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Wang J, Wang X, Luo H, Xie Y, Cao H, Mao L, Liu T, Yue Y, Qian H. Extracellular vesicles in Helicobacter pylori-mediated diseases: mechanisms and therapeutic potential. Cell Commun Signal 2025; 23:79. [PMID: 39934861 DOI: 10.1186/s12964-025-02074-6] [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: 09/27/2024] [Accepted: 01/29/2025] [Indexed: 02/13/2025] Open
Abstract
Extracellular vesicles (EVs) are relevant elements for cell-to-cell communication and are considered crucial in host-pathogen interactions by transferring molecules between the pathogen and the host during infections. These structures participate in various physiological and pathological processes and are considered promising candidates as disease markers, therapeutic reagents, and drug carriers. Both H. pylori and the host epithelial cells infected by H. pylori secrete EVs, which contribute to inflammation and the development of disease phenotypes. However, many aspects of the cellular and molecular biology of EV functions remain incompletely understood due to methodological challenges in studying these small structures. This review also highlights the roles of EVs derived from H. pylori-infected cells in the pathogenesis of gastric and extragastric diseases. Understanding the specific functions of these EVs during H. pylori infections, whether are advantageous to the host or the pathogen, may help the development new therapeutic approaches to prevent disease.
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Affiliation(s)
- Jianjun Wang
- Department of Clinical Laboratory, Kunshan Hospital Affiliated to Jiangsu University, Suzhou, Jiangsu, 215300, China
| | - Xiuping Wang
- Department of Clinical Laboratory, Kunshan Hospital Affiliated to Jiangsu University, Suzhou, Jiangsu, 215300, China
| | - Hao Luo
- Department of Clinical Laboratory, The Second People's Hospital of Kunshan, Suzhou, Jiangsu, 215300, China
| | - Yiping Xie
- Department of Clinical Laboratory, Kunshan Hospital Affiliated to Jiangsu University, Suzhou, Jiangsu, 215300, China
| | - Hui Cao
- Department of Food and Nutrition Safety, Jiangsu Provincial Center for Disease Control and Prevention, Nanjing, Jiangsu, 210003, China
| | - Lingxiang Mao
- Department of Clinical Laboratory, Kunshan Hospital Affiliated to Jiangsu University, Suzhou, Jiangsu, 215300, China
| | - Tingting Liu
- Science and Technology Talent Department, Kunshan Hospital Affiliated to Jiangsu University, Suzhou, Jiangsu, 215300, China
| | - Yushan Yue
- Department of Rehabilitative Medicine, Kunshan Hospital Affiliated to Jiangsu University, Suzhou, Jiangsu, 215300, China
| | - Hui Qian
- Jiangsu Key Laboratory of Medical Science and Laboratory Medicine, Department of Laboratory Medicine, School of Medicine, Jiangsu University, 301 Xuefu Road, Zhengjiang, Jiangsu, 212013, China.
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2
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Grahl MVC, Hohl KS, Smaniotto T, Carlini CR. Microbial Trojan Horses: Virulence Factors as Key Players in Neurodegenerative Diseases. Molecules 2025; 30:687. [PMID: 39942791 PMCID: PMC11820544 DOI: 10.3390/molecules30030687] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2024] [Revised: 02/01/2025] [Accepted: 02/01/2025] [Indexed: 02/16/2025] Open
Abstract
Changes in population demographics indicate that the elderly population will reach 2.1 billion worldwide by 2050. In parallel, there will be an increase in neurodegenerative diseases such as Alzheimer's and Parkinson's. This review explores dysbiosis occurring in these pathologies and how virulence factors contribute to the worsening or development of clinical conditions, and it summarizes existing and potential ways to combat microorganisms related to these diseases. Microbiota imbalances can contribute to the progression of neurodegenerative diseases by increasing intestinal permeability, exchanging information through innervation, and even acting as a Trojan horse affecting immune cells. The microorganisms of the microbiota produce virulence factors to protect themselves from host defenses, many of which contribute to neurodegenerative diseases. These virulence factors are expressed according to the genetic composition of each microorganism, leading to a wide range of factors to be considered. Among the main virulence factors are LPS, urease, curli proteins, amyloidogenic proteins, VacA, and CagA. These factors can also be packed into bacterial outer membrane vesicles, which transport proteins, RNA, and DNA, enabling distal communication that impacts various diseases, including Alzheimer's and Parkinson's.
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Affiliation(s)
- Matheus V. C. Grahl
- Graduate Program in Medicine and Health Sciences, Pontifical Catholic University of Rio Grande do Sul, Porto Alegre 90619-900, RS, Brazil
| | - Kelvin Siqueira Hohl
- Graduate Program in Biochemistry, Institute of Health Basic Sciences, Federal University of Rio Grande do Sul, Porto Alegre 90035-003, RS, Brazil; (K.S.H.); (T.S.)
| | - Thiago Smaniotto
- Graduate Program in Biochemistry, Institute of Health Basic Sciences, Federal University of Rio Grande do Sul, Porto Alegre 90035-003, RS, Brazil; (K.S.H.); (T.S.)
| | - Célia R. Carlini
- Center of Biotechnology, Department of Biochemistry, Federal University of Rio Grande do Sul, Porto Alegre 91501-970, RS, Brazil
- Graduate Program of Biosciences, Federal University of Health Sciences of Porto Alegre, Porto Alegre 90050-170, RS, Brazil
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3
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Gao S, Li X, Han B. Bacterial and bacterial derivatives-based drug delivery systems: a novel approach for treating central nervous system disorders. Expert Opin Drug Deliv 2025; 22:163-180. [PMID: 39688950 DOI: 10.1080/17425247.2024.2444364] [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: 12/06/2024] [Revised: 12/13/2024] [Accepted: 12/16/2024] [Indexed: 12/19/2024]
Abstract
INTRODUCTION Bacteria and their derivatives show great potential as drug delivery systems due to their unique chemotaxis, biocompatibility, and targeting abilities. In CNS disease treatment, bacterial carriers can cross the blood-brain barrier (BBB) and deliver drugs precisely, overcoming limitations of traditional methods. Advances in genetic engineering, synthetic biology, and nanotechnology have transformed these systems into multifunctional platforms for personalized CNS treatment. AREAS COVERED This review examines the latest research on bacterial carriers for treating ischemic brain injury, neurodegenerative diseases, and gliomas. Bacteria efficiently cross the blood-brain barrier via active targeting, endocytosis, paracellular transport, and the nose-to-brain route for precise drug delivery. Various bacterial drug delivery systems, such as OMVs and bacterial ghosts, are explored for their design and application. Databases were searched in Google Scholar for the period up to December 2024. EXPERT OPINION Future developments in bacterial drug delivery will rely on AI-driven design and high-throughput engineering, enhancing treatment precision. Personalized medicine will further optimize bacterial carriers for individual patients, but challenges such as biosafety, immune rejection, and scalability must be addressed. As multimodal diagnostic and therapeutic strategies advance, bacterial carriers are expected to play a central role in CNS disease treatment, offering novel precision medicine solutions.
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Affiliation(s)
- Shizhu Gao
- Department of Biopharmacy, School of Pharmaceutical Sciences, Jilin University, Changchun, PR China
| | - Xin Li
- Orthopedic Medical Center, 2nd hospital of Jilin University, Changchun, PR China
| | - Bing Han
- Department of Biopharmacy, School of Pharmaceutical Sciences, Jilin University, Changchun, PR China
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4
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Liu J, Chen S, Zhao J. The role and mechanisms of Helicobacter pylori outer membrane vesicles in the pathogenesis of extra-gastrointestinal diseases. Microb Pathog 2025; 200:107312. [PMID: 39855489 DOI: 10.1016/j.micpath.2025.107312] [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: 05/27/2024] [Revised: 12/20/2024] [Accepted: 01/18/2025] [Indexed: 01/27/2025]
Abstract
Helicobacter pylori (H. pylori) infection have been closely associated with several extra-gastrointestinal disorders. Outer membrane vesicles (OMVs), as lipid-membrane-bounded nanoparticles, are usually shed from Gram-negative both in vitro and in vivo. H. pylori is also capable of producing OMVs, which can enter the systemic circulation and be delivered to various cells, tissues or organs, eliciting a range of inflammatory and immune modulation responses. In this current review, we summarize the biogenesis and functions of H. pylori OMVs, describe the contribution of H. pylori OMVs to the generation and progression of extra-gastrointestinal diseases, such as neuronal damage, Alzheimer disease, hepatic fibrosis and atherosclerosis. We also explored the effect of H. pylori OMVs in inflammatory and immune modulation of diverse immune cells, including macrophages, mononuclear cells and dendritic cells. By elucidating the molecular mechanism of H. pylori OMVs-mediated extra-gastrointestinal diseases and immunomodulatory effect, it may promote the development of efficient treatments and vaccinations against H. pylori.
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Affiliation(s)
- Jin Liu
- Department of Pharmaceutical Engineering, School of Biomedical and Pharmaceutical Sciences, Guangdong University of Technology, Guangzhou, 510006, People's Republic of China
| | - Sheqing Chen
- Department of Pharmaceutical Engineering, School of Biomedical and Pharmaceutical Sciences, Guangdong University of Technology, Guangzhou, 510006, People's Republic of China
| | - Jingjing Zhao
- Department of Pharmaceutical Engineering, School of Biomedical and Pharmaceutical Sciences, Guangdong University of Technology, Guangzhou, 510006, People's Republic of China.
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5
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Govender P, Ghai M. Population-specific differences in the human microbiome: Factors defining the diversity. Gene 2025; 933:148923. [PMID: 39244168 DOI: 10.1016/j.gene.2024.148923] [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: 05/24/2024] [Revised: 08/15/2024] [Accepted: 09/03/2024] [Indexed: 09/09/2024]
Abstract
Differences in microbial communities at different body habitats define the microbiome composition of the human body. The gut, oral, skin vaginal fluid and tissue microbiome, are pivotal for human development and immune response and cross talk between these microbiomes is evident. Population studies reveal that various factors, such as host genetics, diet, lifestyle, aging, and geographical location are strongly associated with population-specific microbiome differences. The present review discusses the factors that shape microbiome diversity in humans, and microbiome differences in African, Asian and Caucasian populations. Gut microbiome studies show that microbial species Bacteroides is commonly found in individuals living in Western countries (Caucasian populations), while Prevotella is prevalent in non-Western countries (African and Asian populations). This association is mainly due to the high carbohydrate, high fat diet in western countries in contrast to high fibre, low fat diets in African/ Asian regions. Majority of the microbiome studies focus on the bacteriome component; however, interesting findings reveal that increased bacteriophage richness, which makes up the virome component, correlates with decreased bacterial diversity, and causes microbiome dysbiosis. An increase of Caudovirales (bacteriophages) is associated with a decrease in enteric bacteria in inflammatory bowel diseases. Future microbiome studies should evaluate the interrelation between bacteriome and virome to fully understand their significance in the pathogenesis and progression of human diseases. With ethnic health disparities becoming increasingly apparent, studies need to emphasize on the association of population-specific microbiome differences and human diseases, to develop microbiome-based therapeutics. Additionally, targeted phage therapy is emerging as an attractive alternative to antibiotics for bacterial infections. With rapid rise in microbiome research, focus should be on standardizing protocols, advanced bioinformatics tools, and reducing sequencing platform related biases. Ultimately, integration of multi-omics data (genomics, transcriptomics, proteomics and metabolomics) will lead to precision models for personalized microbiome therapeutics advancement.
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Affiliation(s)
- Priyanka Govender
- Discipline of Genetics, School of Life Sciences, University of KwaZulu-Natal, Westville, South Africa
| | - Meenu Ghai
- Discipline of Genetics, School of Life Sciences, University of KwaZulu-Natal, Westville, South Africa.
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6
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Liu C, Udawatte NS, Liaw A, Staples R, Salomon C, Seneviratne CJ, Ivanovski S, Han P. Microbial DNA Profiles of Bacterial Extracellular Vesicles from 3D Salivary Polymicrobial Biofilms - A Pilot Study. Adv Healthc Mater 2025:e2403300. [PMID: 39748613 DOI: 10.1002/adhm.202403300] [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: 09/17/2024] [Revised: 12/19/2024] [Indexed: 01/04/2025]
Abstract
With the advent of multi-layered and 3D scaffolds, the understanding of microbiome composition and pathogenic mechanisms within polymicrobial biofilms is continuously evolving. A fundamental component in mediating the microenvironment and bacterial-host communication within the biofilm are bilayered nanoparticles secreted by bacteria, known as bacterial extracellular vesicles (BEVs), which transport key biomolecules including proteins, nucleic acids, and metabolites. Their characteristics and microbiome profiles are yet to be explored in the context of in vitro salivary polymicrobial biofilm. This pilot study aimed to compare the profiles of BEVs from salivary biofilm cultured on a 2D tissue culture plate and 3D melt electrowritten medical-grade polycaprolactone (MEW mPCL) scaffold. BEVs derived from MEW mPCL biofilm exhibited enhanced purity and yield without altered EV morphology and lipopolysaccharide (LPS) content, with enriched BEVs-associated DNA from Capnocytophaga, porphyromonas, and veillonella genus. Moreover, compared to saliva controls, MEW mPCL BEVs showed comparable DNA expression of Tannerella forsythia, and Treponema denticola and significantly higher expression in Porphyromonas gingivalis, Eikenella corrodens and Lactobacillus acidophilus. Together, these findings highlight a more detailed microbial profile with BEVs derived from salivary biofilms cultured on 3D MEW PCL scaffolds, which facilitates an effective in vitro model with a greater resemblance to naturally occurring biofilms.
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Affiliation(s)
- Chun Liu
- School of Dentistry, Center for Oral-facial Regeneration, Rehabilitation and Reconstruction (COR3), Epigenetics nanodiagnostic and therapeutic group, The University of Queensland, Brisbane, QLD, 4006, Australia
| | - Nadeeka S Udawatte
- School of Dentistry, Center for Oral-facial Regeneration, Rehabilitation and Reconstruction (COR3), Epigenetics nanodiagnostic and therapeutic group, The University of Queensland, Brisbane, QLD, 4006, Australia
| | - Andrew Liaw
- School of Dentistry, Center for Oral-facial Regeneration, Rehabilitation and Reconstruction (COR3), Epigenetics nanodiagnostic and therapeutic group, The University of Queensland, Brisbane, QLD, 4006, Australia
| | - Reuben Staples
- School of Dentistry, Center for Oral-facial Regeneration, Rehabilitation and Reconstruction (COR3), Epigenetics nanodiagnostic and therapeutic group, The University of Queensland, Brisbane, QLD, 4006, Australia
| | - Carlos Salomon
- Translational Extracellular Vesicles in Obstetrics and Gynae-Oncology Group, The University of Queensland Centre for Clinical Research, Royal Brisbane and Women's Hospital, Faculty of Medicine, The University of Queensland, Brisbane, QLD, 4029, Australia
- UQ Centre for Extracellular Vesicle Nanomedicine, The University of Queensland, Brisbane, 4029, Australia
| | - Chaminda Jayampath Seneviratne
- School of Dentistry, Center for Oral-facial Regeneration, Rehabilitation and Reconstruction (COR3), Epigenetics nanodiagnostic and therapeutic group, The University of Queensland, Brisbane, QLD, 4006, Australia
| | - Sašo Ivanovski
- School of Dentistry, Center for Oral-facial Regeneration, Rehabilitation and Reconstruction (COR3), Epigenetics nanodiagnostic and therapeutic group, The University of Queensland, Brisbane, QLD, 4006, Australia
- UQ Centre for Extracellular Vesicle Nanomedicine, The University of Queensland, Brisbane, 4029, Australia
| | - Pingping Han
- School of Dentistry, Center for Oral-facial Regeneration, Rehabilitation and Reconstruction (COR3), Epigenetics nanodiagnostic and therapeutic group, The University of Queensland, Brisbane, QLD, 4006, Australia
- UQ Centre for Extracellular Vesicle Nanomedicine, The University of Queensland, Brisbane, 4029, Australia
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7
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Dai X, Liang R, Dai M, Li X, Zhao W. Smoking Impacts Alzheimer's Disease Progression Through Oral Microbiota Modulation. Mol Neurobiol 2025; 62:19-44. [PMID: 38795302 DOI: 10.1007/s12035-024-04241-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/26/2023] [Accepted: 05/13/2024] [Indexed: 05/27/2024]
Abstract
Alzheimer's disease (AD) is an important public health challenge with a limited understanding of its pathogenesis. Smoking is a significant modifiable risk factor for AD progression, and its specific mechanism is often interpreted from a toxicological perspective. However, microbial infections also contribute to AD, with oral microbiota playing a crucial role in its progression. Notably, smoking alters the ecological structure and pathogenicity of the oral microbiota. Currently, there is no systematic review or summary of the relationship between these three factors; thus, understanding this association can help in the development of new treatments. This review summarizes the connections between smoking, AD, and oral microbiota from existing research. It also explores how smoking affects the occurrence and development of AD through oral microbiota, and examines treatments for oral microbiota that delay the progression of AD. Furthermore, this review emphasizes the potential of the oral microbiota to act as a biomarker for AD. Finally, it considers the feasibility of probiotics and oral antibacterial therapy to expand treatment methods for AD.
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Affiliation(s)
- Xingzhu Dai
- Department of Stomatology, Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou, China
- Department of Stomatology, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Rui Liang
- Department of Stomatology, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Manqiong Dai
- Department of Stomatology, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Xiaoyu Li
- Department of Stomatology, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Wanghong Zhao
- Department of Stomatology, Nanfang Hospital, Southern Medical University, Guangzhou, China.
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8
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Meng D, Lai Y, Zhang L, Hu W, Wei H, Guo C, Jing X, Zhou H, Xiao R, Zhu L, Luo S, Xu Z, Chen Y, Wang X, Liu R, Zeng J. Helicobacter pylori outer membrane vesicles directly promote Aβ aggregation and enhance Aβ toxicity in APP/PS1 mice. Commun Biol 2024; 7:1474. [PMID: 39516239 PMCID: PMC11549467 DOI: 10.1038/s42003-024-07125-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/24/2024] [Accepted: 10/22/2024] [Indexed: 11/16/2024] Open
Abstract
Helicobacter pylori (H. pylori) infection has been found associated with Alzheimer's disease (AD) with unclear mechanisms. Outer Membrane Vesicles (OMVs) are spherical particles secreted by Gram-negative bacteria. Here we explore the effect of H. pylori OMVs on Aβ aggregation and toxicity. We show intraperitoneally-injected H. pylori OMVs enter the brain and co-localize with Aβ plaques in APP/PS1 mice, accompanied by aggravated Aβ pathology, exacerbated cognitive deficits and synaptic impairment, indicating that H. pylori OMVs promote β-amyloidosis and AD development. The in vitro results further identify that H. pylori OMVs significantly accelerate Aβ aggregation and increase Aβ-induced neurotoxicity. Through lipidomic analysis, we reveal that lipid components, particularly LPC 18:0 in H. pylori OMVs accelerate Aβ aggregation and enhance Aβ neurotoxicity. Moreover, H. pylori OMVs-enhanced Aβ neurotoxicity is mediated by Ca2+. These findings reveal a mechanism of H. pylori OMVs in accelerating AD development in which the bacterial OMVs-originated lipid components play a key role in promoting Aβ aggregation and neurotoxicity.
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Affiliation(s)
- Dongli Meng
- Department of Pathophysiology, School of Basic Medicine, Key Laboratory of Education Ministry of China/Hubei Province for Neurological Disorders, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Sino-UK Joint Laboratory of Brain Function and Injury of Henan Province, Department of Physiology and Pathophysiology, Xinxiang Medical University, Xinxiang, China
| | - Yiwen Lai
- Department of Pathophysiology, School of Basic Medicine, Key Laboratory of Education Ministry of China/Hubei Province for Neurological Disorders, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Lun Zhang
- Department of Pathophysiology, School of Basic Medicine, Key Laboratory of Education Ministry of China/Hubei Province for Neurological Disorders, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Department of Clinical Laboratory, Wuhan Fourth Hospital, Wuhan, China
| | - Wenting Hu
- Department of Pathophysiology, School of Basic Medicine, Key Laboratory of Education Ministry of China/Hubei Province for Neurological Disorders, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Department of Pathology, Peking University Shenzhen Hospital, Shenzhen, China
| | - Hui Wei
- Department of Pathophysiology, School of Basic Medicine, Key Laboratory of Education Ministry of China/Hubei Province for Neurological Disorders, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Cuiping Guo
- Department of Pathophysiology, School of Basic Medicine, Key Laboratory of Education Ministry of China/Hubei Province for Neurological Disorders, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Xiaopeng Jing
- Department of Clinical Laboratory, Wuhan Fourth Hospital, Wuhan, China
| | - Huan Zhou
- Department of Pathophysiology, School of Basic Medicine, Key Laboratory of Education Ministry of China/Hubei Province for Neurological Disorders, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Rui Xiao
- Department of Pathophysiology, School of Basic Medicine, Key Laboratory of Education Ministry of China/Hubei Province for Neurological Disorders, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Liping Zhu
- Department of Pathophysiology, School of Basic Medicine, Key Laboratory of Education Ministry of China/Hubei Province for Neurological Disorders, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Shengquan Luo
- Department of Pathophysiology, School of Basic Medicine, Key Laboratory of Education Ministry of China/Hubei Province for Neurological Disorders, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Zhendong Xu
- Department of Pathophysiology, School of Basic Medicine, Key Laboratory of Education Ministry of China/Hubei Province for Neurological Disorders, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Yu Chen
- Department of Pediatrics, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Xiaochuan Wang
- Department of Pathophysiology, School of Basic Medicine, Key Laboratory of Education Ministry of China/Hubei Province for Neurological Disorders, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Shenzhen Huazhong University of Science and Technology Research Institute, Shenzhen, China
| | - Rong Liu
- Department of Pathophysiology, School of Basic Medicine, Key Laboratory of Education Ministry of China/Hubei Province for Neurological Disorders, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
- Department of Pediatrics, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
- Shenzhen Huazhong University of Science and Technology Research Institute, Shenzhen, China.
- Institute for Brain Research, Wuhan Center of Brain Science, Huazhong University of Science and Technology, Wuhan, China.
| | - Ji Zeng
- Department of Clinical Laboratory, Wuhan Fourth Hospital, Wuhan, China.
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Wei S, Ma X, Chen Y, Wang J, Hu L, Liu Z, Mo L, Zhou N, Chen W, Zhu H, Yan S. Alzheimer's Disease-Derived Outer Membrane Vesicles Exacerbate Cognitive Dysfunction, Modulate the Gut Microbiome, and Increase Neuroinflammation and Amyloid-β Production. Mol Neurobiol 2024:10.1007/s12035-024-04579-6. [PMID: 39514171 DOI: 10.1007/s12035-024-04579-6] [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: 06/16/2024] [Accepted: 10/22/2024] [Indexed: 11/16/2024]
Abstract
Although our understanding of the molecular biology of Alzheimer's disease (AD) continues to improve, the etiology of the disease, particularly the involvement of gut microbiota disturbances, remains a challenge. Outer membrane vesicles (OMVs) play a key role in central nervous system diseases, but the impact of OMVs on AD progression remains unclear. In this study, we hypothesized that AD-derived OMVs (OMVsAD) were a risk factor in AD pathology. To test our hypothesis, young APP/PS1 mice (AD mice) were given OMVsAD by gavage. Young AD mice were euthanized 120 days after gavage to assess the intestinal barrier, gut microbiota diversity, mediators of neuroinflammation, glial markers, amyloid burden, and short-chain fatty acid (SCFA) levels. Our results showed that OMVsAD accelerated cognitive dysfunction after 120 days of intragastric administration. Morris water maze experiment and new object recognition test showed that OMVsAD caused significantly poorer spatial ability learning and memory of the AD mice. We observed the OMVsAD-treated APP/PS1 mice display OMVs disrupting the intestinal barrier compared with controls of normal human-derived OMVs. Compared with the OMVsHC group, claudin-5 and ZO-1 related to the intestinal barrier were significantly downregulated in the OMVsAD group. The OMVsAD activate microglia in the cerebral cortex and hippocampus of AD mice, and the levels of IL-1β, IL-6, TNF-α, and NF-Κb were upregulated. We also found that OMVsAD increased Aβ production. 16S rRNA sequencing showed that OMVsAD negatively regulated the α- and β-diversity index of intestinal flora and reduced the levels of SCFA. OMVsAD may change the intestinal flora of young AD, damage the intestinal mucosa and blood-brain barrier, and accelerate AD neuropathological damage.
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Affiliation(s)
- Shouchao Wei
- The Third Department of Neurology, Central People's Hospital of Zhanjiang, Zhanjiang, Guangdong, China
- Zhanjiang Institute of Clinical Medicine, Central People's Hospital of Zhanjiang, Zhanjiang, Guangdong, China
| | - Xiaochen Ma
- The Third Department of Neurology, Central People's Hospital of Zhanjiang, Zhanjiang, Guangdong, China
- Zhanjiang Institute of Clinical Medicine, Central People's Hospital of Zhanjiang, Zhanjiang, Guangdong, China
| | - Yating Chen
- Guangdong Key Laboratory of Age-Related Cardiac and Cerebral Diseases, Institute of Neurology, Affiliated Hospital of Guangdong Medical University, Zhanjiang, Guangdong, China
| | - Junjun Wang
- Guangdong Key Laboratory of Age-Related Cardiac and Cerebral Diseases, Institute of Neurology, Affiliated Hospital of Guangdong Medical University, Zhanjiang, Guangdong, China
- Basic Medicine College, Guangdong Medical University, Zhanjiang, Guangdong, China
| | - Li Hu
- Guangdong Key Laboratory of Age-Related Cardiac and Cerebral Diseases, Institute of Neurology, Affiliated Hospital of Guangdong Medical University, Zhanjiang, Guangdong, China
- Basic Medicine College, Guangdong Medical University, Zhanjiang, Guangdong, China
| | - Zhou Liu
- Guangdong Key Laboratory of Age-Related Cardiac and Cerebral Diseases, Institute of Neurology, Affiliated Hospital of Guangdong Medical University, Zhanjiang, Guangdong, China
| | - Lang Mo
- The Third Department of Neurology, Central People's Hospital of Zhanjiang, Zhanjiang, Guangdong, China
| | - Ning Zhou
- The Third Department of Neurology, Central People's Hospital of Zhanjiang, Zhanjiang, Guangdong, China
- Zhanjiang Institute of Clinical Medicine, Central People's Hospital of Zhanjiang, Zhanjiang, Guangdong, China
| | - Wenrong Chen
- The Third Department of Neurology, Central People's Hospital of Zhanjiang, Zhanjiang, Guangdong, China
| | - He Zhu
- Zhanjiang Institute of Clinical Medicine, Central People's Hospital of Zhanjiang, Zhanjiang, Guangdong, China.
| | - Shian Yan
- The Third Department of Neurology, Central People's Hospital of Zhanjiang, Zhanjiang, Guangdong, China.
- Zhanjiang Institute of Clinical Medicine, Central People's Hospital of Zhanjiang, Zhanjiang, Guangdong, China.
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10
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Daskoulidou N, Carpanini SM, Zelek WM, Morgan BP. Involvement of Complement in Alzheimer's Disease: From Genetics Through Pathology to Therapeutic Strategies. Curr Top Behav Neurosci 2024. [PMID: 39455500 DOI: 10.1007/7854_2024_524] [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: 10/28/2024]
Abstract
Complement is a critical component of innate immunity, evolved to defend against pathogens and clear toxic debris ranging from dead and dying cells to immune complexes. These roles make complement a key player in homeostasis; however, complement has a dark side. When the rigid control mechanisms fail, complement becomes dysregulated, acting as a driver of inflammation and resultant pathology in numerous diseases. Roles of complement in Alzheimer's disease (AD) and other dementias have emerged in recent years, supported by genetic, biomarker and pathological evidence and animal model studies. Numerous questions remain regarding the precise roles of complement in the brain in health and disease, including where and when complement is expressed, how it contributes to immune defence and garbage disposal in the healthy brain, and exactly how complement contributes to pathology in dementias. In this brief review, we will summarise current knowledge on complement roles in brain, present the evidence implicating complement in AD and explore whether complement represents an attractive therapeutic target for AD.
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Affiliation(s)
| | - Sarah M Carpanini
- UK Dementia Research Institute Cardiff, Cardiff University, Cardiff, UK
| | - Wioleta M Zelek
- UK Dementia Research Institute Cardiff, Cardiff University, Cardiff, UK
| | - B Paul Morgan
- UK Dementia Research Institute Cardiff, Cardiff University, Cardiff, UK.
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11
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Wang W, Hou Y, Zhang J, Sun Z, Sun H. Improved Isolation Optimizes Downstream Application of Extracellular Vesicles Derived from Mycobacterium tuberculosis. Microorganisms 2024; 12:2129. [PMID: 39597520 PMCID: PMC11596817 DOI: 10.3390/microorganisms12112129] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/22/2024] [Revised: 10/04/2024] [Accepted: 10/21/2024] [Indexed: 11/29/2024] Open
Abstract
Mycobacterium tuberculosis (Mtb), the causative agent of tuberculosis, secretes extracellular vesicles (EVs), which may play an important role in mediating interactions between bacteria and host cells. Mtb EVs can be isolated by means of various techniques, which differ in terms of their effectiveness. In the present study, we found that an exosome isolation kit (EI) yielded higher numbers of EVs than either differential centrifugation (DC) or exosome detection via an ultrafast-isolation system (EXODUS). We also found that the EXODUS method revealed a greater abundance of H37Rv components within EVs, compared with the DC and EI methods. Analysis of the downstream application of H37Rv EVs revealed their internalization by RAW264.7 macrophages, peaking at 6 h, with subsequent activation of the TLR2 signaling pathway leading to the expression of inflammatory cytokines including IL-6 and TNF-α. It was also found that H37Rv EVs could cross the blood-brain barrier (BBB) and enter the brain, peaking at 12 h post-injection, eliciting an inflammatory response in the cerebral parenchyma, cerebellum, and hippocampus that persisted for up to 6 days. These findings offer novel insights into the pathogenesis of Mtb-induced diseases and may guide the development of therapeutic strategies.
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Affiliation(s)
- Wenjing Wang
- Beijing Chest Hospital affiliated to Capital Medical University, Beijing 100000, China; (W.W.); (Y.H.); (J.Z.)
| | - Yue Hou
- Beijing Chest Hospital affiliated to Capital Medical University, Beijing 100000, China; (W.W.); (Y.H.); (J.Z.)
| | - Jingfang Zhang
- Beijing Chest Hospital affiliated to Capital Medical University, Beijing 100000, China; (W.W.); (Y.H.); (J.Z.)
- Beijing Tuberculosis and Thoracic Tumor Research Institute, Beijing 100000, China
| | - Zhaogang Sun
- Beijing Chest Hospital affiliated to Capital Medical University, Beijing 100000, China; (W.W.); (Y.H.); (J.Z.)
- Beijing Tuberculosis and Thoracic Tumor Research Institute, Beijing 100000, China
| | - Hong Sun
- Beijing Chest Hospital affiliated to Capital Medical University, Beijing 100000, China; (W.W.); (Y.H.); (J.Z.)
- Beijing Tuberculosis and Thoracic Tumor Research Institute, Beijing 100000, China
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12
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Xie L, Wu Q, Li K, Khan MAS, Zhang A, Sinha B, Li S, Chang SL, Brody DL, Grinstaff MW, Zhou S, Alterovitz G, Liu P, Wang X. Tryptophan Metabolism in Alzheimer's Disease with the Involvement of Microglia and Astrocyte Crosstalk and Gut-Brain Axis. Aging Dis 2024; 15:2168-2190. [PMID: 38916729 PMCID: PMC11346405 DOI: 10.14336/ad.2024.0134] [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: 02/02/2024] [Accepted: 05/03/2024] [Indexed: 06/26/2024] Open
Abstract
Alzheimer's disease (AD) is an age-dependent neurodegenerative disease characterized by extracellular Amyloid Aβ peptide (Aβ) deposition and intracellular Tau protein aggregation. Glia, especially microglia and astrocytes are core participants during the progression of AD and these cells are the mediators of Aβ clearance and degradation. The microbiota-gut-brain axis (MGBA) is a complex interactive network between the gut and brain involved in neurodegeneration. MGBA affects the function of glia in the central nervous system (CNS), and microbial metabolites regulate the communication between astrocytes and microglia; however, whether such communication is part of AD pathophysiology remains unknown. One of the potential links in bilateral gut-brain communication is tryptophan (Trp) metabolism. The microbiota-originated Trp and its metabolites enter the CNS to control microglial activation, and the activated microglia subsequently affect astrocyte functions. The present review highlights the role of MGBA in AD pathology, especially the roles of Trp per se and its metabolism as a part of the gut microbiota and brain communications. We (i) discuss the roles of Trp derivatives in microglia-astrocyte crosstalk from a bioinformatics perspective, (ii) describe the role of glia polarization in the microglia-astrocyte crosstalk and AD pathology, and (iii) summarize the potential of Trp metabolism as a therapeutic target. Finally, we review the role of Trp in AD from the perspective of the gut-brain axis and microglia, as well as astrocyte crosstalk, to inspire the discovery of novel AD therapeutics.
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Affiliation(s)
- Lushuang Xie
- Department of Neurosurgery, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA 02115, USA.
- Acupuncture and Moxibustion College, Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan, 610075, China.
| | - Qiaofeng Wu
- Acupuncture and Moxibustion College, Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan, 610075, China.
| | - Kelin Li
- Department of Neurosurgery, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA 02115, USA.
- Department of Chemistry, Boston University, Boston, MA 02215, USA.
| | - Mohammed A. S. Khan
- Department of Neurosurgery, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA 02115, USA.
| | - Andrew Zhang
- Biomedical Cybernetics Laboratory, Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA 02115, USA.
| | - Bharati Sinha
- Department of Neurosurgery, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA 02115, USA.
| | - Sihui Li
- Acupuncture and Moxibustion College, Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan, 610075, China.
| | - Sulie L. Chang
- Department of Biological Sciences, Institute of NeuroImmune Pharmacology, Seton Hall University, South Orange, NJ 07079, USA.
| | - David L. Brody
- Department of Neurology, Uniformed Services University of the Health Sciences, Bethesda, MD 20814, USA.
| | | | - Shuanhu Zhou
- Harvard Medical School, Harvard Stem Cell Institute, Boston, MA 02115, USA.
| | - Gil Alterovitz
- Biomedical Cybernetics Laboratory, Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA 02115, USA.
| | - Pinghua Liu
- Department of Chemistry, Boston University, Boston, MA 02215, USA.
| | - Xin Wang
- Department of Neurosurgery, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA 02115, USA.
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13
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Zhang S, Lu J, Jin Z, Xu H, Zhang D, Chen J, Wang J. Gut microbiota metabolites: potential therapeutic targets for Alzheimer's disease? Front Pharmacol 2024; 15:1459655. [PMID: 39355779 PMCID: PMC11442227 DOI: 10.3389/fphar.2024.1459655] [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: 07/04/2024] [Accepted: 09/05/2024] [Indexed: 10/03/2024] Open
Abstract
Background Alzheimer's disease (AD) is a neurodegenerative disease characterized by progressive decline in cognitive function, which significantly increases pain and social burden. However, few therapeutic interventions are effective in preventing or mitigating the progression of AD. An increasing number of recent studies support the hypothesis that the gut microbiome and its metabolites may be associated with upstream regulators of AD pathology. Methods In this review, we comprehensively explore the potential mechanisms and currently available interventions targeting the microbiome for the improvement of AD. Our discussion is structured around modern research advancements in AD, the bidirectional communication between the gut and brain, the multi-target regulatory effects of microbial metabolites on AD, and therapeutic strategies aimed at modulating gut microbiota to manage AD. Results The gut microbiota plays a crucial role in the pathogenesis of AD through continuous bidirectional communication via the microbiota-gut-brain axis. Among these, microbial metabolites such as lipids, amino acids, bile acids and neurotransmitters, especially sphingolipids and phospholipids, may serve as central components of the gut-brain axis, regulating AD-related pathogenic mechanisms including β-amyloid metabolism, Tau protein phosphorylation, and neuroinflammation. Additionally, interventions such as probiotic administration, fecal microbiota transplantation, and antibiotic use have also provided evidence supporting the association between gut microbiota and AD. At the same time, we propose an innovative strategy for treating AD: a healthy lifestyle combined with targeted probiotics and other potential therapeutic interventions, aiming to restore intestinal ecology and microbiota balance. Conclusion Despite previous efforts, the molecular mechanisms by which gut microbes act on AD have yet to be fully described. However, intestinal microorganisms may become an essential target for connecting the gut-brain axis and improving the symptoms of AD. At the same time, it requires joint exploration by multiple centers and multiple disciplines.
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Affiliation(s)
- Shanshan Zhang
- The School to Changchun University of Chinese Medicine, Changchun, China
| | - Jing Lu
- Research Center of Traditional Chinese Medicine, The Affiliated Hospital to Changchun University of Chinese Medicine, Changchun, China
| | - Ziqi Jin
- The School to Changchun University of Chinese Medicine, Changchun, China
| | - Hanying Xu
- Department of Encephalopathy, The Affiliated Hospital to Changchun University of Chinese Medicine, Changchun, China
| | - Dongmei Zhang
- Research Center of Traditional Chinese Medicine, The Affiliated Hospital to Changchun University of Chinese Medicine, Changchun, China
| | - Jianan Chen
- The School to Changchun University of Chinese Medicine, Changchun, China
| | - Jian Wang
- Department of Encephalopathy, The Affiliated Hospital to Changchun University of Chinese Medicine, Changchun, China
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14
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Liu E, Zhang Y, Wang JZ. Updates in Alzheimer's disease: from basic research to diagnosis and therapies. Transl Neurodegener 2024; 13:45. [PMID: 39232848 PMCID: PMC11373277 DOI: 10.1186/s40035-024-00432-x] [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: 03/12/2024] [Accepted: 07/11/2024] [Indexed: 09/06/2024] Open
Abstract
Alzheimer's disease (AD) is the most common neurodegenerative disorder, characterized pathologically by extracellular deposition of β-amyloid (Aβ) into senile plaques and intracellular accumulation of hyperphosphorylated tau (pTau) as neurofibrillary tangles. Clinically, AD patients show memory deterioration with varying cognitive dysfunctions. The exact molecular mechanisms underlying AD are still not fully understood, and there are no efficient drugs to stop or reverse the disease progression. In this review, we first provide an update on how the risk factors, including APOE variants, infections and inflammation, contribute to AD; how Aβ and tau become abnormally accumulated and how this accumulation plays a role in AD neurodegeneration. Then we summarize the commonly used experimental models, diagnostic and prediction strategies, and advances in periphery biomarkers from high-risk populations for AD. Finally, we introduce current status of development of disease-modifying drugs, including the newly officially approved Aβ vaccines, as well as novel and promising strategies to target the abnormal pTau. Together, this paper was aimed to update AD research progress from fundamental mechanisms to the clinical diagnosis and therapies.
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Affiliation(s)
- Enjie Liu
- Department of Pathology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, China
| | - Yao Zhang
- Department of Endocrine, Liyuan Hospital, Key Laboratory of Ministry of Education for Neurological Disorders, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430077, China
| | - Jian-Zhi Wang
- Department of Pathology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, China.
- Department of Pathophysiology, Key Laboratory of Ministry of Education for Neurological Disorders, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China.
- Co-Innovation Center of Neuroregeneration, Nantong University, Nantong, 226000, China.
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15
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Dhurve G, Behera SR, Kodetham G, Siddavattam D. Outer membrane vesicles of Acinetobacter baumannii DS002 carry circular DNA similar to bovine meat and milk factors (BMMFs) and SPHINX 2.36 and probably play a role in interdomain lateral gene transfer. Microbiol Spectr 2024; 12:e0081724. [PMID: 39101807 PMCID: PMC11370262 DOI: 10.1128/spectrum.00817-24] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/02/2024] [Accepted: 06/20/2024] [Indexed: 08/06/2024] Open
Abstract
The discovery of Replication Competent Circular DNA molecules in mammalian cells and tissues is being linked to debilitating diseases, such as multiple sclerosis (MS), bovine spongiform encephalopathy (BSE), and colorectal cancer (CRC). These circular DNA molecules, otherwise known as bovine meat and milk factors (BMMFs) and Slow Progressive Hidden INfections of variable (X) latency (SPHINX), bear significant (80%) sequence similarity with the plasmids of Acinetobacter baumannii strains. Nanostructures, such as bacterial outer membrane vesicles (OMVs) serve as vehicles for transporting biomolecular cargo and have the potential to facilitate interkingdom lateral mobility of DNA. Strengthening the proposed hypothesis, this study demonstrates that OMVs derived from A. baumannii DS002 carrying four plasmids and genome (pTS236) of phage, AbDs1, successfully reached different parts of the body, including the central nervous system, following the injection of fluorescein isothiocyanate (FITC)-labeled OMVs into experimental mice. Out of the four OMV-associated plasmids, three (pTS4586, pTS9900, and pTS134338) were identified within the lumen, and the fourth one (pTS11291) was found on the surface of OMVs. In addition to the indigenous plasmids, the phage-encoded protein, Orf96, anchored on the surface of the OMVs by establishing a strong interaction with the OMV-associated porin, OmpA. Intriguingly, a subset of labeled OMVs, when incubated with Neuro2A cells, translocated across the membrane and reached to the cytoplasmic space of the cells. Collectively, the experimental evidence presented herein underscores the promising potential of OMVs as vehicles for delivering molecular cargo containing plasmids and phage genomes to diverse mammalian tissues and cells. IMPORTANCE Several independent studies have demonstrated the existence of replication competent circular DNA molecules of bacterial and viral origin in mammalian cells and tissues. However, studies about their origin and lateral mobility to mammalian cells are scarce. Our work describes the existence of circular DNA, similar to that of DNA molecules identified in mammalian cells, OMVs derived from soil isolate of A. baumannii DS002. Furthermore, the work also provides visual evidence that demonstrates the passage of labeled OMVs to different organs of experimental mice within hours after intravenously administering OMVs into experimental mice. Some of the labeled OMVs have even crossed the membrane of Neuro2A, suggesting the existence of interkingdom horizontal mobility between bacteria and mammals.
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Affiliation(s)
- Ganeshwari Dhurve
- Department of Animal Biology, School of Life Sciences, University of Hyderabad, Hyderabad, Telangana, India
| | - Sandhya Rani Behera
- Department of Animal Biology, School of Life Sciences, University of Hyderabad, Hyderabad, Telangana, India
| | - Gopinath Kodetham
- Department of Plant Sciences, School of Life Sciences, University of Hyderabad, Hyderabad, Telangana, India
| | - Dayananda Siddavattam
- Department of Animal Biology, School of Life Sciences, University of Hyderabad, Hyderabad, Telangana, India
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16
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Huang Y, Sun J, Cui X, Li X, Hu Z, Ji Q, Bao G, Liu Y. Enhancing protective immunity against bacterial infection via coating nano-Rehmannia glutinosa polysaccharide with outer membrane vesicles. J Extracell Vesicles 2024; 13:e12514. [PMID: 39315589 PMCID: PMC11420661 DOI: 10.1002/jev2.12514] [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: 10/12/2023] [Accepted: 08/28/2024] [Indexed: 09/25/2024] Open
Abstract
With the coming of the post-antibiotic era, there is an increasingly urgent need for safe and efficient antibacterial vaccines. Bacterial outer membrane vesicles (OMVs) have received increased attention recently as a potential subunit vaccine. OMVs are non-replicative and contain the principle immunogenic bacterial antigen, which circumvents the safety concerns of live-attenuated vaccines. Here, we developed a novel nano-vaccine by coating OMVs onto PEGylated nano-Rehmannia glutinosa polysaccharide (pRL) in a structure consisting of concentric circles, resulting in a more stable vaccine with improved immunogenicity. The immunological function of the pRL-OMV formulation was evaluated in vivo and in vitro, and the underlying mechanism was studied though transcriptomic analysis. The pRL-OMV formulation significantly increased dendritic cell (DC) proliferation and cytokine secretion. Efficient phagocytosis of the formulation by DCs was accompanied by DC maturation. Further, the formulation demonstrated superior lymph node targeting, contributing to a potent mixed cellular response and bacterial-specific antibody response against Bordetella bronchiseptica infection. Specifically, transcriptomic analysis revealed that the immune protection function correlated with T-cell receptor signalling and Th1/Th2/Th17 differentiation, among other markers of enhanced immunological activity. These findings have implications for the future application of OMV-coated nano-carriers in antimicrobial immunotherapy.
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Affiliation(s)
- Yee Huang
- Institute of Animal Husbandry and Veterinary ScienceZhejiang Academy of Agricultural SciencesHangzhouZhejiangChina
| | - Jiaying Sun
- Institute of Animal Husbandry and Veterinary ScienceZhejiang Academy of Agricultural SciencesHangzhouZhejiangChina
- College of Life SciencesChina Jiliang UniversityHangzhouZhejiangChina
| | - Xuemei Cui
- Institute of Animal Husbandry and Veterinary ScienceZhejiang Academy of Agricultural SciencesHangzhouZhejiangChina
| | - Xuefeng Li
- Institute of Animal Husbandry and Veterinary ScienceZhejiang Academy of Agricultural SciencesHangzhouZhejiangChina
| | - Zizhe Hu
- Institute of Animal Husbandry and Veterinary ScienceZhejiang Academy of Agricultural SciencesHangzhouZhejiangChina
| | - Quanan Ji
- Institute of Animal Husbandry and Veterinary ScienceZhejiang Academy of Agricultural SciencesHangzhouZhejiangChina
| | - Guolian Bao
- Institute of Animal Husbandry and Veterinary ScienceZhejiang Academy of Agricultural SciencesHangzhouZhejiangChina
| | - Yan Liu
- Institute of Animal Husbandry and Veterinary ScienceZhejiang Academy of Agricultural SciencesHangzhouZhejiangChina
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17
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Margutti P, D’Ambrosio A, Zamboni S. Microbiota-Derived Extracellular Vesicle as Emerging Actors in Host Interactions. Int J Mol Sci 2024; 25:8722. [PMID: 39201409 PMCID: PMC11354844 DOI: 10.3390/ijms25168722] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/18/2024] [Revised: 07/26/2024] [Accepted: 08/01/2024] [Indexed: 09/02/2024] Open
Abstract
The human microbiota is an intricate micro-ecosystem comprising a diverse range of dynamic microbial populations mainly consisting of bacteria, whose interactions with hosts strongly affect several physiological and pathological processes. The gut microbiota is being increasingly recognized as a critical player in maintaining homeostasis, contributing to the main functions of the intestine and distal organs such as the brain. However, gut dysbiosis, characterized by composition and function alterations of microbiota with intestinal barrier dysfunction has been linked to the development and progression of several pathologies, including intestinal inflammatory diseases, systemic autoimmune diseases, such as rheumatic arthritis, and neurodegenerative diseases, such as Alzheimer's disease. Moreover, oral microbiota research has gained significant interest in recent years due to its potential impact on overall health. Emerging evidence on the role of microbiota-host interactions in health and disease has triggered a marked interest on the functional role of bacterial extracellular vesicles (BEVs) as mediators of inter-kingdom communication. Accumulating evidence reveals that BEVs mediate host interactions by transporting and delivering into host cells effector molecules that modulate host signaling pathways and cell processes, influencing health and disease. This review discusses the critical role of BEVs from the gut, lung, skin and oral cavity in the epithelium, immune system, and CNS interactions.
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Affiliation(s)
- Paola Margutti
- Department of Neurosciences, Istituto Superiore di Sanità, 00161 Rome, Italy; (A.D.); (S.Z.)
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18
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Teng S, Han C, Zhou J, He Z, Qian W. m 5C RNA methylation: a potential mechanism for infectious Alzheimer's disease. Front Cell Dev Biol 2024; 12:1440143. [PMID: 39175875 PMCID: PMC11338875 DOI: 10.3389/fcell.2024.1440143] [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: 05/30/2024] [Accepted: 07/30/2024] [Indexed: 08/24/2024] Open
Abstract
Alzheimer's disease (AD) is a neurodegenerative disorder caused by a variety of factors, including age, genetic susceptibility, cardiovascular disease, traumatic brain injury, and environmental factors. The pathogenesis of AD is largely associated with the overproduction and accumulation of amyloid-β peptides and the hyperphosphorylation of tau protein in the brain. Recent studies have identified the presence of diverse pathogens, including viruses, bacteria, and parasites, in the tissues of AD patients, underscoring the critical role of central nervous system infections in inducing pathological changes associated with AD. Nevertheless, it remains unestablished about the specific mechanism by which infections lead to the occurrence of AD. As an important post-transcriptional RNA modification, RNA 5-methylcytosine (m5C) methylation regulates a wide range of biological processes, including RNA splicing, nuclear export, stability, and translation, therefore affecting cellular function. Moreover, it has been recently demonstrated that multiple pathogenic microbial infections are associated with the m5C methylation of the host. However, the role of m5C methylation in infectious AD is still uncertain. Therefore, this review discusses the mechanisms of pathogen-induced AD and summarizes research on the molecular mechanisms of m5C methylation in infectious AD, thereby providing new insight into exploring the mechanism underlying infectious AD.
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Affiliation(s)
- Sisi Teng
- Department of Neurology, Shangjinnanfu Hospital, West China Hospital, Sichuan University, Chengdu, Sichuan, China
| | - Cunqiao Han
- Department of Emergency, Shangjinnanfu Hospital, West China Hospital, Sichuan University, Chengdu, Sichuan, China
| | - Jian Zhou
- Department of Immunology, International Cancer Center, Shenzhen University Health Science Center, Shenzhen, Guangdong, China
- National-Regional Key Technology Engineering Laboratory for Medical Ultrasound, School of Biomedical Engineering, Shenzhen University Medical School, Shenzhen, Guangdong, China
| | - Zhenyan He
- Department of Neurosurgery, The Affiliated Cancer Hospital of Zhengzhou University and Henan Cancer Hospital, Zhengzhou, China
| | - Weiwei Qian
- Department of Emergency, Shangjinnanfu Hospital, West China Hospital, Sichuan University, Chengdu, Sichuan, China
- Department of Emergency Medicine, Laboratory of Emergency Medicine, West China Hospital, and Disaster Medical Center, Sichuan University, Chengdu, Sichuan, China
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19
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Li J, Liao T, Chua EG, Zhang M, Shen Y, Song X, Marshall BJ, Benghezal M, Tang H, Li H. Helicobacter pylori Outer Membrane Vesicles: Biogenesis, Composition, and Biological Functions. Int J Biol Sci 2024; 20:4029-4043. [PMID: 39113715 PMCID: PMC11302881 DOI: 10.7150/ijbs.94156] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/11/2024] [Accepted: 07/06/2024] [Indexed: 08/10/2024] Open
Abstract
Helicobacter pylori has been recognized not only as a causative agent of a spectrum of gastroduodenal diseases including chronic gastritis, peptic ulcer, mucosa-associated lymphoid tissue lymphoma, and gastric cancer, but also as the culprit in several extra-gastric diseases. However, the association of H. pylori infection with extra-gastric diseases remains elusive, prompting a reevaluation of the role of H. pylori-derived outer membrane vesicles (OMVs). Like other gram-negative bacteria, H. pylori constitutively sheds biologically active OMVs for long-distance delivery of bacterial virulence factors in a concentrated and protected form, averting the need of direct bacterial contact with distant host cells to induce extra-gastric diseases associated with this gastric pathogen. Additionally, H. pylori-derived OMVs contribute to bacterial survival and chronic gastric pathogenesis. Moreover, the immunogenic activity, non-replicable nature, and anti-bacterial adhesion effect of H. pylori OMVs make them a desirable vaccine candidate against infection. The immunogenic potency and safety concerns of the OMV contents are challenges in the development of H. pylori OMV-based vaccines. In this review, we discuss recent advances regarding H. pylori OMVs, focusing on new insights into their biogenesis mechanisms and biological functions.
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Affiliation(s)
- Jiao Li
- Center of Infectious Diseases, West China Hospital, Sichuan University, Chengdu, China
- Laboratory of Infectious and Liver Diseases, Institute of Infectious Diseases, West China Hospital of Sichuan University, Chengdu 610041, China
| | | | - Eng Guan Chua
- Helicobacter Research Laboratory, The Marshall Centre for Infectious Disease Research and Training, University of Western Australia, Nedlands WA 6009, Australia
| | - Mingming Zhang
- Center of Infectious Diseases, West China Hospital, Sichuan University, Chengdu, China
- Laboratory of Infectious and Liver Diseases, Institute of Infectious Diseases, West China Hospital of Sichuan University, Chengdu 610041, China
| | - Yalin Shen
- Center of Infectious Diseases, West China Hospital, Sichuan University, Chengdu, China
- Laboratory of Infectious and Liver Diseases, Institute of Infectious Diseases, West China Hospital of Sichuan University, Chengdu 610041, China
| | - Xiaona Song
- Center of Infectious Diseases, West China Hospital, Sichuan University, Chengdu, China
- Laboratory of Infectious and Liver Diseases, Institute of Infectious Diseases, West China Hospital of Sichuan University, Chengdu 610041, China
| | - Barry J. Marshall
- Helicobacter Research Laboratory, The Marshall Centre for Infectious Disease Research and Training, University of Western Australia, Nedlands WA 6009, Australia
| | - Mohammed Benghezal
- Center of Infectious Diseases, West China Hospital, Sichuan University, Chengdu, China
- Laboratory of Infectious and Liver Diseases, Institute of Infectious Diseases, West China Hospital of Sichuan University, Chengdu 610041, China
| | - Hong Tang
- Center of Infectious Diseases, West China Hospital, Sichuan University, Chengdu, China
- Laboratory of Infectious and Liver Diseases, Institute of Infectious Diseases, West China Hospital of Sichuan University, Chengdu 610041, China
| | - Hong Li
- Center of Infectious Diseases, West China Hospital, Sichuan University, Chengdu, China
- Laboratory of Infectious and Liver Diseases, Institute of Infectious Diseases, West China Hospital of Sichuan University, Chengdu 610041, China
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20
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Kettunen P, Koistinaho J, Rolova T. Contribution of CNS and extra-CNS infections to neurodegeneration: a narrative review. J Neuroinflammation 2024; 21:152. [PMID: 38845026 PMCID: PMC11157808 DOI: 10.1186/s12974-024-03139-y] [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: 03/17/2024] [Accepted: 05/23/2024] [Indexed: 06/09/2024] Open
Abstract
Central nervous system infections have been suggested as a possible cause for neurodegenerative diseases, particularly sporadic cases. They trigger neuroinflammation which is considered integrally involved in neurodegenerative processes. In this review, we will look at data linking a variety of viral, bacterial, fungal, and protozoan infections to Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, multiple sclerosis and unspecified dementia. This narrative review aims to bring together a broad range of data currently supporting the involvement of central nervous system infections in the development of neurodegenerative diseases. The idea that no single pathogen or pathogen group is responsible for neurodegenerative diseases will be discussed. Instead, we suggest that a wide range of susceptibility factors may make individuals differentially vulnerable to different infectious pathogens and subsequent pathologies.
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Affiliation(s)
- Pinja Kettunen
- Helsinki Institute of Life Science, University of Helsinki, Helsinki, Finland
| | - Jari Koistinaho
- Helsinki Institute of Life Science, University of Helsinki, Helsinki, Finland.
| | - Taisia Rolova
- Helsinki Institute of Life Science, University of Helsinki, Helsinki, Finland
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21
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Peregrino ES, Castañeda-Casimiro J, Vázquez-Flores L, Estrada-Parra S, Wong-Baeza C, Serafín-López J, Wong-Baeza I. The Role of Bacterial Extracellular Vesicles in the Immune Response to Pathogens, and Therapeutic Opportunities. Int J Mol Sci 2024; 25:6210. [PMID: 38892397 PMCID: PMC11172497 DOI: 10.3390/ijms25116210] [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: 05/01/2024] [Revised: 05/28/2024] [Accepted: 05/30/2024] [Indexed: 06/21/2024] Open
Abstract
Pathogenic bacteria have several mechanisms to evade the host's immune response and achieve an efficient infection. Bacterial extracellular vesicles (EVs) are a relevant cellular communication mechanism, since they can interact with other bacterial cells and with host cells. In this review, we focus on the EVs produced by some World Health Organization (WHO) priority Gram-negative and Gram-positive pathogenic bacteria; by spore-producing bacteria; by Mycobacterium tuberculosis (a bacteria with a complex cell wall); and by Treponema pallidum (a bacteria without lipopolysaccharide). We describe the classification and the general properties of bacterial EVs, their role during bacterial infections and their effects on the host immune response. Bacterial EVs contain pathogen-associated molecular patterns that activate innate immune receptors, which leads to cytokine production and inflammation, but they also contain antigens that induce the activation of B and T cell responses. Understanding the many effects of bacterial EVs on the host's immune response can yield new insights on the pathogenesis of clinically important infections, but it can also lead to the development of EV-based diagnostic and therapeutic strategies. In addition, since EVs are efficient activators of both the innate and the adaptive immune responses, they constitute a promising platform for vaccine development.
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Affiliation(s)
- Eliud S. Peregrino
- Posgrado en Inmunología, Escuela Nacional de Ciencias Biológicas (ENCB), Instituto Politécnico Nacional (IPN), Mexico City 11340, Mexico; (E.S.P.); (J.C.-C.)
| | - Jessica Castañeda-Casimiro
- Posgrado en Inmunología, Escuela Nacional de Ciencias Biológicas (ENCB), Instituto Politécnico Nacional (IPN), Mexico City 11340, Mexico; (E.S.P.); (J.C.-C.)
- Departamento de Inmunología, Escuela Nacional de Ciencias Biológicas (ENCB), Instituto Politécnico Nacional (IPN), Mexico City 11340, Mexico; (S.E.-P.); (J.S.-L.)
| | - Luis Vázquez-Flores
- Departamento de Bioquímica, Escuela Nacional de Ciencias Biológicas (ENCB), Instituto Politécnico Nacional (IPN), Mexico City 11340, Mexico; (L.V.-F.); (C.W.-B.)
| | - Sergio Estrada-Parra
- Departamento de Inmunología, Escuela Nacional de Ciencias Biológicas (ENCB), Instituto Politécnico Nacional (IPN), Mexico City 11340, Mexico; (S.E.-P.); (J.S.-L.)
| | - Carlos Wong-Baeza
- Departamento de Bioquímica, Escuela Nacional de Ciencias Biológicas (ENCB), Instituto Politécnico Nacional (IPN), Mexico City 11340, Mexico; (L.V.-F.); (C.W.-B.)
| | - Jeanet Serafín-López
- Departamento de Inmunología, Escuela Nacional de Ciencias Biológicas (ENCB), Instituto Politécnico Nacional (IPN), Mexico City 11340, Mexico; (S.E.-P.); (J.S.-L.)
| | - Isabel Wong-Baeza
- Departamento de Inmunología, Escuela Nacional de Ciencias Biológicas (ENCB), Instituto Politécnico Nacional (IPN), Mexico City 11340, Mexico; (S.E.-P.); (J.S.-L.)
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22
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Shao Z, Lu Y, Xing A, He X, Xie H, Hu M. Effect of outer membrane vesicles of Lactobacillus pentosus on Tau phosphorylation and CDK5-Calpain pathway in mice. Exp Gerontol 2024; 189:112400. [PMID: 38484904 DOI: 10.1016/j.exger.2024.112400] [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: 12/29/2023] [Revised: 02/16/2024] [Accepted: 03/11/2024] [Indexed: 03/18/2024]
Abstract
Alzheimer's disease (AD) stands as a neurodegenerative disorder causing cognitive decline, posing a significant health concern for the elderly population in China. This study explored the effects of outer membrane vesicles (OMVs) from the gut microbiota of AD patients on learning and memory abilities and Tau protein phosphorylation in mice. In contrast to the OMVs from healthy controls and the PBS treatment group, mice treated with AD-OMVs exhibited notable declines in learning and memory capabilities, as evidenced by results from the Morris water maze, Y-maze, and novel object recognition tests. Immunohistochemistry and Western blot assessments unveiled elevated levels of hyperphosphorylated Tau in the cortex and hippocampus of mice treated with AD-OMVs. However, there were no alterations observed in the total Tau levels. In addition, AD-OMVs treated mice showed increased neuroinflammation indicated by elevated astrocytes and microglia. Molecular mechanism studies demonstrated that AD-OMVs could activate GSK3β, CDK5-Calpain and NF-κB pathways in mice hippocampus. These studies suggest AD patient gut microbiota derived OMVs can promote host Tau phosphorylation and improved neuroinflammation.
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Affiliation(s)
- Zhongying Shao
- Department of liver diseases, Tai'an Traditional Chinese Medicine Hospital, Tai'an City, Shandong Province, China
| | - Yanjun Lu
- Department of liver diseases, Tai'an Traditional Chinese Medicine Hospital, Tai'an City, Shandong Province, China
| | - Aihong Xing
- TCM Prevent&Health Care Dept Tai'an Traditional Chinese Medicine Hospital, Tai'an City, Shandong Province, China
| | - Xiying He
- Department of Neurology, The Second Affiliated Hospital of Shandong First Medical University, Tai'an City, Shandong Province, China
| | - Hongyan Xie
- Department of Neurology, The Second Affiliated Hospital of Shandong First Medical University, Tai'an City, Shandong Province, China
| | - Ming Hu
- Department of Neurology, The Second Affiliated Hospital of Shandong First Medical University, Tai'an City, Shandong Province, China.
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23
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Lai Y, Liao F, Zhao J, Zhu C, Hu Y, Li Z. Exploring the capacities of ChatGPT: A comprehensive evaluation of its accuracy and repeatability in addressing helicobacter pylori-related queries. Helicobacter 2024; 29:e13078. [PMID: 38867649 DOI: 10.1111/hel.13078] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/13/2023] [Revised: 04/01/2024] [Accepted: 04/03/2024] [Indexed: 06/14/2024]
Abstract
BACKGROUND Educational initiatives on Helicobacter pylori (H. pylori) constitute a highly effective approach for preventing its infection and establishing standardized protocols for its eradication. ChatGPT, a large language model, is a potentially patient-friendly online tool capable of providing health-related knowledge. This study aims to assess the accuracy and repeatability of ChatGPT in responding to questions related to H. pylori. MATERIALS AND METHODS Twenty-one common questions about H. pylori were collected and categorized into four domains: basic knowledge, diagnosis, treatment, and prevention. ChatGPT was utilized to individually answer the aforementioned 21 questions. Its responses were independently assessed by two experts on H. pylori. Questions with divergent ratings were resolved by a third reviewer. Cohen's kappa coefficient was calculated to assess the consistency between the scores of the two reviewers. RESULTS The responses of ChatGPT on H. pylori-related questions were generally satisfactory, with 61.9% marked as "completely correct" and 33.33% as "correct but inadequate." The repeatability of the responses of ChatGPT to H. pylori-related questions was 95.23%. Among the responses, those related to prevention (comprehensive: 75%) had the best response, followed by those on treatment (comprehensive: 66.7%), basic knowledge (comprehensive: 60%), and diagnosis (comprehensive: 50%). In the "treatment" domain, 16.6% of the ChatGPT responses were categorized as "mixed with correct or incorrect/outdated data." However, ChatGPT still lacks relevant knowledge regarding H. pylori resistance and the use of sensitive antibiotics. CONCLUSIONS ChatGPT can provide correct answers to the majority of H. pylori-related queries. It exhibited good reproducibility and delivered responses that were easily comprehensible to patients. Further enhancement of real-time information updates and correction of inaccurate information will make ChatGPT an essential auxiliary tool for providing accurate H. pylori-related health information to patients.
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Affiliation(s)
- Yongkang Lai
- Department of Gastroenterology, Ganzhou People's Hospital, Jiangxi Medical College, Nanchang University, Nanchang, China
- Department of Gastroenterology, Shanghai Changhai Hospital, Naval Medical University, Shanghai, China
| | - Foqiang Liao
- Department of Gastroenterology, The First Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, China
| | - Jiulong Zhao
- Department of Gastroenterology, Shanghai Changhai Hospital, Naval Medical University, Shanghai, China
| | - Chunping Zhu
- Department of Gastroenterology, Ganzhou People's Hospital, Jiangxi Medical College, Nanchang University, Nanchang, China
| | - Yi Hu
- Department of Gastroenterology, The First Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, China
| | - Zhaoshen Li
- Department of Gastroenterology, Ganzhou People's Hospital, Jiangxi Medical College, Nanchang University, Nanchang, China
- Department of Gastroenterology, Shanghai Changhai Hospital, Naval Medical University, Shanghai, China
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24
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Zhao M, Ma G, Yan X, Li X, Wang E, Xu XX, Zhao JB, Ma X, Zeng J. Microbial infection promotes amyloid pathology in a mouse model of Alzheimer's disease via modulating γ-secretase. Mol Psychiatry 2024; 29:1491-1500. [PMID: 38273109 DOI: 10.1038/s41380-024-02428-5] [Citation(s) in RCA: 7] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/30/2023] [Revised: 12/20/2023] [Accepted: 01/10/2024] [Indexed: 01/27/2024]
Abstract
Microbial infection as a type of environmental risk factors is considered to be associated with long-term increased risk of dementia, including Alzheimer's disease (AD). AD is characterized by two neuropathologically molecular hallmarks of hyperphosphorylated tau and amyloid-β (Aβ), the latter generated by several biochemically reactive enzymes, including γ-secretase. However, how infectious risk factors contribute to pathological development of the AD core molecules remains to be addressed. In this work, we utilized a modified herpes simplex virus type 1 (mHSV-1) and found that its hippocampal infection locally promotes Aβ pathology in 5 × FAD mice, the commonly used amyloid model. Mechanistically, we identified HSV-1 membrane glycoprotein US7 (Envelope gI) that interacts with and modulates γ-secretase and consequently facilitates Aβ production. Furthermore, we presented evidence that adenovirus-associated virus-mediated locally hippocampal overexpression of the US7 aggravates Aβ pathology in 5 × FAD mice. Collectively, these findings identify a herpesviral factor regulating γ-secretase in the development and progression of AD and represent a causal molecular link between infectious pathogens and neurodegeneration.
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Affiliation(s)
- Meng Zhao
- Songjiang Research Institute, Songjiang Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 201600, China
- Department of Neurology, The Fourth Affiliated Hospital of Harbin Medical University, Harbin, 150001, Heilongjiang, China
| | - Guanqin Ma
- Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, 650201, Yunnan, China
- Kunming College of Life Science, University of Chinese Academy of Sciences, Kunming, 650204, Yunnan, China
| | - Xiaoxu Yan
- Songjiang Research Institute, Songjiang Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 201600, China
- Department of Neurology, The Fourth Affiliated Hospital of Harbin Medical University, Harbin, 150001, Heilongjiang, China
| | - Xiaohong Li
- Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, 650201, Yunnan, China
| | - Erlin Wang
- Songjiang Research Institute, Songjiang Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 201600, China
- Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, 650201, Yunnan, China
| | - Xiang-Xiong Xu
- Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, 650201, Yunnan, China
- Kunming College of Life Science, University of Chinese Academy of Sciences, Kunming, 650204, Yunnan, China
| | - Jie-Bin Zhao
- Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, 650201, Yunnan, China
- Kunming College of Life Science, University of Chinese Academy of Sciences, Kunming, 650204, Yunnan, China
| | - Xueling Ma
- Department of Neurology, The Fourth Affiliated Hospital of Harbin Medical University, Harbin, 150001, Heilongjiang, China.
| | - Jianxiong Zeng
- Songjiang Research Institute, Songjiang Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 201600, China.
- Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, 650201, Yunnan, China.
- Kunming College of Life Science, University of Chinese Academy of Sciences, Kunming, 650204, Yunnan, China.
- Yunnan Key Laboratory of Biodiversity Information, Kunming, 650201, Yunnan, China.
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25
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Ayyubova G, Fazal N. Beneficial versus Detrimental Effects of Complement-Microglial Interactions in Alzheimer's Disease. Brain Sci 2024; 14:434. [PMID: 38790413 PMCID: PMC11119363 DOI: 10.3390/brainsci14050434] [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: 04/04/2024] [Revised: 04/24/2024] [Accepted: 04/25/2024] [Indexed: 05/26/2024] Open
Abstract
Research indicates that brain-region-specific synapse loss and dysfunction are early hallmarks and stronger neurobiological correlates of cognitive decline in Alzheimer's disease (AD) than amyloid plaque and neurofibrillary tangle counts or neuronal loss. Even though the precise mechanisms underlying increased synaptic pruning in AD are still unknown, it has been confirmed that dysregulation of the balance between complement activation and inhibition is a crucial driver of its pathology. The complement includes three distinct activation mechanisms, with the activation products C3a and C5a, potent inflammatory effectors, and a membrane attack complex (MAC) leading to cell lysis. Besides pro-inflammatory cytokines, the dysregulated complement proteins released by activated microglia bind to amyloid β at the synaptic regions and cause the microglia to engulf the synapses. Additionally, research indicating that microglia-removed synapses are not always degenerating and that suppression of synaptic engulfment can repair cognitive deficits points to an essential opportunity for intervention that can prevent the loss of intact synapses. In this study, we focus on the latest research on the role and mechanisms of complement-mediated microglial synaptic pruning at different stages of AD to find the right targets that could interfere with complement dysregulation and be relevant for therapeutic intervention at the early stages of the disease.
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Affiliation(s)
- Gunel Ayyubova
- Department of Cytology, Embryology and Histology, Azerbaijan Medical University, Baku 370022, Azerbaijan;
| | - Nadeem Fazal
- College of Health Sciences and Pharmacy, Chicago State University, Chicago, IL 60628, USA
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26
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Liu X, Shen L, Wan M, Xie H, Wang Z. Peripheral extracellular vesicles in neurodegeneration: pathogenic influencers and therapeutic vehicles. J Nanobiotechnology 2024; 22:170. [PMID: 38610012 PMCID: PMC11015679 DOI: 10.1186/s12951-024-02428-1] [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: 11/17/2023] [Accepted: 03/19/2024] [Indexed: 04/14/2024] Open
Abstract
Neurodegenerative diseases (NDDs) such as Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis epitomize a class of insidious and relentless neurological conditions that are difficult to cure. Conventional therapeutic regimens often fail due to the late onset of symptoms, which occurs well after irreversible neurodegeneration has begun. The integrity of the blood-brain barrier (BBB) further impedes efficacious drug delivery to the central nervous system, presenting a formidable challenge in the pharmacological treatment of NDDs. Recent scientific inquiries have shifted focus toward the peripheral biological systems, investigating their influence on central neuropathology through the lens of extracellular vesicles (EVs). These vesicles, distinguished by their ability to breach the BBB, are emerging as dual operatives in the context of NDDs, both as conveyors of pathogenic entities and as prospective vectors for therapeutic agents. This review critically summarizes the burgeoning evidence on the role of extracerebral EVs, particularly those originating from bone, adipose tissue, and gut microbiota, in modulating brain pathophysiology. It underscores the duplicity potential of peripheral EVs as modulators of disease progression and suggests their potential as novel vehicles for targeted therapeutic delivery, positing a transformative impact on the future landscape of NDD treatment strategies. Search strategy A comprehensive literature search was conducted using PubMed, Web of Science, and Scopus from January 2000 to December 2023. The search combined the following terms using Boolean operators: "neurodegenerative disease" OR "Alzheimer's disease" OR "Parkinson's disease" OR "Amyotrophic lateral sclerosis" AND "extracellular vesicles" OR "exosomes" OR "outer membrane vesicles" AND "drug delivery systems" AND "blood-brain barrier". MeSH terms were employed when searching PubMed to refine the results. Studies were included if they were published in English, involved human subjects, and focused on the peripheral origins of EVs, specifically from bone, adipose tissue, and gut microbiota, and their association with related diseases such as osteoporosis, metabolic syndrome, and gut dysbiosis. Articles were excluded if they did not address the role of EVs in the context of NDDs or did not discuss therapeutic applications. The titles and abstracts of retrieved articles were screened using a dual-review process to ensure relevance and accuracy. The reference lists of selected articles were also examined to identify additional relevant studies.
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Affiliation(s)
- Xixi Liu
- Department of Orthopedics, Movement System Injury and Repair Research Center, Xiangya Hospital, Central South University, Changsha, Hunan, 410008, China
- Department of Neurology, Xiangya Hospital, Central South University, Changsha, Hunan, 410008, China
| | - Lu Shen
- Department of Neurology, Xiangya Hospital, Central South University, Changsha, Hunan, 410008, China
- National Clinical Research Center for Geriatric Disorders (Xiangya Hospital), Changsha, Hunan, 410008, China
- Engineering Research Center of Hunan Province in Cognitive Impairment Disorders, Changsha, Hunan, 410008, China
- Hunan International Scientific and Technological Cooperation Base of Neurodegenerative and Neurogenetic Diseases, Changsha, Hunan, 410008, China
| | - Meidan Wan
- Department of Neurology, Xiangya Hospital, Central South University, Changsha, Hunan, 410008, China
| | - Hui Xie
- Department of Orthopedics, Movement System Injury and Repair Research Center, Xiangya Hospital, Central South University, Changsha, Hunan, 410008, China.
- Hunan Key Laboratory of Angmedicine, Changsha, Hunan, 410008, China.
- National Clinical Research Center for Geriatric Disorders (Xiangya Hospital), Changsha, Hunan, 410008, China.
| | - Zhenxing Wang
- Department of Orthopedics, Movement System Injury and Repair Research Center, Xiangya Hospital, Central South University, Changsha, Hunan, 410008, China.
- Hunan Key Laboratory of Angmedicine, Changsha, Hunan, 410008, China.
- National Clinical Research Center for Geriatric Disorders (Xiangya Hospital), Changsha, Hunan, 410008, China.
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27
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Nimmo J, Byrne R, Daskoulidou N, Watkins L, Carpanini S, Zelek W, Morgan B. The complement system in neurodegenerative diseases. Clin Sci (Lond) 2024; 138:387-412. [PMID: 38505993 PMCID: PMC10958133 DOI: 10.1042/cs20230513] [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: 10/31/2023] [Revised: 02/15/2024] [Accepted: 03/01/2024] [Indexed: 03/21/2024]
Abstract
Complement is an important component of innate immune defence against pathogens and crucial for efficient immune complex disposal. These core protective activities are dependent in large part on properly regulated complement-mediated inflammation. Dysregulated complement activation, often driven by persistence of activating triggers, is a cause of pathological inflammation in numerous diseases, including neurological diseases. Increasingly, this has become apparent not only in well-recognized neuroinflammatory diseases like multiple sclerosis but also in neurodegenerative and neuropsychiatric diseases where inflammation was previously either ignored or dismissed as a secondary event. There is now a large and rapidly growing body of evidence implicating complement in neurological diseases that cannot be comprehensively addressed in a brief review. Here, we will focus on neurodegenerative diseases, including not only the 'classical' neurodegenerative diseases such as Alzheimer's disease and Parkinson's disease, but also two other neurological diseases where neurodegeneration is a neglected feature and complement is implicated, namely, schizophrenia, a neurodevelopmental disorder with many mechanistic features of neurodegeneration, and multiple sclerosis, a demyelinating disorder where neurodegeneration is a major cause of progressive decline. We will discuss the evidence implicating complement as a driver of pathology in these diverse diseases and address briefly the potential and pitfalls of anti-complement drug therapy for neurodegenerative diseases.
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Affiliation(s)
- Jacqui Nimmo
- UK Dementia Research Institute Cardiff, Cardiff University, Cardiff CF24 4HQ, U.K
| | - Robert A.J. Byrne
- UK Dementia Research Institute Cardiff, Cardiff University, Cardiff CF24 4HQ, U.K
| | - Nikoleta Daskoulidou
- UK Dementia Research Institute Cardiff, Cardiff University, Cardiff CF24 4HQ, U.K
| | - Lewis M. Watkins
- UK Dementia Research Institute Cardiff, Cardiff University, Cardiff CF24 4HQ, U.K
| | - Sarah M. Carpanini
- UK Dementia Research Institute Cardiff, Cardiff University, Cardiff CF24 4HQ, U.K
| | - Wioleta M. Zelek
- UK Dementia Research Institute Cardiff, Cardiff University, Cardiff CF24 4HQ, U.K
| | - B. Paul Morgan
- UK Dementia Research Institute Cardiff, Cardiff University, Cardiff CF24 4HQ, U.K
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28
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Huang J, Liu Y, Xu D, Chen M, Xie Q, Chen J, Xia L, Yu L, Wu Q, Li Z, Wang J, Tian L. Causal associations between Helicobacter pylori infection and pregnancy and neonatal outcomes: a two-sample Mendelian randomization study. Front Cell Infect Microbiol 2024; 14:1343499. [PMID: 38558850 PMCID: PMC10979540 DOI: 10.3389/fcimb.2024.1343499] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/05/2023] [Accepted: 02/13/2024] [Indexed: 04/04/2024] Open
Abstract
Background Observational studies have reported that Helicobacter pylori (H. pylori) infection is associated with a series of pregnancy and neonatal outcomes. However, the results have been inconsistent, and the causal effect is unknown. Methods A two-sample Mendelian randomization (MR) study was performed using summary-level statistics for anti-H. pylori IgG levels from the Avon Longitudinal Study of Parents and Children Cohort. Outcome data for pregnancy (miscarriage, preeclampsia-eclampsia, gestational diabetes mellitus, placental abruption, premature rupture of membranes, postpartum hemorrhage) and neonates (birthweight, gestational age, and preterm birth) were sourced from genome-wide association meta-analysis as well as the FinnGen and Early Growth Genetics Consortium. Causal estimates were calculated by five methods including inverse variance weighted (IVW). The heterogeneity of instrumental variables was quantified by Cochran's Q test, while sensitivity analyses were performed via MR-Egger, MR-PRESSO, and leave-one-out tests. Results IVW estimates suggested that genetically predicted anti-H. pylori IgG levels were significantly associated with increased risks of preeclampsia-eclampsia (odds ratio [OR] = 1.12, 95% confidence interval [CI] 1.01-1.24, P = 0.026) and premature rupture of membranes (OR = 1.17, 95% CI 1.05-1.30, P = 0.004). Similar results were obtained for preeclampsia-eclampsia from the MR-Egger method (OR = 1.32, 95% CI 1.06-1.64, P = 0.027) and for premature rupture of membranes from the weighted median method (OR = 1.22, 95% CI 1.06-1.41, P = 0.006). No significant causal effects were found for other outcomes. There was no obvious heterogeneity and horizontal pleiotropy across the MR analysis. Conclusion Our two-sample MR study demonstrated a causal relationship of H. pylori infection with preeclampsia-eclampsia and premature rupture of membranes. The findings confirm the epidemiological evidence on the adverse impact of H. pylori in pregnancy. Further studies are needed to elucidate the pathophysiological mechanisms and assess the effectiveness of pre-pregnancy screening and preventive eradication.
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Affiliation(s)
- Jialyu Huang
- Center for Reproductive Medicine, Jiangxi Maternal and Child Health Hospital, National Clinical Research Center for Obstetrics and Gynecology, Nanchang Medical College, Nanchang, China
| | - Yuxin Liu
- Department of Clinical Medicine, School of Queen Mary, Nanchang University, Nanchang, China
| | - Dingfei Xu
- Center for Reproductive Medicine, Jiangxi Maternal and Child Health Hospital, National Clinical Research Center for Obstetrics and Gynecology, Nanchang Medical College, Nanchang, China
| | - Mengyi Chen
- Center for Reproductive Medicine, Jiangxi Maternal and Child Health Hospital, National Clinical Research Center for Obstetrics and Gynecology, Nanchang Medical College, Nanchang, China
| | - Qiqi Xie
- Center for Reproductive Medicine, Jiangxi Maternal and Child Health Hospital, National Clinical Research Center for Obstetrics and Gynecology, Nanchang Medical College, Nanchang, China
| | - Jia Chen
- Center for Reproductive Medicine, Jiangxi Maternal and Child Health Hospital, National Clinical Research Center for Obstetrics and Gynecology, Nanchang Medical College, Nanchang, China
| | - Leizhen Xia
- Center for Reproductive Medicine, Jiangxi Maternal and Child Health Hospital, National Clinical Research Center for Obstetrics and Gynecology, Nanchang Medical College, Nanchang, China
| | - Lamei Yu
- Department of Obstetrics, Jiangxi Maternal and Child Health Hospital, National Clinical Research Center for Obstetrics and Gynecology, Nanchang Medical College, Nanchang, China
| | - Qiongfang Wu
- Center for Reproductive Medicine, Jiangxi Maternal and Child Health Hospital, National Clinical Research Center for Obstetrics and Gynecology, Nanchang Medical College, Nanchang, China
| | - Zengming Li
- Key Laboratory of Women’s Reproductive Health of Jiangxi Province, Jiangxi Maternal and Child Health Hospital, National Clinical Research Center for Obstetrics and Gynecology, Nanchang Medical College, Nanchang, China
| | - Jiawei Wang
- Reproductive and Genetic Hospital, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China
| | - Lifeng Tian
- Center for Reproductive Medicine, Jiangxi Maternal and Child Health Hospital, National Clinical Research Center for Obstetrics and Gynecology, Nanchang Medical College, Nanchang, China
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29
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Zou X, Zou G, Zou X, Wang K, Chen Z. Gut microbiota and its metabolites in Alzheimer's disease: from pathogenesis to treatment. PeerJ 2024; 12:e17061. [PMID: 38495755 PMCID: PMC10944166 DOI: 10.7717/peerj.17061] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2023] [Accepted: 02/15/2024] [Indexed: 03/19/2024] Open
Abstract
Introduction An increasing number of studies have demonstrated that altered microbial diversity and function (such as metabolites), or ecological disorders, regulate bowel-brain axis involvement in the pathophysiologic processes in Alzheimer's disease (AD). The dysregulation of microbes and their metabolites can be a double-edged sword in AD, presenting the possibility of microbiome-based treatment options. This review describes the link between ecological imbalances and AD, the interactions between AD treatment modalities and the microbiota, and the potential of interventions such as prebiotics, probiotics, synbiotics, fecal microbiota transplantation, and dietary interventions as complementary therapeutic strategies targeting AD pathogenesis and progression. Survey methodology Articles from PubMed and china.com on intestinal flora and AD were summarized to analyze the data and conclusions carefully to ensure the comprehensiveness, completeness, and accuracy of this review. Conclusions Regulating the gut flora ecological balance upregulates neurotrophic factor expression, regulates the microbiota-gut-brain (MGB) axis, and suppresses the inflammatory responses. Based on emerging research, this review explored novel directions for future AD research and clinical interventions, injecting new vitality into microbiota research development.
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Affiliation(s)
- Xinfu Zou
- Subject of Integrated Chinese and Western Medicine, Shandong University of Traditional Chinese Medicine, Jinan, Shandong, China
| | - Guoqiang Zou
- Subject of Traditional Chinese Medicine, Shandong University Of Traditional Chinese Medicine, Jinan, Shandong, China
| | - Xinyan Zou
- College of Traditional Chinese Medicine, Hebei University, Baoding, Hebei, China
| | - Kangfeng Wang
- Traditional Chinese Medicine, Shandong University of Traditional Chinese Medicine, Jinan, Shandong, China
| | - Zetao Chen
- Subject of Integrated Chinese and Western Medicine, Shandong University of Traditional Chinese Medicine, Jinan, Shandong, China
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30
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Yuan S, Dan L, Zhang Y, Wu J, Zhao J, Kivipelto M, Chen J, Ludvigsson JF, Li X, Larsson SC. Digestive System Diseases, Genetic Risk, and Incident Dementia: A Prospective Cohort Study. Am J Prev Med 2024; 66:516-525. [PMID: 37918457 DOI: 10.1016/j.amepre.2023.10.017] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/28/2023] [Revised: 10/24/2023] [Accepted: 10/25/2023] [Indexed: 11/04/2023]
Abstract
INTRODUCTION Although digestive system disease affects gut microbiota and their metabolites associated with dementia risk, the association between digestive system diseases and incident dementia has not yet been established. METHODS This cohort analysis included 458,181 participants free of baseline dementia in the UK Biobank (2006-2021). The associations of 14 digestive system diseases with dementia incidence were examined in 2022 using Cox proportional hazards regression models. Analyses were performed to differentiate the associations for early-onset (age <65 years) and late-onset (age ≥65 years) dementia. Interaction and stratification analyses were performed for polygenic risk score and APOE. RESULTS During a median follow-up of 12.4 years, 6,415 incident dementia cases were diagnosed. Eleven digestive system diseases showed significant associations with an increased risk of dementia after controlling for covariates and multiple testing. Compared with hazard ratios for individuals without digestive system diseases, the hazard ratios of dementia increased from 1.15 (95% confidence interval=1.09, 1.23) for patients with intestinal diverticular disease to 2.31 (95% confidence interval=1.98, 2.70) for patients with cirrhosis. The associations were different between certain digestive system diseases and dementia by onset age. The associations appeared to be stronger for cirrhosis (Q=0.001), irritable bowel syndrome (Q<0.001), gastritis and duodenitis (Q=0.002), gastroesophageal reflux disease (Q<0.001), ulcerative colitis (Q=0.047), gallbladder disease (Q=0.012), and peptic ulcer (Q=0.030) with early-onset dementia. There were no interactions for polygenic risk score or APOE (p>0.05). CONCLUSIONS These findings suggest an increased need for dementia prevention among patients with digestive system diseases.
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Affiliation(s)
- Shuai Yuan
- Department of Big Data in Health Science, School of Public Health and The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China; Unit of Cardiovascular and Nutritional Epidemiology, Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden
| | - Lintao Dan
- Department of Big Data in Health Science, School of Public Health and The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Yao Zhang
- Department of Gastroenterology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Jing Wu
- Aging Research Center (ARC), Department of Neurobiology, Care Sciences and Society, Karolinska Institutet, Stockholm, Sweden
| | - Jianhui Zhao
- Department of Big Data in Health Science, School of Public Health and The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Miia Kivipelto
- Division of Clinical Geriatrics, Department of Neurobiology, Care Sciences and Society, Karolinska Institutet, Stockholm, Sweden; Population Health Unit, Department of Public Health and Welfare, Finnish Institute for Health and Welfare, Helsinki, Finland; Ageing Epidemiology Research Unit, School of Public Health, Imperial College London, London, United Kingdom; Institute of Public Health and Clinical Nutrition, University of Eastern Finland, Kuopio, Finland; Theme Aging, Karolinska University Hospital, Stockholm, Sweden
| | - Jie Chen
- Department of Big Data in Health Science, School of Public Health and The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China.
| | - Jonas F Ludvigsson
- Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden; Department of Pediatrics, Örebro University Hospital, Örebro, Sweden
| | - Xue Li
- Department of Big Data in Health Science, School of Public Health and The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China.
| | - Susanna C Larsson
- Unit of Cardiovascular and Nutritional Epidemiology, Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden; Unit of Medical Epidemiology, Department of Surgical Sciences, Uppsala University, Uppsala, Sweden
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Wu M, Chen K, Zhao Y, Jiang M, Bao B, Yu W, Chen Z, Yin X. Normobaric hyperoxia alleviates complement C3-mediated synaptic pruning and brain injury after intracerebral hemorrhage. CNS Neurosci Ther 2024; 30:e14694. [PMID: 38532579 PMCID: PMC10966135 DOI: 10.1111/cns.14694] [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: 11/22/2023] [Revised: 02/02/2024] [Accepted: 03/11/2024] [Indexed: 03/28/2024] Open
Abstract
BACKGROUND Intracerebral hemorrhage (ICH) is a common cerebrovascular disease, and the complement cascade exacerbates brain injury after ICH. As the most abundant component of the complement system, complement component 3 (C3) plays essential roles in all three complement pathways. However, the effects of C3 on neurological impairment and brain injury in ICH patients and the related mechanism have not been fully elucidated. Normobaric hyperoxia (NBO) is regarded as a treatment for ICH patients, and recent clinical studies also have confirmed the neuroprotective role of NBO against acute ICH-mediated brain damage, but the underlying mechanism still remains elusive. AIMS In the present study, we investigated the effects of complement C3 on NBO-treated ICH patients and model mice, and the underlying mechanism of NBO therapy in ICH-mediated brain injury. RESULTS Hemorrhagic injury resulted in the high plasma C3 levels in ICH patients, and the plasma C3 levels were closely related to hemorrhagic severity and clinical outcomes after ICH. BO treatment alleviated neurologic impairments and rescued the hemorrhagic-induced increase in plasma C3 levels in ICH patients and model mice. Moreover, the results indicated that NBO exerted its protective effects of on brain injury after ICH by downregulating the expression of C3 in microglia and alleviating microglia-mediated synaptic pruning. CONCLUSIONS Our results revealed that NBO exerts its neuroprotective effects by reducing C3-mediated synaptic pruning, which suggested that NBO therapy could be used for the clinical treatment of ICH.
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Affiliation(s)
- Moxin Wu
- Department of Medical LaboratoryAffiliated Hospital of Jiujiang UniversityJiujiangJiangxiChina
- Jiujiang Clinical Precision Medicine Research CenterJiujiangJiangxiChina
| | - Kai Chen
- Department of Dermatology, Traditional Chinese and Western Medicine Hospital of Wuhan, Tongji Medical CollegeHuazhong University of Science and TechnologyWuhanChina
| | - Yasong Zhao
- Department of Dermatology, Traditional Chinese and Western Medicine Hospital of Wuhan, Tongji Medical CollegeHuazhong University of Science and TechnologyWuhanChina
| | - Min Jiang
- Jiujiang Clinical Precision Medicine Research CenterJiujiangJiangxiChina
| | - Bing Bao
- Jiujiang Clinical Precision Medicine Research CenterJiujiangJiangxiChina
- Department of NeurologyAffiliated Hospital of Jiujiang UniversityJiujiangChina
| | - Wenmin Yu
- Jiangxi Provincial Key Laboratory of Cell Precision Therapy, School of Basic Medical SciencesJiujiang UniversityJiujiangJiangxiChina
| | - Zhiying Chen
- Jiujiang Clinical Precision Medicine Research CenterJiujiangJiangxiChina
- Department of NeurologyAffiliated Hospital of Jiujiang UniversityJiujiangChina
| | - Xiaoping Yin
- Jiujiang Clinical Precision Medicine Research CenterJiujiangJiangxiChina
- Department of NeurologyAffiliated Hospital of Jiujiang UniversityJiujiangChina
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32
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Wang YM, Chen MY, Chen J, Zhang XH, Feng Y, Han YX, Li YL. Success of susceptibility-guided eradication of Helicobacter pylori in a region with high secondary clarithromycin and levofloxacin resistance rates. World J Gastroenterol 2024; 30:184-195. [PMID: 38312120 PMCID: PMC10835524 DOI: 10.3748/wjg.v30.i2.184] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/30/2023] [Revised: 12/12/2023] [Accepted: 12/28/2023] [Indexed: 01/12/2024] Open
Abstract
BACKGROUND Resistance to clarithromycin (CLA) and levofloxacin (LFX) of Helicobacter pylori (H. pylori) is increasing in severity, and successful eradication is essential. Presently, the eradication success rate has greatly declined, leaving a large number of patients with previous treatment histories. AIM To investigate secondary resistance rates, explore risk factors for antibiotic resistance, and assess the efficacy of susceptibility-guided therapy. METHODS We recruited 154 subjects positive for Urea Breath Test who attended The First Affiliated Hospital of China Medical University between July 2022 and April 2023. Participants underwent a string test after an overnight fast. The gastric juice was obtained and transferred to vials containing storage solution. Subsequently, DNA extraction and the specific DNA amplification were performed using quantitative polymerase chain reaction (qPCR). Demographic information was also analyzed as part of the study. Based on these results, the participants were administered susceptibility-guided treatment. Efficacy was compared with that of the empiric treatment group. RESULTS A total of 132 individuals tested positive for the H. pylori ureA gene by qPCR technique. CLA resistance rate reached a high level of 82.6% (n = 109), LFX resistance rate was 69.7% (n = 92) and dual resistance was 62.1% (n = 82). Gastric symptoms [odds ratio (OR) = 2.782; 95% confidence interval (95%CI): 1.076-7.194; P = 0.035] and rural residence (OR = 5.152; 95%CI: 1.407-18.861; P = 0.013) were independent risk factors for secondary resistance to CLA and LFX, respectively. A total of 102 and 100 individuals received susceptibility-guided therapies and empiric treatment, respectively. The antibiotic susceptibility-guided treatment and empiric treatment groups achieved successful eradication rates of 75.5% (77/102) and 59.0% (59/411) by the intention-to-treat (ITT) analysis and 90.6% (77/85) and 70.2% (59/84) by the per-protocol (PP) analysis, respectively. The eradication rates of these two treatment strategies were significantly different in both ITT (P = 0.001) and PP (P = 0.012) analyses. CONCLUSION H. pylori presented high secondary resistance rates to CLA and LFX. For patients with previous treatment failures, treatments should be guided by antibiotic susceptibility tests or regional antibiotic resistance profile.
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Affiliation(s)
- Yan-Meng Wang
- Department of Gastroenterology, The First Affiliated Hospital of China Medical University, Shenyang 110000, Liaoning Province, China
| | - Mo-Ye Chen
- Department of Gastroenterology, The First Affiliated Hospital of China Medical University, Shenyang 110000, Liaoning Province, China
| | - Jing Chen
- Key Laboratory of Cancer Etiology and Prevention in Liaoning Education Department, The First Hospital of China Medical University, Shenyang 110000, Liaoning Province, China
| | - Xin-He Zhang
- Department of Gastroenterology, The First Affiliated Hospital of China Medical University, Shenyang 110000, Liaoning Province, China
| | - Yan Feng
- Department of Gastroenterology, The First Affiliated Hospital of China Medical University, Shenyang 110000, Liaoning Province, China
| | - Yu-Xi Han
- Department of Gastroenterology, The First Affiliated Hospital of China Medical University, Shenyang 110000, Liaoning Province, China
| | - Yi-Ling Li
- Department of Gastroenterology, The First Affiliated Hospital of China Medical University, Shenyang 110000, Liaoning Province, China
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Batista AF, Khan KA, Papavergi MT, Lemere CA. The Importance of Complement-Mediated Immune Signaling in Alzheimer's Disease Pathogenesis. Int J Mol Sci 2024; 25:817. [PMID: 38255891 PMCID: PMC10815224 DOI: 10.3390/ijms25020817] [Citation(s) in RCA: 5] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2023] [Revised: 01/05/2024] [Accepted: 01/07/2024] [Indexed: 01/24/2024] Open
Abstract
As an essential component of our innate immune system, the complement system is responsible for our defense against pathogens. The complement cascade has complex roles in the central nervous system (CNS), most of what we know about it stems from its role in brain development. However, in recent years, numerous reports have implicated the classical complement cascade in both brain development and decline. More specifically, complement dysfunction has been implicated in neurodegenerative disorders, such as Alzheimer's disease (AD), which is the most common form of dementia. Synapse loss is one of the main pathological hallmarks of AD and correlates with memory impairment. Throughout the course of AD progression, synapses are tagged with complement proteins and are consequently removed by microglia that express complement receptors. Notably, astrocytes are also capable of secreting signals that induce the expression of complement proteins in the CNS. Both astrocytes and microglia are implicated in neuroinflammation, another hallmark of AD pathogenesis. In this review, we provide an overview of previously known and newly established roles for the complement cascade in the CNS and we explore how complement interactions with microglia, astrocytes, and other risk factors such as TREM2 and ApoE4 modulate the processes of neurodegeneration in both amyloid and tau models of AD.
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Affiliation(s)
- André F. Batista
- Ann Romney Center for Neurologic Diseases, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA 02115, USA; (A.F.B.); (K.A.K.); (M.-T.P.)
| | - Khyrul A. Khan
- Ann Romney Center for Neurologic Diseases, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA 02115, USA; (A.F.B.); (K.A.K.); (M.-T.P.)
| | - Maria-Tzousi Papavergi
- Ann Romney Center for Neurologic Diseases, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA 02115, USA; (A.F.B.); (K.A.K.); (M.-T.P.)
- School for Mental Health and Neuroscience (MHeNs), Department of Psychiatry and Neuropsychology, Maastricht University, P.O. Box 616, 6200 MD Maastricht, The Netherlands
| | - Cynthia A. Lemere
- Ann Romney Center for Neurologic Diseases, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA 02115, USA; (A.F.B.); (K.A.K.); (M.-T.P.)
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Pirolli NH, Jay SM. Analysis of Bacterial Extracellular Vesicles by Immunogold Transmission Electron Microscopy. Methods Mol Biol 2024; 2843:15-23. [PMID: 39141291 DOI: 10.1007/978-1-0716-4055-5_2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 08/15/2024]
Abstract
Bacterial extracellular vesicles (BEVs) have emerged as mediators of transkingdom communication with numerous potential biotechnological applications. As such, investigation of BEV's protein composition holds promise to uncover new biological mechanisms, such as in microbiome-host communication or pathogen infection. Additionally, bioengineering of BEV protein composition can enhance their therapeutic potential. However, accurate assessment of BEV protein cargo is limited by their nanometer size, which precludes light microscopy imaging, as well as by co-isolation of protein impurities during separation processes. A solution to these challenges is found in immunogold transmission electron microscopy (TEM), which combines antibody-based labeling with direct visualization of BEVs. Several challenges are commonly encountered during immunogold TEM analysis of BEVs, most notably inefficient antibody labeling and poor contrast. Here, we present an optimized protocol for immunogold TEM analysis of BEVs that overcomes such challenges.
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Affiliation(s)
- Nicholas H Pirolli
- Fischell Department of Bioengineering, University of Maryland, College Park, MD, USA
| | - Steven M Jay
- Fischell Department of Bioengineering, University of Maryland, College Park, MD, USA.
- Program in Molecular and Cell Biology, University of Maryland, College Park, MD, USA.
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Awogbindin I, Wanklin M, Verkhratsky A, Tremblay MÈ. Microglia in Neurodegenerative Diseases. ADVANCES IN NEUROBIOLOGY 2024; 37:497-512. [PMID: 39207709 DOI: 10.1007/978-3-031-55529-9_27] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 09/04/2024]
Abstract
Neurodegenerative diseases are manifested by a progressive death of neural cells, resulting in the deterioration of central nervous system (CNS) functions, ultimately leading to specific behavioural and cognitive symptoms associated with affected brain regions. Several neurodegenerative disorders are caused by genetic variants or mutations, although the majority of cases are sporadic and linked to various environmental risk factors, with yet an unknown aetiology. Neuroglial changes are fundamental and often lead to the pathophysiology of neurodegenerative diseases. In particular, microglial cells, which are essential for maintaining CNS health, become compromised in their physiological functions with the exposure to environmental risk factors, genetic variants or mutations, as well as disease pathology. In this chapter, we cover the contribution of neuroglia, especially microglia, to several neurodegenerative diseases, including Nasu-Hakola disease, Parkinson's disease, amyotrophic lateral sclerosis, Alzheimer's disease, Huntington's disease, infectious disease-associated neurodegeneration, and metal-precipitated neurodegeneration. Future research perspectives for the field pertaining to the therapeutic targeting of microglia across these disease conditions are also discussed.
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Affiliation(s)
- Ifeoluwa Awogbindin
- Department of Biochemistry, Neuroimmunology Group, Molecular Drug Metabolism and Toxicology Laboratory, College of Medicine, University of Ibadan, Ibadan, Nigeria
- Division of Medical Sciences, Medical Sciences Building, University of Victoria, Victoria, BC, Canada
- Institute on Aging and Lifelong Health, University of Victoria, Victoria, BC, Canada
| | - Michael Wanklin
- Division of Medical Sciences, Medical Sciences Building, University of Victoria, Victoria, BC, Canada
| | - Alexei Verkhratsky
- Faculty of Life Sciences, The University of Manchester, Manchester, UK.
- Department of Neurosciences, University of the Basque Country, Leioa, Bizkaia, Spain.
- Department of Stem Cell Biology, State Research Institute Centre for Innovative Medicine, Vilnius, Lithuania.
- Department of Forensic Analytical Toxicology, School of Forensic Medicine, China Medical University, Shenyang, China.
- Axe neurosciences, Centre de recherche du CHU de Québec-Université Laval, Québec City, QC, Canada.
- IKERBASQUE, Basque Foundation for Science, Bilbao, Spain.
| | - Marie-Ève Tremblay
- Division of Medical Sciences, Medical Sciences Building, University of Victoria, Victoria, BC, Canada.
- Institute on Aging and Lifelong Health, University of Victoria, Victoria, BC, Canada.
- Axe neurosciences, Centre de recherche du CHU de Québec-Université Laval, Québec City, QC, Canada.
- Department of Neurology and Neurosurgery, McGill University, Montreal, QC, Canada.
- Department of Molecular Medicine, Université Laval, Pavillon Ferdinand-Vandry, Québec City, QC, Canada.
- Department of Biochemistry and Molecular Biology, The University of British Columbia, Life Sciences Center, Vancouver, BC, Canada.
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Mercado G, Kaeufer C, Richter F, Peelaerts W. Infections in the Etiology of Parkinson's Disease and Synucleinopathies: A Renewed Perspective, Mechanistic Insights, and Therapeutic Implications. JOURNAL OF PARKINSON'S DISEASE 2024; 14:1301-1329. [PMID: 39331109 PMCID: PMC11492057 DOI: 10.3233/jpd-240195] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Accepted: 09/06/2024] [Indexed: 09/28/2024]
Abstract
Increasing evidence suggests a potential role for infectious pathogens in the etiology of synucleinopathies, a group of age-related neurodegenerative disorders including Parkinson's disease (PD), multiple system atrophy and dementia with Lewy bodies. In this review, we discuss the link between infections and synucleinopathies from a historical perspective, present emerging evidence that supports this link, and address current research challenges with a focus on neuroinflammation. Infectious pathogens can elicit a neuroinflammatory response and modulate genetic risk in PD and related synucleinopathies. The mechanisms of how infections might be linked with synucleinopathies as well as the overlap between the immune cellular pathways affected by virulent pathogens and disease-related genetic risk factors are discussed. Here, an important role for α-synuclein in the immune response against infections is emerging. Critical methodological and knowledge gaps are addressed, and we provide new future perspectives on how to address these gaps. Understanding how infections and neuroinflammation influence synucleinopathies will be essential for the development of early diagnostic tools and novel therapies.
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Affiliation(s)
- Gabriela Mercado
- Division of Neurobiology, Department of Psychiatry, Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Christopher Kaeufer
- Center for Systems Neuroscience, Hannover, Germany
- Department of Pharmacology, Toxicology and Pharmacy, University of Veterinary Medicine Hannover, Hannover, Germany
| | - Franziska Richter
- Department of Pharmacology, Toxicology and Pharmacy, University of Veterinary Medicine Hannover, Hannover, Germany
| | - Wouter Peelaerts
- Laboratory for Virology and Gene Therapy, Department of Pharmacy and Pharmaceutical Sciences, KU Leuven, Leuven, Belgium
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37
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Koukoulis TF, Beauchamp LC, Kaparakis-Liaskos M, McQuade RM, Purnianto A, Finkelstein DI, Barnham KJ, Vella LJ. Do Bacterial Outer Membrane Vesicles Contribute to Chronic Inflammation in Parkinson's Disease? JOURNAL OF PARKINSON'S DISEASE 2024; 14:227-244. [PMID: 38427502 PMCID: PMC10977405 DOI: 10.3233/jpd-230315] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Accepted: 01/16/2024] [Indexed: 03/03/2024]
Abstract
Parkinson's disease (PD) is an increasingly common neurodegenerative disease. It has been suggested that the etiology of idiopathic PD is complex and multifactorial involving environmental contributions, such as viral or bacterial infections and microbial dysbiosis, in genetically predisposed individuals. With advances in our understanding of the gut-brain axis, there is increasing evidence that the intestinal microbiota and the mammalian immune system functionally interact. Recent findings suggest that a shift in the gut microbiome to a pro-inflammatory phenotype may play a role in PD onset and progression. While there are links between gut bacteria, inflammation, and PD, the bacterial products involved and how they traverse the gut lumen and distribute systemically to trigger inflammation are ill-defined. Mechanisms emerging in other research fields point to a role for small, inherently stable vesicles released by Gram-negative bacteria, called outer membrane vesicles in disease pathogenesis. These vesicles facilitate communication between bacteria and the host and can shuttle bacterial toxins and virulence factors around the body to elicit an immune response in local and distant organs. In this perspective article, we hypothesize a role for bacterial outer membrane vesicles in PD pathogenesis. We present evidence suggesting that these outer membrane vesicles specifically from Gram-negative bacteria could potentially contribute to PD by traversing the gut lumen to trigger local, systemic, and neuroinflammation. This perspective aims to facilitate a discussion on outer membrane vesicles in PD and encourage research in the area, with the goal of developing strategies for the prevention and treatment of the disease.
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Affiliation(s)
- Tiana F. Koukoulis
- The Florey Institute of Neuroscience and Mental Health, The University of Melbourne, Parkville, VIC, Australia
| | - Leah C. Beauchamp
- The Florey Institute of Neuroscience and Mental Health, The University of Melbourne, Parkville, VIC, Australia
- Ann Romney Center for Neurologic Diseases, Brighamand Women’s Hospital, Harvard Medical School, Boston, MA, USA
| | - Maria Kaparakis-Liaskos
- Department of Microbiology, Anatomy, Physiology and Pharmacology, La Trobe University, Melbourne, VIC, Australia
| | - Rachel M. McQuade
- The Florey Institute of Neuroscience and Mental Health, The University of Melbourne, Parkville, VIC, Australia
- Department of Medicine, Gut-Axis Injury and Repair Laboratory, Western Centre for Health Research and Education (WCHRE), The University of Melbourne, Sunshine Hospital, St Albans, VIC, Australia
- Australian Institute of Musculoskeletal Science (AIMSS), Western Centre for Health Research and Education (WCHRE), Sunshine Hospital, St Albans, VIC, Australia
| | - Adityas Purnianto
- The Florey Institute of Neuroscience and Mental Health, The University of Melbourne, Parkville, VIC, Australia
| | - David I. Finkelstein
- The Florey Institute of Neuroscience and Mental Health, The University of Melbourne, Parkville, VIC, Australia
| | - Kevin J. Barnham
- The Florey Institute of Neuroscience and Mental Health, The University of Melbourne, Parkville, VIC, Australia
| | - Laura J. Vella
- The Florey Institute of Neuroscience and Mental Health, The University of Melbourne, Parkville, VIC, Australia
- Department of Surgery, The University of Melbourne, The Royal Melbourne Hospital, Parkville, VIC, Australia
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Candelli M, Franza L, Cianci R, Pignataro G, Merra G, Piccioni A, Ojetti V, Gasbarrini A, Franceschi F. The Interplay between Helicobacter pylori and Gut Microbiota in Non-Gastrointestinal Disorders: A Special Focus on Atherosclerosis. Int J Mol Sci 2023; 24:17520. [PMID: 38139349 PMCID: PMC10744166 DOI: 10.3390/ijms242417520] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/27/2023] [Revised: 12/07/2023] [Accepted: 12/14/2023] [Indexed: 12/24/2023] Open
Abstract
The discovery of Helicobacter pylori (H. pylori) in the early 1980s by Nobel Prize winners in medicine Robin Warren and Barry Marshall led to a revolution in physiopathology and consequently in the treatment of peptic ulcer disease. Subsequently, H. pylori has also been linked to non-gastrointestinal diseases, such as autoimmune thrombocytopenia, acne rosacea, and Raynaud's syndrome. In addition, several studies have shown an association with cardiovascular disease and atherosclerosis. Our narrative review aims to investigate the connection between H. pylori infection, gut microbiota, and extra-gastric diseases, with a particular emphasis on atherosclerosis. We conducted an extensive search on PubMed, Google Scholar, and Scopus, using the keywords "H. pylori", "dysbiosis", "microbiota", "atherosclerosis", "cardiovascular disease" in the last ten years. Atherosclerosis is a complex condition in which the arteries thicken or harden due to plaque deposits in the inner lining of an artery and is associated with several cardiovascular diseases. Recent research has highlighted the role of the microbiota in the pathogenesis of this group of diseases. H. pylori is able to both directly influence the onset of atherosclerosis and negatively modulate the microbiota. H. pylori is an important factor in promoting atherosclerosis. Progress is being made in understanding the underlying mechanisms, which could open the way to interesting new therapeutic perspectives.
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Affiliation(s)
- Marcello Candelli
- Emergency, Anesthesiological and Reanimation Sciences Department, Fondazione Policlinico Universitario A. Gemelli—IRCCS of Rome, 00168 Rome, Italy; (L.F.); (G.P.); (A.P.); (V.O.); (F.F.)
| | - Laura Franza
- Emergency, Anesthesiological and Reanimation Sciences Department, Fondazione Policlinico Universitario A. Gemelli—IRCCS of Rome, 00168 Rome, Italy; (L.F.); (G.P.); (A.P.); (V.O.); (F.F.)
| | - Rossella Cianci
- Department of Translational Medicine and Surgery, Catholic University, Fondazione Policlinico Universitario A. Gemelli—IRCCS, 00168 Rome, Italy;
| | - Giulia Pignataro
- Emergency, Anesthesiological and Reanimation Sciences Department, Fondazione Policlinico Universitario A. Gemelli—IRCCS of Rome, 00168 Rome, Italy; (L.F.); (G.P.); (A.P.); (V.O.); (F.F.)
| | - Giuseppe Merra
- Biomedicine and Prevention Department, Section of Clinical Nutrition and Nutrigenomics, Facoltà di Medicina e Chirurgia, Università degli Studi di Roma Tor Vergata, 00133 Rome, Italy;
| | - Andrea Piccioni
- Emergency, Anesthesiological and Reanimation Sciences Department, Fondazione Policlinico Universitario A. Gemelli—IRCCS of Rome, 00168 Rome, Italy; (L.F.); (G.P.); (A.P.); (V.O.); (F.F.)
| | - Veronica Ojetti
- Emergency, Anesthesiological and Reanimation Sciences Department, Fondazione Policlinico Universitario A. Gemelli—IRCCS of Rome, 00168 Rome, Italy; (L.F.); (G.P.); (A.P.); (V.O.); (F.F.)
| | - Antonio Gasbarrini
- Medical, Abdominal Surgery and Endocrine-Metabolic Science Department, Fondazione Policlinico Universitario A. Gemelli—IRCCS of Rome, 00168 Rome, Italy;
| | - Francesco Franceschi
- Emergency, Anesthesiological and Reanimation Sciences Department, Fondazione Policlinico Universitario A. Gemelli—IRCCS of Rome, 00168 Rome, Italy; (L.F.); (G.P.); (A.P.); (V.O.); (F.F.)
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Xie J, Haesebrouck F, Van Hoecke L, Vandenbroucke RE. Bacterial extracellular vesicles: an emerging avenue to tackle diseases. Trends Microbiol 2023; 31:1206-1224. [PMID: 37330381 DOI: 10.1016/j.tim.2023.05.010] [Citation(s) in RCA: 34] [Impact Index Per Article: 17.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/08/2022] [Revised: 05/20/2023] [Accepted: 05/22/2023] [Indexed: 06/19/2023]
Abstract
A growing body of research, especially in recent years, has shown that bacterial extracellular vesicles (bEVs) are one of the key underlying mechanisms behind the pathogenesis of various diseases like pulmonary fibrosis, sepsis, systemic bone loss, and Alzheimer's disease. Given these new insights, bEVs are proposed as an emerging vehicle that can be used as a diagnostic tool or to tackle diseases when used as a therapeutic target. To further boost the understanding of bEVs in health and disease we thoroughly discuss the contribution of bEVs in disease pathogenesis and the underlying mechanisms. In addition, we speculate on their potential as novel diagnostic biomarkers and how bEV-related mechanisms can be exploited as therapeutic targets.
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Affiliation(s)
- Junhua Xie
- VIB Center for Inflammation Research, VIB, 9052 Ghent, Belgium; Department of Biomedical Molecular Biology, Ghent University, 9000 Ghent, Belgium; Department of Pathobiology, Pharmacology, and Zoological Medicine, Faculty of Veterinary Medicine, Ghent University, 9820 Merelbeke, Belgium
| | - Freddy Haesebrouck
- Department of Pathobiology, Pharmacology, and Zoological Medicine, Faculty of Veterinary Medicine, Ghent University, 9820 Merelbeke, Belgium
| | - Lien Van Hoecke
- VIB Center for Inflammation Research, VIB, 9052 Ghent, Belgium; Department of Biomedical Molecular Biology, Ghent University, 9000 Ghent, Belgium
| | - Roosmarijn E Vandenbroucke
- VIB Center for Inflammation Research, VIB, 9052 Ghent, Belgium; Department of Biomedical Molecular Biology, Ghent University, 9000 Ghent, Belgium.
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Ji N, Wang F, Wang M, Zhang W, Liu H, Su J. Engineered bacterial extracellular vesicles for central nervous system diseases. J Control Release 2023; 364:46-60. [PMID: 37866404 DOI: 10.1016/j.jconrel.2023.10.027] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/10/2023] [Revised: 10/17/2023] [Accepted: 10/18/2023] [Indexed: 10/24/2023]
Abstract
The prevalence of central nervous system (CNS) diseases is on the rise as the population ages. The presence of various obstacles, particularly the blood-brain barrier (BBB), poses a challenge for drug delivery to the CNS. An expanding body of study suggests that gut microbiota (GM) plays an important role in CNS diseases. The communication between GM and CNS diseases has received increasing attention. Accumulating evidence indicates that the GM can modulate host signaling pathways to regulate distant organ functions by delivering bioactive substances to host cells via bacterial extracellular vesicles (BEVs). BEVs have emerged as a promising platform for the treatment of CNS diseases due to their nanostructure, ability to penetrate the BBB, as well as their low toxicity, high biocompatibility, ease of modification and large-scale culture. Here, we discuss the biogenesis, internalization mechanism and engineering modification methods of BEVs. We then focus on the use and potential role of BEVs in the treatment of CNS diseases. Finally, we outline the main challenges and future prospects for the application of BEVs in CNS diseases. We hope that the comprehensive understanding of the BEVs-based gut-brain axis will provide new insights into the treatment of CNS diseases.
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Affiliation(s)
- Ning Ji
- Institute of Translational Medicine, Shanghai University, Shanghai 200444, China; Organoid Research Center, Shanghai University, Shanghai 200444, China; National Center for Translational Medicine (Shanghai) SHU Branch, Shanghai University, Shanghai 200444, China
| | - Fuxiao Wang
- Institute of Translational Medicine, Shanghai University, Shanghai 200444, China; Organoid Research Center, Shanghai University, Shanghai 200444, China; National Center for Translational Medicine (Shanghai) SHU Branch, Shanghai University, Shanghai 200444, China
| | - Miaomiao Wang
- Department of Rehabilitation Medicine, Shanghai Zhongye Hospital, Shanghai 200941, China
| | - Wencai Zhang
- Department of Orthopedics, The First Affiliated Hospital of Jinan University, Guangdong, Guangzhou 510630, China.
| | - Han Liu
- Institute of Translational Medicine, Shanghai University, Shanghai 200444, China; Organoid Research Center, Shanghai University, Shanghai 200444, China; National Center for Translational Medicine (Shanghai) SHU Branch, Shanghai University, Shanghai 200444, China.
| | - Jiacan Su
- Institute of Translational Medicine, Shanghai University, Shanghai 200444, China; Organoid Research Center, Shanghai University, Shanghai 200444, China; National Center for Translational Medicine (Shanghai) SHU Branch, Shanghai University, Shanghai 200444, China; Department of Orthopedics, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200092, China.
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Lee HJ, Lee Y, Hong SH, Park JW. Decoding the Link between Periodontitis and Neuroinflammation: The Journey of Bacterial Extracellular Vesicles. Curr Genomics 2023; 24:132-135. [PMID: 38178987 PMCID: PMC10761334 DOI: 10.2174/0113892029258657231010065320] [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: 04/19/2023] [Revised: 07/26/2023] [Accepted: 09/08/2023] [Indexed: 01/06/2024] Open
Affiliation(s)
- Heon-Jin Lee
- Department of Microbiology and Immunology, School of Dentistry, Kyungpook National University, Daegu, 41940, Korea, South
| | - Youngkyun Lee
- Department of Biochemistry, School of Dentistry, Kyungpook National University, Daegu, 41940, Korea, South
| | - Su-Hyung Hong
- Department of Microbiology and Immunology, School of Dentistry, Kyungpook National University, Daegu, 41940, Korea, South
| | - Jin-Woo Park
- Department of Periodontology, School of Dentistry, Kyungpook National University, Daegu, 41940, Korea, South
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Wang C, Li W, Shao L, Zhou A, Zhao M, Li P, Zhang Z, Wu J. Both extracellular vesicles from helicobacter pylori-infected cells and helicobacter pylori outer membrane vesicles are involved in gastric/extragastric diseases. Eur J Med Res 2023; 28:484. [PMID: 37932800 PMCID: PMC10626716 DOI: 10.1186/s40001-023-01458-z] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/23/2023] [Accepted: 10/18/2023] [Indexed: 11/08/2023] Open
Abstract
Bacterial-derived extracellular vesicles (EVs) have emerged as crucial mediators in the cross-talk between hosts and pathogens, playing a significant role in infectious diseases and cancers. Among these pathogens, Helicobacter pylori (H. pylori) is a particularly important bacterium implicated in various gastrointestinal disorders, gastric cancers, and systemic illnesses. H. pylori achieves these effects by stimulating host cells to secrete EVs and generating internal outer membrane vesicles (OMVs). The EVs derived from H. pylori-infected host cells modulate inflammatory signaling pathways, thereby affecting cell proliferation, apoptosis, cytokine release, immune cell modification, and endothelial dysfunction, as well as disrupting cellular junctional structures and inducing cytoskeletal reorganization. In addition, OMVs isolated from H. pylori play a pivotal role in shaping subsequent immunopathological responses. These vesicles incite both inflammatory and immunosuppressive reactions within the host environment, facilitating pathogen evasion of host defenses and invasion of host cells. Despite this growing understanding, research involving H. pylori-derived EVs remains in its early stages across different domains. In this comprehensive review, we present recent advancements elucidating the contributions of EV components, such as non-coding RNAs (ncRNAs) and proteins, to the pathogenesis of gastric and extragastric diseases. Furthermore, we highlight their potential utility as biomarkers, therapeutic targets, and vehicles for targeted delivery.
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Affiliation(s)
- Chengyao Wang
- Department of Gastroenterology National Clinical Research Center for Digestive Disease, Beijing Digestive Disease Center, BeijingKey Laboratory for Precancerous Lesion of Digestive Disease, Beijing Friendship Hospital, Capital Medical University, Beijing, 100050, People's Republic of China
| | - Wenkun Li
- Department of Gastroenterology National Clinical Research Center for Digestive Disease, Beijing Digestive Disease Center, BeijingKey Laboratory for Precancerous Lesion of Digestive Disease, Beijing Friendship Hospital, Capital Medical University, Beijing, 100050, People's Republic of China
| | - Linlin Shao
- Department of Gastroenterology National Clinical Research Center for Digestive Disease, Beijing Digestive Disease Center, BeijingKey Laboratory for Precancerous Lesion of Digestive Disease, Beijing Friendship Hospital, Capital Medical University, Beijing, 100050, People's Republic of China
| | - Anni Zhou
- Department of Gastroenterology National Clinical Research Center for Digestive Disease, Beijing Digestive Disease Center, BeijingKey Laboratory for Precancerous Lesion of Digestive Disease, Beijing Friendship Hospital, Capital Medical University, Beijing, 100050, People's Republic of China
| | - Mengran Zhao
- Department of Gastroenterology National Clinical Research Center for Digestive Disease, Beijing Digestive Disease Center, BeijingKey Laboratory for Precancerous Lesion of Digestive Disease, Beijing Friendship Hospital, Capital Medical University, Beijing, 100050, People's Republic of China
| | - Peng Li
- Department of Gastroenterology National Clinical Research Center for Digestive Disease, Beijing Digestive Disease Center, BeijingKey Laboratory for Precancerous Lesion of Digestive Disease, Beijing Friendship Hospital, Capital Medical University, Beijing, 100050, People's Republic of China
| | - Zheng Zhang
- Department of Gastroenterology National Clinical Research Center for Digestive Disease, Beijing Digestive Disease Center, BeijingKey Laboratory for Precancerous Lesion of Digestive Disease, Beijing Friendship Hospital, Capital Medical University, Beijing, 100050, People's Republic of China.
| | - Jing Wu
- Department of Gastroenterology National Clinical Research Center for Digestive Disease, Beijing Digestive Disease Center, BeijingKey Laboratory for Precancerous Lesion of Digestive Disease, Beijing Friendship Hospital, Capital Medical University, Beijing, 100050, People's Republic of China.
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Northuis CA, Bell EJ, Lutsey PL, George KM, Gottesman RF, Mosley TH, Whitsel EA, Lakshminarayan K. Cumulative Use of Proton Pump Inhibitors and Risk of Dementia: The Atherosclerosis Risk in Communities Study. Neurology 2023; 101:e1771-e1778. [PMID: 37558503 PMCID: PMC10634644 DOI: 10.1212/wnl.0000000000207747] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/04/2023] [Accepted: 06/20/2023] [Indexed: 08/11/2023] Open
Abstract
BACKGROUND AND OBJECTIVES Studies on the association between proton pump inhibitor (PPI) use and dementia report mixed results and do not examine the impact of cumulative PPI use. We evaluated the associations between current and cumulative PPI use and risk of incident dementia in the Atherosclerosis Risk in Communities (ARIC) Study. METHODS These analyses used participants from a community-based cohort (ARIC) from the time of enrollment (1987-1989) through 2017. PPI use was assessed through visual medication inventory at clinic visits 1 (1987-1989) to 5 (2011-2013) and reported annually in study phone calls (2006-2011). This study uses ARIC visit 5 as baseline because this was the first visit in which PPI use was common. PPI use was examined 2 ways: current use at visit 5 and duration of use before visit 5 (from visit 1 to 2011, exposure categories: 0 day, 1 day-2.8 years, 2.8-4.4 years, >4.4 years). The outcome was incident dementia after visit 5. Cox proportional hazard models were used, adjusted for demographics, comorbid conditions, and other medication use. RESULTS A total of 5,712 dementia-free participants at visit 5 (mean age 75.4 ± 5.1 years; 22% Black race; 58% female) were included in our analysis. The median follow-up was 5.5 years. The minimum cumulative PPI use was 112 days, and the maximum use was 20.3 years. There were 585 cases of incident dementia identified during follow-up. Participants using PPIs at visit 5 were not at a significantly higher risk of developing dementia during subsequent follow-up than those not using PPIs (hazard ratio (HR): 1.1 [95% confidence interval (CI) 0.9-1.3]). Those who used PPIs for >4.4 cumulative years before visit 5 were at 33% higher risk of developing dementia during follow-up (HR: 1.3 [95% CI 1.0-1.8]) than those reporting no use. Associations were not significant for lesser durations of PPI use. DISCUSSION Future studies are needed to understand possible pathways between cumulative PPI use and the development of dementia. CLASSIFICATION OF EVIDENCE This study provides Class III evidence that the use of prescribed PPIs for >4.4 years by individuals aged 45 years and older is associated with a higher incidence of newly diagnosed dementia.
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Affiliation(s)
- Carin A Northuis
- From the University of Minnesota (C.A.N., P.L.L., K.L.), Minneapolis; Optum (E.J.B.), Minneapolis, MN; University of California, Davis (K.M.G.); National Institute of Neurological Disorders and Stroke (R.F.G.), Washington, DC; University of Mississippi Medical Center (T.H.M.), Jackson; and University of North Carolina (E.A.W.), Chapel Hill
| | - Elizabeth J Bell
- From the University of Minnesota (C.A.N., P.L.L., K.L.), Minneapolis; Optum (E.J.B.), Minneapolis, MN; University of California, Davis (K.M.G.); National Institute of Neurological Disorders and Stroke (R.F.G.), Washington, DC; University of Mississippi Medical Center (T.H.M.), Jackson; and University of North Carolina (E.A.W.), Chapel Hill
| | - Pamela L Lutsey
- From the University of Minnesota (C.A.N., P.L.L., K.L.), Minneapolis; Optum (E.J.B.), Minneapolis, MN; University of California, Davis (K.M.G.); National Institute of Neurological Disorders and Stroke (R.F.G.), Washington, DC; University of Mississippi Medical Center (T.H.M.), Jackson; and University of North Carolina (E.A.W.), Chapel Hill
| | - Kristen M George
- From the University of Minnesota (C.A.N., P.L.L., K.L.), Minneapolis; Optum (E.J.B.), Minneapolis, MN; University of California, Davis (K.M.G.); National Institute of Neurological Disorders and Stroke (R.F.G.), Washington, DC; University of Mississippi Medical Center (T.H.M.), Jackson; and University of North Carolina (E.A.W.), Chapel Hill
| | - Rebecca F Gottesman
- From the University of Minnesota (C.A.N., P.L.L., K.L.), Minneapolis; Optum (E.J.B.), Minneapolis, MN; University of California, Davis (K.M.G.); National Institute of Neurological Disorders and Stroke (R.F.G.), Washington, DC; University of Mississippi Medical Center (T.H.M.), Jackson; and University of North Carolina (E.A.W.), Chapel Hill
| | - Tom H Mosley
- From the University of Minnesota (C.A.N., P.L.L., K.L.), Minneapolis; Optum (E.J.B.), Minneapolis, MN; University of California, Davis (K.M.G.); National Institute of Neurological Disorders and Stroke (R.F.G.), Washington, DC; University of Mississippi Medical Center (T.H.M.), Jackson; and University of North Carolina (E.A.W.), Chapel Hill
| | - Eric A Whitsel
- From the University of Minnesota (C.A.N., P.L.L., K.L.), Minneapolis; Optum (E.J.B.), Minneapolis, MN; University of California, Davis (K.M.G.); National Institute of Neurological Disorders and Stroke (R.F.G.), Washington, DC; University of Mississippi Medical Center (T.H.M.), Jackson; and University of North Carolina (E.A.W.), Chapel Hill
| | - Kamakshi Lakshminarayan
- From the University of Minnesota (C.A.N., P.L.L., K.L.), Minneapolis; Optum (E.J.B.), Minneapolis, MN; University of California, Davis (K.M.G.); National Institute of Neurological Disorders and Stroke (R.F.G.), Washington, DC; University of Mississippi Medical Center (T.H.M.), Jackson; and University of North Carolina (E.A.W.), Chapel Hill.
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Arabi TZ, Alabdulqader AA, Sabbah BN, Ouban A. Brain-inhabiting bacteria and neurodegenerative diseases: the "brain microbiome" theory. Front Aging Neurosci 2023; 15:1240945. [PMID: 37927338 PMCID: PMC10620799 DOI: 10.3389/fnagi.2023.1240945] [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: 06/15/2023] [Accepted: 09/29/2023] [Indexed: 11/07/2023] Open
Abstract
Controversies surrounding the validity of the toxic proteinopathy theory of Alzheimer's disease have led the scientific community to seek alternative theories in the pathogenesis of neurodegenerative disorders (ND). Recent studies have provided evidence of a microbiome in the central nervous system. Some have hypothesized that brain-inhabiting organisms induce chronic neuroinflammation, leading to the development of a spectrum of NDs. Bacteria such as Chlamydia pneumoniae, Helicobacter pylori, and Cutibacterium acnes have been found to inhabit the brains of ND patients. Furthermore, several fungi, including Candida and Malassezia species, have been identified in the central nervous system of these patients. However, there remains several limitations to the brain microbiome hypothesis. Varying results across the literature, concerns regarding sample contamination, and the presence of exogenous deoxyribonucleic acids have led to doubts about the hypothesis. These results provide valuable insight into the pathogenesis of NDs. Herein, we provide a review of the evidence for and against the brain microbiome theory and describe the difficulties facing the hypothesis. Additionally, we define possible mechanisms of bacterial invasion of the brain and organism-related neurodegeneration in NDs and the potential therapeutic premises of this theory.
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Affiliation(s)
| | | | | | - Abderrahman Ouban
- College of Medicine, Alfaisal University, Riyadh, Saudi Arabia
- Department of Pathology, College of Medicine, Alfaisal University, Riyadh, Saudi Arabia
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Stolzer I, Scherer E, Süß P, Rothhammer V, Winner B, Neurath MF, Günther C. Impact of Microbiome-Brain Communication on Neuroinflammation and Neurodegeneration. Int J Mol Sci 2023; 24:14925. [PMID: 37834373 PMCID: PMC10573483 DOI: 10.3390/ijms241914925] [Citation(s) in RCA: 12] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/15/2023] [Revised: 09/27/2023] [Accepted: 10/01/2023] [Indexed: 10/15/2023] Open
Abstract
The gut microbiome plays a pivotal role in maintaining human health, with numerous studies demonstrating that alterations in microbial compositions can significantly affect the development and progression of various immune-mediated diseases affecting both the digestive tract and the central nervous system (CNS). This complex interplay between the microbiota, the gut, and the CNS is referred to as the gut-brain axis. The role of the gut microbiota in the pathogenesis of neurodegenerative diseases has gained increasing attention in recent years, and evidence suggests that gut dysbiosis may contribute to disease development and progression. Clinical studies have shown alterations in the composition of the gut microbiota in multiple sclerosis patients, with a decrease in beneficial bacteria and an increase in pro-inflammatory bacteria. Furthermore, changes within the microbial community have been linked to the pathogenesis of Parkinson's disease and Alzheimer's disease. Microbiota-gut-brain communication can impact neurodegenerative diseases through various mechanisms, including the regulation of immune function, the production of microbial metabolites, as well as modulation of host-derived soluble factors. This review describes the current literature on the gut-brain axis and highlights novel communication systems that allow cross-talk between the gut microbiota and the host that might influence the pathogenesis of neuroinflammation and neurodegeneration.
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Affiliation(s)
- Iris Stolzer
- Department of Medicine 1, Universitätsklinikum Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg (FAU), 91054 Erlangen, Germany
| | - Eveline Scherer
- Department of Medicine 1, Universitätsklinikum Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg (FAU), 91054 Erlangen, Germany
| | - Patrick Süß
- Department of Molecular Neurology, Universitätsklinikum Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg (FAU), 91054 Erlangen, Germany
| | - Veit Rothhammer
- Department of Neurology, Universitätsklinikum Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg (FAU), 91054 Erlangen, Germany
| | - Beate Winner
- Department of Stem Cell Biology, Universitätsklinikum Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg (FAU), 91054 Erlangen, Germany
- Center of Rare Diseases Erlangen (ZSEER), Universitätsklinikum Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg (FAU), 91054 Erlangen, Germany
- Deutsches Zentrum Immuntherapie (DZI), Universitätsklinikum Erlangen, 91054 Erlangen, Germany
| | - Markus F. Neurath
- Department of Medicine 1, Universitätsklinikum Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg (FAU), 91054 Erlangen, Germany
- Deutsches Zentrum Immuntherapie (DZI), Universitätsklinikum Erlangen, 91054 Erlangen, Germany
| | - Claudia Günther
- Department of Medicine 1, Universitätsklinikum Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg (FAU), 91054 Erlangen, Germany
- Deutsches Zentrum Immuntherapie (DZI), Universitätsklinikum Erlangen, 91054 Erlangen, Germany
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Shegefti S, Bolori S, Nabavi-Rad A, Dabiri H, Yadegar A, Baghaei K. Helicobacter pylori-derived outer membrane vesicles suppress liver autophagy: A novel mechanism for H. pylori-mediated hepatic disorder. Microb Pathog 2023; 183:106319. [PMID: 37619914 DOI: 10.1016/j.micpath.2023.106319] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/11/2023] [Revised: 08/18/2023] [Accepted: 08/22/2023] [Indexed: 08/26/2023]
Abstract
BACKGROUND Helicobacter pylori outer membrane vesicles (OMVs) are nano-sized structures, which have been recently suggested to play a crucial role in H. pylori pathogenesis. There are growing evidence indicating the relationship of H. pylori infection with extra-gastroduodenal diseases, especially liver-related disorders. This study was aimed to investigate the effects of H. pylori-derived OMVs on autophagy in hepatic stellate cells (HSCs). MATERIAL AND METHODS A selection of five clinical strains of H. pylori with different virulence genotypes were included. The OMVs were isolated by ultracentrifugation and characterized by scanning electron microscopy (SEM) and dynamic light scattering (DLS). The protein concentration of OMVs was measured by BCA assay. MTT assay was used to determine the viability of LX-2 cells (human HSCs) treated with OMVs. The expression level of MTOR, AKT, PI3K, BECN1, ATG16 and LC3B genes was assessed in OMVs-treated LX-2 cells using quantitative real-time PCR. Moreover, immunocytochemistry was performed to evaluate the protein expression of MTOR and LC3B autophagy markers. RESULTS H. pylori strains produced round shape nano-vesicles ranging from 50 to 500 nm. Treatment of HSCs with H. pylori-derived OMVs at concentration of 10 μg/mL for 24 h significantly elevated the expression of autophagy inhibitory markers (PI3K, AKT, and MTOR) and suppressed the mRNA expression level of autophagy core proteins (BECN1, ATG16 and LC3B). Immunocytochemistry also presented a substantial reduction in the concentration of LC3B autophagy core protein, and a marked elevation in the amount of MTOR autophagy inhibitory protein. CONCLUSION This study revealed that H. pylori-derived OMVs could potentially suppress autophagy flux in HSCs as a novel mechanism for H. pylori-mediated liver autophagy impairment and liver disease development. Further studies are required to elucidate the exact role of OMV-carried contents in liver autophagy, and liver-associated disorders.
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Affiliation(s)
- Saina Shegefti
- Foodborne and Waterborne Diseases Research Center, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Shahin Bolori
- Foodborne and Waterborne Diseases Research Center, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Ali Nabavi-Rad
- Foodborne and Waterborne Diseases Research Center, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Hossein Dabiri
- Microbiology Department, Faculty of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Abbas Yadegar
- Foodborne and Waterborne Diseases Research Center, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran, Iran; Gastroenterology and Liver Diseases Research Center, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
| | - Kaveh Baghaei
- Basic and Molecular Epidemiology of Gastrointestinal Disorder Research Center, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
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Wang Y, Luo X, Xiang X, Hao C, Ma D. Roles of bacterial extracellular vesicles in systemic diseases. Front Microbiol 2023; 14:1258860. [PMID: 37840728 PMCID: PMC10569430 DOI: 10.3389/fmicb.2023.1258860] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/14/2023] [Accepted: 09/05/2023] [Indexed: 10/17/2023] Open
Abstract
Accumulating evidence suggests that in various systems, not all bidirectional microbiota-host interactions involve direct cell contact. Bacterial extracellular vesicles (BEVs) may be key participants in this interkingdom crosstalk. BEVs mediate microbiota functions by delivering effector molecules that modulate host signaling pathways, thereby facilitating host-microbe interactions. BEV production during infections by both pathogens and probiotics has been observed in various host tissues. Therefore, these vesicles released by microbiota may have the ability to drive or inhibit disease pathogenesis in different systems within the host. Here, we review the current knowledge of BEVs and particularly emphasize their interactions with the host and the pathogenesis of systemic diseases.
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Affiliation(s)
- Yanzhen Wang
- Department of Endodontics, Stomatological Hospital, School of Stomatology, Southern Medical University, Guangzhou, Guangdong, China
| | - Xinghong Luo
- Department of Endodontics, Stomatological Hospital, School of Stomatology, Southern Medical University, Guangzhou, Guangdong, China
| | - Xiaozhen Xiang
- Department of Stomatology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, China
| | - Chunbo Hao
- Hainan General Hospital (Hainan Affiliated Hospital of Hainan Medical University), Haikou, Hainan, China
| | - Dandan Ma
- Department of Endodontics, Stomatological Hospital, School of Stomatology, Southern Medical University, Guangzhou, Guangdong, China
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Kaisanlahti A, Salmi S, Kumpula S, Amatya SB, Turunen J, Tejesvi M, Byts N, Tapiainen T, Reunanen J. Bacterial extracellular vesicles - brain invaders? A systematic review. Front Mol Neurosci 2023; 16:1227655. [PMID: 37781094 PMCID: PMC10537964 DOI: 10.3389/fnmol.2023.1227655] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/23/2023] [Accepted: 08/28/2023] [Indexed: 10/03/2023] Open
Abstract
Introduction Knowledge on the human gut microbiota in health and disease continues to rapidly expand. In recent years, changes in the gut microbiota composition have been reported as a part of the pathology in numerous neurodegenerative diseases. Bacterial extracellular vesicles (EVs) have been suggested as a novel mechanism for the crosstalk between the brain and gut microbiota, physiologically connecting the observed changes in the brain to gut microbiota dysbiosis. Methods Publications reporting findings on bacterial EVs passage through the blood-brain barrier were identified in PubMed and Scopus databases. Results The literature search yielded 138 non-duplicate publications, from which 113 records were excluded in title and abstract screening step. From 25 publications subjected to full-text screening, 8 were excluded. The resulting 17 publications were considered for the review. Discussion Bacterial EVs have been described with capability to cross the blood-brain barrier, but the mechanisms behind the crossing remain largely unknown. Importantly, very little data exists in this context on EVs secreted by the human gut microbiota. This systematic review summarizes the present evidence of bacterial EVs crossing the blood-brain barrier and highlights the importance of future research on gut microbiota-derived EVs in the context of gut-brain communication across the blood-brain barrier.
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Affiliation(s)
- Anna Kaisanlahti
- Biocenter Oulu, University of Oulu, Oulu, Finland
- Research Unit of Translational Medicine, University of Oulu, Oulu, Finland
| | - Sonja Salmi
- Disease Networks Research Unit, Faculty of Biochemistry and Molecular Medicine, University of Oulu, Oulu, Finland
| | - Sohvi Kumpula
- Biocenter Oulu, University of Oulu, Oulu, Finland
- Research Unit of Translational Medicine, University of Oulu, Oulu, Finland
| | - Sajeen Bahadur Amatya
- Biocenter Oulu, University of Oulu, Oulu, Finland
- Research Unit of Translational Medicine, University of Oulu, Oulu, Finland
| | - Jenni Turunen
- Biocenter Oulu, University of Oulu, Oulu, Finland
- Research Unit of Clinical Medicine, University of Oulu, Oulu, Finland
| | - Mysore Tejesvi
- Biocenter Oulu, University of Oulu, Oulu, Finland
- Department of Ecology and Genetics, Faculty of Science, University of Oulu, Oulu, Finland
| | - Nadiya Byts
- Biocenter Oulu, University of Oulu, Oulu, Finland
- Research Unit of Translational Medicine, University of Oulu, Oulu, Finland
| | - Terhi Tapiainen
- Biocenter Oulu, University of Oulu, Oulu, Finland
- Research Unit of Clinical Medicine, University of Oulu, Oulu, Finland
- Department of Pediatrics and Adolescent Medicine, Oulu University Hospital, Oulu, Finland
| | - Justus Reunanen
- Biocenter Oulu, University of Oulu, Oulu, Finland
- Research Unit of Translational Medicine, University of Oulu, Oulu, Finland
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Thomas R, Connolly KJ, Brekk OR, Hinrich AJ, Hastings ML, Isacson O, Hallett PJ. Viral-like TLR3 induction of cytokine networks and α-synuclein are reduced by complement C3 blockade in mouse brain. Sci Rep 2023; 13:15164. [PMID: 37704739 PMCID: PMC10499893 DOI: 10.1038/s41598-023-41240-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: 03/17/2023] [Accepted: 08/23/2023] [Indexed: 09/15/2023] Open
Abstract
Inflammatory processes and mechanisms are of central importance in neurodegenerative diseases. In the brain, α-synucleinopathies such as Parkinson's disease (PD) and Lewy body dementia (LBD) show immune cytokine network activation and increased toll like receptor 3 (TLR3) levels for viral double-stranded RNA (dsRNA). Brain inflammatory reactions caused by TLR3 activation are also relevant to understand pathogenic cascades by viral SARS-CoV-2 infection causing post- COVID-19 brain-related syndromes. In the current study, following regional brain TLR3 activation induced by dsRNA in mice, an acute complement C3 response was seen at 2 days. A C3 splice-switching antisense oligonucleotide (ASO) that promotes the splicing of a non-productive C3 mRNA, prevented downstream cytokines, such as IL-6, and α-synuclein changes. This report is the first demonstration that α-synuclein increases occur downstream of complement C3 activation. Relevant to brain dysfunction, post-COVID-19 syndromes and pathological changes leading to PD and LBD, viral dsRNA TLR3 activation in the presence of C3 complement blockade further revealed significant interactions between complement systems, inflammatory cytokine networks and α-synuclein changes.
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Affiliation(s)
- Ria Thomas
- Neuroregeneration Institute, McLean Hospital/Harvard Medical School, Belmont, MA, 02478, USA
| | - Kyle J Connolly
- Neuroregeneration Institute, McLean Hospital/Harvard Medical School, Belmont, MA, 02478, USA
| | - Oeystein R Brekk
- Neuroregeneration Institute, McLean Hospital/Harvard Medical School, Belmont, MA, 02478, USA
| | - Anthony J Hinrich
- Center for Genetic Diseases, Chicago Medical School, Rosalind Franklin University of Medicine and Science, North Chicago, IL, 60064, USA
| | - Michelle L Hastings
- Center for Genetic Diseases, Chicago Medical School, Rosalind Franklin University of Medicine and Science, North Chicago, IL, 60064, USA
| | - Ole Isacson
- Neuroregeneration Institute, McLean Hospital/Harvard Medical School, Belmont, MA, 02478, USA.
| | - Penelope J Hallett
- Neuroregeneration Institute, McLean Hospital/Harvard Medical School, Belmont, MA, 02478, USA.
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Noori M, Mahboobi R, Nabavi-Rad A, Jamshidizadeh S, Fakharian F, Yadegar A, Zali MR. Helicobacter pylori infection contributes to the expression of Alzheimer's disease-associated risk factors and neuroinflammation. Heliyon 2023; 9:e19607. [PMID: 37810022 PMCID: PMC10558876 DOI: 10.1016/j.heliyon.2023.e19607] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/12/2023] [Revised: 08/25/2023] [Accepted: 08/28/2023] [Indexed: 10/10/2023] Open
Abstract
Over time, mounting evidence has demonstrated extra-gastric manifestations of Helicobacter pylori infection. As such, a number of studies demonstrated the potential contribution of H. pylori infection to the incidence and progression of Alzheimer's disease (AD). Considering unanswered questions regarding the effect of H. pylori infection on brain activity, we sought to investigate the impact of H. pylori infection on the expression of AD-associated risk factors. We used two H. pylori clinical strains obtained from two patients with peptic ulcer and evaluated their influence on the expression level of AD-associated genes (APP, ApoE2, ApoE4, ABCA7, BIN1, Clu, CD33) and genes for inflammatory markers (TLR-4, IL-8, TNF-α) by RT-qPCR in human glioblastoma (U87MG) and astrocyte (1321N1) cell lines. The expression of inflammatory cytokines was further assessed by ELISA assay. The exposure of U97MG and 1321N1 cells to H. pylori strains resulted in a significant enhancement in the expression level of the risk allele ApoE4, while reducing the expression of the protective allele ApoE2. H. pylori infection remarkably increased the expression level of main AD-associated risk genes, and also pro-inflammatory cytokines. Furthermore, we noticed a substantial elevation in the mRNA expression level of transmembrane receptor TLR-4 following H. pylori infection. Our findings presented the potential for H. pylori to stimulate the expression of AD-associated risk genes and trigger neuroinflammation in the brain tissue. This, in principle, leads to the recommendation that AD patients should perhaps test for H. pylori infection and receive treatments upon positive detection.
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Affiliation(s)
- Maryam Noori
- Foodborne and Waterborne Diseases Research Center, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Ramina Mahboobi
- Basic and Molecular Epidemiology of Gastrointestinal Disorders Research Center, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Ali Nabavi-Rad
- Foodborne and Waterborne Diseases Research Center, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Shaghayegh Jamshidizadeh
- Foodborne and Waterborne Diseases Research Center, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Farzaneh Fakharian
- Foodborne and Waterborne Diseases Research Center, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Abbas Yadegar
- Foodborne and Waterborne Diseases Research Center, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Mohammad Reza Zali
- Gastroenterology and Liver Diseases Research Center, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran, Iran
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