (dehydroepiandrosterone, progesterone, and allopregnanolone). Interestingly, we demonstrate that compound 42 also promotes the proliferation of glia (in particular oligodendrocytes) and that the glial function is critical for its neuron growth support. Computational analysis of the biological data and calculated physicochemical properties of tested NS and NAS demonstrated that their biological activity is proportional to their lipophilicity. Together, the screen proves useful for the selection of neuron-active NAS and the comparative evaluation of their biologically relevant structural and physicochemical features.
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Affiliation(s)
- Marie Munawar Cheema
- Laboratory of Molecular Neurobiology, Institute of Physiology, Czech Academy of Sciences, Videnska 1083, 14220 Prague 4, Czech Republic
| | - Zuzana Macakova Kotrbova
- CZ-OPENSCREEN: National Infrastructure for Chemical Biology, Institute of Molecular Genetics, Czech Academy of Sciences, Videnska 1083, 14220 Prague 4, Czech Republic
| | - Barbora Hrcka Krausova
- Laboratory of Cellular Neurophysiology, Institute of Physiology, Czech Academy of Sciences, Videnska 1083, 14220 Prague 4, Czech Republic
| | - Santosh Kumar Adla
- Dept. of Neurosteroids, Institute of Organic Chemistry and Biochemistry, Czech Academy of Sciences, Flemingovo namesti 2, 16610 Prague 6, Czech Republic
| | - Barbora Slavikova
- Dept. of Neurosteroids, Institute of Organic Chemistry and Biochemistry, Czech Academy of Sciences, Flemingovo namesti 2, 16610 Prague 6, Czech Republic
| | - Hana Chodounska
- Dept. of Neurosteroids, Institute of Organic Chemistry and Biochemistry, Czech Academy of Sciences, Flemingovo namesti 2, 16610 Prague 6, Czech Republic
| | - Miroslav Kratochvil
- Dept. of Bioinformatics, Institute of Organic Chemistry and Biochemistry, Czech Academy of Sciences, Flemingovo namesti 2, 16610 Prague 6, Czech Republic
| | - Jiri Vondrasek
- Dept. of Bioinformatics, Institute of Organic Chemistry and Biochemistry, Czech Academy of Sciences, Flemingovo namesti 2, 16610 Prague 6, Czech Republic
| | - David Sedlak
- CZ-OPENSCREEN: National Infrastructure for Chemical Biology, Institute of Molecular Genetics, Czech Academy of Sciences, Videnska 1083, 14220 Prague 4, Czech Republic
| | - Martin Balastik
- Laboratory of Molecular Neurobiology, Institute of Physiology, Czech Academy of Sciences, Videnska 1083, 14220 Prague 4, Czech Republic.
| | - Eva Kudova
- Dept. of Neurosteroids, Institute of Organic Chemistry and Biochemistry, Czech Academy of Sciences, Flemingovo namesti 2, 16610 Prague 6, Czech Republic.
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20
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Jia W, Li Y, Cheung KCP, Zheng X. Bile acid signaling in the regulation of whole body metabolic and immunological homeostasis. SCIENCE CHINA. LIFE SCIENCES 2024; 67:865-878. [PMID: 37515688 DOI: 10.1007/s11427-023-2353-0] [Citation(s) in RCA: 41] [Impact Index Per Article: 41.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/21/2023] [Accepted: 04/23/2023] [Indexed: 07/31/2023]
Abstract
Bile acids (BAs) play a crucial role in nutrient absorption and act as key regulators of lipid and glucose metabolism and immune homeostasis. Through the enterohepatic circulation, BAs are synthesized, metabolized, and reabsorbed, with a portion entering the vascular circulation and distributing systemically. This allows BAs to interact with receptors in all major organs, leading to organ-organ interactions that regulate both local and global metabolic processes, as well as the immune system. This review focuses on the whole-body effects of BA-mediated metabolic and immunological regulation, including in the brain, heart, liver, intestine, eyes, skin, adipose tissue, and muscle. Targeting BA synthesis and receptor signaling is a promising strategy for the development of novel therapies for various diseases throughout the body.
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Affiliation(s)
- Wei Jia
- School of Chinese Medicine, Hong Kong Baptist University, Hong Kong, China.
| | - Yitao Li
- School of Chinese Medicine, Hong Kong Baptist University, Hong Kong, China
| | - Kenneth C P Cheung
- School of Chinese Medicine, Hong Kong Baptist University, Hong Kong, China
| | - Xiaojiao Zheng
- Center for Translational Medicine and Shanghai Key Laboratory of Diabetes Mellitus, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, 200233, China.
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21
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Ye D, He J, He X. The role of bile acid receptor TGR5 in regulating inflammatory signalling. Scand J Immunol 2024; 99:e13361. [PMID: 38307496 DOI: 10.1111/sji.13361] [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: 08/09/2023] [Revised: 10/12/2023] [Accepted: 01/18/2024] [Indexed: 02/04/2024]
Abstract
Takeda G protein-coupled receptor 5 (TGR5) is a bile acid receptor, and its role in regulating metabolism after binding with bile acids has been established. Since the immune response depends on metabolism to provide biomolecules and energy to cope with challenging conditions, emerging evidence reveals the regulatory effects of TGR5 on the immune response. An in-depth understanding of the effect of TGR5 on immune regulation can help us disentangle the interaction of metabolism and immune response, accelerating the development of TGR5 as a therapeutic target. Herein, we reviewed more than 200 articles published in the last 20 years in PubMed, to discuss the roles of TGR5 in regulating inflammatory response, the molecular mechanism, as well as existing problems. Particularly, its anti-inflammation effect is emphasized.
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Affiliation(s)
- Daijiao Ye
- Medical Research Center, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang Province, China
| | - Jiayao He
- Medical Research Center, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang Province, China
| | - Xiaofei He
- Medical Research Center, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang Province, China
- The Key Laboratory of Pediatric Hematology and Oncology Disease of Wenzhou, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, Zhejiang Province, China
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22
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Lun W, Yan Q, Guo X, Zhou M, Bai Y, He J, Cao H, Che Q, Guo J, Su Z. Mechanism of action of the bile acid receptor TGR5 in obesity. Acta Pharm Sin B 2024; 14:468-491. [PMID: 38322325 PMCID: PMC10840437 DOI: 10.1016/j.apsb.2023.11.011] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/15/2023] [Revised: 09/17/2023] [Accepted: 10/24/2023] [Indexed: 02/08/2024] Open
Abstract
G protein-coupled receptors (GPCRs) are a large family of membrane protein receptors, and Takeda G protein-coupled receptor 5 (TGR5) is a member of this family. As a membrane receptor, TGR5 is widely distributed in different parts of the human body and plays a vital role in regulating metabolism, including the processes of energy consumption, weight loss and blood glucose homeostasis. Recent studies have shown that TGR5 plays an important role in glucose and lipid metabolism disorders such as fatty liver, obesity and diabetes. With the global obesity situation becoming more and more serious, a comprehensive explanation of the mechanism of TGR5 and filling the gaps in knowledge concerning clinical ligand drugs are urgently needed. In this review, we mainly explain the anti-obesity mechanism of TGR5 to promote the further study of this target, and show the electron microscope structure of TGR5 and review recent studies on TGR5 ligands to illustrate the specific binding between TGR5 receptor binding sites and ligands, which can effectively provide new ideas for ligand research and promote drug research.
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Affiliation(s)
- Weijun Lun
- Guangdong Engineering Research Center of Natural Products and New Drugs, Guangdong Provincial University Engineering Technology Research Center of Natural Products and Drugs, Guangdong Pharmaceutical University, Guangzhou 510006, China
- Guangdong Metabolic Disease Research Center of Integrated Chinese and Western Medicine, Key Laboratory of Glucolipid Metabolic Disorder, Ministry of Education of China, Guangdong TCM Key Laboratory for Metabolic Diseases, Guangdong Pharmaceutical University, Guangzhou 510006, China
| | - Qihao Yan
- Guangdong Engineering Research Center of Natural Products and New Drugs, Guangdong Provincial University Engineering Technology Research Center of Natural Products and Drugs, Guangdong Pharmaceutical University, Guangzhou 510006, China
- Guangdong Metabolic Disease Research Center of Integrated Chinese and Western Medicine, Key Laboratory of Glucolipid Metabolic Disorder, Ministry of Education of China, Guangdong TCM Key Laboratory for Metabolic Diseases, Guangdong Pharmaceutical University, Guangzhou 510006, China
| | - Xinghua Guo
- Guangdong Engineering Research Center of Natural Products and New Drugs, Guangdong Provincial University Engineering Technology Research Center of Natural Products and Drugs, Guangdong Pharmaceutical University, Guangzhou 510006, China
- Guangdong Metabolic Disease Research Center of Integrated Chinese and Western Medicine, Key Laboratory of Glucolipid Metabolic Disorder, Ministry of Education of China, Guangdong TCM Key Laboratory for Metabolic Diseases, Guangdong Pharmaceutical University, Guangzhou 510006, China
| | - Minchuan Zhou
- Guangdong Engineering Research Center of Natural Products and New Drugs, Guangdong Provincial University Engineering Technology Research Center of Natural Products and Drugs, Guangdong Pharmaceutical University, Guangzhou 510006, China
- Guangdong Metabolic Disease Research Center of Integrated Chinese and Western Medicine, Key Laboratory of Glucolipid Metabolic Disorder, Ministry of Education of China, Guangdong TCM Key Laboratory for Metabolic Diseases, Guangdong Pharmaceutical University, Guangzhou 510006, China
| | - Yan Bai
- School of Public Health, Guangdong Pharmaceutical University, Guangzhou 510310, China
| | - Jincan He
- School of Public Health, Guangdong Pharmaceutical University, Guangzhou 510310, China
| | - Hua Cao
- School of Chemistry and Chemical Engineering, Guangdong Pharmaceutical University, Zhongshan 528458, China
| | - Qishi Che
- Guangzhou Rainhome Pharm & Tech Co., Ltd., Science City, Guangzhou 510663, China
| | - Jiao Guo
- Guangdong Metabolic Disease Research Center of Integrated Chinese and Western Medicine, Key Laboratory of Glucolipid Metabolic Disorder, Ministry of Education of China, Guangdong TCM Key Laboratory for Metabolic Diseases, Guangdong Pharmaceutical University, Guangzhou 510006, China
| | - Zhengquan Su
- Guangdong Engineering Research Center of Natural Products and New Drugs, Guangdong Provincial University Engineering Technology Research Center of Natural Products and Drugs, Guangdong Pharmaceutical University, Guangzhou 510006, China
- Guangdong Metabolic Disease Research Center of Integrated Chinese and Western Medicine, Key Laboratory of Glucolipid Metabolic Disorder, Ministry of Education of China, Guangdong TCM Key Laboratory for Metabolic Diseases, Guangdong Pharmaceutical University, Guangzhou 510006, China
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23
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Martin FP, Cominetti O, Berger B, Combremont S, Marquis J, Xie G, Jia W, Pinto-Sanchez MI, Bercik P, Bergonzelli G. Metabolome-associated psychological comorbidities improvement in irritable bowel syndrome patients receiving a probiotic. Gut Microbes 2024; 16:2347715. [PMID: 38717445 PMCID: PMC11085950 DOI: 10.1080/19490976.2024.2347715] [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] [Received: 07/07/2023] [Accepted: 04/22/2024] [Indexed: 05/12/2024] Open
Abstract
Our recent randomized, placebo-controlled study in Irritable Bowel Syndrome (IBS) patients with diarrhea or alternating bowel habits showed that the probiotic Bifidobacterium longum (BL) NCC3001 improves depression scores and decreases brain emotional reactivity. However, the involved metabolic pathways remain unclear. This analysis aimed to investigate the biochemical pathways underlying the beneficial effects of BL NCC3001 using metabolomic profiling. Patients received probiotic (1x 1010CFU, n=16) or placebo (n=19) daily for 6 weeks. Anxiety and depression were measured using the Hospital Anxiety and Depression Scale. Brain activity in response to negative emotional stimuli was assessed by functional Magnetic Resonance Imaging. Probiotic fecal abundance was quantified by qPCR. Quantitative measurement of specific panels of plasma host-microbial metabolites was performed by mass spectrometry-based metabolomics. Probiotic abundance in feces was associated with improvements in anxiety and depression scores, and a decrease in amygdala activation. The probiotic treatment increased the levels of butyric acid, tryptophan, N-acetyl tryptophan, glycine-conjugated bile acids, and free fatty acids. Butyric acid concentration correlated with lower anxiety and depression scores, and decreased amygdala activation. Furthermore, butyric acid concentration correlated with the probiotic abundance in feces. In patients with non-constipation IBS, improvements in psychological comorbidities and brain emotional reactivity were associated with an increased abundance of BL NCC3001 in feces and specific plasma metabolites, mainly butyric acid. These findings suggest the importance of a probiotic to thrive in the gut and highlight butyric acid as a potential biochemical marker linking microbial metabolism with beneficial effects on the gut-brain axis.
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Affiliation(s)
- Francois-Pierre Martin
- Nestlé Institute of Health Sciences, Société des Produits Nestlé S.A, Lausanne, Switzerland
| | - Ornella Cominetti
- Nestlé Institute of Food Safety and Analytical Sciences, Société des Produits Nestlé S.A, Lausanne, Switzerland
| | - Bernard Berger
- Nestlé Institute of Health Sciences, Société des Produits Nestlé S.A, Lausanne, Switzerland
| | - Séverine Combremont
- Nestlé Institute of Health Sciences, Société des Produits Nestlé S.A, Lausanne, Switzerland
| | - Julien Marquis
- Nestlé Institute of Health Sciences, Société des Produits Nestlé S.A, Lausanne, Switzerland
| | - Guoxiang Xie
- University of Hawaii Cancer Center (UHCC), Honolulu, HI, USA
- Human Metabolomics Institute, Inc, Shenzhen, Guangdong, China
| | - Wei Jia
- University of Hawaii Cancer Center (UHCC), Honolulu, HI, USA
- School of Chinese Medicine, Hong Kong Baptist University, Hong Kong, China
| | - Maria Inés Pinto-Sanchez
- Department of Medicine, Farncombe Family Digestive Health Research Institute, McMaster University, Hamilton, ON, Canada
| | - Premysl Bercik
- Department of Medicine, Farncombe Family Digestive Health Research Institute, McMaster University, Hamilton, ON, Canada
| | - Gabriela Bergonzelli
- Nestlé Institute of Health Sciences, Société des Produits Nestlé S.A, Lausanne, Switzerland
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24
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Zhang F, Deng Y, Wang H, Fu J, Wu G, Duan Z, Zhang X, Cai Y, Zhou H, Yin J, He Y. Gut microbiota-mediated ursodeoxycholic acids regulate the inflammation of microglia through TGR5 signaling after MCAO. Brain Behav Immun 2024; 115:667-679. [PMID: 37989444 DOI: 10.1016/j.bbi.2023.11.021] [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] [Received: 07/14/2023] [Revised: 11/17/2023] [Accepted: 11/18/2023] [Indexed: 11/23/2023] Open
Abstract
Ischemic stroke has been demonstrated to cause an imbalance of gut microbiota. However, the change in gut microbiota-mediated bile acids (BAs) metabolites remains unclear. Here, we observed a decrease in gut microbiota-mediated BAs, especially ursodeoxycholic acid (UDCA), in the serum of stroke patients as well as in the intestine, serum and brain of stroke mice. Restoration of UDCA could decrease the area of infarction and improve the neurological function and cognitive function in mice in association with inhibition of NLRP3-related pro-inflammatory cytokines through TGR5/PKA pathway. Furthermore, knocking out TGR5 and inhibiting PKA activity reduce the protective effect of UDCA. Taken together, our results suggest that microbiota-mediated UDCA plays an important role in alleviating inflammatory responses and might be a promising therapeutic target in ischemic stroke.
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Affiliation(s)
- Feng Zhang
- Microbiome Medicine Centre, Department of Laboratory Medicine, Zhujiang Hospital, Southern Medical University, Guangzhou, Guangdong 510282, PR China; Department of Neurosurgery, Huzhou Central Hospital, Zhejiang University School of Medicine, Huzhou, PR China
| | - Yiting Deng
- Department of Neurology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, PR China
| | - Huidi Wang
- Microbiome Medicine Centre, Department of Laboratory Medicine, Zhujiang Hospital, Southern Medical University, Guangzhou, Guangdong 510282, PR China
| | - Jingxiang Fu
- Microbiome Medicine Centre, Department of Laboratory Medicine, Zhujiang Hospital, Southern Medical University, Guangzhou, Guangdong 510282, PR China
| | - Guangyan Wu
- Microbiome Medicine Centre, Department of Laboratory Medicine, Zhujiang Hospital, Southern Medical University, Guangzhou, Guangdong 510282, PR China
| | - Zhuo Duan
- Microbiome Medicine Centre, Department of Laboratory Medicine, Zhujiang Hospital, Southern Medical University, Guangzhou, Guangdong 510282, PR China
| | - Xiru Zhang
- Microbiome Medicine Centre, Department of Laboratory Medicine, Zhujiang Hospital, Southern Medical University, Guangzhou, Guangdong 510282, PR China
| | - Yijia Cai
- Microbiome Medicine Centre, Department of Laboratory Medicine, Zhujiang Hospital, Southern Medical University, Guangzhou, Guangdong 510282, PR China
| | - Hongwei Zhou
- Microbiome Medicine Centre, Department of Laboratory Medicine, Zhujiang Hospital, Southern Medical University, Guangzhou, Guangdong 510282, PR China; Guangdong Provincial Clinical Research Center for Laboratory Medicine, Guangzhou, Guangdong 510033, PR China; State Key Laboratory of Organ Failure Research, Southern Medical University, Guangzhou, Guangdong 510515, PR China
| | - Jia Yin
- Department of Neurology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, PR China.
| | - Yan He
- Microbiome Medicine Centre, Department of Laboratory Medicine, Zhujiang Hospital, Southern Medical University, Guangzhou, Guangdong 510282, PR China; Guangdong Provincial Clinical Research Center for Laboratory Medicine, Guangzhou, Guangdong 510033, PR China; State Key Laboratory of Organ Failure Research, Southern Medical University, Guangzhou, Guangdong 510515, PR China; Key Laboratory of Mental Health of the Ministry of Education, Guangzhou, Guangdong 510515, PR China.
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25
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Rosatelli E, Carotti A, Cerra B, De Franco F, Passeri D, Pellicciari R, Gioiello A. Chemical exploration of TGR5 functional hot-spots: Synthesis and structure-activity relationships of C7- and C23-Substituted cholic acid derivatives. Eur J Med Chem 2023; 261:115851. [PMID: 37813065 DOI: 10.1016/j.ejmech.2023.115851] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/28/2023] [Revised: 09/27/2023] [Accepted: 09/29/2023] [Indexed: 10/11/2023]
Abstract
The activation of TGR5 bestows on bile acids the ability to modulate nongenomic signaling pathways, which are responsible of physiological actions including immunosuppressive and anti-inflammatory properties as well as the regulation of glucose metabolism and energy homeostasis. TGR5 agonists have therefore emerged in drug discovery and preclinical appraisals as promising compounds for the treatment of liver diseases and metabolic syndrome. In this study, we have been devising site-selected chemical modifications of the bile acid scaffold to provide novel chemical tools able to modulate the functions of TGR5 in different tissues. Biological results of the tested collection of semisynthetic cholic acid derivatives were used to extend the structure-activity relationships of TGR5 agonists and to clarify the molecular basis and functional role of TGR5 hot-spots in the receptor activation and selectivity. Some unexpected properties deriving from the molecular structure of bile acids have been unveiled as relevant to the receptor activation and may hence be used to design novel, selective and potent TGR5 agonists.
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Affiliation(s)
| | - Andrea Carotti
- Department of Pharmaceutical Sciences, University of Perugia, Via del Liceo 1, I-06122, Perugia, Italy
| | - Bruno Cerra
- Department of Pharmaceutical Sciences, University of Perugia, Via del Liceo 1, I-06122, Perugia, Italy
| | | | | | | | - Antimo Gioiello
- Department of Pharmaceutical Sciences, University of Perugia, Via del Liceo 1, I-06122, Perugia, Italy.
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26
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Li M, Pang X, Guo Z, Yang Y, Gu Z, Zhang L. Integrated metabolomics and network pharmacology to reveal the mechanism of areca nut addiction. Addict Biol 2023; 28:e13352. [PMID: 38017647 DOI: 10.1111/adb.13352] [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: 04/03/2023] [Revised: 09/09/2023] [Accepted: 10/16/2023] [Indexed: 11/30/2023]
Abstract
As a chewing hobby, areca nut (Areca catechu L.) has become the most common psychoactive substance in the world, besides tobacco, alcohol and caffeinated beverages. Moreover, as a first-class carcinogen designated by International Agency for Research on Cancer, long-term chewing areca nut can result in oral mucosal diseases and even oral cancer. To clarify the potential mechanism of areca nut addiction, an integrated strategy of metabolomics and network pharmacology was adopted in this study. Network pharmacology study indicated that all the key targets related to areca nut addiction could be regulated by arecoline and pointed out the importance of G-protein coupled receptor signalling pathway. Analysis results of mice plasma metabolome and faeces metabolome intervened by arecoline suggested that the component may affect the dopamine system and 5-HT system by regulating phenylalanine, tyrosine and tryptophan biosynthesis, phenylalanine metabolism, primary bile acid biosynthesis, glycerophospholipid metabolism and intestinal flora structure. Moreover, the potential importance of bile acids in formation of addictive behaviour of chewing areca nut was investigated by integrative analysis of the relationships between metabolites and intestinal flora. The study can provide scientific basis for the addiction intervention and treatment of areca nut chewers.
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Affiliation(s)
- Moying Li
- School of Environment and Civil Engineering, Jiangnan University, Wuxi, Jiangsu, China
- National Engineering Research Center of Cereal Fermentation and Food Biomanufacturing, Jiangnan University, Wuxi, Jiangsu, China
- Yixing Institute of Food and Biotechnology Co., Ltd, Yixing, Jiangsu, China
| | - Xin Pang
- National Engineering Research Center of Cereal Fermentation and Food Biomanufacturing, Jiangnan University, Wuxi, Jiangsu, China
| | - Zitao Guo
- National Engineering Research Center of Cereal Fermentation and Food Biomanufacturing, Jiangnan University, Wuxi, Jiangsu, China
| | - Yuliang Yang
- National Engineering Research Center of Cereal Fermentation and Food Biomanufacturing, Jiangnan University, Wuxi, Jiangsu, China
| | - Zhenghua Gu
- National Engineering Research Center of Cereal Fermentation and Food Biomanufacturing, Jiangnan University, Wuxi, Jiangsu, China
| | - Liang Zhang
- National Engineering Research Center of Cereal Fermentation and Food Biomanufacturing, Jiangnan University, Wuxi, Jiangsu, China
- Yixing Institute of Food and Biotechnology Co., Ltd, Yixing, Jiangsu, China
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27
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Gilbert MC, Setayesh T, Wan YJY. The contributions of bacteria metabolites to the development of hepatic encephalopathy. LIVER RESEARCH 2023; 7:296-303. [PMID: 38221945 PMCID: PMC10786625 DOI: 10.1016/j.livres.2022.11.005] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/17/2022]
Abstract
Over 20% of mortality during acute liver failure is associated with the development of hepatic encephalopathy (HE). Thus, HE is a complication of acute liver failure with a broad spectrum of neuropsychiatric abnormalities ranging from subclinical alterations to coma. HE is caused by the diversion of portal blood into systemic circulation through portosystemic collateral vessels. Thus, the brain is exposed to intestinal-derived toxic substances. Moreover, the strategies to prevent advancement and improve the prognosis of such a liver-brain disease rely on intestinal microbial modulation. This is supported by the findings that antibiotics such as rifaximin and laxative lactulose can alleviate hepatic cirrhosis and/or prevent HE. Together, the significance of the gut-liver-brain axis in human health warrants attention. This review paper focuses on the roles of bacteria metabolites, mainly ammonia and bile acids (BAs) as well as BA receptors in HE. The literature search conducted for this review included searches for phrases such as BA receptors, BAs, ammonia, farnesoid X receptor (FXR), G protein-coupled bile acid receptor 1 (GPBAR1 or TGR5), sphingosine-1-phosphate receptor 2 (S1PR2), and cirrhosis in conjunction with the phrase hepatic encephalopathy and portosystemic encephalopathy. PubMed, as well as Google Scholar, was the search engines used to find relevant publications.
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Affiliation(s)
- Miranda Claire Gilbert
- Department of Pathology and Laboratory Medicine, University of California, Davis, Sacramento, CA, USA
| | - Tahereh Setayesh
- Department of Pathology and Laboratory Medicine, University of California, Davis, Sacramento, CA, USA
| | - Yu-Jui Yvonne Wan
- Department of Pathology and Laboratory Medicine, University of California, Davis, Sacramento, CA, USA
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28
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Chen S, Shao Q, Chen J, Lv X, Ji J, Liu Y, Song Y. Bile acid signalling and its role in anxiety disorders. Front Endocrinol (Lausanne) 2023; 14:1268865. [PMID: 38075046 PMCID: PMC10710157 DOI: 10.3389/fendo.2023.1268865] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/28/2023] [Accepted: 11/06/2023] [Indexed: 12/18/2023] Open
Abstract
Anxiety disorder is a prevalent neuropsychiatric disorder that afflicts 7.3%~28.0% of the world's population. Bile acids are synthesized by hepatocytes and modulate metabolism via farnesoid X receptor (FXR), G protein-coupled receptor (TGR5), etc. These effects are not limited to the gastrointestinal tract but also extend to tissues and organs such as the brain, where they regulate emotional centers and nerves. A rise in serum bile acid levels can promote the interaction between central FXR and TGR5 across the blood-brain barrier or activate intestinal FXR and TGR5 to release fibroblast growth factor 19 (FGF19) and glucagon-like peptide-1 (GLP-1), respectively, which in turn, transmit signals to the brain via these indirect pathways. This review aimed to summarize advancements in the metabolism of bile acids and the physiological functions of their receptors in various tissues, with a specific focus on their regulatory roles in brain function. The contribution of bile acids to anxiety via sending signals to the brain via direct or indirect pathways was also discussed. Different bile acid ligands trigger distinct bile acid signaling cascades, producing diverse downstream effects, and these pathways may be involved in anxiety regulation. Future investigations from the perspective of bile acids are anticipated to lead to novel mechanistic insights and potential therapeutic targets for anxiety disorders.
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Affiliation(s)
| | | | | | | | | | - Yan Liu
- College of Traditional Chinese Medicine, Beijing University of Chinese Medicine, Beijing, China
| | - Yuehan Song
- College of Traditional Chinese Medicine, Beijing University of Chinese Medicine, Beijing, China
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Wang L, Bai Y, Tao Y, Shen W, Zhou H, He Y, Wu H, Huang F, Shi H, Wu X. Bear bile powder alleviates Parkinson's disease-like behavior in mice by inhibiting astrocyte-mediated neuroinflammation. Chin J Nat Med 2023; 21:710-720. [PMID: 37777320 DOI: 10.1016/s1875-5364(23)60449-2] [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: 03/21/2023] [Indexed: 10/02/2023]
Abstract
Parkinson's disease (PD) is a common neurodegenerative disease in middle-aged and elderly people. In particular, increasing evidence has showed that astrocyte-mediated neuroinflammation is involved in the pathogenesis of PD. As a precious traditional Chinese medicine, bear bile powder (BBP) has a long history of use in clinical practice. It has numerous activities, such as clearing heat, calming the liver wind and anti-inflammation, and also exhibits good therapeutic effect on convulsive epilepsy. However, whether BBP can prevent the development of PD has not been elucidated. Hence, this study was designed to explore the effect and mechanism of BBP on suppressing astrocyte-mediated neuroinflammation in a mouse model of PD. PD-like behavior was induced in the mice by intraperitoneal injection of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) (30 mg·kg-1) for five days, followed by BBP (50, 100, and 200 mg·kg-1) treatment daily for ten days. LPS stimulated rat C6 astrocytic cells were used as a cell model of neuroinflammation. THe results indicated that BBP treatment significantly ameliorated dyskinesia, increased the levels of tyrosine hydroxylase (TH) and inhibited astrocyte hyperactivation in the substantia nigra (SN) of PD mice. Furthermore, BBP decreased the protein levels of glial fibrillary acidic protein (GFAP), cyclooxygenase 2 (COX2) and inducible nitric oxide synthase (iNOS), and up-regulated the protein levels of takeda G protein-coupled receptor 5 (TGR5) in the SN. Moreover, BBP significantly activated TGR5 in a dose-dependent manner, and decreased the protein levels of GFAP, iNOS and COX2, as well as the mRNA levels of GFAP, iNOS, COX2, interleukin (IL) -1β, IL-6 and tumor necrosis factor-α (TNF-α) in LPS-stimulated C6 cells. Notably, BBP suppressed the phosphorylation of protein kinase B (AKT), inhibitor of NF-κB (IκBα) and nuclear factor-κB (NF-κB) proteins in vivo and in vitro. We also observed that TGR5 inhibitor triamterene attenuated the anti-neuroinflammatory effect of BBP on LPS-stimulated C6 cells. Taken together, BBP alleviates the progression of PD mice by suppressing astrocyte-mediated inflammation via TGR5.
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Affiliation(s)
- Lupeng Wang
- Shanghai Key Laboratory of Compound Chinese Medicines, The Ministry of Education (MOE) Key Laboratory for Standardization of Chinese Medicines, The State Administration of TCM (SATCM) Key Laboratory for New Resources and Quality Evaluation of Chinese Medicine, Institute of Chinese Materia Medica, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China
| | - Yuyan Bai
- Shanghai Key Laboratory of Compound Chinese Medicines, The Ministry of Education (MOE) Key Laboratory for Standardization of Chinese Medicines, The State Administration of TCM (SATCM) Key Laboratory for New Resources and Quality Evaluation of Chinese Medicine, Institute of Chinese Materia Medica, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China
| | - Yanlin Tao
- Shanghai Key Laboratory of Compound Chinese Medicines, The Ministry of Education (MOE) Key Laboratory for Standardization of Chinese Medicines, The State Administration of TCM (SATCM) Key Laboratory for New Resources and Quality Evaluation of Chinese Medicine, Institute of Chinese Materia Medica, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China
| | - Wei Shen
- Shanghai Key Laboratory of Compound Chinese Medicines, The Ministry of Education (MOE) Key Laboratory for Standardization of Chinese Medicines, The State Administration of TCM (SATCM) Key Laboratory for New Resources and Quality Evaluation of Chinese Medicine, Institute of Chinese Materia Medica, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China
| | - Houyuan Zhou
- Shanghai Key Laboratory of Compound Chinese Medicines, The Ministry of Education (MOE) Key Laboratory for Standardization of Chinese Medicines, The State Administration of TCM (SATCM) Key Laboratory for New Resources and Quality Evaluation of Chinese Medicine, Institute of Chinese Materia Medica, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China
| | - Yixin He
- Shanghai Key Laboratory of Compound Chinese Medicines, The Ministry of Education (MOE) Key Laboratory for Standardization of Chinese Medicines, The State Administration of TCM (SATCM) Key Laboratory for New Resources and Quality Evaluation of Chinese Medicine, Institute of Chinese Materia Medica, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China
| | - Hui Wu
- Shanghai Key Laboratory of Compound Chinese Medicines, The Ministry of Education (MOE) Key Laboratory for Standardization of Chinese Medicines, The State Administration of TCM (SATCM) Key Laboratory for New Resources and Quality Evaluation of Chinese Medicine, Institute of Chinese Materia Medica, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China
| | - Fei Huang
- Shanghai Key Laboratory of Compound Chinese Medicines, The Ministry of Education (MOE) Key Laboratory for Standardization of Chinese Medicines, The State Administration of TCM (SATCM) Key Laboratory for New Resources and Quality Evaluation of Chinese Medicine, Institute of Chinese Materia Medica, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China
| | - Hailian Shi
- Shanghai Key Laboratory of Compound Chinese Medicines, The Ministry of Education (MOE) Key Laboratory for Standardization of Chinese Medicines, The State Administration of TCM (SATCM) Key Laboratory for New Resources and Quality Evaluation of Chinese Medicine, Institute of Chinese Materia Medica, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China
| | - Xiaojun Wu
- Shanghai Key Laboratory of Compound Chinese Medicines, The Ministry of Education (MOE) Key Laboratory for Standardization of Chinese Medicines, The State Administration of TCM (SATCM) Key Laboratory for New Resources and Quality Evaluation of Chinese Medicine, Institute of Chinese Materia Medica, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China.
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30
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Cheung KCP, Ma J, Loiola RA, Chen X, Jia W. Bile acid-activated receptors in innate and adaptive immunity: targeted drugs and biological agents. Eur J Immunol 2023; 53:e2250299. [PMID: 37172599 DOI: 10.1002/eji.202250299] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2022] [Revised: 03/10/2023] [Accepted: 05/11/2023] [Indexed: 05/15/2023]
Abstract
Bile acid-activated receptors (BARs) such as a G-protein bile acid receptor 1 and the farnesol X receptor are activated by bile acids (BAs) and have been implicated in the regulation of microbiota-host immunity in the intestine. The mechanistic roles of these receptors in immune signaling suggest that they may also influence the development of metabolic disorders. In this perspective, we provide a summary of recent literature describing the main regulatory pathways and mechanisms of BARs and how they affect both innate and adaptive immune system, cell proliferation, and signaling in the context of inflammatory diseases. We also discuss new approaches for therapy and summarize clinical projects on BAs for the treatment of diseases. In parallel, some drugs that are classically used for other therapeutic purposes and BAR activity have recently been proposed as regulators of immune cells phenotype. Another strategy consists of using specific strains of gut bacteria to regulate BA production in the intestine.
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Affiliation(s)
- Kenneth C P Cheung
- Hong Kong Phenome Research Center, Hong Kong Baptist University, Kowloon Tong, Hong Kong, China
| | - Jiao Ma
- Hong Kong Phenome Research Center, Hong Kong Baptist University, Kowloon Tong, Hong Kong, China
| | | | - Xingxuan Chen
- Hong Kong Phenome Research Center, Hong Kong Baptist University, Kowloon Tong, Hong Kong, China
| | - Wei Jia
- Hong Kong Phenome Research Center, Hong Kong Baptist University, Kowloon Tong, Hong Kong, China
- Center for Translational Medicine and Shanghai Key Laboratory of Diabetes Mellitus, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, China
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31
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Rusch JA, Layden BT, Dugas LR. Signalling cognition: the gut microbiota and hypothalamic-pituitary-adrenal axis. Front Endocrinol (Lausanne) 2023; 14:1130689. [PMID: 37404311 PMCID: PMC10316519 DOI: 10.3389/fendo.2023.1130689] [Citation(s) in RCA: 64] [Impact Index Per Article: 32.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/23/2022] [Accepted: 05/25/2023] [Indexed: 07/06/2023] Open
Abstract
Cognitive function in humans depends on the complex and interplay between multiple body systems, including the hypothalamic-pituitary-adrenal (HPA) axis. The gut microbiota, which vastly outnumbers human cells and has a genetic potential that exceeds that of the human genome, plays a crucial role in this interplay. The microbiota-gut-brain (MGB) axis is a bidirectional signalling pathway that operates through neural, endocrine, immune, and metabolic pathways. One of the major neuroendocrine systems responding to stress is the HPA axis which produces glucocorticoids such as cortisol in humans and corticosterone in rodents. Appropriate concentrations of cortisol are essential for normal neurodevelopment and function, as well as cognitive processes such as learning and memory, and studies have shown that microbes modulate the HPA axis throughout life. Stress can significantly impact the MGB axis via the HPA axis and other pathways. Animal research has advanced our understanding of these mechanisms and pathways, leading to a paradigm shift in conceptual thinking about the influence of the microbiota on human health and disease. Preclinical and human trials are currently underway to determine how these animal models translate to humans. In this review article, we summarize the current knowledge of the relationship between the gut microbiota, HPA axis, and cognition, and provide an overview of the main findings and conclusions in this broad field.
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Affiliation(s)
- Jody A. Rusch
- Division of Chemical Pathology, Department of Pathology, University of Cape Town, Cape Town, South Africa
- C17 Chemical Pathology Laboratory, Groote Schuur Hospital, National Health Laboratory Service, Cape Town, South Africa
| | - Brian T. Layden
- Division of Endocrinology, Diabetes, and Metabolism, Department of Medicine, University of Illinois at Chicago, Chicago, IL, United States
- Department of Medicine, Jesse Brown Veterans Affairs Medical Center, Chicago, IL, United States
| | - Lara R. Dugas
- Division of Epidemiology and Biostatistics, School of Public Health, University of Cape Town, Cape Town, South Africa
- Public Health Sciences, Parkinson School of Health Sciences and Public Health, Loyola University Chicago, Maywood, IL, United States
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32
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Romanazzi T, Zanella D, Bhatt M, Di Iacovo A, Galli A, Bossi E. Bile acid interactions with neurotransmitter transporters. Front Cell Neurosci 2023; 17:1161930. [PMID: 37180953 PMCID: PMC10169653 DOI: 10.3389/fncel.2023.1161930] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/17/2023] [Accepted: 04/11/2023] [Indexed: 05/16/2023] Open
Abstract
Synthesized in the liver from cholesterol, the bile acids (BAs) primary role is emulsifying fats to facilitate their absorption. BAs can cross the blood-brain barrier (BBB) and be synthesized in the brain. Recent evidence suggests a role for BAs in the gut-brain signaling by modulating the activity of various neuronal receptors and transporters, including the dopamine transporter (DAT). In this study, we investigated the effects of BAs and their relationship with substrates in three transporters of the solute carrier 6 family. The exposure to obeticholic acid (OCA), a semi-synthetic BA, elicits an inward current (IBA) in the DAT, the GABA transporter 1 (GAT1), and the glycine transporter 1 (GlyT1b); this current is proportional to the current generated by the substrate, respective to the transporter. Interestingly, a second consecutive OCA application to the transporter fails to elicit a response. The full displacement of BAs from the transporter occurs only after exposure to a saturating concentration of a substrate. In DAT, perfusion of secondary substrates norepinephrine (NE) and serotonin (5-HT) results in a second OCA current, decreased in amplitude and proportional to their affinity. Moreover, co-application of 5-HT or NE with OCA in DAT, and GABA with OCA in GAT1, did not alter the apparent affinity or the Imax, similar to what was previously reported in DAT in the presence of DA and OCA. The findings support the previous molecular model that suggested the ability of BAs to lock the transporter in an occluded conformation. The physiological significance is that it could possibly avoid the accumulation of small depolarizations in the cells expressing the neurotransmitter transporter. This achieves better transport efficiency in the presence of a saturating concentration of the neurotransmitter and enhances the action of the neurotransmitter on their receptors when they are present at reduced concentrations due to decreased availability of transporters.
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Affiliation(s)
- Tiziana Romanazzi
- Laboratory of Cellular and Molecular Physiology, Department of Biotechnology and Life Sciences, University of Insubria, Varese, Italy
- Ph.D. School in Experimental and Translational Medicine, University of Insubria, Varese, Italy
| | - Daniele Zanella
- Department of Surgery, University of Alabama at Birmingham, Birmingham, AL, United States
| | - Manan Bhatt
- Laboratory of Cellular and Molecular Physiology, Department of Biotechnology and Life Sciences, University of Insubria, Varese, Italy
- Ph.D. School in Experimental and Translational Medicine, University of Insubria, Varese, Italy
| | - Angela Di Iacovo
- Laboratory of Cellular and Molecular Physiology, Department of Biotechnology and Life Sciences, University of Insubria, Varese, Italy
- Ph.D. School in Experimental and Translational Medicine, University of Insubria, Varese, Italy
| | - Aurelio Galli
- Department of Surgery, University of Alabama at Birmingham, Birmingham, AL, United States
| | - Elena Bossi
- Laboratory of Cellular and Molecular Physiology, Department of Biotechnology and Life Sciences, University of Insubria, Varese, Italy
- Center for Research in Neuroscience, University of Insubria, Varese, Italy
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33
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Du Y, Wang M, Xu J, Zhong R, Jia J, Huang J, Yao C, Huang L, Huang G, Ke X, Wang H, Fu L. Investigation of therapeutic effects of rhubarb decoction retention enema on minimal hepatic encephalopathy in rats based on 16S rDNA gene sequencing and bile acid metabolomics. J Pharm Biomed Anal 2023; 230:115392. [PMID: 37059036 DOI: 10.1016/j.jpba.2023.115392] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2022] [Revised: 04/06/2023] [Accepted: 04/09/2023] [Indexed: 04/16/2023]
Abstract
Minimal hepatic encephalopathy (MHE) is an early stage of hepatic encephalopathy (HE), with high incidence and a high rate of clinically missed diagnosis. Early diagnosis of MHE and effective clinical intervention are of great importance. Rhubarb decoction (RD)-induced retention enema can effectively improve the cognitive function of patients with MHE, whereas disturbances in the enterohepatic circulation of bile acid (BAs) can induce MHE. However, the molecular mechanisms underlying the therapeutic effects of RD have not been examined from the perspective of intestinal microbiota and bile metabolomics. In this study, we investigated the effects of RD-induced retention enema on intestinal microbiota and bile metabolites in rats with CCl4- and TAA-induced MHE. RD-induced retention enema significantly improved liver function, reduced blood ammonia levels, alleviated cerebral oedema and restored cognitive function in rats with MHE. In addition, it increased the abundance of intestinal microbes; partially reversed the disorder in the composition of intestinal microbiota, including the Bifidobacterium and Bacteroides genera; and regulated BA metabolism, such as taurine combined with increased BA synthesis. In conclusion, this study highlights the potential importance of BA enterohepatic circulation for RD to improve cognitive function in MHE rats, providing a new perspective on the mechanism of this herb. The findings of this study will facilitate experimental research on RD and help to develop RD-based strategies for clinical application.
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Affiliation(s)
- Yuanqin Du
- Guangxi University of Chinese Medicine, Nanning, China
| | - Meng Wang
- Department of Spleen and Stomach Liver Diseases, The First Affiliated Hospital of Guangxi University of Traditional Chinese Medicine, Xianhu District, Nanning, China.
| | - Jian Xu
- Guangxi University of Chinese Medicine, Nanning, China
| | - Ruixi Zhong
- Guangxi University of Chinese Medicine, Nanning, China
| | - Juhong Jia
- Guangxi University of Chinese Medicine, Nanning, China
| | - Jingjing Huang
- Department of Spleen and Stomach Liver Diseases, The First Affiliated Hospital of Guangxi University of Traditional Chinese Medicine, Xianhu District, Nanning, China; Guangxi Key Laboratory of Translational Medicine of Integrated Traditional Chinese and Western Medicine, Nanning, China.
| | - Chun Yao
- Guangxi University of Chinese Medicine, Nanning, China
| | | | - Guochu Huang
- Department of Spleen and Stomach Liver Diseases, The First Affiliated Hospital of Guangxi University of Traditional Chinese Medicine, Xianhu District, Nanning, China
| | - Xuan Ke
- Guangxi University of Chinese Medicine, Nanning, China
| | - Han Wang
- Guangxi University of Chinese Medicine, Nanning, China
| | - Lei Fu
- Guangxi University of Chinese Medicine, Nanning, China
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34
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Sivcev S, Kudova E, Zemkova H. Neurosteroids as positive and negative allosteric modulators of ligand-gated ion channels: P2X receptor perspective. Neuropharmacology 2023; 234:109542. [PMID: 37040816 DOI: 10.1016/j.neuropharm.2023.109542] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/23/2022] [Revised: 03/06/2023] [Accepted: 04/07/2023] [Indexed: 04/13/2023]
Abstract
Neurosteroids are steroids synthesized de novo in the brain from cholesterol in an independent manner from peripheral steroid sources. The term "neuroactive steroid" includes all steroids independent of their origin, and newly synthesized analogs of neurosteroids that modify neuronal activities. In vivo application of neuroactive steroids induces potent anxiolytic, antidepressant, anticonvulsant, sedative, analgesic and amnesic effects, mainly through interaction with the γ-aminobutyric acid type-A receptor (GABAAR). However, neuroactive steroids also act as positive or negative allosteric regulators on several ligand-gated channels including N-methyl-d-aspartate receptors (NMDARs), nicotinic acetylcholine receptors (nAChRs) and ATP-gated purinergic P2X receptors. Seven different P2X subunits (P2X1-7) can assemble to form homotrimeric or heterotrimeric ion channels permeable for monovalent cations and calcium. Among them, P2X2, P2X4, and P2X7 are the most abundant within the brain and can be regulated by neurosteroids. Transmembrane domains are necessary for neurosteroid binding, however, no generic motif of amino acids can accurately predict the neurosteroid binding site for any of the ligand-gated ion channels including P2X. Here, we will review what is currently known about the modulation of rat and human P2X by neuroactive steroids and the possible structural determinants underlying neurosteroid-induced potentiation and inhibition of the P2X2 and P2X4 receptors.
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Affiliation(s)
- Sonja Sivcev
- Institute of Physiology, Czech Academy of Sciences, Prague, Czech Republic; Faculty of Science, Charles University, Prague, Czech Republic
| | - Eva Kudova
- Institute of Organic Chemistry and Biochemistry, Czech Academy of Sciences, Prague, Czech Republic
| | - Hana Zemkova
- Institute of Physiology, Czech Academy of Sciences, Prague, Czech Republic.
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35
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Ehtezazi T, Rahman K, Davies R, Leach AG. The Pathological Effects of Circulating Hydrophobic Bile Acids in Alzheimer's Disease. J Alzheimers Dis Rep 2023; 7:173-211. [PMID: 36994114 PMCID: PMC10041467 DOI: 10.3233/adr-220071] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/19/2023] Open
Abstract
Recent clinical studies have revealed that the serum levels of toxic hydrophobic bile acids (deoxy cholic acid, lithocholic acid [LCA], and glycoursodeoxycholic acid) are significantly higher in patients with Alzheimer's disease (AD) and amnestic mild cognitive impairment (aMCI) when compared to control subjects. The elevated serum bile acids may be the result of hepatic peroxisomal dysfunction. Circulating hydrophobic bile acids are able to disrupt the blood-brain barrier and promote the formation of amyloid-β plaques through enhancing the oxidation of docosahexaenoic acid. Hydrophobic bile acid may find their ways into the neurons via the apical sodium-dependent bile acid transporter. It has been shown that hydrophobic bile acids impose their pathological effects by activating farnesoid X receptor and suppressing bile acid synthesis in the brain, blocking NMDA receptors, lowering brain oxysterol levels, and interfering with 17β-estradiol actions such as LCA by binding to E2 receptors (molecular modelling data exclusive to this paper). Hydrophobic bile acids may interfere with the sonic hedgehog signaling through alteration of cell membrane rafts and reducing brain 24(S)-hydroxycholesterol. This article will 1) analyze the pathological roles of circulating hydrophobic bile acids in the brain, 2) propose therapeutic approaches, and 3) conclude that consideration be given to reducing/monitoring toxic bile acid levels in patients with AD or aMCI, prior/in combination with other treatments.
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Affiliation(s)
- Touraj Ehtezazi
- School of Pharmacy and Biomolecular Sciences, Liverpool John Moores University, Liverpool, UK
| | - Khalid Rahman
- School of Pharmacy and Biomolecular Sciences, Liverpool John Moores University, Liverpool, UK
| | - Rhys Davies
- The Walton Centre, NHS Foundation Trust, Liverpool, UK
| | - Andrew G Leach
- School of Pharmacy, University of Manchester, Manchester, UK
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36
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Cellular Pathogenesis of Hepatic Encephalopathy: An Update. Biomolecules 2023; 13:biom13020396. [PMID: 36830765 PMCID: PMC9953810 DOI: 10.3390/biom13020396] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/01/2022] [Revised: 01/01/2023] [Accepted: 02/17/2023] [Indexed: 02/22/2023] Open
Abstract
Hepatic encephalopathy (HE) is a neuropsychiatric syndrome derived from metabolic disorders due to various liver failures. Clinically, HE is characterized by hyperammonemia, EEG abnormalities, and different degrees of disturbance in sensory, motor, and cognitive functions. The molecular mechanism of HE has not been fully elucidated, although it is generally accepted that HE occurs under the influence of miscellaneous factors, especially the synergistic effect of toxin accumulation and severe metabolism disturbance. This review summarizes the recently discovered cellular mechanisms involved in the pathogenesis of HE. Among the existing hypotheses, ammonia poisoning and the subsequent oxidative/nitrosative stress remain the mainstream theories, and reducing blood ammonia is thus the main strategy for the treatment of HE. Other pathological mechanisms mainly include manganese toxicity, autophagy inhibition, mitochondrial damage, inflammation, and senescence, proposing new avenues for future therapeutic interventions.
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37
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Yeo XY, Tan LY, Chae WR, Lee DY, Lee YA, Wuestefeld T, Jung S. Liver's influence on the brain through the action of bile acids. Front Neurosci 2023; 17:1123967. [PMID: 36816113 PMCID: PMC9932919 DOI: 10.3389/fnins.2023.1123967] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/14/2022] [Accepted: 01/18/2023] [Indexed: 02/05/2023] Open
Abstract
The liver partakes as a sensor and effector of peripheral metabolic changes and a regulator of systemic blood and nutrient circulation. As such, abnormalities arising from liver dysfunction can influence the brain in multiple ways, owing to direct and indirect bilateral communication between the liver and the brain. Interestingly, altered bile acid composition resulting from perturbed liver cholesterol metabolism influences systemic inflammatory responses, blood-brain barrier permeability, and neuron synaptic functions. Furthermore, bile acids produced by specific bacterial species may provide a causal link between dysregulated gut flora and neurodegenerative disease pathology through the gut-brain axis. This review will cover the role of bile acids-an often-overlooked category of active metabolites-in the development of neurological disorders associated with neurodegeneration. Further studies into bile acid signaling in the brain may provide insights into novel treatments against neurological disorders.
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Affiliation(s)
- Xin Yi Yeo
- Institute of Molecular and Cell Biology (IMCB), Agency for Science, Technology and Research (A*STAR), Singapore, Singapore,Department of Psychological Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
| | - Li Yang Tan
- Institute of Molecular and Cell Biology (IMCB), Agency for Science, Technology and Research (A*STAR), Singapore, Singapore,Department of Psychological Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
| | - Woo Ri Chae
- Institute of Molecular and Cell Biology (IMCB), Agency for Science, Technology and Research (A*STAR), Singapore, Singapore,Department of BioNano Technology, Gachon University, Seongnam, South Korea
| | - Dong-Yup Lee
- School of Chemical Engineering, Sungkyunkwan University, Suwon, South Korea
| | - Yong-An Lee
- Genome Institute of Singapore (GIS), Agency for Science, Technology and Research (A*STAR), Singapore, Singapore,*Correspondence: Yong-An Lee,
| | - Torsten Wuestefeld
- Genome Institute of Singapore (GIS), Agency for Science, Technology and Research (A*STAR), Singapore, Singapore,School of Biological Sciences, Nanyang Technological University, Singapore, Siingapore,National Cancer Centre Singapore, Singapore, Singapore,Torsten Wuestefeld,
| | - Sangyong Jung
- Institute of Molecular and Cell Biology (IMCB), Agency for Science, Technology and Research (A*STAR), Singapore, Singapore,Department of Physiology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore,Sangyong Jung,
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38
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Smaling A, Romero-Ramírez L, Mey J. Is TGR5 a therapeutic target for the treatment of spinal cord injury? J Neurochem 2023; 164:454-467. [PMID: 36409000 DOI: 10.1111/jnc.15727] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2022] [Revised: 11/03/2022] [Accepted: 11/17/2022] [Indexed: 11/23/2022]
Abstract
Bile acids, which are synthesized in liver and colon, facilitate the digestion of dietary lipids. In addition to this metabolic function, they also act as molecular signals with activities in the nervous system. These are mediated primarily by a G-protein-coupled bile acid receptor (known as TGR5). Preceded by a long tradition in Chinese medicine, bile acids are now being investigated as therapeutic options in several neuropathologies. Specifically, one bile acid, tauroursodeoxycholic acid (TUDCA), which passes the blood-brain barrier and shows anti-inflammatory and anti-apoptotic effects, has been tested in animal models of spinal cord injury (SCI). In this review, we discuss the evidence for a therapeutic benefit in these preclinical experiments. At the time of writing, 12 studies with TGR5 agonists have been published that report functional outcomes with rodent models of SCI. Most investigations found cytoprotective effects and benefits regarding the recovery of sensorimotor function in the subacute phase. When TUDCA was applied in a hydrogel into the lesion site, a significant improvement was obtained at 2 weeks after SCI. However, no lasting improvements with TUDCA treatment were found, when animals were assessed in later, chronic stages. A combination of TUDCA with stem cell injection failed to improve the effect of the cellular treatment. We conclude that the evidence does not support the use of TUDCA as a treatment of SCI. Nevertheless, cytoprotective effects suggest that different modes of application or combinatorial therapies might still be explored.
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Affiliation(s)
- Anna Smaling
- School of Mental Health and Neuroscience and EURON Graduate School of Neuroscience, Maastricht University, Maastricht, The Netherlands
| | | | - Jörg Mey
- School of Mental Health and Neuroscience and EURON Graduate School of Neuroscience, Maastricht University, Maastricht, The Netherlands.,Hospital Nacional de Parapléjicos, SESCAM, Toledo, Spain
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39
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Ackerman HD, Gerhard GS. Bile Acids Induce Neurite Outgrowth in Nsc-34 Cells via TGR5 and a Distinct Transcriptional Profile. Pharmaceuticals (Basel) 2023; 16:174. [PMID: 37259326 PMCID: PMC9963315 DOI: 10.3390/ph16020174] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/09/2022] [Revised: 01/16/2023] [Accepted: 01/19/2023] [Indexed: 09/24/2024] Open
Abstract
Increasing evidence supports a neuroprotective role for bile acids in major neurodegenerative disorders. We studied major human bile acids as signaling molecules for their two cellular receptors, farnesoid X receptor (FXR or NR1H4) and G protein-coupled bile acid receptor 1 (GPBAR1 or TGR5), as potential neurotrophic agents. Using quantitative image analysis, we found that 20 μM deoxycholic acid (DCA) could induce neurite outgrowth in NSC-34 cells that was comparable to the neurotrophic effects of the culture control 1 μM retinoic acid (RA), with lesser effects observed for chenodexoycholic acid (CDCA) at 20 μM, and similar though less robust neurite outgrowth in SH-SY5Y cells. Using chemical agonists and antagonists of FXR, LXR, and TGR5, we found that TGR5 agonism was comparable to DCA stimulation and stronger than RA, and that neither FXR nor liver X receptor (LXR) inhibition could block bile acid-induced neurite growth. RNA sequencing identified a core set of genes whose expression was regulated by DCA, CDCA, and RA. Our data suggest that bile acid signaling through TGR5 may be a targetable pathway to stimulate neurite outgrowth.
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Affiliation(s)
- Hayley D Ackerman
- Lewis Katz School of Medicine, Temple University, Philadelphia, PA 19140, USA
- Department of Molecular Oncology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL 33612, USA
| | - Glenn S Gerhard
- Lewis Katz School of Medicine, Temple University, Philadelphia, PA 19140, USA
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40
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Bile acids and their receptors in regulation of gut health and diseases. Prog Lipid Res 2023; 89:101210. [PMID: 36577494 DOI: 10.1016/j.plipres.2022.101210] [Citation(s) in RCA: 41] [Impact Index Per Article: 20.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/13/2022] [Revised: 12/21/2022] [Accepted: 12/22/2022] [Indexed: 12/26/2022]
Abstract
It is well established that bile acids play important roles in lipid metabolism. In recent decades, bile acids have also been shown to function as signaling molecules via interacting with various receptors. Bile acids circulate continuously through the enterohepatic circulation and go through microbial transformation by gut microbes, and thus bile acids metabolism has profound effects on the liver and intestinal tissues as well as the gut microbiota. Farnesoid X receptor and G protein-coupled bile acid receptor 1 are two pivotal bile acid receptors that highly expressed in the intestinal tissues, and they have emerged as pivotal regulators in bile acids metabolism, innate immunity and inflammatory responses. There is considerable interest in manipulating the metabolism of bile acids and the expression of bile acid receptors as this may be a promising strategy to regulate intestinal health and disease. This review aims to summarize the roles of bile acids and their receptors in regulation of gut health and diseases.
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41
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Feris F, McRae A, Kellogg TA, McKenzie T, Ghanem O, Acosta A. Mucosal and hormonal adaptations after Roux-en-Y gastric bypass. Surg Obes Relat Dis 2023; 19:37-49. [PMID: 36243547 PMCID: PMC9797451 DOI: 10.1016/j.soard.2022.08.020] [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: 04/18/2022] [Revised: 08/26/2022] [Accepted: 08/30/2022] [Indexed: 01/12/2023]
Abstract
The aim of this study was to perform a comprehensive literature review regarding the relevant hormonal and histologic changes observed after Roux-en-Y gastric bypass (RYGB). We aimed to describe the relevant hormonal (glucagon-like peptides 1 and 2 [GLP-1 and GLP-2], peptide YY [PYY], oxyntomodulin [OXM], bile acids [BA], cholecystokinin [CCK], ghrelin, glucagon, gastric inhibitory polypeptide [GIP], and amylin) profiles, as well as the histologic (mucosal cellular) adaptations happening after patients undergo RYGB. Our review compiles the current evidence and furthers the understanding of the rationale behind the food intake regulatory adaptations occurring after RYGB surgery. We identify gaps in the literature where the potential for future investigations and therapeutics may lie. We performed a comprehensive database search without language restrictions looking for RYGB bariatric surgery outcomes in patients with pre- and postoperative blood work hormonal profiling and/or gut mucosal biopsies. We gathered the relevant study results and describe them in this review. Where human findings were lacking, we included animal model studies. The amalgamation of physiologic, metabolic, and cellular adaptations following RYGB is yet to be fully characterized. This constitutes a fundamental aspiration for enhancing and individualizing obesity therapy.
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Affiliation(s)
- Fauzi Feris
- Precision Medicine for Obesity Program, Division of Gastroenterology and Hepatology, Department of Medicine, Mayo Clinic, Rochester, Minnesota
| | - Alison McRae
- Precision Medicine for Obesity Program, Division of Gastroenterology and Hepatology, Department of Medicine, Mayo Clinic, Rochester, Minnesota
| | - Todd A Kellogg
- Division of Endocrine and Metabolic Surgery, Department of Surgery, Mayo Clinic, Rochester, Minnesota
| | - Travis McKenzie
- Division of Endocrine and Metabolic Surgery, Department of Surgery, Mayo Clinic, Rochester, Minnesota
| | - Omar Ghanem
- Division of Endocrine and Metabolic Surgery, Department of Surgery, Mayo Clinic, Rochester, Minnesota
| | - Andres Acosta
- Precision Medicine for Obesity Program, Division of Gastroenterology and Hepatology, Department of Medicine, Mayo Clinic, Rochester, Minnesota.
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42
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Bile acids and neurological disease. Pharmacol Ther 2022; 240:108311. [PMID: 36400238 DOI: 10.1016/j.pharmthera.2022.108311] [Citation(s) in RCA: 32] [Impact Index Per Article: 10.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/12/2022] [Revised: 10/29/2022] [Accepted: 11/14/2022] [Indexed: 11/17/2022]
Abstract
This review will focus on how bile acids are being used in clinical trials to treat neurological diseases due to their central involvement with the gut-liver-brain axis and their physiological and pathophysiological roles in both normal brain function and multiple neurological diseases. The synthesis of primary and secondary bile acids species and how the regulation of the bile acid pool may differ between the gut and brain is discussed. The expression of several bile acid receptors in brain and their currently known functions along with the tools available to manipulate them pharmacologically are examined, together with discussion of the interaction of bile acids with the gut microbiome and their lesser-known effects upon brain glucose and lipid metabolism. How dysregulation of the gut microbiome, aging and sex differences may lead to disruption of bile acid signalling and possible causal roles in a number of neurological disorders are also considered. Finally, we discuss how pharmacological treatments targeting bile acid receptors are currently being tested in an array of clinical trials for several different neurodegenerative diseases.
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Fiaschini N, Mancuso M, Tanori M, Colantoni E, Vitali R, Diretto G, Lorenzo Rebenaque L, Stronati L, Negroni A. Liver Steatosis and Steatohepatitis Alter Bile Acid Receptors in Brain and Induce Neuroinflammation: A Contribution of Circulating Bile Acids and Blood-Brain Barrier. Int J Mol Sci 2022; 23:ijms232214254. [PMID: 36430732 PMCID: PMC9697805 DOI: 10.3390/ijms232214254] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/20/2022] [Revised: 11/14/2022] [Accepted: 11/15/2022] [Indexed: 11/21/2022] Open
Abstract
A tight relationship between gut-liver diseases and brain functions has recently emerged. Bile acid (BA) receptors, bacterial-derived molecules and the blood-brain barrier (BBB) play key roles in this association. This study was aimed to evaluate how non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH) impact the BA receptors Farnesoid X receptor (FXR) and Takeda G-protein coupled receptor 5 (TGR5) expression in the brain and to correlate these effects with circulating BAs composition, BBB integrity and neuroinflammation. A mouse model of NAFLD was set up by a high-fat and sugar diet, and NASH was induced with the supplementation of dextran-sulfate-sodium (DSS) in drinking water. FXR, TGR5 and ionized calcium-binding adaptor molecule 1 (Iba-1) expression in the brain was detected by immunohistochemistry, while Zonula occludens (ZO)-1, Occludin and Plasmalemmal Vesicle Associated Protein-1 (PV-1) were analyzed by immunofluorescence. Biochemical analyses investigated serum BA composition, lipopolysaccharide-binding protein (LBP) and S100β protein (S100β) levels. Results showed a down-regulation of FXR in NASH and an up-regulation of TGR5 and Iba-1 in the cortex and hippocampus in both treated groups as compared to the control group. The BA composition was altered in the serum of both treated groups, and LBP and S100β were significantly augmented in NASH. ZO-1 and Occludin were attenuated in the brain capillary endothelial cells of both treated groups versus the control group. We demonstrated that NAFLD and NASH provoke different grades of brain dysfunction, which are characterized by the altered expression of BA receptors, FXR and TGR5, and activation of microglia. These effects are somewhat promoted by a modification of circulating BAs composition and by an increase in LBP that concur to damage BBB, thus favoring neuroinflammation.
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Affiliation(s)
- Noemi Fiaschini
- Biomedical Technologies Laboratory, Division of Health Protection Technologies, Agenzia Nazionale per le Nuove Tecnologie, l’Energia e lo Sviluppo Economico Sostenibile (ENEA), 00123 Rome, Italy
| | - Mariateresa Mancuso
- Biomedical Technologies Laboratory, Division of Health Protection Technologies, Agenzia Nazionale per le Nuove Tecnologie, l’Energia e lo Sviluppo Economico Sostenibile (ENEA), 00123 Rome, Italy
| | - Mirella Tanori
- Biomedical Technologies Laboratory, Division of Health Protection Technologies, Agenzia Nazionale per le Nuove Tecnologie, l’Energia e lo Sviluppo Economico Sostenibile (ENEA), 00123 Rome, Italy
| | - Eleonora Colantoni
- Biomedical Technologies Laboratory, Division of Health Protection Technologies, Agenzia Nazionale per le Nuove Tecnologie, l’Energia e lo Sviluppo Economico Sostenibile (ENEA), 00123 Rome, Italy
| | - Roberta Vitali
- Biomedical Technologies Laboratory, Division of Health Protection Technologies, Agenzia Nazionale per le Nuove Tecnologie, l’Energia e lo Sviluppo Economico Sostenibile (ENEA), 00123 Rome, Italy
| | - Gianfranco Diretto
- Biotechnology Laboratory, Division of Biotechnologies and Agroindustry, Agenzia Nazionale per le Nuove Tecnologie, l’Energia e lo Sviluppo Economico Sostenibile (ENEA), 00123 Rome, Italy
| | - Laura Lorenzo Rebenaque
- Departamento Producción y Sanidad Animal, Salud Pública Veterinaria y Ciencia y Tecnología de los Alimentos, Universidad CEU-Cardenal Herrera, CEU Universities, Alfara del Patriarca, 46115 Valencia, Spain
| | - Laura Stronati
- Department of Molecular Medicine, Sapienza University, 00161 Rome, Italy
| | - Anna Negroni
- Biomedical Technologies Laboratory, Division of Health Protection Technologies, Agenzia Nazionale per le Nuove Tecnologie, l’Energia e lo Sviluppo Economico Sostenibile (ENEA), 00123 Rome, Italy
- Correspondence:
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44
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Liao XX, Wu XY, Zhou YL, Li JJ, Wen YL, Zhou JJ. Gut microbiome metabolites as key actors in atherosclerosis co-depression disease. Front Microbiol 2022; 13:988643. [PMID: 36439791 PMCID: PMC9686300 DOI: 10.3389/fmicb.2022.988643] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/07/2022] [Accepted: 10/24/2022] [Indexed: 02/26/2024] Open
Abstract
Cardiovascular diseases, mainly characterized by atherosclerosis (AS), and depression have a high comorbidity rate. However, previous studies have been conducted under a single disease, and there is a lack of studies in comorbid states to explore the commonalities in the pathogenesis of both diseases. Modern high-throughput technologies have made it clear that the gut microbiome can affect the development of the host's own disorders and have shown that their metabolites are crucial to the pathophysiology of AS and depression. The aim of this review is to summarize the current important findings on the role of gut microbiome metabolites such as pathogen-associated molecular patterns, bile acids, tryptophan metabolites, short-chain fatty acids, and trimethylamine N -oxide in depression and AS disease, with the aim of identifying potential biological targets for the early diagnosis and treatment of AS co-depression disorders.
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Affiliation(s)
- Xing-Xing Liao
- School of Rehabilitation Medicine, Gannan Medical University, Ganzhou, China
| | - Xiao-Yun Wu
- School of Basic Medicine, Gannan Medical University, Ganzhou, China
| | - Yu-Long Zhou
- School of Rehabilitation Medicine, Gannan Medical University, Ganzhou, China
| | - Jia-Jun Li
- School of Rehabilitation Medicine, Gannan Medical University, Ganzhou, China
| | - You-Liang Wen
- School of Rehabilitation Medicine, Gannan Medical University, Ganzhou, China
| | - Jun-Jie Zhou
- School of Rehabilitation Medicine, Gannan Medical University, Ganzhou, China
- Key Laboratory of Prevention and Treatment of Cardiovascular and Cerebrovascular Diseases of Ministry of Education, Gannan Medical University, Ganzhou, China
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45
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Ren ZL, Li CX, Ma CY, Chen D, Chen JH, Xu WX, Chen CA, Cheng FF, Wang XQ. Linking Nonalcoholic Fatty Liver Disease and Brain Disease: Focusing on Bile Acid Signaling. Int J Mol Sci 2022; 23:13045. [PMID: 36361829 PMCID: PMC9654021 DOI: 10.3390/ijms232113045] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/14/2022] [Revised: 10/21/2022] [Accepted: 10/25/2022] [Indexed: 11/01/2023] Open
Abstract
A metabolic illness known as non-alcoholic fatty liver disease (NAFLD), affects more than one-quarter of the world's population. Bile acids (BAs), as detergents involved in lipid digestion, show an abnormal metabolism in patients with NAFLD. However, BAs can affect other organs as well, such as the brain, where it has a neuroprotective effect. According to a series of studies, brain disorders may be extrahepatic manifestations of NAFLD, such as depression, changes to the cerebrovascular system, and worsening cognitive ability. Consequently, we propose that NAFLD affects the development of brain disease, through the bile acid signaling pathway. Through direct or indirect channels, BAs can send messages to the brain. Some BAs may operate directly on the central Farnesoid X receptor (FXR) and the G protein bile acid-activated receptor 1 (GPBAR1) by overcoming the blood-brain barrier (BBB). Furthermore, glucagon-like peptide-1 (GLP-1) and the fibroblast growth factor (FGF) 19 are released from the intestine FXR and GPBAR1 receptors, upon activation, both of which send signals to the brain. Inflammatory, systemic metabolic disorders in the liver and brain are regulated by the bile acid-activated receptors FXR and GPBAR1, which are potential therapeutic targets. From a bile acid viewpoint, we examine the bile acid signaling changes in NAFLD and brain disease. We also recommend the development of dual GPBAR1/FXR ligands to reduce side effects and manage NAFLD and brain disease efficiently.
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Affiliation(s)
- Zi-Lin Ren
- School of Traditional Chinese Medicine, Beijing University of Chinese Medicine, Beijing 100029, China
| | - Chang-Xiang Li
- School of Traditional Chinese Medicine, Beijing University of Chinese Medicine, Beijing 100029, China
| | - Chong-Yang Ma
- School of Traditional Chinese Medicine, Capital Medical University, Beijing 100069, China
| | - Dan Chen
- School of Traditional Chinese Medicine, Beijing University of Chinese Medicine, Beijing 100029, China
| | - Jia-Hui Chen
- Dongzhimen Hospital, Beijing University of Traditional Chinese Medicine, Beijing 100700, China
| | - Wen-Xiu Xu
- School of Traditional Chinese Medicine, Beijing University of Chinese Medicine, Beijing 100029, China
| | - Cong-Ai Chen
- Dongzhimen Hospital, Beijing University of Traditional Chinese Medicine, Beijing 100700, China
| | - Fa-Feng Cheng
- School of Traditional Chinese Medicine, Beijing University of Chinese Medicine, Beijing 100029, China
| | - Xue-Qian Wang
- School of Traditional Chinese Medicine, Beijing University of Chinese Medicine, Beijing 100029, China
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46
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Abstract
Bile acids wear many hats, including those of an emulsifier to facilitate nutrient absorption, a cholesterol metabolite, and a signaling molecule in various tissues modulating itching to metabolism and cellular functions. Bile acids are synthesized in the liver but exhibit wide-ranging effects indicating their ability to mediate organ-organ crosstalk. So, how does a steroid metabolite orchestrate such diverse functions? Despite the inherent chemical similarity, the side chain decorations alter the chemistry and biology of the different bile acid species and their preferences to bind downstream receptors distinctly. Identification of new modifications in bile acids is burgeoning, and some of it is associated with the microbiota within the intestine. Here, we provide a brief overview of the history and the various receptors that mediate bile acid signaling in addition to its crosstalk with the gut microbiota.
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Affiliation(s)
| | | | - Sayeepriyadarshini Anakk
- Correspondence: Sayeepriyadarshini Anakk, PhD, Department of Molecular & Integrative Physiology, University of Illinois at Urbana-Champaign, 506 S Mathews Ave, 453 Medical Sciences Bldg, Urbana, IL 61801, USA.
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47
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GPBAR1 preserves neurite and synapse of dopaminergic neurons via RAD21-OPCML signaling: Role in preventing Parkinson's disease in mouse model and human patients. Pharmacol Res 2022; 184:106459. [PMID: 36152741 DOI: 10.1016/j.phrs.2022.106459] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/22/2022] [Revised: 09/17/2022] [Accepted: 09/19/2022] [Indexed: 11/20/2022]
Abstract
Parkinson's disease (PD) exhibits systemic impacts on the metabolism, while metabolic alteration contributes to the risk and progression of PD. Bile acids (BA) metabolism disturbance has been linked to PD pathology. Membrane-bound G protein-coupled bile acid receptor 1 (GPBAR1) is expressed in the brain and thought to be neuroprotective; however, the role of GPBAR1 in PD remains unknown. The current study aimed to explore the effect of GPBAR1 in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced PD mice with dopaminergic (DA) neuron-specific Gpbar1 knockdown or central GPBAR1 activation. The underlying mechanisms were investigated using mesencephalic primary neurons analyzed. Our study found that GPBAR1 was reduced in the substantia nigra of PD patients and MPTP-PD mice, and its expression was negatively correlated with the severity of PD-related features. Genetic downregulation of Gpbar1 in mouse mesencephalic DA neurons exacerbated MPTP-induced neurobehavioral and neuropathological deficits, whereas activation of central GPBAR1 with INT-777 (INT) relieved it. Moreover, in vivo and in vitro experiments showed the neurite- and synapse-protective effects of GPBAR1 activation in PD model. Mechanistically, by promoting the nuclear localization of cohesin subunit RAD21, GPBAR1 activation increased opioid-binding cell adhesion molecule (Opcml) expression, thereby inhibiting neurite and synapse degeneration of DA neurons in PD model. Collectively, our findings demonstrate that GPBAR1 is implicated in PD pathogenesis and activation of central GPBAR1 with INT antagonizes neurodegenerative pathology in PD model. This neuroprotection, at least in part, is attributed to the RAD21-OPCML signaling in neurons. Hence, GPBAR1 may serve as a promising candidate target for PD treatment.
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48
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Fiorucci S, Zampella A, Ricci P, Distrutti E, Biagioli M. Immunomodulatory functions of FXR. Mol Cell Endocrinol 2022; 551:111650. [PMID: 35472625 DOI: 10.1016/j.mce.2022.111650] [Citation(s) in RCA: 26] [Impact Index Per Article: 8.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/19/2022] [Revised: 03/31/2022] [Accepted: 04/04/2022] [Indexed: 02/08/2023]
Abstract
The Farnesoid-x-receptor (FXR) is a bile acids sensor activated in humans by primary bile acids. FXR is mostly expressed in liver, intestine and adrenal glands but also by cells of innate immunity, including macrophages, liver resident macrophages, the Kupffer cells, natural killer cells and dendritic cells. In normal physiology and clinical disorders, cells of innate immunity mediate communications between liver, intestine and adipose tissues. In addition to FXR, the G protein coupled receptor (GPBAR1), that is mainly activated by secondary bile acids, whose expression largely overlaps FXR, modulates chemical communications from the intestinal microbiota and the host's immune system, integrating epithelial cells and immune cells in the entero-hepatic system, providing a mechanism for development of a tolerogenic state toward the intestinal microbiota. Disruption of FXR results in generalized inflammation and disrupted bile acids metabolism. While FXR agonism in preclinical models provides counter-regulatory signals that attenuate inflammation-driven immune dysfunction in a variety of liver and intestinal disease models, the clinical relevance of these mechanisms in the setting of FXR-related disorders remain poorly defined.
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Affiliation(s)
- Stefano Fiorucci
- Dipartimento di Medicina e Chirurgia, Università di Perugia, Perugia, Italy. http://www.gastroenterologia.unipg.it
| | - Angela Zampella
- University of Naples Federico II, Department of Pharmacy, Naples, Italy
| | - Patrizia Ricci
- Dipartimento di Medicina e Chirurgia, Università di Perugia, Perugia, Italy
| | - Eleonora Distrutti
- SC di Gastroenterologia ed Epatologia, Azienda Ospedaliera di Perugia, Perugia, Italy
| | - Michele Biagioli
- Dipartimento di Medicina e Chirurgia, Università di Perugia, Perugia, Italy
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49
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Tauroursodeoxycholic Acid Reduces Neuroinflammation but Does Not Support Long Term Functional Recovery of Rats with Spinal Cord Injury. Biomedicines 2022; 10:biomedicines10071501. [PMID: 35884805 PMCID: PMC9313003 DOI: 10.3390/biomedicines10071501] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/04/2022] [Revised: 06/18/2022] [Accepted: 06/23/2022] [Indexed: 11/17/2022] Open
Abstract
The bile acid tauroursodeoxycholic acid (TUDCA) reduces cell death under oxidative stress and inflammation. Implants of bone marrow-derived stromal cells (bmSC) are currently under investigation in clinical trials of spinal cord injury (SCI). Since cell death of injected bmSC limits the efficacy of this treatment, the cytoprotective effect of TUDCA may enhance its benefit. We therefore studied the therapeutic effect of TUDCA and its use as a combinatorial treatment with human bmSC in a rat model of SCI. A spinal cord contusion injury was induced at thoracic level T9. Treatment consisted of i.p. injections of TUDCA alone or in combination with one injection of human bmSC into the cisterna magna. The recovery of motor functions was assessed during a surveillance period of six weeks. Biochemical and histological analysis of spinal cord tissue confirmed the anti-inflammatory activity of TUDCA. Treatment improved the recovery of autonomic bladder control and had a positive effect on motor functions in the subacute phase, however, benefits were only transient, such that no significant differences between vehicle and TUDCA-treated animals were observed 1–6 weeks after the lesion. Combinatorial treatment with TUDCA and bmSC failed to have an additional effect compared to treatment with bmSC only. Our data do not support the use of TUDCA as a treatment of SCI.
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50
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Häussinger D, Dhiman RK, Felipo V, Görg B, Jalan R, Kircheis G, Merli M, Montagnese S, Romero-Gomez M, Schnitzler A, Taylor-Robinson SD, Vilstrup H. Hepatic encephalopathy. Nat Rev Dis Primers 2022; 8:43. [PMID: 35739133 DOI: 10.1038/s41572-022-00366-6] [Citation(s) in RCA: 98] [Impact Index Per Article: 32.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 05/12/2022] [Indexed: 01/18/2023]
Abstract
Hepatic encephalopathy (HE) is a prognostically relevant neuropsychiatric syndrome that occurs in the course of acute or chronic liver disease. Besides ascites and variceal bleeding, it is the most serious complication of decompensated liver cirrhosis. Ammonia and inflammation are major triggers for the appearance of HE, which in patients with liver cirrhosis involves pathophysiologically low-grade cerebral oedema with oxidative/nitrosative stress, inflammation and disturbances of oscillatory networks in the brain. Severity classification and diagnostic approaches regarding mild forms of HE are still a matter of debate. Current medical treatment predominantly involves lactulose and rifaximin following rigorous treatment of so-called known HE precipitating factors. New treatments based on an improved pathophysiological understanding are emerging.
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Affiliation(s)
- Dieter Häussinger
- Department of Gastroenterology, Hepatology and Infectious Diseases, Medical Faculty and University Hospital Düsseldorf, Heinrich Heine University Düsseldorf, Düsseldorf, Germany.
| | - Radha K Dhiman
- Department of Hepatology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, (Uttar Pradesh), India
| | - Vicente Felipo
- Laboratory of Neurobiology, Centro de Investigación Principe Felipe, Valencia, Spain
| | - Boris Görg
- Department of Gastroenterology, Hepatology and Infectious Diseases, Medical Faculty and University Hospital Düsseldorf, Heinrich Heine University Düsseldorf, Düsseldorf, Germany
| | - Rajiv Jalan
- Liver Failure Group ILDH, Division of Medicine, UCL Medical School, Royal Free Campus, London, UK.,European Foundation for the Study of Chronic Liver Failure, Barcelona, Spain
| | - Gerald Kircheis
- Department of Gastroenterology, Diabetology and Hepatology, University Hospital Brandenburg an der Havel, Brandenburg Medical School, Brandenburg an der Havel, Germany
| | - Manuela Merli
- Department of Translational and Precision Medicine, Universita' degli Studi di Roma - Sapienza, Roma, Italy
| | | | - Manuel Romero-Gomez
- UCM Digestive Diseases, Virgen del Rocío University Hospital, Institute of Biomedicine of Seville (HUVR/CSIC/US), University of Seville, Seville, Spain
| | - Alfons Schnitzler
- Institute of Clinical Neuroscience and Medical Psychology, Heinrich Heine University Düsseldorf, Düsseldorf, Germany
| | - Simon D Taylor-Robinson
- Department of Surgery and Cancer, St. Mary's Hospital Campus, Imperial College London, London, UK
| | - Hendrik Vilstrup
- Department of Hepatology and Gastroenterology, Aarhus University Hospital, Aarhus, Denmark
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