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Lee SH, Han C, Shin C. IUPHAR Review: Microbiota-Gut-Brain Axis and its role in Neuropsychiatric Disorders. Pharmacol Res 2025; 216:107749. [PMID: 40306604 DOI: 10.1016/j.phrs.2025.107749] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/23/2025] [Revised: 04/20/2025] [Accepted: 04/25/2025] [Indexed: 05/02/2025]
Abstract
The human gut microbiome, composed of a vast array of microorganisms that have co-evolved with humans, is crucial for the development and function of brain systems. Research has consistently shown bidirectional communication between the gut and the brain through neuronal, endocrine, and immunological, and chemical pathways. Recent neuroscience studies have linked changes in the microbiome and microbial metabolites to various neuropsychiatric disorders such as autism, depression, anxiety, schizophrenia, eating disorders, and neurocognitive disorders. Novel metagenome-wide association studies have confirmed these microbiome variations in large samples and expanded our understanding of the interactions between human genes and the gut microbiome. The causal relationship between gut microbiota and neuropsychiatric disorders is being elucidated through the establishment of large cohort studies incorporating microbiome data and advanced statistical techniques. Ongoing animal and human studies focused on the microbiota-gut-brain axis are promising for developing new prevention and treatment strategies for neuropsychiatric conditions. The scope of these studies has broadened from microbiome-modulating therapies including prebiotics, probiotics, synbiotics and postbiotics to more extensive approaches such as fecal microbiota transplantation. Recent systematic reviews and meta-analyses have strengthened the evidence base for these innovative treatments. Despite extensive research over the past decade, many intriguing aspects still need to be elucidated regarding the role and therapeutic interventions of the microbiota-gut-brain axis in neuropsychiatric disorders.
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Affiliation(s)
- Seung-Hoon Lee
- Department of Psychiatry, Korea University Guro Hospital, Korea University College of Medicine, Seoul, Republic of Korea
| | - Changsu Han
- Department of Psychiatry, Korea University Guro Hospital, Korea University College of Medicine, Seoul, Republic of Korea
| | - Cheolmin Shin
- Department of Psychiatry, Korea University Ansan Hospital, Korea University College of Medicine, Seoul, Republic of Korea.
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Akbari R, Salimi Y, Dehghani-Aarani F, Rezayat E. Attention in irritable bowel syndrome: A systematic review of affected domains and brain-gut axis interactions. J Psychosom Res 2025; 191:112067. [PMID: 40048890 DOI: 10.1016/j.jpsychores.2025.112067] [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: 01/05/2025] [Revised: 01/29/2025] [Accepted: 02/17/2025] [Indexed: 03/16/2025]
Abstract
BACKGROUND Irritable bowel syndrome (IBS) is a disorder characterized by gut-brain interactions, leading to abdominal pain and altered stool patterns, which significantly affect patients' quality of life. Recent research suggests that attention may be impaired in individuals with IBS, potentially influencing symptom perception and emotional distress. OBJECTIVE This systematic review aims to examine the relationship between attention and IBS, focusing on the affected domains of attention and the interactions within the brain-gut axis. METHODS A comprehensive search was conducted across MEDLINE/PubMed, PsychINFO, and Scopus from January 1990 to December 2024. Studies included were those that assessed attention in adult IBS patients using valid measurement tools. A total of 24 studies were analyzed, incorporating neuroimaging and behavioral methods. RESULTS IBS individuals exhibit specific attentional impairments, including deficits in sustained attention, selective attentional biases toward gastrointestinal (GI)-related and symptom-specific stimuli, and heightened vigilance to threat and pain cues. Neurofunctional studies reveal altered brain activity in areas such as the insula, anterior cingulate cortex, and amygdala, indicating increased interoceptive awareness and cognitive load. Pre-attentive processing and sensory gating show exaggerated responses, while sustained attention and attentional control demand additional cognitive resources. These patterns reflect an interplay between heightened sensitivity to internal stimuli and cognitive processing challenges in IBS. CONCLUSION This review highlights specific attentional deficits and biases in IBS, suggesting they may contribute to symptom exacerbation and emotional distress. Further research is needed to explore the underlying mechanisms and potential therapeutic interventions.
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Affiliation(s)
- Reyhaneh Akbari
- Department of Psychology, Faculty of Psychology and Education, University of Tehran, Tehran, Iran
| | - Yeganeh Salimi
- Department of Cognitive Sciences, Faculty of Psychology and Education, University of Tehran, Tehran, Iran
| | - Fateme Dehghani-Aarani
- Department of Psychology, Faculty of Psychology and Education, University of Tehran, Tehran, Iran.
| | - Ehsan Rezayat
- Department of Cognitive Sciences, Faculty of Psychology and Education, University of Tehran, Tehran, Iran; School of Cognitive Sciences, Institute for Research in Fundamental Sciences (IPM), Niavaran, Tehran, Iran.
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Loupy KM, Dawud LM, Zambrano CA, Lee T, Heinze JD, Elsayed AI, Hassell JE, D'Angelo HM, Frank MG, Maier SF, Brenner LA, Lowry CA. Effects of Oral Administration of the Probiotic Lactobacillus rhamnosus GG on the Proteomic Profiles of Cerebrospinal Fluid and Immunoregulatory Signaling in the Hippocampus of Adult Male Rats. Neuroimmunomodulation 2025; 32:94-109. [PMID: 40031897 DOI: 10.1159/000544842] [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: 11/24/2024] [Accepted: 02/08/2025] [Indexed: 03/05/2025] Open
Abstract
INTRODUCTION The microbiome-gut-brain axis, by modulating bidirectional immune, metabolic, and neural signaling pathways in the host, has emerged as a target for the prevention and treatment of psychiatric and neurological disorders. Oral administration of the probiotic bacterium Lactobacillus rhamnosus GG (LGG; ATCC 53103) exhibits anti-inflammatory effects, although the precise mechanisms by which LGG benefits host physiology and behavior are not known. The goal of this study was to explore the general effects of LGG on the cerebrospinal fluid (CSF) proteome and a biological signature of anti-inflammatory signaling in the central nervous system (CNS) of undisturbed, adult male rats. METHODS Liquid chromatography-tandem mass spectrometry-based proteomics were conducted using CSF samples collected after 21 days of oral treatment with live LGG (3.34 × 107 colony-forming units (CFU)/mL in the drinking water (resulting in an estimated delivery of ∼1.17 × 109 CFU/day/rat) or water vehicle. Gene enrichment analysis (using DAVID, v. 6.8) and protein-protein interactions (using STRING, v. 11) were used to explore physiological network changes in CSF. Real-time reverse transcription polymerase chain reaction (real-time RT-PCR) was performed to assess gene expression changes of anti-inflammatory cytokines in the hippocampus. Genes associated with anti-inflammatory signaling that were analyzed included Il10, Tgfb1, Il4, and IL-4-responsive genes, Cd200, Cd200r1, and Mrc1 (Cd206). RESULTS Oral LGG administration altered the abundance of CSF proteins, increasing the abundance of five proteins (cochlin, NPTXR, reelin, Sez6l, and VPS13C) and decreasing the abundance of two proteins (CPQ, IGFBP-7) in the CSF. Simultaneously, LGG increased the expression of Il10 mRNA, encoding the anti-inflammatory cytokine interleukin 10, in the hippocampus. CONCLUSION Oral LGG altered the abundance of CSF proteins associated with extracellular scaffolding, synaptic plasticity, and glutamatergic signaling. These data are consistent with the hypothesis that oral administration of LGG improves memory and cognition, and promotes a physiological resilience to neurodegenerative disease, by increasing glutamatergic signaling and promoting an anti-inflammatory environment in the brain.
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Affiliation(s)
- Kelsey M Loupy
- Department of Integrative Physiology, University of Colorado Boulder, Boulder, Colorado, USA
| | - Lamya'a M Dawud
- Department of Integrative Physiology, University of Colorado Boulder, Boulder, Colorado, USA
| | - Cristian A Zambrano
- Department of Integrative Physiology, University of Colorado Boulder, Boulder, Colorado, USA
| | - Thomas Lee
- Central Analytical Laboratory and Mass Spectrometry Facility, Department of Biochemistry, University of Colorado Boulder, Boulder, Colorado, USA
| | - Jared D Heinze
- Department of Integrative Physiology, University of Colorado Boulder, Boulder, Colorado, USA
| | - Ahmed I Elsayed
- Department of Integrative Physiology, University of Colorado Boulder, Boulder, Colorado, USA
| | - James E Hassell
- Department of Integrative Physiology, University of Colorado Boulder, Boulder, Colorado, USA
| | - Heather M D'Angelo
- Department of Psychology and Neuroscience, University of Colorado Boulder, Boulder, Colorado, USA
| | - Matthew G Frank
- Department of Psychology and Neuroscience, University of Colorado Boulder, Boulder, Colorado, USA
- Center for Neuroscience, University of Colorado Boulder, Boulder, Colorado, USA
| | - Steven F Maier
- Department of Psychology and Neuroscience, University of Colorado Boulder, Boulder, Colorado, USA
- Center for Neuroscience, University of Colorado Boulder, Boulder, Colorado, USA
| | - Lisa A Brenner
- Rocky Mountain Regional VA Medical Center (RMRVAMC), Aurora, Colorado, USA
- Department of Physical Medicine and Rehabilitation, University of Colorado Anschutz Medical Campus, Aurora, Colorado, USA
- Department of Neurology, University of Colorado Anschutz Medical Campus, Aurora, Colorado, USA
- Department of Psychiatry, University of Colorado Anschutz Medical Campus, Aurora, Colorado, USA
- Military and Veteran Microbiome: Consortium for Research and Education (MVM-CoRE), Aurora, Colorado, USA
| | - Christopher A Lowry
- Department of Integrative Physiology, University of Colorado Boulder, Boulder, Colorado, USA
- Department of Psychology and Neuroscience, University of Colorado Boulder, Boulder, Colorado, USA
- Center for Neuroscience, University of Colorado Boulder, Boulder, Colorado, USA
- Rocky Mountain Regional VA Medical Center (RMRVAMC), Aurora, Colorado, USA
- Department of Physical Medicine and Rehabilitation, University of Colorado Anschutz Medical Campus, Aurora, Colorado, USA
- Military and Veteran Microbiome: Consortium for Research and Education (MVM-CoRE), Aurora, Colorado, USA
- Center for Microbial Exploration, University of Colorado Boulder, Boulder, Colorado, USA
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Junyi L, Yueyang W, Bin L, Xiaohong D, Wenhui C, Ning Z, Hong Z. Gut Microbiota Mediates Neuroinflammation in Alzheimer's Disease: Unraveling Key Factors and Mechanistic Insights. Mol Neurobiol 2025; 62:3746-3763. [PMID: 39317889 DOI: 10.1007/s12035-024-04513-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/24/2024] [Accepted: 09/18/2024] [Indexed: 09/26/2024]
Abstract
The gut microbiota, the complex community of microorganisms that inhabit the gastrointestinal tract, has emerged as a key player in the pathogenesis of neurodegenerative disorders, including Alzheimer's disease (AD). AD is characterized by progressive cognitive decline and neuronal loss, associated with the accumulation of amyloid-β plaques, neurofibrillary tangles, and neuroinflammation in the brain. Increasing evidence suggests that alterations in the composition and function of the gut microbiota, known as dysbiosis, may contribute to the development and progression of AD by modulating neuroinflammation, a chronic and maladaptive immune response in the central nervous system. This review aims to comprehensively analyze the current role of the gut microbiota in regulating neuroinflammation and glial cell function in AD. Its objective is to deepen our understanding of the pathogenesis of AD and to discuss the potential advantages and challenges of using gut microbiota modulation as a novel approach for the diagnosis, treatment, and prevention of AD.
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Affiliation(s)
- Liang Junyi
- Heilongjiang University of Traditional Chinese Medicine, Harbin, 150040, Heilongjiang Province, China
| | - Wang Yueyang
- Heilongjiang University of Traditional Chinese Medicine, Harbin, 150040, Heilongjiang Province, China
| | - Liu Bin
- Heilongjiang University of Traditional Chinese Medicine, Harbin, 150040, Heilongjiang Province, China.
| | - Dong Xiaohong
- Jiamusi College, Heilongjiang University of Traditional Chinese Medicine, Jiamusi, Heilongjiang Province, China
| | - Cai Wenhui
- Heilongjiang University of Traditional Chinese Medicine, Harbin, 150040, Heilongjiang Province, China
| | - Zhang Ning
- Heilongjiang University of Traditional Chinese Medicine, Harbin, 150040, Heilongjiang Province, China
| | - Zhang Hong
- Heilongjiang Jiamusi Central Hospital, Jiamusi, Heilongjiang Province, China
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Findeisen K, Guymer E, Littlejohn G. Neuroinflammatory and Immunological Aspects of Fibromyalgia. Brain Sci 2025; 15:206. [PMID: 40002538 PMCID: PMC11852494 DOI: 10.3390/brainsci15020206] [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: 01/21/2025] [Revised: 02/10/2025] [Accepted: 02/13/2025] [Indexed: 02/27/2025] Open
Abstract
Fibromyalgia is a common, high-impact condition of chronic widespread pain and sensory dysfunction associated with altered central and peripheral sensory processing. A growing body of evidence supports the role of neuroinflammation and immune changes in fibromyalgia, and a narrative review of this literature was undertaken. Published data suggest that the interactions between the neural pain networks and the immune system in fibromyalgia appear to be bidirectional and operate both centrally and peripherally. There is a growing focus on processes occurring in the dorsal root ganglia and the role of maladaptive microglial cell activation. Ongoing insight into neuroinflammatory mechanisms in fibromyalgia opens potential avenues for the development of mechanism-based therapies in what is, at present, a challenging-to-manage condition.
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Affiliation(s)
- Kate Findeisen
- Department of Rheumatology, Monash Health, Melbourne, VIC 3168, Australia; (K.F.); (G.L.)
| | - Emma Guymer
- Department of Rheumatology, Monash Health, Melbourne, VIC 3168, Australia; (K.F.); (G.L.)
- Department of Medicine, Monash University, Melbourne, VIC 3800, Australia
| | - Geoffrey Littlejohn
- Department of Rheumatology, Monash Health, Melbourne, VIC 3168, Australia; (K.F.); (G.L.)
- Department of Medicine, Monash University, Melbourne, VIC 3800, Australia
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Li Y, Zheng Y, Rong L, Zhou Y, Zhu Z, Xie Q, Liang Z, Zhao X. Altered Function and Structure of the Cerebellum Associated with Gut-Brain Regulation in Crohn's Disease: a Structural and Functional MRI Study. CEREBELLUM (LONDON, ENGLAND) 2024; 23:2285-2296. [PMID: 39096431 DOI: 10.1007/s12311-024-01715-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Accepted: 06/22/2024] [Indexed: 08/05/2024]
Abstract
This study employed structural and functional magnetic resonance imaging (MRI) to investigate changes in the function and structure of the cerebellum associated with gut-brain axis (GBA) regulation in patients diagnosed with Crohn's disease (CD). The study comprised 20 CD patients, including 12 with active disease (CD-A) and 8 in remission (CD-R), as well as 21 healthy controls. Voxel-based morphometry (VBM) was utilized for structural analysis of cerebellar gray matter volume, while independent component analysis (ICA) was applied for functional analysis of cerebellar functional connectivity (FC). The results showed significant GMV reduction in the left posterior cerebellar lobe across all CD patients compared to HCs, with more pronounced differences in the CD-A subgroup. Additionally, an increase in mean FC of the cerebellar network was observed in all CD patients, particularly in the CD-A subgroup, which demonstrated elevated FC in the vermis and bilateral posterior cerebellum. Correlation analysis revealed a positive relationship between cerebellar FC and the Crohn's Disease Activity Index (CDAI) and a trend toward a negative association with the reciprocal of the Self-rating Depression Scale (SDS) score in CD patients. The study's findings suggest that the cerebellum may play a role in the abnormal regulation of the GBA in CD patients, contributing to a better understanding of the neural mechanisms underlying CD and highlighting the cerebellum's potential role in modulating gut-brain interactions.
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Affiliation(s)
- Yunfei Li
- Department of Radiology, The Fifth People's Hospital of Shanghai Fudan University, Shanghai, China
| | - Yanling Zheng
- Department of Radiology, Jing'an District Centre Hospital of Shanghai, Fudan University, Shanghai, China
| | - Lan Rong
- Department of Gastroenterology, Huashan Hospital, Fudan University, Shanghai, China
| | - Yan Zhou
- Department of Radiology, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Zhen Zhu
- Department of Radiology, Putuo People's Hospital, Tongji University, Shanghai, China
| | - Qian Xie
- Department of Radiology, Jing'an District Centre Hospital of Shanghai, Fudan University, Shanghai, China
| | - Zonghui Liang
- Department of Radiology, Jing'an District Centre Hospital of Shanghai, Fudan University, Shanghai, China.
| | - Xiaohu Zhao
- Department of Radiology, The Fifth People's Hospital of Shanghai Fudan University, Shanghai, China.
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Azarfarin M, Moradikor N, Matin S, Dadkhah M. Association Between Stress, Neuroinflammation, and Irritable Bowel Syndrome: The Positive Effects of Probiotic Therapy. Cell Biochem Funct 2024; 42:e70009. [PMID: 39487668 DOI: 10.1002/cbf.70009] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/22/2024] [Revised: 09/23/2024] [Accepted: 10/14/2024] [Indexed: 11/04/2024]
Abstract
Stress refers to an organism's response to environmental threats in normal condition to maintain homeostasis in the body. In addition, strong inflammatory reactions induced by the hypothalamic-pituitary-adrenal (HPA) axis under stress condition during a long time. Reciprocally, chronic stress can induce the irritable bowel syndrome (IBS) which is a well-known gut disorder thereby play an important role in the promotion and pathophysiology of neuropsychiatric diseases. It has been demonstrated that leaky gut is a hallmark of IBS, leads to the entrance the microbiota into the bloodstream and consequent low-grade systemic inflammation. In the current review, we will discuss the mechanisms by which stress can influence the risk and severity of IBS and its relationship with neuroinflammation. Also, the role of probiotics in IBS co-existing with chronic stress conditions is highlighted.
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Affiliation(s)
- Maryam Azarfarin
- Department of Neuroscience, Faculty of Advanced Medical, Tabriz University of Medical Sciences, Tabriz, Iran
- Student Research Committee, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Nasrollah Moradikor
- International Center for Neuroscience Research, Institute for Intelligent Research, Tbilisi, Georgia
| | - Somaieh Matin
- Digestive Diseases Research Center, Ardabil University of Medical Sciences, Ardabil, Iran
| | - Masoomeh Dadkhah
- Lung Diseases Research Center, Ardabil University of Medical Sciences, Ardabil, Iran
- Pharmaceutical Sciences Research Center, Ardabil University of Medical Sciences, Ardabil, Iran
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Li C, Zhao X, Xu H, Liu X, He Y, Gu J. NMN Synbiotics: A Multifaceted Therapeutic Approach for Alzheimer's Disease. Neurochem Res 2024; 49:2888-2896. [PMID: 39037560 DOI: 10.1007/s11064-024-04210-z] [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: 05/27/2024] [Revised: 07/08/2024] [Accepted: 07/10/2024] [Indexed: 07/23/2024]
Abstract
With the aging global population, Alzheimer's disease (AD) has become a significant social and economic burden, necessitating the development of novel therapeutic strategies. This study investigates the therapeutic potential of nicotinamide mononucleotide (NMN) synbiotics, a combination of NMN, Lactiplantibacillus plantarum CGMCC 1.16089, and lactulose, in mitigating AD pathology. APP/PS1 mice were supplemented with NMN synbiotics and compared against control groups. The effects on amyloid-β (Aβ) deposition, intestinal histopathology, tight junction proteins, inflammatory cytokines, and reactive oxygen species (ROS) levels were assessed. NMN synbiotics intervention significantly reduced Aβ deposition in the cerebral cortex and hippocampus by 67% and 60%, respectively. It also ameliorated histopathological changes in the colon, reducing crypt depth and restoring goblet cell numbers. The expression of tight junction proteins Claudin-1 and ZO-1 was significantly upregulated, enhancing intestinal barrier integrity. Furthermore, NMN synbiotics decreased the expression of proinflammatory cytokines IL-1β, IL-6, and TNF-α, and reduced ROS levels, indicative of attenuated oxidative stress. The reduction in Aβ deposition, enhancement of intestinal barrier function, decrease in neuroinflammation, and alleviation of oxidative stress suggest that NMN synbiotics present a promising therapeutic intervention for AD by modulating multiple pathological pathways. Further research is required to elucidate the precise mechanisms, particularly the role of the NLRP3 inflammasome pathway, which may offer a novel target for AD treatment.
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Affiliation(s)
- Caifeng Li
- College of Biological Science and Technology, University of Jinan, Jinan, 250022, China
| | - Xiaodong Zhao
- College of Biological Science and Technology, University of Jinan, Jinan, 250022, China
| | - Huilian Xu
- College of Biological Science and Technology, University of Jinan, Jinan, 250022, China
| | - Xiaoyong Liu
- College of Biological Science and Technology, University of Jinan, Jinan, 250022, China
| | - Yan He
- Department of Neurology, The First Affiliated Hospital of Shandong First Medical University, Jinan, 250014, China
| | - Jinsong Gu
- College of Biological Science and Technology, University of Jinan, Jinan, 250022, China.
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Yang J, Liang J, Hu N, He N, Liu B, Liu G, Qin Y. The Gut Microbiota Modulates Neuroinflammation in Alzheimer's Disease: Elucidating Crucial Factors and Mechanistic Underpinnings. CNS Neurosci Ther 2024; 30:e70091. [PMID: 39460538 PMCID: PMC11512114 DOI: 10.1111/cns.70091] [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: 08/07/2024] [Revised: 09/18/2024] [Accepted: 10/08/2024] [Indexed: 10/28/2024] Open
Abstract
BACKGROUND AND PURPOSE Alzheimer's disease (AD) is characterized by progressive cognitive decline and neuronal loss, commonly linked to amyloid-β plaques, neurofibrillary tangles, and neuroinflammation. Recent research highlights the gut microbiota as a key player in modulating neuroinflammation, a critical pathological feature of AD. Understanding the role of the gut microbiota in this process is essential for uncovering new therapeutic avenues and gaining deeper insights into AD pathogenesis. METHODS This review provides a comprehensive analysis of how gut microbiota influences neuroinflammation and glial cell function in AD. A systematic literature search was conducted, covering studies from 2014 to 2024, including reviews, clinical trials, and animal studies. Keywords such as "gut microbiota," "Alzheimer's disease," "neuroinflammation," and "blood-brain barrier" were used. RESULTS Dysbiosis, or the imbalance in gut microbiota composition, has been implicated in the modulation of key AD-related mechanisms, including neuroinflammation, blood-brain barrier integrity, and neurotransmitter regulation. These disruptions may accelerate the onset and progression of AD. Additionally, therapeutic strategies targeting gut microbiota, such as probiotics, prebiotics, and fecal microbiota transplantation, show promise in modulating AD pathology. CONCLUSIONS The gut microbiota is a pivotal factor in AD pathogenesis, influencing neuroinflammation and disease progression. Understanding the role of gut microbiota in AD opens avenues for innovative diagnostic, preventive, and therapeutic strategies.
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Affiliation(s)
- Jianshe Yang
- Harbin Institute of Physical EducationHarbinHeilongjiang ProvinceChina
| | - Junyi Liang
- Heilongjiang University of Traditional Chinese MedicineHarbinHeilongjiang ProvinceChina
| | - Niyuan Hu
- Harbin Institute of Physical EducationHarbinHeilongjiang ProvinceChina
| | - Ningjuan He
- Harbin Institute of Physical EducationHarbinHeilongjiang ProvinceChina
| | - Bin Liu
- Heilongjiang University of Traditional Chinese MedicineHarbinHeilongjiang ProvinceChina
| | - Guoliang Liu
- Harbin Institute of Physical EducationHarbinHeilongjiang ProvinceChina
| | - Ying Qin
- Harbin Institute of Physical EducationHarbinHeilongjiang ProvinceChina
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Yang Y, Qiu L. Research Progress on the Pathogenesis, Diagnosis, and Drug Therapy of Alzheimer's Disease. Brain Sci 2024; 14:590. [PMID: 38928590 PMCID: PMC11201671 DOI: 10.3390/brainsci14060590] [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: 05/15/2024] [Revised: 06/03/2024] [Accepted: 06/06/2024] [Indexed: 06/28/2024] Open
Abstract
As the population ages worldwide, Alzheimer's disease (AD), the most prevalent kind of neurodegenerative disorder among older people, has become a significant factor affecting quality of life, public health, and economies. However, the exact pathogenesis of Alzheimer's remains elusive, and existing highly recognized pathogenesis includes the amyloid cascade hypothesis, Tau neurofibrillary tangles hypothesis, and neuroinflammation hypothesis. The major diagnoses of Alzheimer's disease include neuroimaging positron emission computed tomography, magnetic resonance imaging, and cerebrospinal fluid molecular diagnosis. The therapy of Alzheimer's disease primarily relies on drugs, and the approved drugs on the market include acetylcholinesterase drugs, glutamate receptor antagonists, and amyloid-β monoclonal antibodies. Still, the existing drugs can only alleviate the symptoms of the disease and cannot completely reverse it. This review aims to summarize existing research results on Alzheimer's disease pathogenesis, diagnosis, and drug therapy, with the objective of facilitating future research in this area.
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Affiliation(s)
- Yixuan Yang
- College of Chemistry and Biological Engineering, University of Science and Technology Beijing, Beijing 100083, China;
| | - Lina Qiu
- College of Chemistry and Biological Engineering, University of Science and Technology Beijing, Beijing 100083, China;
- Beijing Key Laboratory for Science and Application of Functional Molecular and Crystalline Materials, University of Science and Technology Beijing, Beijing 100083, China
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Nabizadeh F, Valizadeh P, Fallahi MS. Bile acid profile associated with CSF and PET biomarkers in Alzheimer's disease. Aging Clin Exp Res 2024; 36:62. [PMID: 38451317 PMCID: PMC10920417 DOI: 10.1007/s40520-024-02729-3] [Citation(s) in RCA: 3] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/04/2023] [Accepted: 02/23/2024] [Indexed: 03/08/2024]
Abstract
BACKGROUND Recent studies have shown that gut microbiota can affect the development of Alzheimer's disease (AD) through various mechanisms. Bile acids (BAs), which are the final byproducts of cholesterol metabolism created through both the human body and gut microbiome, appear to be influenced by gut microbiota and may impact AD pathological characteristics such as the accumulation of tau and amyloid-β. We aimed to investigate the associations between various serum BAs and CSF biomarkers (including Aβ, total tau, and p-tau). Additionally, we sought to examine the longitudinal changes in brain Aβ and tau through PET imaging in relation to BAs profile. METHODS The data of 828 subjects including 491 diagnosed with mild cognitive impairment (MCI), 119 patients diagnosed with AD, and 267 cognitively normal (CN) participants were obtained from ADNI. The baseline and longitudinal [18F] florbetapir and [18F] flortaucipir PET standard uptake value ratios (SUVR) measures were obtained to assess the accumulation of tau and Aβ. Moreover, baseline levels of serum BAs and CSF Aβ1-42, tau, and p-tau were used. RESULTS After FDR correction we observed that five BAs level and relevant calculated ratios were associated with CSF p-tau and tau, three with CSF Aβ1-42. Furthermore, three BAs level and relevant calculated ratios were associated with the tau-PET rate of change, and two with the Aβ rate of change. CONCLUSION The findings from our study suggest a correlation between altered profiles of BAs and CSF and imaging biomarkers associated with AD. These results provide supporting evidence for the link between the gut microbiome and the pathological features of AD.
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Affiliation(s)
- Fardin Nabizadeh
- School of Medicine, Iran University of Medical Sciences, Tehran, Iran.
| | - Parya Valizadeh
- School of Medicine, Tehran University of Medical Science, Tehran, Iran
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Al‐kuraishy HM, Al‐Gareeb AI, Albuhadily AK, Elewa YHA, AL‐Farga A, Aqlan F, Zahran MH, Batiha GE. Sleep disorders cause Parkinson's disease or the reverse is true: Good GABA good night. CNS Neurosci Ther 2024; 30:e14521. [PMID: 38491789 PMCID: PMC10943276 DOI: 10.1111/cns.14521] [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: 07/13/2023] [Revised: 10/03/2023] [Accepted: 10/23/2023] [Indexed: 03/18/2024] Open
Abstract
BACKGROUND Parkinson's disease (PD) is a progressive neurodegenerative brain disease due to degeneration of dopaminergic neurons (DNs) presented with motor and non-motor symptoms. PD symptoms are developed in response to the disturbance of diverse neurotransmitters including γ-aminobutyric acid (GABA). GABA has a neuroprotective effect against PD neuropathology by protecting DNs in the substantia nigra pars compacta (SNpc). It has been shown that the degeneration of GABAergic neurons is linked with the degeneration of DNs and the progression of motor and non-motor PD symptoms. GABA neurotransmission is a necessary pathway for normal sleep patterns, thus deregulation of GABAergic neurotransmission in PD could be the potential cause of sleep disorders in PD. AIM Sleep disorders affect GABA neurotransmission leading to memory and cognitive dysfunction in PD. For example, insomnia and short sleep duration are associated with a reduction of brain GABA levels. Moreover, PD-related disorders including rigidity and nocturia influence sleep patterns leading to fragmented sleep which may also affect PD neuropathology. However, the mechanistic role of GABA in PD neuropathology regarding motor and non-motor symptoms is not fully elucidated. Therefore, this narrative review aims to clarify the mechanistic role of GABA in PD neuropathology mainly in sleep disorders, and how good GABA improves PD. In addition, this review of published articles tries to elucidate how sleep disorders such as insomnia and REM sleep behavior disorder (RBD) affect PD neuropathology and severity. The present review has many limitations including the paucity of prospective studies and most findings are taken from observational and preclinical studies. GABA involvement in the pathogenesis of PD has been recently discussed by recent studies. Therefore, future prospective studies regarding the use of GABA agonists in the management of PD are suggested to observe their distinct effects on motor and non-motor symptoms. CONCLUSION There is a bidirectional relationship between the pathogenesis of PD and sleep disorders which might be due to GABA deregulation.
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Affiliation(s)
- Hayder M. Al‐kuraishy
- Department of Clinical Pharmacology and Medicine, College of MedicineAl‐Mustansiriya UniversityBaghdadIraq
| | - Ali I. Al‐Gareeb
- Department of Clinical Pharmacology and Medicine, College of MedicineAl‐Mustansiriya UniversityBaghdadIraq
| | - Ali K. Albuhadily
- Department of Clinical Pharmacology and Medicine, College of MedicineAl‐Mustansiriya UniversityBaghdadIraq
| | - Yaser Hosny Ali Elewa
- Department of Histology and Cytology, Faculty of Veterinary MedicineZagazig UniversityZagazigEgypt
- Faculty of Veterinary MedicineHokkaido UniversitySapporoJapan
| | - Ammar AL‐Farga
- Biochemistry Department, College of SciencesUniversity of JeddahJeddahSaudia Arbia
| | - Faisal Aqlan
- Department of Chemistry, College of SciencesIbb UniversityIbb GovernorateYemen
| | | | - Gaber El‐Saber Batiha
- Department of Pharmacology and Therapeutics, Faculty of Veterinary MedicineDamanhur UniversityDamanhurEgypt
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13
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Schwarz A, Hernandez L, Arefin S, Sartirana E, Witasp A, Wernerson A, Stenvinkel P, Kublickiene K. Sweet, bloody consumption - what we eat and how it affects vascular ageing, the BBB and kidney health in CKD. Gut Microbes 2024; 16:2341449. [PMID: 38686499 PMCID: PMC11062370 DOI: 10.1080/19490976.2024.2341449] [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: 08/07/2023] [Accepted: 04/04/2024] [Indexed: 05/02/2024] Open
Abstract
In today's industrialized society food consumption has changed immensely toward heightened red meat intake and use of artificial sweeteners instead of grains and vegetables or sugar, respectively. These dietary changes affect public health in general through an increased incidence of metabolic diseases like diabetes and obesity, with a further elevated risk for cardiorenal complications. Research shows that high red meat intake and artificial sweeteners ingestion can alter the microbial composition and further intestinal wall barrier permeability allowing increased transmission of uremic toxins like p-cresyl sulfate, indoxyl sulfate, trimethylamine n-oxide and phenylacetylglutamine into the blood stream causing an array of pathophysiological effects especially as a strain on the kidneys, since they are responsible for clearing out the toxins. In this review, we address how the burden of the Western diet affects the gut microbiome in altering the microbial composition and increasing the gut permeability for uremic toxins and the detrimental effects thereof on early vascular aging, the kidney per se and the blood-brain barrier, in addition to the potential implications for dietary changes/interventions to preserve the health issues related to chronic diseases in future.
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Affiliation(s)
- Angelina Schwarz
- Department of Clinical Science, Intervention and Technology, Division of Renal Medicine, Karolinska Institutet, Stockholm, Sweden
| | - Leah Hernandez
- Department of Clinical Science, Intervention and Technology, Division of Renal Medicine, Karolinska Institutet, Stockholm, Sweden
| | - Samsul Arefin
- Department of Clinical Science, Intervention and Technology, Division of Renal Medicine, Karolinska Institutet, Stockholm, Sweden
| | - Elisa Sartirana
- Department of Translational Medicine, Nephrology and Kidney Transplantation Unit, University of Piemonte Orientale, Novara, Italy
| | - Anna Witasp
- Department of Clinical Science, Intervention and Technology, Division of Renal Medicine, Karolinska Institutet, Stockholm, Sweden
| | - Annika Wernerson
- Department of Clinical Science, Intervention and Technology, Division of Renal Medicine, Karolinska Institutet, Stockholm, Sweden
| | - Peter Stenvinkel
- Department of Clinical Science, Intervention and Technology, Division of Renal Medicine, Karolinska Institutet, Stockholm, Sweden
- Department of Renal Medicine, Karolinska University Hospital, Stockholm, Sweden
| | - Karolina Kublickiene
- Department of Clinical Science, Intervention and Technology, Division of Renal Medicine, Karolinska Institutet, Stockholm, Sweden
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14
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Ishioh M, Nozu T, Okumura T. Brain Neuropeptides, Neuroinflammation, and Irritable Bowel Syndrome. Digestion 2023; 105:34-39. [PMID: 37673052 DOI: 10.1159/000533275] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/27/2023] [Accepted: 07/21/2023] [Indexed: 09/08/2023]
Abstract
BACKGROUND Irritable bowel syndrome (IBS) is a functional bowel disorder characterized by chronic abdominal symptoms, but its pathogenesis is not fully understood. SUMMARY We have recently shown in rats that neuropeptides such as orexin, ghrelin, and oxytocin act in the brain to improve the intestinal barrier dysfunction, which is a major pathophysiology of IBS. We have additionally shown that the neuropeptides injected intracisternally induced a visceral antinociceptive action against colonic distension. Since it has been known that intestinal barrier dysfunction causes visceral hypersensitivity, the other main pathophysiology of IBS, the neuropeptides act centrally to reduce leaky gut, followed by improvement of visceral sensation, leading to therapeutic action on IBS. It has been recently reported that there is a bidirectional relationship between neuroinflammation in the brain and the pathophysiology of IBS. For example, activation of microglia in the brain causes visceral hypersensitivity. Accumulating evidence has suggested that orexin, ghrelin, or oxytocin could improve neuroinflammation in the CNS. All these results suggest that neuropeptides such as orexin, ghrelin, and oxytocin act in the brain to improve intestinal barrier function and visceral sensation and also induce a protective action against neuroinflammation in the brain. KEY MESSAGES We therefore speculated that orexin, ghrelin, or oxytocin in the brain possess dual actions, improvement of visceral sensation/leaky gut in the gut, and reduction of neuroinflammation in the brain, thereby inducing a therapeutic effect on IBS in a convergent manner.
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Affiliation(s)
- Masatomo Ishioh
- Division of Metabolism, Biosystemic Science, Gastroenterology and Hematology/Oncology, Department of Medicine, Asahikawa Medical University, Asahikawa, Japan
| | - Tsukasa Nozu
- Department of Regional Medicine and Education, Asahikawa Medical University, Asahikawa, Japan
| | - Toshikatsu Okumura
- Division of Metabolism, Biosystemic Science, Gastroenterology and Hematology/Oncology, Department of Medicine, Asahikawa Medical University, Asahikawa, Japan
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15
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Solanki R, Karande A, Ranganathan P. Emerging role of gut microbiota dysbiosis in neuroinflammation and neurodegeneration. Front Neurol 2023; 14:1149618. [PMID: 37255721 PMCID: PMC10225576 DOI: 10.3389/fneur.2023.1149618] [Citation(s) in RCA: 54] [Impact Index Per Article: 27.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/22/2023] [Accepted: 04/17/2023] [Indexed: 06/01/2023] Open
Abstract
Alzheimer's disease (AD), is a chronic age-related progressive neurodegenerative disorder, characterized by neuroinflammation and extracellular aggregation of Aβ peptide. Alzheimer's affects every 1 in 14 individuals aged 65 years and above. Recent studies suggest that the intestinal microbiota plays a crucial role in modulating neuro-inflammation which in turn influences Aβ deposition. The gut and the brain interact with each other through the nervous system and chemical means via the blood-brain barrier, which is termed the Microbiota Gut Brain Axis (MGBA). It is suggested that the gut microbiota can impact the host's health, and numerous factors, such as nutrition, pharmacological interventions, lifestyle, and geographic location, can alter the gut microbiota composition. Although, the exact relationship between gut dysbiosis and AD is still elusive, several mechanisms have been proposed as drivers of gut dysbiosis and their implications in AD pathology, which include, action of bacteria that produce bacterial amyloids and lipopolysaccharides causing macrophage dysfunction leading to increased gut permeability, hyperimmune activation of inflammatory cytokines (IL-1β, IL-6, IL-8, and NLRP3), impairment of gut- blood brain barrier causing deposition of Aβ in the brain, etc. The study of micro-organisms associated with dysbiosis in AD with the aid of appropriate model organisms has recognized the phyla Bacteroidetes and Firmicutes which contain organisms of the genus Escherichia, Lactobacillus, Clostridium, etc., to contribute significantly to AD pathology. Modulating the gut microbiota by various means, such as the use of prebiotics, probiotics, antibiotics or fecal matter transplantation, is thought to be a potential therapeutic intervention for the treatment of AD. This review aims to summarize our current knowledge on possible mechanisms of gut microbiota dysbiosis, the role of gut brain microbiota axis in neuroinflammation, and the application of novel targeted therapeutic approaches that modulate the gut microbiota in treatment of AD.
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16
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Zhang T, Wu X, Liu B, Huang H, Zhou C, Liang P. The contribution of probiotics for the double-edge effect of cefazolin on postoperative neurocognitive disorders by rebalancing the gut microbiota. Front Neurosci 2023; 17:1156453. [PMID: 37179548 PMCID: PMC10174111 DOI: 10.3389/fnins.2023.1156453] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2023] [Accepted: 04/04/2023] [Indexed: 05/15/2023] Open
Abstract
INTRODUCTION Emerging data suggest that perioperative gut dysbiosis is prevalent and may be associated with postoperative neurocognitive disorders (PND). Antibiotics and probiotics are key factors influencing the microbiota. Many antibiotics have anti-microorganisms and direct anti-inflammatory properties, which may have cognitive repercussions. NLRP3 inflammasome activation has been reported to be involved with cognitive deficits. This study aimed to determine the effect and mechanism of probiotics on neurocognitive problems associated with perioperative gut dysbiosis by the NLRP3 pathway. METHODS In a randomized, controlled trial, adult male Kunming mice undergoing surgery were administered cefazolin, FOS + probiotics, CY-09, or a placebo in four distinct experimental cohorts. Fear conditioning (FC) tests evaluate learning and memory. Following FC tests to evaluate inflammatory response (IR) and the permeability of barrier systems, the hippocampus and colon were extracted, and feces were collected for 16 s rRNA. RESULTS One week after surgery, surgery/anesthesia decreased the frozen behavior. Cefazolin attenuated this declination but aggravated postoperative freezing behavior 3 weeks after surgery. Probiotics ameliorated surgery/anesthesia-induced memory deficits and perioperative cefazolin-induced postoperative memory deficits 3 weeks after surgery. NLRP3, caspase-1, Interleukin-1β (IL-1β), and Interleukin-18 (IL-18) levels were increased 1 week after the hippocampus and colon surgery, which were attenuated by CY-09 and probiotics, respectively. DISCUSSION Probiotics could correct dysbacteria and IR caused by surgery/anesthesia stress and cefazolin alone. These findings imply that probiotics are an efficient and effective way of maintaining the balance of gut microbiota, which may reduce NLRP3-related inflammation and alleviate PND.
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Affiliation(s)
- Tianyao Zhang
- Department of Anesthesiology, West China Hospital of Sichuan University, Chengdu, China
- Department of Anesthesiology, The First Affiliated Hospital of Chengdu Medical College, Chengdu, China
| | - Xiaochu Wu
- National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, Chengdu, China
| | - Bin Liu
- Department of Anesthesiology, West China Hospital of Sichuan University, Chengdu, China
- Laboratory of Anesthesia and Critical Care Medicine, Translational Neuroscience Center, West China Hospital of Sichuan University, Chengdu, China
| | - Han Huang
- Department of Anesthesiology and Key Laboratory of Birth Defects and Related Diseases of Women and Children, Ministry of Education, West China Second Hospital of Sichuan University, Chengdu, Sichuan, China
| | - Cheng Zhou
- Department of Anesthesiology, West China Hospital of Sichuan University, Chengdu, China
- Laboratory of Anesthesia and Critical Care Medicine, Translational Neuroscience Center, West China Hospital of Sichuan University, Chengdu, China
| | - Peng Liang
- Department of Anesthesiology, West China Hospital of Sichuan University, Chengdu, China
- Day Surgery Center, General Practice Medical Center, West China Hospital, Sichuan University and the Research Units of West China (2018RU012), Chinese Academy of Medical Sciences, Chengdu, China
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17
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Zhang X, Guo F, Cao D, Yan Y, Zhang N, Zhang K, Li X, Kumar P, Zhang X. Neuroprotective Effect of Ponicidin Alleviating the Diabetic Cognitive Impairment: Regulation of Gut Microbiota. Appl Biochem Biotechnol 2023; 195:735-752. [PMID: 36155887 DOI: 10.1007/s12010-022-04113-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 08/28/2022] [Indexed: 01/24/2023]
Abstract
Cognitive impairment is a major complication of diabetes mellitus, which is caused by constitutive hyperglycaemia. Ponicidin is a diterpenoid isolated from a Chinese traditional herb (Rabdosia rubescens) and demonstrates the various pharmacological effects. The goal of this study was to scrutinise the neuroprotective effect of ponicidin against diabetic nephropathy (DN) induced by streptozotocin (STZ). Intraperitoneal administration of STZ (55 mg/kg) was used for the induction of diabetes and rats were received oral administration of ponicidin (5, 10 and 15 mg/kg) until 28 days. The body weight, food intake, water intake and blood glucose level were assessed at regular time interval. Plasma insulin level, antioxidant, inflammatory cytokines, apoptosis marker and faecal gut microbiota compositions were estimated. DN-induced group rats revealed the augmented glucose level, water intake, food intake and reduced body weight. Ponicidin significantly (P < 0.001) repressed the glucose level and water food intake and improved the body weight and plasma insulin. Ponicidin significantly (P < 0.001) repressed the malonaldehyde (MDA) level and boosted the level of glutathione (GSH), glutathione reductase (GR) and superoxide dismutase (SOD) in the brain and serum level. Ponicidin significantly (P < 0.001) repressed the level of interleukin-1β (IL-1β), tumour necrosis factor-α (TNF-α) and interleukin-6 (IL-6) and enhanced the level of interleukin-4 (IL-4), interleukin-10 (IL-10) in the brain and serum level. DN group rats exhibited the enhanced relative abundance of Firmicutes, along with enhancing the Firmicutes/Bacteroidetes ratio and repressing the Bacteroidetes relative abundance. Ponicidin effectually restored the relative abundance of Allobaculum, Lactobacillus and Ruminococcus genera. Our findings clearly demonstrated that ponicidin has a neuroprotective effect against diabetic cognitive impairment through modulating the gut microbiome.
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Affiliation(s)
- Xiaojuan Zhang
- Department of Neurology, Shanxi Bethune Hospital, Shanxi Academy of Medical Sciences, Tongji Shanxi Hospital, Third Hospital of Shanxi Medical University, Taiyuan, 030032, China.,Department of Neurology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China
| | - Feng Guo
- People's Hospital of Lvliang, Shanxi, 033000, China
| | - Dujuan Cao
- Department of Neurology, Shanxi Bethune Hospital, Shanxi Academy of Medical Sciences, Tongji Shanxi Hospital, Third Hospital of Shanxi Medical University, Taiyuan, 030032, China.,Department of Neurology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China
| | - Yinan Yan
- Department of Neurology, Shanxi Bethune Hospital, Shanxi Academy of Medical Sciences, Tongji Shanxi Hospital, Third Hospital of Shanxi Medical University, Taiyuan, 030032, China.,Department of Neurology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China
| | - Ning Zhang
- Department of Neurology, Shanxi Bethune Hospital, Shanxi Academy of Medical Sciences, Tongji Shanxi Hospital, Third Hospital of Shanxi Medical University, Taiyuan, 030032, China.,Department of Neurology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China
| | - Kaili Zhang
- Department of Neurology, Shanxi Bethune Hospital, Shanxi Academy of Medical Sciences, Tongji Shanxi Hospital, Third Hospital of Shanxi Medical University, Taiyuan, 030032, China.,Department of Neurology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China
| | - Xinyi Li
- Department of Neurology, Shanxi Bethune Hospital, Shanxi Academy of Medical Sciences, Tongji Shanxi Hospital, Third Hospital of Shanxi Medical University, Taiyuan, 030032, China. .,Department of Neurology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China.
| | | | - Xiaojuan Zhang
- Department of Neurology, Shanxi Bethune Hospital, Shanxi Academy of Medical Sciences, Tongji Shanxi Hospital, Third Hospital of Shanxi Medical University, Taiyuan, 030032, China.,Department of Neurology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China
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18
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Bellavite P. Neuroprotective Potentials of Flavonoids: Experimental Studies and Mechanisms of Action. Antioxidants (Basel) 2023; 12:antiox12020280. [PMID: 36829840 PMCID: PMC9951959 DOI: 10.3390/antiox12020280] [Citation(s) in RCA: 65] [Impact Index Per Article: 32.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/12/2023] [Revised: 01/23/2023] [Accepted: 01/25/2023] [Indexed: 01/31/2023] Open
Abstract
Neurological and neurodegenerative diseases, particularly those related to aging, are on the rise, but drug therapies are rarely curative. Functional disorders and the organic degeneration of nervous tissue often have complex causes, in which phenomena of oxidative stress, inflammation and cytotoxicity are intertwined. For these reasons, the search for natural substances that can slow down or counteract these pathologies has increased rapidly over the last two decades. In this paper, studies on the neuroprotective effects of flavonoids (especially the two most widely used, hesperidin and quercetin) on animal models of depression, neurotoxicity, Alzheimer's disease (AD) and Parkinson's disease are reviewed. The literature on these topics amounts to a few hundred publications on in vitro and in vivo models (notably in rodents) and provides us with a very detailed picture of the action mechanisms and targets of these substances. These include the decrease in enzymes that produce reactive oxygen and ferroptosis, the inhibition of mono-amine oxidases, the stimulation of the Nrf2/ARE system, the induction of brain-derived neurotrophic factor production and, in the case of AD, the prevention of amyloid-beta aggregation. The inhibition of neuroinflammatory processes has been documented as a decrease in cytokine formation (mainly TNF-alpha and IL-1beta) by microglia and astrocytes, by modulating a number of regulatory proteins such as Nf-kB and NLRP3/inflammasome. Although clinical trials on humans are still scarce, preclinical studies allow us to consider hesperidin, quercetin, and other flavonoids as very interesting and safe dietary molecules to be further investigated as complementary treatments in order to prevent neurodegenerative diseases or to moderate their deleterious effects.
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19
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Jia Y, Yan S, Sun M, Yang Y, Wang L, Wu C, Li P. Association between dietary inflammatory index and cognitive impairment: A meta-analysis. Front Aging Neurosci 2023; 14:1007629. [PMID: 36688153 PMCID: PMC9845281 DOI: 10.3389/fnagi.2022.1007629] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/30/2022] [Accepted: 11/18/2022] [Indexed: 01/05/2023] Open
Abstract
Aims Cognitive impairment is an increasingly urgent global public health challenge. Dietary Inflammatory Index (DII) is a literature-derived score that links diet to inflammation. The relationship between DII and cognitive impairment remains controversial. Therefore, our study aimed to analysis the role of DII on the risk of cognitive impairment by meta-analysis. Methods PubMed, Cochrane Library, MEDLINE, Web of Science and EMBASE databases were searched up to July 2022. Newcastle-Ottawa scale (NOS) and Joanna Briggs Institute (JBI) Checklist were performed to estimate the quality of studies. Results Nine observational studies with 19,379 subjects were included. Our study found that higher DII could elevate the risk of cognitive impairment (OR = 1.46, 95%CI = 1.26, 1.69). Meanwhile, the OR of cognitive impairment was 1.49 (95%CI = 1.21, 1.83) for cross-sectional studies and 1.42 (95%CI = 1.12, 1.79) for cohort studies, respectively. Conclusion Our meta-analysis indicated that higher DII (indicating a more pro-inflammatory diet) is related to increased risk of cognitive impairment.
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Affiliation(s)
- Yuxi Jia
- Application Demonstration Center of Precision Medicine Molecular Diagnosis, The Second Hospital of Jilin University, Changchun, China,Department of Orthopedics, The Second Hospital of Jilin University, Changchun, China
| | - Shoumeng Yan
- Department of Nursing Humanities, School of Nursing, Jilin University, Changchun, China
| | - Mengzi Sun
- Department of Epidemiology and Biostatistics, School of Public Health, Jilin University, Changchun, China
| | - Yixue Yang
- Department of Epidemiology and Biostatistics, School of Public Health, Jilin University, Changchun, China
| | - Ling Wang
- Department of Epidemiology and Biostatistics, School of Public Health, Jilin University, Changchun, China
| | - Caihong Wu
- Department of Nutrition and Food Hygiene, School of Public Health, Jilin University, Changchun, China
| | - Ping Li
- Department of Developmental Pediatrics, The Second Hospital of Jilin University, Changchun, China,*Correspondence: Ping Li
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20
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Shin C, Kim YK. Microbiota-Gut-Brain Axis: Pathophysiological Mechanism in Neuropsychiatric Disorders. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2023; 1411:17-37. [PMID: 36949304 DOI: 10.1007/978-981-19-7376-5_2] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 03/24/2023]
Abstract
Gut microbiota influence human behavior. The immunological, metabolic, and endocrine systems are involved in bidirectional communication between the gut and the brain, which is regulated by microbes through the microbiota-derived neurochemicals and metabolites. Gut microbiota have certain effects on neurodevelopment and maturation of immunity. However, gut dysbiosis can lead to neuropsychiatric disorders. Animal research and clinical case-control studies have demonstrated that gut dysbiosis has an adverse effect on human behavior through a variety of mechanisms. Recent meta-analysis on clinical studies confirmed gut dysbiosis in several major neuropsychiatric disorders. Microbiota-targeted intervention has recently been in the spotlight and meta-analyses have confirmed its effectiveness. In this chapter, we summarize the evidence for the interactions between microbiota and brain-gut network, as well as the potential pathophysiological mechanisms involved.
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Affiliation(s)
- Cheolmin Shin
- Department of Psychiatry, College of Medicine, Korea University Ansan Hospital, Ansan, Republic of Korea
| | - Yong-Ku Kim
- Department of Psychiatry, College of Medicine, Korea University Ansan Hospital, Ansan, Republic of Korea.
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21
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Dai CL, Liu F, Iqbal K, Gong CX. Gut Microbiota and Immunotherapy for Alzheimer's Disease. Int J Mol Sci 2022; 23:15230. [PMID: 36499564 PMCID: PMC9741026 DOI: 10.3390/ijms232315230] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2022] [Revised: 11/29/2022] [Accepted: 12/01/2022] [Indexed: 12/08/2022] Open
Abstract
Alzheimer's disease (AD) is a progressive neurodegenerative disorder that eventually leads to dementia and death of the patient. Currently, no effective treatment is available that can slow or halt the progression of the disease. The gut microbiota can modulate the host immune system in the peripheral and central nervous system through the microbiota-gut-brain axis. Growing evidence indicates that gut microbiota dysbiosis plays an important role in the pathogenesis of AD, and modulation of the gut microbiota may represent a new avenue for treating AD. Immunotherapy targeting Aβ and tau has emerged as the most promising disease-modifying therapy for the treatment of AD. However, the underlying mechanism of AD immunotherapy is not known. Importantly, preclinical and clinical studies have highlighted that the gut microbiota exerts a major influence on the efficacy of cancer immunotherapy. However, the role of the gut microbiota in AD immunotherapy has not been explored. We found that immunotherapy targeting tau can modulate the gut microbiota in an AD mouse model. In this article, we focused on the crosstalk between the gut microbiota, immunity, and AD immunotherapy. We speculate that modulation of the gut microbiota induced by AD immunotherapy may partially underlie the efficacy of the treatment.
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Affiliation(s)
| | | | | | - Cheng-Xin Gong
- Department of Neurochemistry, Inge Grundke-Iqbal Research Floor, New York State Institute for Basic Research in Developmental Disabilities, Staten Island, New York, NY 10314, USA
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22
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Golan N, Engelberg Y, Landau M. Structural Mimicry in Microbial and Antimicrobial Amyloids. Annu Rev Biochem 2022; 91:403-422. [PMID: 35729071 DOI: 10.1146/annurev-biochem-032620-105157] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/09/2022]
Abstract
The remarkable variety of microbial species of human pathogens and microbiomes generates significant quantities of secreted amyloids, which are structured protein fibrils that serve diverse functions related to virulence and interactions with the host. Human amyloids are associated largely with fatal neurodegenerative and systemic aggregation diseases, and current research has put forward the hypothesis that the interspecies amyloid interactome has physiological and pathological significance. Moreover, functional and molecular-level connections between antimicrobial activity and amyloid structures suggest a neuroimmune role for amyloids that are otherwise known to be pathological. Compared to the extensive structural information that has been accumulated for human amyloids, high-resolution structures of microbial and antimicrobial amyloids are only emerging. These recent structures reveal both similarities and surprising departures from the typical amyloid motif, in accordance with their diverse activities, and advance the discovery of novel antivirulence and antimicrobial agents. In addition, the structural information has led researchers to postulate that amyloidogenic sequences are natural targets for structural mimicry, for instance in host-microbe interactions. Microbial amyloid research could ultimately be used to fight aggressive infections and possibly processes leading to autoimmune and neurodegenerative diseases.
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Affiliation(s)
- Nimrod Golan
- Department of Biology, Technion-Israel Institute of Technology, Haifa, Israel;
| | - Yizhaq Engelberg
- Department of Biology, Technion-Israel Institute of Technology, Haifa, Israel;
| | - Meytal Landau
- Department of Biology, Technion-Israel Institute of Technology, Haifa, Israel; .,European Molecular Biology Laboratory (EMBL) and Center for Structural Systems Biology (CSSB), Hamburg, Germany
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23
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He Q, Si C, Sun Z, Chen Y, Zhang X. The Intervention of Prebiotics on Depression via the Gut-Brain Axis. MOLECULES (BASEL, SWITZERLAND) 2022; 27:molecules27123671. [PMID: 35744797 PMCID: PMC9230023 DOI: 10.3390/molecules27123671] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 04/26/2022] [Revised: 05/20/2022] [Accepted: 06/05/2022] [Indexed: 12/12/2022]
Abstract
The imbalance of intestinal microbiota can cause the accumulation of endotoxin in the main circulation system of the human body, which has a great impact on human health. Increased work and life pressure have led to a rise in the number of people falling into depression, which has also reduced their quality of life. The gut–brain axis (GBA) is closely related to the pathological basis of depression, and intestinal microbiota can improve depressive symptoms through GBA. Previous studies have proven that prebiotics can modulate intestinal microbiota and thus participate in human health regulation. We reviewed the regulatory mechanism of intestinal microbiota on depression through GBA, and discussed the effects of prebiotics, including plant polysaccharides and polyphenols on the regulation of intestinal microbiota, providing new clues for the prevention and treatment of depression.
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Affiliation(s)
- Qinghui He
- Amway (China) R&D Centre Co., Ltd., Guangzhou 510730, China;
| | - Congcong Si
- Ningbo Tech-inno Health Industry Co., Ltd., Ningbo 315211, China; (C.S.); (Z.S.); (Y.C.)
| | - Zhenjiao Sun
- Ningbo Tech-inno Health Industry Co., Ltd., Ningbo 315211, China; (C.S.); (Z.S.); (Y.C.)
| | - Yuhui Chen
- Ningbo Tech-inno Health Industry Co., Ltd., Ningbo 315211, China; (C.S.); (Z.S.); (Y.C.)
| | - Xin Zhang
- Department of Food Science and Engineering, Ningbo University, Ningbo 315211, China
- Correspondence:
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24
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Wang Y, Li L, Zhao X, Sui S, Wang Q, Shi G, Xu H, Zhang X, He Y, Gu J. Intestinal Microflora Changes in Patients with Mild Alzheimer's Disease in a Chinese Cohort. J Alzheimers Dis 2022; 88:563-575. [PMID: 35662119 DOI: 10.3233/jad-220076] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
BACKGROUND Understanding the relationship between Alzheimer's disease (AD) and intestinal flora is still a major scientific topic that continues to advance. OBJECTIVE To determine characterized changes in the intestinal microbe community of patients with mild AD. METHODS Comparison of the 16S ribosomal RNA (rRNA) high-throughput sequencing data was obtained from the Illumina MiSeq platform of fecal microorganisms of the patients and healthy controls (HC) which were selected from cohabiting caregivers of AD patients to exclude environmental and dietary factors. RESULTS We found that the abundance of several bacteria taxa in AD patients was different from that in HC at the genus level, such as Anaerostipes, Mitsuokella, Prevotella, Bosea, Fusobacterium, Anaerotruncus, Clostridium, and Coprobacillus. Interestingly, the abundance of Akkermansia, an emerging probiotic, increased significantly in the AD group compared with that in the HC group. Meanwhile, the quantity of traditional probiotic Bifidobacteria of the AD group also rose. CONCLUSION These alterations in fecal microbiome of the AD group indicate that patients with mild AD have unique gut microbial characteristics. These specific AD-associated intestinal microbes could serve as novel potential targets for early intervention of AD.
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Affiliation(s)
- Yilin Wang
- College of Biological Science and Technology, University of Jinan, Jinan, China
| | - Lei Li
- Department of Neurology, Shandong Provincial Qianfoshan Hospital, the First Hospital Affiliated with Shandong First Medical University, China
| | - Xiaodong Zhao
- College of Biological Science and Technology, University of Jinan, Jinan, China
| | - Shaomei Sui
- Department of Neurology, Shandong Provincial Qianfoshan Hospital, the First Hospital Affiliated with Shandong First Medical University, China
| | - Qi Wang
- Department of Neurology, Shandong Provincial Qianfoshan Hospital, the First Hospital Affiliated with Shandong First Medical University, China
| | - Guizhi Shi
- Institute of Biophysics, Chinese Academy of Sciences, Beijing, China.,University of Chinese Academy of Sciences, Beijing, China
| | - Huilian Xu
- College of Biological Science and Technology, University of Jinan, Jinan, China
| | - Xiujun Zhang
- College of Biological Science and Technology, University of Jinan, Jinan, China
| | - Yan He
- Department of Neurology, Shandong Provincial Qianfoshan Hospital, the First Hospital Affiliated with Shandong First Medical University, China
| | - Jinsong Gu
- College of Biological Science and Technology, University of Jinan, Jinan, China
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Salehipour A, Bagheri M, Sabahi M, Dolatshahi M, Boche D. Combination Therapy in Alzheimer’s Disease: Is It Time? J Alzheimers Dis 2022; 87:1433-1449. [DOI: 10.3233/jad-215680] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
Alzheimer’s disease (AD) is the most common cause of dementia globally. There is increasing evidence showing AD has no single pathogenic mechanism, and thus treatment approaches focusing only on one mechanism are unlikely to be meaningfully effective. With only one potentially disease modifying treatment approved, targeting amyloid-β (Aβ), AD is underserved regarding effective drug treatments. Combining multiple drugs or designing treatments that target multiple pathways could be an effective therapeutic approach. Considering the distinction between added and combination therapies, one can conclude that most trials fall under the category of added therapies. For combination therapy to have an actual impact on the course of AD, it is likely necessary to target multiple mechanisms including but not limited to Aβ and tau pathology. Several challenges have to be addressed regarding combination therapy, including choosing the correct agents, the best time and stage of AD to intervene, designing and providing proper protocols for clinical trials. This can be achieved by a cooperation between the pharmaceutical industry, academia, private research centers, philanthropic institutions, and the regulatory bodies. Based on all the available information, the success of combination therapy to tackle complicated disorders such as cancer, and the blueprint already laid out on how to implement combination therapy and overcome its challenges, an argument can be made that the field has to move cautiously but quickly toward designing new clinical trials, further exploring the pathological mechanisms of AD, and re-examining the previous studies with combination therapies so that effective treatments for AD may be finally found.
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Affiliation(s)
- Arash Salehipour
- Neurosurgery Research Group (NRG), Student Research Committee, Hamadan University of Medical Sciences, Hamadan, Iran
- NeuroImaging Network (NIN), Universal Scientific Education and Research Network (USERN), Tehran, Iran
| | - Motahareh Bagheri
- Neurosurgery Research Group (NRG), Student Research Committee, Hamadan University of Medical Sciences, Hamadan, Iran
| | - Mohammadmahdi Sabahi
- Neurosurgery Research Group (NRG), Student Research Committee, Hamadan University of Medical Sciences, Hamadan, Iran
- NeuroImaging Network (NIN), Universal Scientific Education and Research Network (USERN), Tehran, Iran
| | - Mahsa Dolatshahi
- NeuroImaging Network (NIN), Universal Scientific Education and Research Network (USERN), Tehran, Iran
- Students’ Scientific Research Center (SSRC), Tehran University of Medical Sciences, Tehran, Iran
| | - Delphine Boche
- Clinical Neurosciences, Clinical and Experimental Sciences, Faculty of Medicine, University of Southampton, United Kingdom
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26
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Kleine-Borgmann J, Schmidt K, Scharmach K, Zunhammer M, Elsenbruch S, Bingel U, Forkmann K. Does pain modality play a role in the interruptive function of acute visceral compared with somatic pain? Pain 2022; 163:735-744. [PMID: 34338242 PMCID: PMC8929302 DOI: 10.1097/j.pain.0000000000002418] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/14/2021] [Revised: 07/13/2021] [Accepted: 07/19/2021] [Indexed: 11/26/2022]
Abstract
ABSTRACT Acute pain captures attentional resources and interferes with ongoing cognitive processes, including memory encoding. Despite broad clinical implications of this interruptive function of pain for the pathophysiology and treatment of chronic pain conditions, existing knowledge exclusively relies on studies using somatic pain models. Visceral pain is highly prevalent and seems to be more salient and threatening, suggesting that the interruptive function of pain may be higher in acute visceral compared with somatic pain. Implementing rectal distensions as a clinically relevant experimental model of visceral pain along with thermal cutaneous pain for the somatic modality, we herein examined the impact of pain modality on visual processing and memory performance in a visual encoding and recognition task and explored the modulatory role of pain-related fear and expectation in 30 healthy participants. Despite careful and dynamically adjusted matching of stimulus intensities to perceived pain unpleasantness over the course of trials, we observed greater impairment of cognition performance for the visceral modality with a medium effect size. Task performance was not modulated by expectations or by pain-related fear. Hence, even at matched unpleasantness levels, acute visceral pain is capable of interfering with memory encoding, and this impact seems to be relatively independent of pain-related cognitions or emotions, at least in healthy individuals. These results likely underestimate the detrimental effect of chronic pain on cognitive performance, which may be particularly pronounced in acute and chronic visceral pain.
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Affiliation(s)
- Julian Kleine-Borgmann
- Center for Translational Neuro- and Behavioral Sciences, Department of Neurology, University Medicine Essen, Germany
- Translational Pain Research Unit, University Medicine Essen, Essen, Germany
| | - Katharina Schmidt
- Center for Translational Neuro- and Behavioral Sciences, Department of Neurology, University Medicine Essen, Germany
- Translational Pain Research Unit, University Medicine Essen, Essen, Germany
| | - Katrin Scharmach
- Center for Translational Neuro- and Behavioral Sciences, Department of Neurology, University Medicine Essen, Germany
| | - Matthias Zunhammer
- Center for Translational Neuro- and Behavioral Sciences, Department of Neurology, University Medicine Essen, Germany
| | - Sigrid Elsenbruch
- Translational Pain Research Unit, University Medicine Essen, Essen, Germany
- Department of Medical Psychology and Medical Sociology, Ruhr University Bochum, Bochum, Germany
| | - Ulrike Bingel
- Center for Translational Neuro- and Behavioral Sciences, Department of Neurology, University Medicine Essen, Germany
- Translational Pain Research Unit, University Medicine Essen, Essen, Germany
| | - Katarina Forkmann
- Center for Translational Neuro- and Behavioral Sciences, Department of Neurology, University Medicine Essen, Germany
- Translational Pain Research Unit, University Medicine Essen, Essen, Germany
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27
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Shukla PK, Meena AS, Rao R. Prevention and mitigation of alcohol-induced neuroinflammation by Lactobacillus plantarum by an EGF receptor-dependent mechanism. Nutr Neurosci 2022; 25:871-883. [PMID: 32945721 PMCID: PMC7969470 DOI: 10.1080/1028415x.2020.1819105] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Neuroinflammation is implicated in the pathogenesis of alcohol use disorders. We investigated the role of Gut-Brain interactions in alcohol-induced neuroinflammation by probiotic-mediated manipulation of intestinal dysbiosis in mice. Chronic ethanol feeding induced dysbiosis, as evidenced by an increase in Firmicutes/Bacteroidetes ratio and depletion of Lactobacillus species in the colon. Ethanol increased the levels of IL-1β, IL-6, and TNFα in plasma and the mRNA for IL-1β, IL-6, TNFα, and MCP1 genes in the cerebral cortex and hippocampus. Ethanol feeding increased inulin flux from the circulation into different brain regions, accompanied by the increase in TLR4 mRNA levels in the cerebral cortex and hippocampus. The immunofluorescence confocal microscopy showed that ethanol elevates the expression of microglial activation marker TMEM119 in the cerebral cortex. Feeding L. plantarum suppressed the ethanol-induced dysbiosis to some extent, as evidenced by attenuation of ethanol effects on Firmicutes/Bacteroidetes ratio and abundance of Lactobacillus spp. L. plantarum blocked ethanol-induced elevation of plasma cytokines, inulin permeability to the brain, mRNA for TLR4, IL-1β, IL-6, TNFα, and MCP1 in brain regions, and the expression of TMEM119 in the cerebral cortex. The L. plantarum effect was absent in mice that express a dominant-negative EGFR, suggesting that the EGFR receptor plays an essential role in the protective effect of L. plantarum against ethanol-induced neuroinflammation. L. plantarum, when administered after chronic ethanol-induced injury, rescued the ethanol-induced systemic inflammation and neuroinflammation. This study demonstrates that L. plantarum in the gut prevents and mitigates ethanol-induced neuroinflammation by an EGFR-dependent mechanism.
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Affiliation(s)
- Pradeep K. Shukla
- Department of Physiology, University of Tennessee Health Science Center, Memphis TN, USA. 38163
| | - Avtar S. Meena
- Department of Physiology, University of Tennessee Health Science Center, Memphis TN, USA. 38163
| | - RadhaKrishna Rao
- Department of Physiology, University of Tennessee Health Science Center, Memphis TN, USA. 38163
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28
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Shobeiri P, Kalantari A, Teixeira AL, Rezaei N. Shedding light on biological sex differences and microbiota-gut-brain axis: a comprehensive review of its roles in neuropsychiatric disorders. Biol Sex Differ 2022; 13:12. [PMID: 35337376 PMCID: PMC8949832 DOI: 10.1186/s13293-022-00422-6] [Citation(s) in RCA: 50] [Impact Index Per Article: 16.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/19/2021] [Accepted: 03/14/2022] [Indexed: 12/15/2022] Open
Abstract
Women and men are suggested to have differences in vulnerability to neuropsychiatric disorders, including major depressive disorder (MDD), generalized anxiety disorder (GAD), schizophrenia, eating disorders, including anorexia nervosa, and bulimia nervosa, neurodevelopmental disorders, such as autism spectrum disorder (ASD), and neurodegenerative disorders including Alzheimer's disease, Parkinson's disease. Genetic factors and sex hormones are apparently the main mediators of these differences. Recent evidence uncovers that reciprocal interactions between sex-related features (e.g., sex hormones and sex differences in the brain) and gut microbiota could play a role in the development of neuropsychiatric disorders via influencing the gut-brain axis. It is increasingly evident that sex-microbiota-brain interactions take part in the occurrence of neurologic and psychiatric disorders. Accordingly, integrating the existing evidence might help to enlighten the fundamental roles of these interactions in the pathogenesis of neuropsychiatric disorders. In addition, an increased understanding of the biological sex differences on the microbiota-brain may lead to advances in the treatment of neuropsychiatric disorders and increase the potential for precision medicine. This review discusses the effects of sex differences on the brain and gut microbiota and the putative underlying mechanisms of action. Additionally, we discuss the consequences of interactions between sex differences and gut microbiota on the emergence of particular neuropsychiatric disorders.
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Affiliation(s)
- Parnian Shobeiri
- School of Medicine, Tehran University of Medical Sciences (TUMS), Children's Medical Center Hospital, Dr. Qarib St., Keshavarz Blvd, 14194, Tehran, Iran
- Network of Immunity in Infection, Malignancy and Autoimmunity (NIIMA), Universal Scientific Education and Research Network (USERN), Tehran, Iran
- Non-Communicable Diseases Research Center, Endocrinology and Metabolism Population Sciences Institute, Tehran University of Medical Sciences, Tehran, Iran
- Research Center for Immunodeficiencies, Pediatrics Center of Excellence, Children's Medical Center, Tehran University of Medical Sciences, Dr. Gharib St, Keshavarz Blvd, Tehran, Iran
| | - Amirali Kalantari
- School of Medicine, Tehran University of Medical Sciences (TUMS), Children's Medical Center Hospital, Dr. Qarib St., Keshavarz Blvd, 14194, Tehran, Iran
- Network of Immunity in Infection, Malignancy and Autoimmunity (NIIMA), Universal Scientific Education and Research Network (USERN), Tehran, Iran
| | - Antônio L Teixeira
- Neuropsychiatry Program, Department of Psychiatry and Behavioral Sciences, McGovern Medical School, The University of Texas Health Science Center at Houston, Houston, TX, USA
| | - Nima Rezaei
- Network of Immunity in Infection, Malignancy and Autoimmunity (NIIMA), Universal Scientific Education and Research Network (USERN), Tehran, Iran.
- Research Center for Immunodeficiencies, Pediatrics Center of Excellence, Children's Medical Center, Tehran University of Medical Sciences, Dr. Gharib St, Keshavarz Blvd, Tehran, Iran.
- Department of Immunology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran.
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Abstract
Several products consist of probiotics that are available in markets, and their potential uses are growing day by day, mainly because some strains of probiotics promote the health of gut microbiota, especially Furmicutes and Bacteroidetes, and may prevent certain gastrointestinal tract (GIT) problems. Some common diseases are inversely linked with the consumption of probiotics, i.e., obesity, type 2 diabetes, autism, osteoporosis, and some immunological disorders, for which the disease progression gets delayed. In addition to disease mitigating properties, these microbes also improve oral, nutritional, and intestinal health, followed by a robust defensive mechanism against particular gut pathogens, specifically by antimicrobial substances and peptides producing probiotics (AMPs). All these positive attributes of probiotics depend upon the type of microbial strains dispensed. Lactic acid bacteria (LAB) and Bifidobacteria are the most common microbes used, but many other microbes are available, and their use depends upon origin and health-promoting properties. This review article focuses on the most common probiotics, their health benefits, and the alleviating mechanisms against chronic kidney diseases (CKD), type 1 diabetes (T1D), type 2 diabetes (T2D), gestational diabetes mellitus (GDM), and obesity.
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30
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Khodabakhsh P, Bazrgar M, Dargahi L, Mohagheghi F, Asgari Taei A, Parvardeh S, Ahmadiani A. Does Alzheimer's disease stem in the gastrointestinal system? Life Sci 2021; 287:120088. [PMID: 34715145 DOI: 10.1016/j.lfs.2021.120088] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/24/2021] [Revised: 10/13/2021] [Accepted: 10/21/2021] [Indexed: 02/07/2023]
Abstract
Over the last decades, our knowledge of the key pathogenic mechanisms of Alzheimer's disease (AD) has dramatically improved. Regarding the limitation of current therapeutic strategies for the treatment of multifactorial diseases, such as AD, to be translated into the clinic, there is a growing trend in research to identify risk factors associated with the onset and progression of AD. Here, we review the current literature with a focus on the relationship between gastrointestinal (GI)/liver diseases during the lifespan and the incidence of AD, and discuss the possible mechanisms underlying the link between the diseases. We also aim to review studies evaluating the possible link between the chronic use of the most common GI medications and the future risk of AD development.
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Affiliation(s)
- Pariya Khodabakhsh
- Department of Pharmacology, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Maryam Bazrgar
- Neuroscience Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Leila Dargahi
- Neuroscience Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Fatemeh Mohagheghi
- Institute of Experimental Hematology, Center for Translational Cancer Research (TranslaTUM), School of Medicine, Technical University of Munich, Munich, Germany
| | - Afsaneh Asgari Taei
- Neuroscience Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Siavash Parvardeh
- Department of Pharmacology, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
| | - Abolhassan Ahmadiani
- Neuroscience Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
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31
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Wang H, Lu J, Zhao X, Qin R, Song K, Xu Y, Zhang J, Chen Y. Alzheimer's disease in elderly COVID-19 patients: potential mechanisms and preventive measures. Neurol Sci 2021; 42:4913-4920. [PMID: 34550494 PMCID: PMC8455804 DOI: 10.1007/s10072-021-05616-1] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/18/2021] [Accepted: 09/17/2021] [Indexed: 12/13/2022]
Abstract
Advanced age correlates with higher morbidity and mortality among patients affected with the novel coronavirus disease 2019 (COVID-19). Because systemic inflammation and neurological symptoms are also common in severe COVID-19 cases, there is concern that COVID-19 may lead to neurodegenerative conditions such as Alzheimer’s disease (AD). In this review, we summarize possible mechanisms by which infection with the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the causative agent of COVID-19, may cause AD in elderly COVID-19 patients and describe preventive measures to mitigate risk. Potential mechanisms include NLRP3 inflammasome activation and IL-1β release, renin-angiotensin system hyperactivation, innate immune activation, oxidative stress, direct viral infection, and direct cytolytic β-cell damage. Anti-inflammatory therapies, including TNF-α inhibitors and nonsteroidal anti-inflammatory drugs, antioxidants such as the vitamin E family, nutritional intervention, physical activity, blood glucose control, and vaccination are proposed as preventive measures to minimize AD risk in COVID-19 patients. Since several risk factors for AD may converge during severe SARS-CoV-2 infection, neurologists should be alert for potential symptoms of AD and actively implement preventive measures in patients presenting with neuropsychiatric symptoms and in high-risk patients such as the elderly.
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Affiliation(s)
- Haili Wang
- Department of Clinical Medicine, Dalian Medical University, Dalian, 116000, Liaoning, China.,Department of Neurology, Clinical Medical College, Yangzhou University, Yangzhou, 225000, Jiangsu, China
| | - Juan Lu
- Department of Neuro Intensive Care Unit, Subei People's Hospital of Jiangsu Province, Yangzhou, 225000, Jiangsu, China
| | - Xia Zhao
- Department of Emergency Medicine, Subei People's Hospital of Jiangsu Province, Yangzhou, 225000, Jiangsu, China
| | - Rongyin Qin
- Department of Neurology, Shanghai General Hospital (Jiading District), Jiading, Shanghai, 201812, China
| | - Kangping Song
- Department of Neurology, Institute of Clinical Neuroscience, The First Affiliated Hospital, Jinan University, Guangzhou, 510632, Guangdong, China
| | - Yao Xu
- Department of Neurology, Clinical Medical College, Yangzhou University, Yangzhou, 225000, Jiangsu, China
| | - Jun Zhang
- Department of Neurosurgery, Huashan Hospital, Fudan University, Jingan, Shanghai, 200040, China.
| | - Yingzhu Chen
- Department of Neurology, Clinical Medical College, Yangzhou University, Yangzhou, 225000, Jiangsu, China.
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32
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El Sayed NS, Kandil EA, Ghoneum MH. Probiotics Fermentation Technology, a Novel Kefir Product, Ameliorates Cognitive Impairment in Streptozotocin-Induced Sporadic Alzheimer's Disease in Mice. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2021; 2021:5525306. [PMID: 34306309 PMCID: PMC8282381 DOI: 10.1155/2021/5525306] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 02/01/2021] [Revised: 03/28/2021] [Accepted: 06/04/2021] [Indexed: 12/25/2022]
Abstract
Alzheimer's disease (AD) is a neurodegenerative disease characterized by cognitive impairment. Gut microbiota dysfunction (dysbiosis) is implicated in the pathology of AD and is associated with several detrimental consequences, including neurotransmitter depletion, oxidative stress, inflammation, apoptosis, and insulin resistance, which all contribute to the onset of AD. The objective of this study was to assess the effectiveness of Probiotics Fermentation Technology (PFT), a kefir product, in alleviating AD symptoms via regulation of the gut microbiota using a streptozotocin- (STZ-) induced AD mouse model and to compare its activity with simvastatin, which has been proven to effectively treat AD. Mice received one intracerebroventricular injection of STZ (3 mg/kg). PFT (100, 300, 600 mg/kg) and simvastatin (20 mg/kg) were administered orally for 3 weeks. PFT supplementation mitigated STZ-induced neuronal degeneration in the cortex and hippocampus, restored hippocampal acetylcholine levels, and improved cognition in a dose-dependent manner. These effects were accompanied by reductions in oxidative damage, proinflammatory cytokine expression, apoptosis, and tau hyperphosphorylation. Moreover, PFT hindered amyloid plaque accumulation via the enhancement of insulin-degrading enzyme. These beneficial effects were comparable to those produced by simvastatin. The results suggest that PFT can alleviate AD symptoms by regulating the gut microbiota and by inhibiting AD-related pathological events.
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Affiliation(s)
- Nesrine S. El Sayed
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Cairo University, Cairo, Egypt
| | - Esraa A. Kandil
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Cairo University, Cairo, Egypt
| | - Mamdooh H. Ghoneum
- Department of Surgery, Charles R. Drew University of Medicine and Science, Los Angeles, California, USA
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Zhang Z, Zhang Y, Li J, Fu C, Zhang X. The Neuroprotective Effect of Tea Polyphenols on the Regulation of Intestinal Flora. Molecules 2021; 26:molecules26123692. [PMID: 34204244 PMCID: PMC8233780 DOI: 10.3390/molecules26123692] [Citation(s) in RCA: 30] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/18/2021] [Revised: 06/11/2021] [Accepted: 06/14/2021] [Indexed: 12/12/2022] Open
Abstract
Tea polyphenols (TPs) are the general compounds of natural polyhydroxyphenols extracted in tea. Although a large number of studies have shown that TPs have obvious neuroprotective and neuro repair effects, they are limited due to the low bioavailability in vivo. However, TPs can act indirectly on the central nervous system by affecting the “microflora–gut–brain axis”, in which the microbiota and its composition represent a factor that determines brain health. Bidirectional communication between the intestinal microflora and the brain (microbe–gut–brain axis) occurs through a variety of pathways, including the vagus nerve, immune system, neuroendocrine pathways, and bacteria-derived metabolites. This axis has been shown to influence neurotransmission and behavior, which is usually associated with neuropsychiatric disorders. In this review, we discuss that TPs and their metabolites may provide benefits by restoring the imbalance of intestinal microbiota and that TPs are metabolized by intestinal flora, to provide a new idea for TPs to play a neuroprotective role by regulating intestinal flora.
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Affiliation(s)
- Zhicheng Zhang
- Key Laboratory of Conservation Biology for Endangered Wildlife of the Ministry of Education, College of Life Sciences, Zhejiang University, Hangzhou 310058, China;
- Taizhou Biomedical Industry Research Institute Co., Ltd., Taizhou 317000, China
- College of Life Sciences, Taizhou University, Taizhou 317000, China
| | - Yuting Zhang
- Department of Food Science and Engineering, Ningbo University, Ningbo 315211, China;
| | - Junmin Li
- Taizhou Biomedical Industry Research Institute Co., Ltd., Taizhou 317000, China
- College of Life Sciences, Taizhou University, Taizhou 317000, China
- Correspondence: (J.L.); (C.F.); (X.Z.)
| | - Chengxin Fu
- Key Laboratory of Conservation Biology for Endangered Wildlife of the Ministry of Education, College of Life Sciences, Zhejiang University, Hangzhou 310058, China;
- Correspondence: (J.L.); (C.F.); (X.Z.)
| | - Xin Zhang
- Department of Food Science and Engineering, Ningbo University, Ningbo 315211, China;
- Correspondence: (J.L.); (C.F.); (X.Z.)
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34
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Bhuiyan P, Chen Y, Karim M, Dong H, Qian Y. Bidirectional communication between mast cells and the gut-brain axis in neurodegenerative diseases: Avenues for therapeutic intervention. Brain Res Bull 2021; 172:61-78. [PMID: 33892083 DOI: 10.1016/j.brainresbull.2021.04.010] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/10/2020] [Revised: 03/02/2021] [Accepted: 04/17/2021] [Indexed: 12/12/2022]
Abstract
Although the global incidence of neurodegenerative diseases has been steadily increasing, especially in adults, there are no effective therapeutic interventions. Neurodegeneration is a heterogeneous group of disorders that is characterized by the activation of immune cells in the central nervous system (CNS) (e.g., mast cells and microglia) and subsequent neuroinflammation. Mast cells are found in the brain and the gastrointestinal tract and play a role in "tuning" neuroimmune responses. The complex bidirectional communication between mast cells and gut microbiota coordinates various dynamic neuro-cellular responses, which propagates neuronal impulses from the gastrointestinal tract into the CNS. Numerous inflammatory mediators from degranulated mast cells alter intestinal gut permeability and disrupt blood-brain barrier, which results in the promotion of neuroinflammatory processes leading to neurological disorders, thereby offsetting the balance in immune-surveillance. Emerging evidence supports the hypothesis that gut-microbiota exert a pivotal role in inflammatory signaling through the activation of immune and inflammatory cells. Communication between inflammatory cytokines and neurocircuits via the gut-brain axis (GBA) affects behavioral responses, activates mast cells and microglia that causes neuroinflammation, which is associated with neurological diseases. In this comprehensive review, we focus on what is currently known about mast cells and the gut-brain axis relationship, and how this relationship is connected to neurodegenerative diseases. We hope that further elucidating the bidirectional communication between mast cells and the GBA will not only stimulate future research on neurodegenerative diseases but will also identify new opportunities for therapeutic interventions.
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Affiliation(s)
- Piplu Bhuiyan
- Department of Anesthesiology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu, 210029, PR China
| | - Yinan Chen
- Department of Anesthesiology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu, 210029, PR China
| | - Mazharul Karim
- College of Pharmacy, Western University of Health Science, 309 East 2nd Street, Pomona, CA, 91766, USA
| | - Hongquan Dong
- Department of Anesthesiology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu, 210029, PR China.
| | - Yanning Qian
- Department of Anesthesiology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu, 210029, PR China.
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Marine Natural Products: Promising Candidates in the Modulation of Gut-Brain Axis towards Neuroprotection. Mar Drugs 2021; 19:md19030165. [PMID: 33808737 PMCID: PMC8003567 DOI: 10.3390/md19030165] [Citation(s) in RCA: 25] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2021] [Revised: 03/16/2021] [Accepted: 03/17/2021] [Indexed: 12/14/2022] Open
Abstract
In recent decades, several neuroprotective agents have been provided in combating neuronal dysfunctions; however, no effective treatment has been found towards the complete eradication of neurodegenerative diseases. From the pathophysiological point of view, growing studies are indicating a bidirectional relationship between gut and brain termed gut-brain axis in the context of health/disease. Revealing the gut-brain axis has survived new hopes in the prevention, management, and treatment of neurodegenerative diseases. Accordingly, introducing novel alternative therapies in regulating the gut-brain axis seems to be an emerging concept to pave the road in fighting neurodegenerative diseases. Growing studies have developed marine-derived natural products as hopeful candidates in a simultaneous targeting of gut-brain dysregulated mediators towards neuroprotection. Of marine natural products, carotenoids (e.g., fucoxanthin, and astaxanthin), phytosterols (e.g., fucosterol), polysaccharides (e.g., fucoidan, chitosan, alginate, and laminarin), macrolactins (e.g., macrolactin A), diterpenes (e.g., lobocrasol, excavatolide B, and crassumol E) and sesquiterpenes (e.g., zonarol) have shown to be promising candidates in modulating gut-brain axis. The aforementioned marine natural products are potential regulators of inflammatory, apoptotic, and oxidative stress mediators towards a bidirectional regulation of the gut-brain axis. The present study aims at describing the gut-brain axis, the importance of gut microbiota in neurological diseases, as well as the modulatory role of marine natural products towards neuroprotection.
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Lee Y, Kim YK. Understanding the Connection Between the Gut-Brain Axis and Stress/Anxiety Disorders. Curr Psychiatry Rep 2021; 23:22. [PMID: 33712947 DOI: 10.1007/s11920-021-01235-x] [Citation(s) in RCA: 24] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 02/23/2021] [Indexed: 12/17/2022]
Abstract
PURPOSE OF REVIEW We review the association of the microbiota-gut-brain axis and anxiety disorder or stress. RECENT FINDING The microbiota-gut-brain axis mechanism encompasses a bidirectional relationship between the brain and gastrointestinal organs. Dysregulation of the microbiota-gut-brain axis has been actively revealed in the context of various psychiatric diseases such as neurodevelopmental disorders, schizophrenia, anxiety disorders, and depression. We suggest that onset of anxiety disorders may be correlated with activation of a microbiota-gut-brain mechanism involving the immune system, neurotransmitters, and the hormonal system. By applying a microbiota-gut-brain axis mechanism, the possibility of using gastrointestinal system drugs such as probiotics and antibiotics as treatments for anxiety disorders is a possibility. Although modification of the microbiota-gut-brain axis mechanism has yet to be adopted clinically, it is expected that novel strategies employing this mechanism will be developed and deployed as new treatments not only for anxiety disorders, but also other psychiatric diseases.
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Affiliation(s)
- Younjung Lee
- Department of Psychiatry, Gyeongsang National University School of Medicine and Gyeongsang National University Hospital, Jinju, 52727, Republic of Korea
| | - Yong-Ku Kim
- Department of Psychiatry, Korea University Ansan Hospital, Korea University College of Medicine, Ansan, 15355, Republic of Korea.
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Tang W, Meng Z, Li N, Liu Y, Li L, Chen D, Yang Y. Roles of Gut Microbiota in the Regulation of Hippocampal Plasticity, Inflammation, and Hippocampus-Dependent Behaviors. Front Cell Infect Microbiol 2021; 10:611014. [PMID: 33585279 PMCID: PMC7873527 DOI: 10.3389/fcimb.2020.611014] [Citation(s) in RCA: 39] [Impact Index Per Article: 9.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/02/2020] [Accepted: 12/08/2020] [Indexed: 12/18/2022] Open
Abstract
The study of the gut microbiota-brain axis has become an intriguing field, attracting attention from both gastroenterologists and neurobiologists. The hippocampus is the center of learning and memory, and plays a pivotal role in neurodegenerative diseases, such as Alzheimer’s disease (AD). Previous studies using diet administration, antibiotics, probiotics, prebiotics, germ-free mice, and fecal analysis of normal and specific pathogen-free animals have shown that the structure and function of the hippocampus are affected by the gut microbiota. Furthermore, hippocampal pathologies in AD are positively correlated with changes in specific microbiota. Genomic and neurochemical analyses revealed significant alterations in genes and amino acids in the hippocampus of AD subjects following a remarkable shift in the gut microbiota. In a recent study, when young animals were transplanted with fecal microbiota derived from AD patients, the recipients showed significant impairment of cognitive behaviors, AD pathologies, and changes in neuronal plasticity and cytokines. Other studies have demonstrated the side effects of antibiotic administration along with the beneficial effects of probiotics, prebiotics, and specific diets on the composition of the gut microbiota and hippocampal functions, but these have been mostly preliminary with unclear mechanisms. Since some specific gut bacteria are positively or negatively correlated to the structure and function of the hippocampus, it is expected that specific gut bacteria administration and other microbiota-based interventions could be potentially applied to prevent or treat hippocampus-based memory impairment and neuropsychiatric disorders such as AD.
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Affiliation(s)
- Wen Tang
- Department of Gastroenterology, Daping Hospital, Army Medical University, Chongqing, China
| | - Zhaoyou Meng
- Department of Neurology, Xinqiao Hospital, Army Medical University, Chongqing, China
| | - Ning Li
- Department of Gastroenterology, Daping Hospital, Army Medical University, Chongqing, China
| | - Yiyan Liu
- College of Basic Medicine, Army Medical University, Chongqing, China
| | - Li Li
- Department of Gastroenterology, The First People's Hospital in Chongqing Liangjiang New Area, Chongqing, China
| | - Dongfeng Chen
- Department of Gastroenterology, Daping Hospital, Army Medical University, Chongqing, China
| | - Yang Yang
- Department of Gastroenterology, Daping Hospital, Army Medical University, Chongqing, China
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García-Cabrerizo R, Carbia C, O Riordan KJ, Schellekens H, Cryan JF. Microbiota-gut-brain axis as a regulator of reward processes. J Neurochem 2021; 157:1495-1524. [PMID: 33368280 DOI: 10.1111/jnc.15284] [Citation(s) in RCA: 81] [Impact Index Per Article: 20.3] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/19/2020] [Revised: 12/08/2020] [Accepted: 12/21/2020] [Indexed: 12/14/2022]
Abstract
Our gut harbours trillions of microorganisms essential for the maintenance of homeostasis and host physiology in health and disease. In the last decade, there has been a growing interest in understanding the bidirectional pathway of communication between our microbiota and the central nervous system. With regard to reward processes there is accumulating evidence from both animal and human studies that this axis may be a key factor in gating reward valence. Focusing on the mesocorticolimbic pathway, we will discuss how the intestinal microbiota is involved in regulating brain reward functions, both in natural (i.e. eating, social or sexual behaviours) and non-natural reinforcers (drug addiction behaviours including those relevant to alcohol, psychostimulants, opioids and cannabinoids). We will integrate preclinical and clinical evidence suggesting that the microbiota-gut-brain axis could be implicated in the development of disorders associated with alterations in the reward system and how it may be targeted as a promising therapeutic strategy. Cover Image for this issue: https://doi.org/10.1111/jnc.15065.
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Affiliation(s)
| | - Carina Carbia
- APC Microbiome Ireland, University College Cork, Cork, Ireland
| | | | - Harriet Schellekens
- APC Microbiome Ireland, University College Cork, Cork, Ireland.,Department of Anatomy and Neuroscience, University College Cork, Cork, Ireland
| | - John F Cryan
- APC Microbiome Ireland, University College Cork, Cork, Ireland.,Department of Anatomy and Neuroscience, University College Cork, Cork, Ireland
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Ao W, Cheng Y, Chen M, Wei F, Yang G, An Y, Mao F, Zhu X, Mao G. Intrinsic brain abnormalities of irritable bowel syndrome with diarrhea: a preliminary resting-state functional magnetic resonance imaging study. BMC Med Imaging 2021; 21:4. [PMID: 33407222 PMCID: PMC7788841 DOI: 10.1186/s12880-020-00541-9] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/27/2020] [Accepted: 12/22/2020] [Indexed: 02/08/2023] Open
Abstract
Background The aim of the present study was to explore the brain active characteristics of patients with irritable bowel syndrome with diarrhea (IBS-D) using resting-state functional magnetic resonance imaging technology. Methods Thirteen IBS-D patients and fourteen healthy controls (HC) were enrolled. All subjects underwent head MRI examination during resting state. A voxel-based analysis of fractional amplitude of low frequency fluctuation (fALFF) maps between IBS-D and HC was performed using a two-sample t-test. The relationship between the fALFF values in abnormal brain regions and the scores of Symptom Severity Scale (IBS-SSS) were analyzed using Pearson correlation analysis. Results Compared with HC, IBS-D patients had lower fALFF values in the left medial superior frontal gyrus and higher fALFF values in the left hippocampus and right precuneus. There was a positive correlation between the duration scores of IBS-SSS and fALFF values in the right precuneus. Conclusion The altered fALFF values in the medial superior frontal gyri, left hippocampus and right precuneus revealed changes of intrinsic neuronal activity, further revealing the abnormality of gut-brain axis of IBS-D.
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Affiliation(s)
- Weiqun Ao
- Department of Radiology, Tongde Hospital of Zhejiang Province, Hangzhou, 310012, Zhejiang Province, China
| | - Yougen Cheng
- Department of Radiology, Tongde Hospital of Zhejiang Province, Hangzhou, 310012, Zhejiang Province, China
| | - Mingxian Chen
- Department of Gastroenterology, Tongde Hospital of Zhejiang Province, Hangzhou, 310012, Zhejiang Province, China
| | - Fuquan Wei
- Department of Radiology, Tongde Hospital of Zhejiang Province, Hangzhou, 310012, Zhejiang Province, China
| | - Guangzhao Yang
- Department of Radiology, Tongde Hospital of Zhejiang Province, Hangzhou, 310012, Zhejiang Province, China
| | - Yongyu An
- Department of Radiology, Tongde Hospital of Zhejiang Province, Hangzhou, 310012, Zhejiang Province, China
| | - Fan Mao
- Department of Radiology, Tongde Hospital of Zhejiang Province, Hangzhou, 310012, Zhejiang Province, China
| | - Xiandi Zhu
- Department of Radiology, Tongde Hospital of Zhejiang Province, Hangzhou, 310012, Zhejiang Province, China
| | - Guoqun Mao
- Department of Radiology, Tongde Hospital of Zhejiang Province, Hangzhou, 310012, Zhejiang Province, China.
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Haran JP, McCormick BA. Aging, Frailty, and the Microbiome-How Dysbiosis Influences Human Aging and Disease. Gastroenterology 2021; 160:507-523. [PMID: 33307030 PMCID: PMC7856216 DOI: 10.1053/j.gastro.2020.09.060] [Citation(s) in RCA: 101] [Impact Index Per Article: 25.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/27/2020] [Revised: 09/08/2020] [Accepted: 09/16/2020] [Indexed: 02/07/2023]
Abstract
The human gut microbiome is a collection of bacteria, protozoa, fungi, and viruses that coexist in our bodies and are essential in protective, metabolic, and physiologic functions of human health. Gut dysbiosis has traditionally been linked to increased risk of infection, but imbalances within the intestinal microbial community structure that correlate with untoward inflammatory responses are increasingly recognized as being involved in disease processes that affect many organ systems in the body. Furthermore, it is becoming more apparent that the connection between gut dysbiosis and age-related diseases may lie in how the gut microbiome communicates with both the intestinal mucosa and the systemic immune system, given that these networks have a common interconnection to frailty. We therefore discuss recent advances in our understanding of the important role the microbiome plays in aging and how this knowledge opens the door for potential novel therapeutics aimed at shaping a less dysbiotic microbiome to prevent or treat age-related diseases.
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Affiliation(s)
- John P Haran
- Department of Emergency Medicine; Department of Microbiology and Physiological Systems; Center for Microbiome Research, University of Massachusetts Medical School, Worcester, Massachusetts.
| | - Beth A McCormick
- Department of Microbiology and Physiological Systems; Center for Microbiome Research, University of Massachusetts Medical School, Worcester, Massachusetts
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Borsom EM, Lee K, Cope EK. Do the Bugs in Your Gut Eat Your Memories? Relationship between Gut Microbiota and Alzheimer's Disease. Brain Sci 2020; 10:E814. [PMID: 33153085 PMCID: PMC7693835 DOI: 10.3390/brainsci10110814] [Citation(s) in RCA: 20] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/02/2020] [Revised: 10/29/2020] [Accepted: 10/31/2020] [Indexed: 02/06/2023] Open
Abstract
The human microbiota is composed of trillions of microbial cells inhabiting the oral cavity, skin, gastrointestinal (GI) tract, airways, and reproductive organs. The gut microbiota is composed of dynamic communities of microorganisms that communicate bidirectionally with the brain via cytokines, neurotransmitters, hormones, and secondary metabolites, known as the gut microbiota-brain axis. The gut microbiota-brain axis is suspected to be involved in the development of neurological diseases, including Alzheimer's disease (AD), Parkinson's disease, and Autism Spectrum Disorder. AD is an irreversible, neurodegenerative disease of the central nervous system (CNS), characterized by amyloid-β plaques, neurofibrillary tangles, and neuroinflammation. Microglia and astrocytes, the resident immune cells of the CNS, play an integral role in AD development, as neuroinflammation is a driving factor of disease severity. The gut microbiota-brain axis is a novel target for Alzheimer's disease therapeutics to modulate critical neuroimmune and metabolic pathways. Potential therapeutics include probiotics, prebiotics, fecal microbiota transplantation, and dietary intervention. This review summarizes our current understanding of the role of the gut microbiota-brain axis and neuroinflammation in the onset and development of Alzheimer's disease, limitations of current research, and potential for gut microbiota-brain axis targeted therapies.
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Inactive bowel movement and stroke are associated with increased risks of mild cognitive impairment among community-living Singapore elderly. Aging (Albany NY) 2020; 12:17257-17270. [PMID: 32903214 PMCID: PMC7521501 DOI: 10.18632/aging.103674] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/03/2020] [Accepted: 06/29/2020] [Indexed: 01/24/2023]
Abstract
Mild cognitive impairment (MCI), as a preclinical phase of dementia, provides an invaluable time window for intervention. Besides several proposed modifiable risk factors, the associations of MCI with dietary habits and bowel movement are not well clarified. We thus conducted a cross-sectional study of community-living Singapore elderly and focused on the relationship of clinically diagnosed MCI with dietary habits and bowel movement frequencies. The multiple logistic regression results showed that frequent (≥4 days per week) fruit consumption (P = 0.004), active (≥4 days per week) bowel movement within 10 minutes (P = 0.027), and years of schooling were negatively associated with MCI occurrence. In contrast, medical comorbidities including hypertension, stroke, and cataract/glaucoma were found to be risk factors. Furthermore, a Bayesian network model of causal inference detected five hypothesized causal-association paths leading to MCI, namely bowel movement, stroke, years of schooling via fruit consumption, hypertension via stroke and hypertension via cataract/glaucoma. The combination of the two direct factors (inactive bowel movement and stroke) reached a maximum conditional probability of 60.00% for MCI occurrence. Taken together, this study was the first to link bowel movement with MCI occurrence. In addition, it suggested five modifiable hypothesized causal-association paths to MCI.
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Noonan S, Zaveri M, Macaninch E, Martyn K. Food & mood: a review of supplementary prebiotic and probiotic interventions in the treatment of anxiety and depression in adults. BMJ Nutr Prev Health 2020; 3:351-362. [PMID: 33521545 PMCID: PMC7841823 DOI: 10.1136/bmjnph-2019-000053] [Citation(s) in RCA: 36] [Impact Index Per Article: 7.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/18/2019] [Revised: 02/19/2020] [Accepted: 02/23/2020] [Indexed: 02/06/2023] Open
Abstract
Background A bidirectional relationship exists between the brain and the gastrointestinal tract. Foods containing bacteria that positively influence the gastrointestinal microbiome are termed, probiotics; compounds that promote the flourishing of these bacteria are termed, prebiotics. Whether microbiome influencing therapies could treat psychiatric conditions, including depression and anxiety, is an area of interest. Presently, no established consensus for such treatment exists. Methods This systematic review analyses databases and grey literature sites to investigate pre and/or probiotics as treatments for depression and/or anxiety disorders. Articles included are from within 15 years. Pre-determined inclusion exclusion criteria were applied, and articles were appraised for their quality using a modified-CASP checklist. This review focuses specifically on quantitative measures from patients with clinical diagnoses of depression and/or anxiety disorders. Results 7 studies were identified. All demonstrated significant improvements in one or more of the outcomes measuring the of effect taking pre/probiotics compared with no treatment/placebo, or when compared to baseline measurements. Discussion Our review suggests utilising pre/probiotic may be a potentially useful adjunctive treatment. Furthermore, patients with certain co-morbidities, such as IBS, might experience greater benefits from such treatments, given that pre/probiotic are useful treatments for other conditions that were not the primary focus of this discourse. Our results are limited by several factors: sample sizes (adequate, though not robust); short study durations, long-term effects and propensity for remission undetermined. Conclusion Our results affirm that pre/probiotic therapy warrants further investigation. Efforts should aim to elucidate whether the perceived efficacy of pre/probiotic therapy in depression and/or anxiety disorders can be replicated in larger test populations, and whether such effects are maintained through continued treatment, or post cessation. Interventions should also be investigated in isolation, not combination, to ascertain where the observed effects are attributable to. Efforts to produce mechanistic explanations for such effect should be a priority.
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Affiliation(s)
| | | | - Elaine Macaninch
- Nutrition and dietetics, Brighton and Sussex University Hospitals NHS Trust, Brighton, East Sussex, UK
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Spinelli M, Fusco S, Grassi C. Brain insulin resistance impairs hippocampal plasticity. VITAMINS AND HORMONES 2020; 114:281-306. [PMID: 32723548 DOI: 10.1016/bs.vh.2020.04.005] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Nutrient-related signals have been demonstrated to influence brain development and cognitive functions. In particular, insulin signaling has been shown to impact on molecular cascades underlying hippocampal plasticity, learning and memory. Alteration of brain insulin signaling interferes with the maintenance of neural stem cell niche and neuronal activity in the hippocampus. Brain insulin resistance is also emerging as key factor causing the cognitive impairment observed in metabolic and neurodegenerative diseases. Here, we review the molecular mechanisms involved in the insulin modulation of both adult neurogenesis and synaptic activity in the hippocampus. We also summarize the effects of altered insulin sensitivity on hippocampal plasticity. Finally, we reassume the experimental and epidemiological evidence highlighting the critical role of brain insulin resistance at the crossroad between type 2 diabetes and Alzheimer's disease.
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Affiliation(s)
- Matteo Spinelli
- Department of Neuroscience, Università Cattolica del Sacro Cuore, Rome, Italy
| | - Salvatore Fusco
- Department of Neuroscience, Università Cattolica del Sacro Cuore, Rome, Italy; Fondazione Policlinico Universitario A. Gemelli IRCCS, Rome, Italy.
| | - Claudio Grassi
- Department of Neuroscience, Università Cattolica del Sacro Cuore, Rome, Italy; Fondazione Policlinico Universitario A. Gemelli IRCCS, Rome, Italy.
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Bellavite P. Causality assessment of adverse events following immunization: the problem of multifactorial pathology. F1000Res 2020; 9:170. [PMID: 32269767 PMCID: PMC7111503 DOI: 10.12688/f1000research.22600.1] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 03/04/2020] [Indexed: 07/22/2023] Open
Abstract
The analysis of Adverse Events Following Immunization (AEFI) is important in a balanced epidemiological evaluation of vaccines and in the issues related to national vaccine injury compensation programs. If manufacturing defects or vaccine storage and delivering errors are excluded, the majority of adverse reactions to vaccines occur as excessive or biased inflammatory and immune responses. These unwanted phenomena, occasionally severe, are associated with many different endogenous and exogenous factors, which often interact in complex ways. The confirmation or denial of the causal link between an AEFI and vaccination is determined pursuant to WHO guidelines, which propose a four-step analysis and algorithmic diagramming. The evaluation process from the onset considers all possible "other causes" that can explain the AEFI and thus exclude the role of the vaccine. Subsequently, even if there was biological plausibility and temporal compatibility for a causal association between the vaccine and the AEFI, the guidelines ask to look for any possible evidence that the vaccine could not have caused that event. Such an algorithmic method presents some concerns that are discussed here, in the light of the multifactorial nature of the inflammatory and immune pathologies induced by vaccines, including emerging knowledge of genetic susceptibility to adverse effects. It is proposed that the causality assessment could exclude a consistent association of the adverse event with the vaccine only when the presumed "other cause" is independent of an interaction with the vaccine. Furthermore, the scientific literature should be viewed not as an exclusion criterion but as a comprehensive analysis of all the evidence for or against the role of the vaccine in causing an adverse reaction. These issues are discussed in relation to the laws that, in some countries, regulate the mandatory vaccinations and the compensation for those who have suffered serious adverse effects.
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Affiliation(s)
- Paolo Bellavite
- Department of Medicine, Section of General Pathology, University of Verona Medical School, Verona, 37134, Italy
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Abstract
The analysis of Adverse Events Following Immunization (AEFI) is important in a balanced epidemiological evaluation of vaccines and in the issues related to vaccine injury compensation programs. The majority of adverse reactions to vaccines occur as excessive or biased inflammatory and immune responses. These unwanted phenomena, occasionally severe, are associated with many different endogenous and exogenous factors, which often interact in complex ways. The confirmation or denial of the causal link between an AEFI and vaccination is determined pursuant to WHO guidelines, which propose a four-step analysis and algorithmic diagramming. The evaluation process from the onset considers all possible "other causes" that might explain the AEFI and thus exclude the role of the vaccine. Subsequently, even if there was biological plausibility and temporal compatibility for a causal association between the vaccine and the AEFI, the guidelines ask to look for any possible evidence that the vaccine could not have caused that event. Such an algorithmic method presents several concerns that are discussed here, in the light of the multifactorial nature of the inflammatory and immune pathologies induced by vaccines, including emerging knowledge of genetic susceptibility to adverse effects. It is proposed that the causality assessment could exclude a consistent association of the adverse event with the vaccine only when the presumed "other cause" is independent of an interaction with the vaccine. Furthermore, the scientific literature should be viewed not as an exclusion criterion but as a comprehensive analysis of all the evidence for or against the role of the vaccine in causing an adverse reaction. Given these inadequacies in the evaluation of multifactorial diseases, the WHO guidelines need to be reevaluated and revised. These issues are discussed in relation to the laws that, in some countries, regulate the mandatory vaccinations and the compensation for those who have suffered serious adverse effects.
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Affiliation(s)
- Paolo Bellavite
- Department of Medicine, Section of General Pathology, University of Verona Medical School, Verona, 37134, Italy
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Liao JY, Lee CTC, Lin TY, Liu CM. Exploring prior diseases associated with incident late-onset Alzheimer's disease dementia. PLoS One 2020; 15:e0228172. [PMID: 31978130 PMCID: PMC6980504 DOI: 10.1371/journal.pone.0228172] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/13/2019] [Accepted: 01/08/2020] [Indexed: 02/06/2023] Open
Abstract
Studies have identified prior conditions associated with late-onset Alzheimer's disease dementia (LOAD), but all prior diseases have rarely been screened simultaneously in the literature. Our objective in the present study was to identify prior conditions associated with LOAD and construct pathways for them. We conducted a population-based matched case-control study based on data collected in the National Health Insurance Research database of Taiwan and the Catastrophic Illness Certificate database for the years 1997-2013. Prior diseases definitions were based on the first three digits of the codes listed in the International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM). Inclusion criteria required that each ICD-code existed for at least 1 year and incurred at least 2 outpatient visits or inpatient diagnosis. The case group comprised 4,600 patients newly diagnosed with LOAD in 2007-2013. The LOAD patients were matched by sex and age to obtain 4,600 controls. Using stepwise multivariate logistic regression analysis, diseases were screened for 1, 2 …, 9 years prior to the first diagnosis of LOAD. Path analysis was used to construct pathways between prior diseases and LOAD. Our results revealed that the following conditions were positively associated with the incidence of LOAD: anxiety (ICD-code 300), functional digestive disorder (ICD code 564), psychopathology-specific symptoms (ICD-code 307), disorders of the vestibular system (ICD-code 386), concussion (ICD-code 850), disorders of the urethra and urinary tract (ICD-code 599), disorders of refraction and accommodation (ICD-code 367), and hearing loss (ICD-code 389). A number of the prior diseases have previously been described in the literature in a manner identical to that in the present study. Our study supports the assertion that mental, hearing, vestibular system, and functional digestive disorders may play an important role in the pathogenesis of LOAD.
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Affiliation(s)
- Jung-Yu Liao
- Department of Health Promotion and Health Education, National Taiwan Normal University, Taipei, Taiwan
| | - Charles Tzu-Chi Lee
- Department of Health Promotion and Health Education, National Taiwan Normal University, Taipei, Taiwan
| | - Tsung-Yi Lin
- Department of Health Promotion and Health Education, National Taiwan Normal University, Taipei, Taiwan
- Department of Marketing and Distribution Management, Hsing Wu University, New Taipei City, Taiwan
| | - Chin-Mei Liu
- Department of Health Promotion and Health Education, National Taiwan Normal University, Taipei, Taiwan
- Taiwan Centers for Disease Control, Taipei, Taiwan
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Mathee K, Cickovski T, Deoraj A, Stollstorff M, Narasimhan G. The gut microbiome and neuropsychiatric disorders: implications for attention deficit hyperactivity disorder (ADHD). J Med Microbiol 2020; 69:14-24. [PMID: 31821133 PMCID: PMC7440676 DOI: 10.1099/jmm.0.001112] [Citation(s) in RCA: 35] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/08/2019] [Accepted: 11/01/2019] [Indexed: 12/11/2022] Open
Abstract
Neuropsychiatric disorders (NPDs) such as depression, anxiety, bipolar disorder, autism spectrum disorder (ASD) and attention deficit hyperactivity disorder (ADHD) all relate to behavioural, cognitive and emotional disturbances that are ultimately rooted in disordered brain function. More specifically, these disorders are linked to various neuromodulators (i.e. serotonin and dopamine), as well as dysfunction in both cognitive and socio-affective brain networks. Increasing evidence suggests that the gut environment, and particularly the microbiome, plays a significant role in individual mental health. Although the presence of a gut-brain communication axis has long been established, recent studies argue that the development and regulation of this axis is dictated by the gut microbiome. Many studies involving both animals and humans have connected the gut microbiome with depression, anxiety and ASD. Microbiome-centred treatments for individuals with these same NPDs have yielded promising results. Despite its recent rise and underlying similarities to other NPDs, both biochemically and symptomatically, connections between the gut microbiome and ADHD currently lag behind those for other NPDs. We demonstrate that all evidence points to the importance of, and dire need for, a comprehensive and in-depth analysis of the role of the gut microbiome in ADHD, to deepen our understanding of a condition that affects millions of individuals worldwide.
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Affiliation(s)
- Kalai Mathee
- Department of Human and Molecular Genetics, Herbert Wertheim College of Medicine, Florida International University, Florida, USA
| | - Trevor Cickovski
- Bioinformatics Research Group (BioRG), School of Computing and Information Sciences, Florida International University, Florida, USA
| | - Alok Deoraj
- Department of Environmental and Occupational Health, Robert Stempel College of Public Health and Social Work, Florida International University, Florida, USA
| | - Melanie Stollstorff
- Department of Psychology, College of Arts, Science and Education, Florida International University, Florida, USA
| | - Giri Narasimhan
- Bioinformatics Research Group (BioRG), School of Computing and Information Sciences, Florida International University, Florida, USA
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Hirshman NA, Hughes FM, Jin H, Harrison WT, White SW, Doan I, Harper SN, Leidig PD, Purves JT. Cyclophosphamide-induced cystitis results in NLRP3-mediated inflammation in the hippocampus and symptoms of depression in rats. Am J Physiol Renal Physiol 2019; 318:F354-F362. [PMID: 31869244 DOI: 10.1152/ajprenal.00408.2019] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/12/2023] Open
Abstract
Recent breakthroughs demonstrate that peripheral diseases can trigger inflammation in the brain, causing psychosocial maladies, including depression. While few direct studies have been made, anecdotal reports associate urological disorders with mental dysfunction. Thus, we investigated if insults targeted at the bladder might elicit behavioral alterations. Moreover, the mechanism of neuroinflammation elicited by other peripheral diseases involves the NOD-like receptor family pyrin domain containing 3 (NLRP3) inflammasome, which is present in microglia in the brain and cleaves and activates proinflammatory cytokines such as IL-1β. Thus, we further explored the importance of NLRP3 in behavioral and neuroinflammatory changes. Here, we used the well-studied cyclophosphamide (CP)-treated rat model. Importantly, CP and its metabolites do not cross the blood-brain barrier or trigger inflammation in the gut, so that any neuroinflammation is likely secondary to bladder injury. We found that CP triggered an increase in inflammasome activity (caspase-1 activity) in the hippocampus but not in the pons. Evans blue extravasation demonstrated breakdown of the blood-brain barrier in the hippocampal region and activated microglia were present in the fascia dentata. Both changes were dependent on NLRP3 activation and prevented with 2-mercaptoethane sulfonate sodium (Mesna), which masks the effects of the CP metabolite acrolein in the urine. Finally, CP-treated rats displayed depressive symptoms that were prevented by NLRP3 inhibition or treatment with Mesna or an antidepressant. Thus, we conclude that CP-induced cystitis causes NLRP3-dependent hippocampal inflammation leading to depression symptoms in rats. This study proposes the first-ever causative explanation of the previously anecdotal link between benign bladder disorders and mood disorders.
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Affiliation(s)
- Nathan A Hirshman
- Division of Urology, Department of Surgery, Duke University Medical Center, Durham, North Carolina
| | - Francis M Hughes
- Division of Urology, Department of Surgery, Duke University Medical Center, Durham, North Carolina.,Department of Bioengineering, Clemson University, Clemson, South Carolina
| | - Huixia Jin
- Division of Urology, Department of Surgery, Duke University Medical Center, Durham, North Carolina
| | - William T Harrison
- Department of Pathology, Duke University Medical Center, Durham, North Carolina
| | - Simon W White
- Division of Urology, Department of Surgery, Duke University Medical Center, Durham, North Carolina
| | - Isabelle Doan
- Division of Urology, Department of Surgery, Duke University Medical Center, Durham, North Carolina
| | - Shelby N Harper
- Division of Urology, Department of Surgery, Duke University Medical Center, Durham, North Carolina
| | - Patrick D Leidig
- Division of Urology, Department of Surgery, Duke University Medical Center, Durham, North Carolina
| | - J Todd Purves
- Division of Urology, Department of Surgery, Duke University Medical Center, Durham, North Carolina.,Department of Bioengineering, Clemson University, Clemson, South Carolina.,Department of Pediatrics, Duke University Medical Center, Durham, North Carolina
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Vasefi M, Hudson M, Ghaboolian-Zare E. Diet Associated with Inflammation and Alzheimer's Disease. J Alzheimers Dis Rep 2019; 3:299-309. [PMID: 31867568 PMCID: PMC6918878 DOI: 10.3233/adr-190152] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022] Open
Abstract
Neurocognitive disorders, such as Alzheimer's disease (AD), affect millions of people worldwide and are characterized by cognitive decline. Human and animal studies have shown that chronic immune response and inflammation are important factors in the pathogenesis of AD. Chronic inflammation can accelerate the aggregation of amyloid-β peptides and later hyperphosphorylation of tau proteins. The exact etiology of AD is not clear, but genetics and environmental factors, such as age, family history, and lifestyle are linked to neurodegenerative diseases. Lifestyle habits, such as poor diet, are associated with inflammation and could accelerate or slow down the progression of neurodegenerative diseases. Here we provide a review of the potential conditions and factors that stimulate the inflammatory processes in AD. An understanding of inflammatory mechanisms influencing the development of AD may help to protect against dementia and AD.
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Affiliation(s)
- Maryam Vasefi
- Department of Biology, Lamar University, Beaumont, TX, USA
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