1
|
Mohsen E, Haffez H, Ahmed S, Hamed S, El-Mahdy TS. Multiple Sclerosis: A Story of the Interaction Between Gut Microbiome and Components of the Immune System. Mol Neurobiol 2025; 62:7762-7775. [PMID: 39934561 PMCID: PMC12078361 DOI: 10.1007/s12035-025-04728-5] [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: 05/29/2024] [Accepted: 01/27/2025] [Indexed: 02/13/2025]
Abstract
Multiple sclerosis (MS) is defined as an inflammatory disorder that chronically affects the central nervous system of young people mostly and is distributed globally. It is associated with degeneration and demyelination of the myelin sheath around the nerves, resulting in multiple neurological disability symptoms ranging from mild to severe cases that end with paralysis sometimes. MS is one of the rising diseases globally that is unfortunately associated with reduced quality of life and adding national economic burdens. The definite MS mechanism is not clearly defined; however, all the previous researches confirm the role of the immune system as the master contributor in the pathogenesis. Innate and adaptive immune cells are activated peripherally then attracted toward the central nervous system (CNS) due to the breakdown of the blood-brain barrier. Recently, the gut-brain axis was shown to depend on gut metabolites that are produced by different microorganisms in the colon. The difference in microbiota composition between individuals is responsible for diversity in secreted metabolites that affect immune responses locally in the gut or systemically when reach blood circulation to the brain. It may enhance or suppress immune responses in the central nervous system (CNS) (repeated short forms); consequently, it may exacerbate or ameliorate MS symptoms. Recent data showed that some metabolites can be used as adjuvant therapy in MS and other inflammatory diseases. This review sheds light on the nature of MS and the possible interaction between gut microbiota and immune system regulation through the gut-brain axis, hence contributing to MS pathogenesis.
Collapse
Affiliation(s)
- Esraa Mohsen
- Department of Microbiology and Immunology, Faculty of Pharmacy, Helwan University, PO Box 11795, Cairo, Egypt
| | - Hesham Haffez
- Department of Biochemistry and Molecular Biology, Faculty of Pharmacy, Helwan University, PO Box 11795, Cairo, Egypt
- Center of Scientific Excellence "Helwan Structural Biology Research (HSBR), Helwan University, Cairo, 11795, Egypt
| | - Sandra Ahmed
- Department of Neurology, Faculty of Medicine, Cairo University, Cairo, Egypt
| | - Selwan Hamed
- Department of Microbiology and Immunology, Faculty of Pharmacy, Helwan University, PO Box 11795, Cairo, Egypt.
| | - Taghrid S El-Mahdy
- Department of Microbiology and Immunology, Faculty of Pharmacy, Helwan University, PO Box 11795, Cairo, Egypt
- Department of Microbiology and Immunology, Faculty of Pharmacy, Modern University for Technology and Information (MTI), Cairo, Egypt
| |
Collapse
|
2
|
Nemati MH, Yazdanpanah E, Kazemi R, Orooji N, Dadfar S, Oksenych V, Haghmorad D. Microbiota-Driven Mechanisms in Multiple Sclerosis: Pathogenesis, Therapeutic Strategies, and Biomarker Potential. BIOLOGY 2025; 14:435. [PMID: 40282300 PMCID: PMC12025160 DOI: 10.3390/biology14040435] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/25/2025] [Revised: 04/11/2025] [Accepted: 04/16/2025] [Indexed: 04/29/2025]
Abstract
Multiple sclerosis (MS) is a well-known, chronic autoimmune disorder of the central nervous system (CNS) involving demyelination and neurodegeneration. Research previously conducted in the area of the gut microbiome has highlighted it as a critical contributor to MS pathogenesis. Changes in the commensal microbiota, or dysbiosis, have been shown to affect immune homeostasis, leading to elevated levels of pro-inflammatory cytokines and disruption of the gut-brain axis. In this review, we provide a comprehensive overview of interactions between the gut microbiota and MS, especially focusing on the immunomodulatory actions of microbiota, such as influencing T-cell balance and control of metabolites, e.g., short-chain fatty acids. Various microbial taxa (e.g., Prevotella and Faecalibacterium) were suggested to lay protective roles, whereas Akkermansia muciniphila was associated with disease aggravation. Interventions focusing on microbiota, including probiotics, prebiotics, fecal microbiota transplantation (FMT), and dietary therapies to normalize gut microbial homeostasis, suppress inflammation and are proven to improve clinical benefits in MS patients. Alterations in gut microbiota represent opportunities for identifying biomarkers for early diagnosis, disease progression and treatment response monitoring. Further studies need to be conducted to potentially address the interplay between genetic predispositions, environmental cues, and microbiota composition to get the precise mechanisms of the gut-brain axis in MS. In conclusion, the gut microbiota plays a central role in MS pathogenesis and offers potential for novel therapeutic approaches, providing a promising avenue for improving clinical outcomes in MS management.
Collapse
Affiliation(s)
- Mohammad Hosein Nemati
- Student Research Committee, Semnan University of Medical Sciences, Semnan 3514799442, Iran
- Department of Immunology, School of Medicine, Semnan University of Medical Sciences, Semnan 3514799442, Iran
| | - Esmaeil Yazdanpanah
- Immunology Research Center, Mashhad University of Medical Sciences, Mashhad 9177948564, Iran
| | - Roya Kazemi
- Student Research Committee, Semnan University of Medical Sciences, Semnan 3514799442, Iran
- Department of Immunology, School of Medicine, Semnan University of Medical Sciences, Semnan 3514799442, Iran
| | - Niloufar Orooji
- Student Research Committee, Semnan University of Medical Sciences, Semnan 3514799442, Iran
- Department of Immunology, School of Medicine, Semnan University of Medical Sciences, Semnan 3514799442, Iran
| | - Sepehr Dadfar
- Student Research Committee, Semnan University of Medical Sciences, Semnan 3514799442, Iran
- Department of Immunology, School of Medicine, Semnan University of Medical Sciences, Semnan 3514799442, Iran
| | - Valentyn Oksenych
- Broegelmann Research Laboratory, Department of Clinical Science, University of Bergen, 5020 Bergen, Norway
| | - Dariush Haghmorad
- Department of Immunology, School of Medicine, Semnan University of Medical Sciences, Semnan 3514799442, Iran
| |
Collapse
|
3
|
Abolhasani FS, Vaghefinanekaran N, Yarahmadi A, Akrami S, Mirmahdavi S, Yousefi MH, Afkhami H, Shafiei M. Outer membrane vesicles in gram-negative bacteria and its correlation with pathogenesis. Front Immunol 2025; 16:1541636. [PMID: 40236702 PMCID: PMC11996793 DOI: 10.3389/fimmu.2025.1541636] [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: 12/08/2024] [Accepted: 03/11/2025] [Indexed: 04/17/2025] Open
Abstract
There is a widespread distribution of gram-negative bacteria worldwide, which are responsible for the deaths of numerous patients each year. The illnesses they cause can be localized and systemic, and these bacteria possess several key virulence factors that contribute to their pathogenicity. In recent years, several distinct mechanisms of pathogenesis have evolved that remain largely unknown to scientists and medical experts. Among these, outer membrane vesicles (OMVs) are undoubtedly one of the most significant factors influencing virulence. OMVs contain various bacterial compounds and can have diverse effects on host organisms and the immune system, potentially exacerbating disease and inflammation while evading immune responses. This review comprehensively examines the role of OMVs in bacterial pathogenesis, their interaction with host cells, and their potential biomedical applications. Understanding the molecular mechanisms governing OMV biogenesis and function could pave the way for novel antimicrobial strategies and therapeutic interventions.
Collapse
Affiliation(s)
- Fatemeh Sadat Abolhasani
- Department of Pathobiology, School of Public Health, Tehran University of Medical Sciences, Tehran, Iran
| | | | - Aref Yarahmadi
- Department of Biology, Khorramabad Branch, Islamic Azad University, Khorramabad, Iran
| | - Sousan Akrami
- Department of Microbiology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Solmaz Mirmahdavi
- Department of Bacteriology and Virology, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran
- Department of Microbiology, Faculty of Medicine, Shahrekord University of Medical Sciences, Shahrekord, Iran
| | - Mohammad Hasan Yousefi
- Student Research Committee, Qom University of Medical Sciences, Qom, Iran
- Department of Tissue Engineering and Applied Cell Sciences, School of Medicine, Qom University of Medical Sciences, Qom, Iran
- Cellular and Molecular Research Center, Qom University of Medical Sciences, Qom, Iran
| | - Hamed Afkhami
- Student Research Committee, Qom University of Medical Sciences, Qom, Iran
- Cellular and Molecular Research Center, Qom University of Medical Sciences, Qom, Iran
- Nervous System Stem Cells Research Center, Semnan University of Medical Sciences, Semnan, Iran
- Department of Medical Microbiology, School of Medicine, Shahed University, Tehran, Iran
| | - Morvarid Shafiei
- Department of Bacteriology, Pasteur Institute of Iran, Tehran, Iran
| |
Collapse
|
4
|
Archer D, Pérez-Muñoz ME, Tollenaar S, Veniamin S, Hotte N, Cheng CC, Nieves K, Oh JH, Morceli L, Muncner S, Barreda DR, Krishnamoorthy G, Power C, van Pijkeren JP, Walter J. A secondary metabolite of Limosilactobacillusreuteri R2lc drives strain-specific pathology in a spontaneous mouse model of multiple sclerosis. Cell Rep 2025; 44:115321. [PMID: 39985770 DOI: 10.1016/j.celrep.2025.115321] [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: 08/23/2024] [Revised: 11/12/2024] [Accepted: 01/27/2025] [Indexed: 02/24/2025] Open
Abstract
Limosilactobacillus reuteri is an immunomodulatory bacterium enriched in non-industrialized microbiomes, making it a therapeutic candidate for chronic diseases. However, effects of L. reuteri strains in mouse models of multiple sclerosis have been contradictory. Here, we show that treatment of spontaneous relapsing-remitting experimental autoimmune encephalomyelitis (EAE) mice with L. reuteri R2lc, a strain that activates the aryl hydrocarbon receptor (AhR) through the pks gene cluster, resulted in severe pathology. In contrast, a pks mutant and a pks-negative strain (PB-W1) failed to exacerbate EAE and exhibited reduced pathology compared to R2lc despite earlier disease onset in PB-W1 mice. Differences in pathology occurred in parallel with a pks-dependent downregulation of AhR-related genes, reduced occludin expression in the forebrain, and altered concentrations of immune cells. This work establishes a molecular foundation for strain-specific effects on autoimmunity, which has implications for our understanding of how microbes contribute to chronic conditions and the selection of microbial therapeutics.
Collapse
Affiliation(s)
- Dale Archer
- Department of Biological Sciences, University of Alberta, Edmonton, AB T6G 2R3, Canada
| | - María Elisa Pérez-Muñoz
- Department of Agricultural, Food and Nutritional Science, University of Alberta, Edmonton, AB T6G 2R3, Canada
| | - Stephanie Tollenaar
- Department of Agricultural, Food and Nutritional Science, University of Alberta, Edmonton, AB T6G 2R3, Canada
| | - Simona Veniamin
- Department of Medicine, University of Alberta, Edmonton, AB T6G 2R3, Canada
| | - Naomi Hotte
- Department of Medicine, University of Alberta, Edmonton, AB T6G 2R3, Canada; Center of Excellence for Gastrointestinal Inflammation and Immunity Research, University of Alberta, Edmonton, AB T6G 2R3, Canada
| | - Christopher C Cheng
- Department of Medicine, University of Alberta, Edmonton, AB T6G 2R3, Canada; Center of Excellence for Gastrointestinal Inflammation and Immunity Research, University of Alberta, Edmonton, AB T6G 2R3, Canada
| | - Kristoff Nieves
- APC Microbiome Ireland, University College Cork, Cork T12 K8AF, County Cork, Ireland; School of Microbiology, University College Cork, Cork T12 K8AF, County Cork, Ireland; Department of Medicine, University College Cork, Cork T12 K8AF, County Cork, Ireland
| | - Jee-Hwan Oh
- Department of Food Science, University of Wisconsin-Madison, Madison, WI 53706, USA
| | - Lilian Morceli
- Department of Agricultural, Food and Nutritional Science, University of Alberta, Edmonton, AB T6G 2R3, Canada
| | - Susan Muncner
- Department of Agricultural, Food and Nutritional Science, University of Alberta, Edmonton, AB T6G 2R3, Canada
| | - Daniel R Barreda
- Department of Biological Sciences, University of Alberta, Edmonton, AB T6G 2R3, Canada; Department of Agricultural, Food and Nutritional Science, University of Alberta, Edmonton, AB T6G 2R3, Canada
| | | | - Christopher Power
- Department of Medicine, University of Alberta, Edmonton, AB T6G 2R3, Canada
| | | | - Jens Walter
- Department of Biological Sciences, University of Alberta, Edmonton, AB T6G 2R3, Canada; Department of Agricultural, Food and Nutritional Science, University of Alberta, Edmonton, AB T6G 2R3, Canada; APC Microbiome Ireland, University College Cork, Cork T12 K8AF, County Cork, Ireland; School of Microbiology, University College Cork, Cork T12 K8AF, County Cork, Ireland; Department of Medicine, University College Cork, Cork T12 K8AF, County Cork, Ireland.
| |
Collapse
|
5
|
Schumacher SM, Doyle WJ, Hill K, Ochoa-Repáraz J. Gut microbiota in multiple sclerosis and animal models. FEBS J 2025; 292:1330-1356. [PMID: 38817090 PMCID: PMC11607183 DOI: 10.1111/febs.17161] [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: 10/17/2023] [Revised: 04/15/2024] [Accepted: 05/10/2024] [Indexed: 06/01/2024]
Abstract
Multiple sclerosis (MS) is a chronic central nervous system (CNS) neurodegenerative and neuroinflammatory disease marked by a host immune reaction that targets and destroys the neuronal myelin sheath. MS and correlating animal disease models show comorbidities, including intestinal barrier disruption and alterations of the commensal microbiome. It is accepted that diet plays a crucial role in shaping the microbiota composition and overall gastrointestinal (GI) tract health, suggesting an interplay between nutrition and neuroinflammation via the gut-brain axis. Unfortunately, poor host health and diet lead to microbiota modifications that could lead to significant responses in the host, including inflammation and neurobehavioral changes. Beneficial microbial metabolites are essential for host homeostasis and inflammation control. This review will highlight the importance of the gut microbiota in the context of host inflammatory responses in MS and MS animal models. Additionally, microbial community restoration and how it affects MS and GI barrier integrity will be discussed.
Collapse
Affiliation(s)
| | | | - Kristina Hill
- Department of Biological Sciences, Boise State University, Boise, ID 83725
| | | |
Collapse
|
6
|
Trisal A, Singh I, Garg G, Jorwal K, Singh AK. Gut-brain axis and brain health: modulating neuroinflammation, cognitive decline, and neurodegeneration. 3 Biotech 2025; 15:25. [PMID: 39735610 PMCID: PMC11680542 DOI: 10.1007/s13205-024-04187-0] [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: 09/23/2024] [Accepted: 11/26/2024] [Indexed: 12/31/2024] Open
Abstract
The microbiota-gut-brain axis is a pivotal medium of crosstalk between the central nervous system (CNS) and the gastrointestinal tract. It is an intricate network of synergistic molecular pathways that exert their effects far beyond their local vicinity and even affect the systemic functioning of the body. The current review explores the involvement of the gut-brain axis (GBA) in the functioning of the nervous system, with a special emphasis on the neurodegeneration, cognitive decline, and neuroinflammation that occur in Alzheimer's disease (AD) and Parkinson's disease (PD). Gut-derived microbial metabolites play an important role in facilitating this interaction. We also highlighted the complex interaction between gut-derived metabolites and CNS processes, demonstrating how microbial dysbiosis might result in clinical disorders. Short-chain fatty acids have neuroprotective properties, whereas branched-chain amino acids, trimethylamine-N-oxide (TMAO), and tryptophan derivatives such as indole have negative effects at high concentrations. Furthermore, we cover pharmaceutical and nonpharmacological approaches for restoring the gut microbial balance and promoting neurological health. We further expanded on nutritional therapies and lifestyle changes, such as the Mediterranean diet and exercise. Next, we focused on food-controlling habits such as caloric restriction and intermittent fasting. Moreover, interventional techniques such as prebiotics, probiotics, and pharmacological medications have also been utilized to modify the GBA. Historical microbiome research from early discoveries to recent studies linking gut health to cognitive and emotional well-being has increased our understanding of the GBA.
Collapse
Affiliation(s)
- Anchal Trisal
- Department of Biosciences, Jamia Millia Islamia, New Delhi, 110025 India
| | - Ishika Singh
- Manipal Centre for Biotherapeutics Research, Manipal Academy of Higher Education, Karnataka Manipal, 576 104 India
| | - Geetika Garg
- Department of Zoology, Savitribai Phule Pune University, Pune, 411007 India
| | | | - Abhishek Kumar Singh
- Manipal Centre for Biotherapeutics Research, Manipal Academy of Higher Education, Karnataka Manipal, 576 104 India
| |
Collapse
|
7
|
Wang J, Hou Y, Mu L, Yang M, Ai X. Gut microbiota contributes to the intestinal and extraintestinal immune homeostasis by balancing Th17/Treg cells. Int Immunopharmacol 2024; 143:113570. [PMID: 39547012 DOI: 10.1016/j.intimp.2024.113570] [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: 08/09/2024] [Revised: 10/31/2024] [Accepted: 11/01/2024] [Indexed: 11/17/2024]
Abstract
Gut microbiota is generally considered to play an important role in host health due to its extensive immunomodulatory activities. Th17 and Treg cells are two important CD4+ T cell subsets involved in immune regulation, and their imbalance is closely tied to many immune diseases. Recently, abundant researches have highlighted the importance of gut microbiota in supporting intestinal and extraintestinal immunity through the balance of Th17 and Treg cells. Here, we presented a comprehensive review of these findings. This review first provided an overview of gut microbiota, along with Th17/Treg cell differentiation and cytokine production. Subsequently, the review summarized the regulatory effects of gut microbiota (in terms of species, components, and metabolites) on the Th17/Treg cell balance in the local intestines and extraintestinal organs, such as lung, liver, brain, kidney, and bone. Specifically, the Th17 and Treg cells that can be modulated by gut microbiota originate not only from the gut and extraintestinal organs, but also from peripheral blood and spleen. Then, the microbial therapeutics, including probiotics, prebiotics, postbiotics, and fecal microbiota transplantation (FMT), were also reviewed because of their therapeutic potentials in addressing intestinal and extraintestinal diseases via the Th17/Treg axis. Finally, the review discussed the clinical applications and future study prospects of microbial therapeutics by targeting the Th17/Treg cell balance. In conclusion, this review focused on elucidating the regulatory effects of gut microbiota in balancing Th17/Treg cells to maintain intestinal and extraintestinal immune homeostasis, contributing to the further development and promotion of microbial therapeutics.
Collapse
Affiliation(s)
- Jing Wang
- Department of Pharmacy, Affiliated Hospital of North Sichuan Medical College, Nanchong 637000, China; Department of Pharmacy, North Sichuan Medical College, Nanchong 637000, China
| | - Yaqin Hou
- Department of Pharmacy, Affiliated Hospital of North Sichuan Medical College, Nanchong 637000, China; Department of Pharmacy, North Sichuan Medical College, Nanchong 637000, China
| | - Lifeng Mu
- Department of Pharmacy, Affiliated Hospital of North Sichuan Medical College, Nanchong 637000, China; Department of Pharmacy, North Sichuan Medical College, Nanchong 637000, China
| | - Ming Yang
- Department of Pharmacy, Affiliated Hospital of North Sichuan Medical College, Nanchong 637000, China; Department of Pharmacy, North Sichuan Medical College, Nanchong 637000, China.
| | - Xiaopeng Ai
- Department of Pharmacy, Affiliated Hospital of North Sichuan Medical College, Nanchong 637000, China; Department of Pharmacy, North Sichuan Medical College, Nanchong 637000, China.
| |
Collapse
|
8
|
Tiwari A, Ika Krisnawati D, Susilowati E, Mutalik C, Kuo TR. Next-Generation Probiotics and Chronic Diseases: A Review of Current Research and Future Directions. JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY 2024; 72:27679-27700. [PMID: 39588716 DOI: 10.1021/acs.jafc.4c08702] [Citation(s) in RCA: 5] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/27/2024]
Abstract
The burgeoning field of microbiome research has profoundly reshaped our comprehension of human health, particularly highlighting the potential of probiotics and fecal microbiota transplantation (FMT) as therapeutic interventions. While the benefits of traditional probiotics are well-recognized, the efficacy and mechanisms remain ambiguous, and FMT's long-term effects are still being investigated. Recent advancements in high-throughput sequencing have identified gut microbes with significant health benefits, paving the way for next-generation probiotics (NGPs). These NGPs, engineered through synthetic biology and bioinformatics, are designed to address specific disease states with enhanced stability and viability. This review synthesizes current research on NGP stability, challenges in delivery, and their applications in preventing and treating chronic diseases such as diabetes, obesity, and cardiovascular diseases. We explore the physiological characteristics, safety profiles, and mechanisms of action of various NGP strains while also addressing the challenges and opportunities presented by their integration into clinical practice. The potential of NGPs to revolutionize microbiome-based therapies and improve clinical outcomes is immense, underscoring the need for further research to optimize their efficacy and ensure their safety.
Collapse
Affiliation(s)
- Ashutosh Tiwari
- International Ph.D. Program in Biomedical Engineering, College of Biomedical Engineering, Taipei Medical University, Taipei 11031, Taiwan
| | - Dyah Ika Krisnawati
- Department of Nursing, Faculty of Nursing and Midwifery, Universitas Nahdlatul Ulama Surabaya, Surabaya, 60237 East Java, Indonesia
| | - Erna Susilowati
- Akademi Kesehatan Dharma Husada Kediri, Kediri, 64118 East Java, Indonesia
| | - Chinmaya Mutalik
- Graduate Institute of Nanomedicine and Medical Engineering, College of Biomedical Engineering, Taipei Medical University, Taipei 11031, Taiwan
| | - Tsung-Rong Kuo
- International Ph.D. Program in Biomedical Engineering, College of Biomedical Engineering, Taipei Medical University, Taipei 11031, Taiwan
- Graduate Institute of Nanomedicine and Medical Engineering, College of Biomedical Engineering, Taipei Medical University, Taipei 11031, Taiwan
| |
Collapse
|
9
|
Lloren KKS, Senevirathne A, Lee JH. Advancing vaccine technology through the manipulation of pathogenic and commensal bacteria. Mater Today Bio 2024; 29:101349. [PMID: 39850273 PMCID: PMC11754135 DOI: 10.1016/j.mtbio.2024.101349] [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: 08/15/2024] [Revised: 10/30/2024] [Accepted: 11/15/2024] [Indexed: 01/25/2025] Open
Abstract
Advancements in vaccine technology are increasingly focused on leveraging the unique properties of both pathogenic and commensal bacteria. This revolutionary approach harnesses the diverse immune modulatory mechanisms and bacterial biology inherent in different bacterial species enhancing vaccine efficacy and safety. Pathogenic bacteria, known for their ability to induce robust immune responses, are being studied for their potential to be engineered into safe, attenuated vectors that can target specific diseases with high precision. Concurrently, commensal bacteria, which coexist harmlessly with their hosts and contribute to immune system regulation, are also being explored as novel delivery systems and in microbiome-based therapy. These bacteria can modulate immune responses, offering a promising avenue for developing effective and personalized vaccines. Integrating the distinctive characteristics of pathogenic and commensal bacteria with advanced bacterial engineering techniques paves the way for innovative vaccine and therapeutic platforms that could address a wide range of infectious diseases and potentially non-infectious conditions. This holistic approach signifies a paradigm shift in vaccine development and immunotherapy, emphasizing the intricate interplay between the bacteria and the immune systems to achieve optimal immunological outcomes.
Collapse
Affiliation(s)
- Khristine Kaith S. Lloren
- College of Veterinary Medicine, Jeonbuk National University, 79 Gobong-ro, Iksan City, Jeollabuk-do, 54596, Republic of Korea
| | - Amal Senevirathne
- College of Veterinary Medicine, Jeonbuk National University, 79 Gobong-ro, Iksan City, Jeollabuk-do, 54596, Republic of Korea
| | - John Hwa Lee
- College of Veterinary Medicine, Jeonbuk National University, 79 Gobong-ro, Iksan City, Jeollabuk-do, 54596, Republic of Korea
| |
Collapse
|
10
|
Chen S, Xue X, Zhang H, Huang X, Lin X, He J, Chen L, Luo S, Gao J. Jianwei Shoutai Pills alleviates miscarriage by modulating gut microbial production of BAs and NLRP3-inflammasome at the maternal-fetal interface of rats. PHYTOMEDICINE : INTERNATIONAL JOURNAL OF PHYTOTHERAPY AND PHYTOPHARMACOLOGY 2024; 135:156000. [PMID: 39293366 DOI: 10.1016/j.phymed.2024.156000] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/18/2024] [Revised: 06/20/2024] [Accepted: 06/24/2024] [Indexed: 09/20/2024]
Abstract
BACKGROUND Miscarriage has the characteristics of recurrent attacks and complex etiology, so it is gradually attracted the wide attention of scholars in the fields of reproduction. Potential association between gut microbiome (GM) and pregnancy disorders has been investigated. Jianwei Shoutai pills (JWP), as a representative formula, have been proven to have protective effect in both clinical and experimental research in miscarriage. However, the specific mechanism of JWP in miscarriage through GM remains unclear. PURPOSE To investigate the underlying mechanism of JWP against miscarriage through the gut-uterus axis. METHODS The effects of JWP on an RU486-induced rat model of miscarriage were evaluated by embryo resorption rate, vaginal bleeding rate, and appearance of the uterus and embryo. We used 16S rRNA sequencing to measure the extent of the effect of JWP on GM of rats with miscarriage. Bile acid (BA) content of the feces of rats treated with JWP was evaluated by high performance liquid chromatography-tandem mass spectrometry (HPLC-MS). The activation of bile acid-associated receptor, Farnesoid X receptor (FXR), was evaluated by immunofluorescence. The expression level of NLRP3 inflammasome-associated protein was detected by Western blot or Elisa. Fecal microbiota transplantation (FMT) was used to confirm that GM was essential for the therapeutic effect of JWP in miscarriage. RESULTS JWP significantly ameliorated miscarriage symptoms and embryo resorption rate caused by RU486-induced miscarriage as well as restored the abnormal activation of NLRP3-inflammasome at the maternal-fetal interface. Furthermore, JWP can significantly regulated GM dysbiosis and closely associated with BA metabolism by KEGG pathway prediction analysis. Several BA content were significantly restored by HPLC-MS. The expression of NLRP3 inflammasome-associated protein at maternal-fetal interface was reversed by JWP. Combined with FMT, JWP could regulate activation of NLRP3 at the maternal-fetal interface by BAs produced by GM. CONCLUSION JWP restored abnormal activation of the NLRP3-inflammasome in an RU486-induced miscarriage rat model, and corrected the BA disorder by regulating imbalance of the GM.
Collapse
Affiliation(s)
- Si Chen
- The First Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou 510405, China; Guangdong Clinical Research Academy of Chinese Medicine, Guangzhou 510405, China
| | - Xiaomeng Xue
- The First Clinical Medical School of Guangzhou University of Chinese Medicine, Guangzhou 510405, China; Lingnan Medical Research Center of Guangzhou University of Chinese Medicine, Guangzhou 510405, China
| | - Huimin Zhang
- The First Clinical Medical School of Guangzhou University of Chinese Medicine, Guangzhou 510405, China; Lingnan Medical Research Center of Guangzhou University of Chinese Medicine, Guangzhou 510405, China
| | - Xuge Huang
- The First Clinical Medical School of Guangzhou University of Chinese Medicine, Guangzhou 510405, China; Lingnan Medical Research Center of Guangzhou University of Chinese Medicine, Guangzhou 510405, China
| | - Xinyi Lin
- The First Clinical Medical School of Guangzhou University of Chinese Medicine, Guangzhou 510405, China; Lingnan Medical Research Center of Guangzhou University of Chinese Medicine, Guangzhou 510405, China
| | - Jiaxin He
- The First Clinical Medical School of Guangzhou University of Chinese Medicine, Guangzhou 510405, China; Lingnan Medical Research Center of Guangzhou University of Chinese Medicine, Guangzhou 510405, China
| | - Lizhu Chen
- The First Clinical Medical School of Guangzhou University of Chinese Medicine, Guangzhou 510405, China; Lingnan Medical Research Center of Guangzhou University of Chinese Medicine, Guangzhou 510405, China
| | - Songping Luo
- The First Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou 510405, China.
| | - Jie Gao
- The First Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou 510405, China; Guangdong Clinical Research Academy of Chinese Medicine, Guangzhou 510405, China; State Key Laboratory of Traditional Chinese Medicine Syndrome, Guangzhou 510006, China.
| |
Collapse
|
11
|
Fu Y, Gu Z, Cao H, Zuo C, Huang Y, Song Y, Jiang Y, Wang F. The role of the gut microbiota in neurodegenerative diseases targeting metabolism. Front Neurosci 2024; 18:1432659. [PMID: 39391755 PMCID: PMC11464490 DOI: 10.3389/fnins.2024.1432659] [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: 05/16/2024] [Accepted: 09/04/2024] [Indexed: 10/12/2024] Open
Abstract
In recent years, the incidence of neurodegenerative diseases (NDs) has gradually increased over the past decades due to the rapid aging of the global population. Traditional research has had difficulty explaining the relationship between its etiology and unhealthy lifestyle and diets. Emerging evidence had proved that the pathogenesis of neurodegenerative diseases may be related to changes of the gut microbiota's composition. Metabolism of gut microbiota has insidious and far-reaching effects on neurodegenerative diseases and provides new directions for disease intervention. Here, we delineated the basic relationship between gut microbiota and neurodegenerative diseases, highlighting the metabolism of gut microbiota in neurodegenerative diseases and also focusing on treatments for NDs based on gut microbiota. Our review may provide novel insights for neurodegeneration and approach a broadly applicable basis for the clinical therapies for neurodegenerative diseases.
Collapse
Affiliation(s)
- Yufeng Fu
- Department of Neurology, Tongji Medical College, Tongji Hospital, Huazhong University of Science and Technology, Wuhan, Hubei, China
| | - Zhongya Gu
- Department of Neurology, Tongji Medical College, Tongji Hospital, Huazhong University of Science and Technology, Wuhan, Hubei, China
| | - Huan Cao
- Department of Neurology, Tongji Medical College, Tongji Hospital, Huazhong University of Science and Technology, Wuhan, Hubei, China
| | - Chengchao Zuo
- Department of Rehabilitation, Tongji Medical College, Tongji Hospital, Huazhong University of Science and Technology, Wuhan, Hubei, China
| | - Yaqi Huang
- Department of Neurology, Tongji Medical College, Tongji Hospital, Huazhong University of Science and Technology, Wuhan, Hubei, China
| | - Yu Song
- Department of Neurology, Tongji Medical College, Tongji Hospital, Huazhong University of Science and Technology, Wuhan, Hubei, China
| | - Yongsheng Jiang
- Cancer Center of Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
| | - Furong Wang
- Department of Neurology, Tongji Medical College, Tongji Hospital, Huazhong University of Science and Technology, Wuhan, Hubei, China
- Key Laboratory of Vascular Aging (HUST), Ministry of Education, Tongji Medical College, Tongji Hospital, Huazhong University of Science and Technology, Wuhan, Hubei, China
| |
Collapse
|
12
|
Luesma MJ, López-Marco L, Monzón M, Santander S. Enteric Nervous System and Its Relationship with Neurological Diseases. J Clin Med 2024; 13:5579. [PMID: 39337066 PMCID: PMC11433641 DOI: 10.3390/jcm13185579] [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: 07/26/2024] [Revised: 09/12/2024] [Accepted: 09/13/2024] [Indexed: 09/30/2024] Open
Abstract
The enteric nervous system (ENS) is a fundamental component of the gastrointestinal system, composed of a vast network of neurons and glial cells. It operates autonomously but is interconnected with the central nervous system (CNS) through the vagus nerve. This communication, known as the gut-brain axis, influences the bidirectional communication between the brain and the gut. Background/Objectives: This study aimed to review neurological pathologies related to the ENS. Methods: To this end, a comprehensive literature search was conducted in the "PubMed" database. Articles available in "free format" were selected, applying the filters "Humans" and limiting the search to publications from the last ten years. Results: The ENS has been linked to various neurological diseases, from autism spectrum disorder to Parkinson's disease including neurological infection with the varicella zoster virus (VZV), even sharing pathologies with the CNS. This finding suggests that the ENS could serve as an early diagnostic marker or therapeutic target for neurological diseases. Gastrointestinal symptoms often precede CNS symptoms, and the ENS's accessibility aids in diagnosis and treatment. Parkinson's patients may show intestinal lesions up to twenty years before CNS symptoms, underscoring the potential for early diagnosis. However, challenges include developing standardized diagnostic protocols and the uneven distribution of dopaminergic neurons in the ENS. Continued research is needed to explore the ENS's potential in improving disease prognosis. Conclusions: The ENS is a promising area for early diagnosis and therapeutic development. Nevertheless, it is essential to continue research in this area, especially to gain a deeper understanding of its organization, function, and regenerative capacity.
Collapse
Affiliation(s)
- María José Luesma
- Department of Human Anatomy and Histology, University of Zaragoza, 50009 Zaragoza, Spain
| | - Liberto López-Marco
- Department of Human Anatomy and Histology, University of Zaragoza, 50009 Zaragoza, Spain
| | - Marta Monzón
- Department of Human Anatomy and Histology, University of Zaragoza, 50009 Zaragoza, Spain
| | - Sonia Santander
- Department of Pharmacology, Physiology, Legal and Forensic Medicine, University of Zaragoza, 50009 Zaragoza, Spain
| |
Collapse
|
13
|
Lin CH, Zeng T, Lu CW, Li DY, Liu YY, Li BM, Chen SQ, Deng YH. Efficacy and safety of Bacteroides fragilis BF839 for pediatric autism spectrum disorder: a randomized clinical trial. Front Nutr 2024; 11:1447059. [PMID: 39290561 PMCID: PMC11407114 DOI: 10.3389/fnut.2024.1447059] [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: 06/11/2024] [Accepted: 08/16/2024] [Indexed: 09/19/2024] Open
Abstract
Background The clinical utility of Bacteroides fragilis in treating autism spectrum disorder (ASD) remains unclear. Therefore, this randomized, double-blind, placebo-controlled study aimed to explore the therapeutic effects and safety of B. fragilis BF839 in the treatment of pediatric ASD. Methods We examined 60 children aged 2-10 years diagnosed with ASD, and participants received either BF839 powder (10 g/bar with ≥106 CFU/bar of viable bacteria, two bars/day) or placebo for 16 weeks. The primary outcomes was Autism Behavior Checklist (ABC) score. The secondary outcomes were Childhood Autism Rating Scale (CARS), Social Responsiveness Scale (SRS), Normal Development of Social Skills from Infants to Junior High School Children (S-M), Gastrointestinal Symptom Rating Scale (GSRS) scores, and fecal microbiome composition. Assessments were performed on day 0 and at weeks 8 and 16. Results Compared with the placebo group, the BF839 group showed significant improvement in the ABC body and object use scores at week 16, which was more pronounced in children with ASD aged <4 years. Among children with a baseline CARS score ≥30, the BF839 group showed significant improvements at week 16 in the ABC total score, ABC body and object use score, CARS score, and GSRS score compared to the placebo group. Only two patients (6.67%) in the BF839 group experienced mild diarrhea. Compared with baseline and placebo group levels, the BF839 group showed a significant post-intervention increase in abundance of bifidobacteria and change in the metabolic function of neuroactive compounds encoded by intestinal microorganisms. Conclusion BF839 significantly and safely improved abnormal behavior and gastrointestinal symptoms in children with ASD.
Collapse
Affiliation(s)
- Chu-Hui Lin
- Department of Clinical Nutrition, The Second Affiliated Hospital of Guangzhou Medical University, Guangzhou, China
| | - Ting Zeng
- Department of Clinical Nutrition, The Second Affiliated Hospital of Guangzhou Medical University, Guangzhou, China
| | - Cui-Wei Lu
- Medical Administration College, Guangzhou Medical University, Guangzhou, China
| | - De-Yang Li
- Medical Administration College, Guangzhou Medical University, Guangzhou, China
- Institute of Psychology, Chinese Academy of Sciences, Beijing, China
| | - Yi-Ying Liu
- Weierkang Specialist Outpatient Department, Guangzhou, China
| | - Bing-Mei Li
- Department of Neurology, Institute of Neuroscience, The Second Affiliated Hospital of Guangzhou Medical University, Guangzhou, China
- Key Laboratory of Neurogenetics and Channelopathies of Guangdong Province and the Ministry of Education of China, Guangzhou, China
| | - Sheng-Qiang Chen
- Medical Administration College, Guangzhou Medical University, Guangzhou, China
| | - Yu-Hong Deng
- Department of Clinical Nutrition, The Second Affiliated Hospital of Guangzhou Medical University, Guangzhou, China
- Department of Neurology, Institute of Neuroscience, The Second Affiliated Hospital of Guangzhou Medical University, Guangzhou, China
- Key Laboratory of Neurogenetics and Channelopathies of Guangdong Province and the Ministry of Education of China, Guangzhou, China
| |
Collapse
|
14
|
Steimle A, Neumann M, Grant ET, Willieme S, De Sciscio A, Parrish A, Ollert M, Miyauchi E, Soga T, Fukuda S, Ohno H, Desai MS. Gut microbial factors predict disease severity in a mouse model of multiple sclerosis. Nat Microbiol 2024; 9:2244-2261. [PMID: 39009690 PMCID: PMC11371644 DOI: 10.1038/s41564-024-01761-3] [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: 06/28/2023] [Accepted: 06/14/2024] [Indexed: 07/17/2024]
Abstract
Gut bacteria are linked to neurodegenerative diseases but the risk factors beyond microbiota composition are limited. Here we used a pre-clinical model of multiple sclerosis (MS), experimental autoimmune encephalomyelitis (EAE), to identify microbial risk factors. Mice with different genotypes and complex microbiotas or six combinations of a synthetic human microbiota were analysed, resulting in varying probabilities of severe neuroinflammation. However, the presence or relative abundances of suspected microbial risk factors failed to predict disease severity. Akkermansia muciniphila, often associated with MS, exhibited variable associations with EAE severity depending on the background microbiota. Significant inter-individual disease course variations were observed among mice harbouring the same microbiota. Evaluation of microbial functional characteristics and host immune responses demonstrated that the immunoglobulin A coating index of certain bacteria before disease onset is a robust individualized predictor of disease development. Our study highlights the need to consider microbial community networks and host-specific bidirectional interactions when aiming to predict severity of neuroinflammation.
Collapse
Affiliation(s)
- Alex Steimle
- Department of Infection and Immunity, Luxembourg Institute of Health, Esch-sur-Alzette, Luxembourg
| | - Mareike Neumann
- Department of Infection and Immunity, Luxembourg Institute of Health, Esch-sur-Alzette, Luxembourg
- Faculty of Science, Technology and Medicine, University of Luxembourg, Esch-sur-Alzette, Luxembourg
| | - Erica T Grant
- Department of Infection and Immunity, Luxembourg Institute of Health, Esch-sur-Alzette, Luxembourg
- Faculty of Science, Technology and Medicine, University of Luxembourg, Esch-sur-Alzette, Luxembourg
| | - Stéphanie Willieme
- Department of Infection and Immunity, Luxembourg Institute of Health, Esch-sur-Alzette, Luxembourg
| | - Alessandro De Sciscio
- Department of Infection and Immunity, Luxembourg Institute of Health, Esch-sur-Alzette, Luxembourg
| | - Amy Parrish
- Department of Infection and Immunity, Luxembourg Institute of Health, Esch-sur-Alzette, Luxembourg
- Faculty of Science, Technology and Medicine, University of Luxembourg, Esch-sur-Alzette, Luxembourg
| | - Markus Ollert
- Department of Infection and Immunity, Luxembourg Institute of Health, Esch-sur-Alzette, Luxembourg
- Department of Dermatology and Allergy Center, Odense Research Center for Anaphylaxis, University of Southern Denmark, Odense, Denmark
| | - Eiji Miyauchi
- RIKEN Center for Integrative Medical Sciences, Yokohama City, Kanagawa, Japan
| | - Tomoyoshi Soga
- Institute for Advanced Biosciences, Keio University, Yamagata, Japan
| | - Shinji Fukuda
- Institute for Advanced Biosciences, Keio University, Yamagata, Japan
| | - Hiroshi Ohno
- RIKEN Center for Integrative Medical Sciences, Yokohama City, Kanagawa, Japan
| | - Mahesh S Desai
- Department of Infection and Immunity, Luxembourg Institute of Health, Esch-sur-Alzette, Luxembourg.
- Department of Dermatology and Allergy Center, Odense Research Center for Anaphylaxis, University of Southern Denmark, Odense, Denmark.
| |
Collapse
|
15
|
Ichikawa Y, Sato B, Hirano SI, Takefuji Y, Satoh F. Realizing brain therapy with "smart medicine": mechanism and case report of molecular hydrogen inhalation for Parkinson's disease. Med Gas Res 2024; 14:89-95. [PMID: 39073335 PMCID: PMC466992 DOI: 10.4103/2045-9912.385949] [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: 02/03/2022] [Revised: 05/11/2022] [Accepted: 03/23/2023] [Indexed: 07/30/2024] Open
Abstract
The Michael J. Fox Foundation has been funding research on Parkinson's disease for 35 years, but has yet to find a cure. This is due to a problem with the philosophy behind the development of modern medical treatments. In this paper, we will introduce "smart medicine" with a substance that can solve all the problems of central nervous system drugs. The substance is the smallest diatomic molecule, the hydrogen molecule. Due to their size, hydrogen molecules can easily penetrate the cell membrane and enter the brain. In the midbrain of Parkinson's disease patients, hydroxyl radicals generated by the Fenton reaction cause a chain reaction of oxidation of dopamine, but hydrogen entering the midbrain can convert the hydroxyl radicals into water molecules and inhibit the oxidation of dopamine. In this paper, we focus on the etiology of neurological diseases, especially Parkinson's disease, and present a case in which hydrogen inhalation improves the symptoms of Parkinson's disease, such as body bending and hand tremor. And we confidently state that if Michael J. Fox encountered "smart medicine" that could be realized with molecular hydrogen, he would not be a "lucky man" but a "super-lucky man."
Collapse
Affiliation(s)
- Yusuke Ichikawa
- Research and Development Department, MiZ Company Limited, Kanagawa, Japan
- MiZ Inc., Newark, CA, USA
| | - Bunpei Sato
- Research and Development Department, MiZ Company Limited, Kanagawa, Japan
- MiZ Inc., Newark, CA, USA
| | - Shin-ichi Hirano
- Research and Development Department, MiZ Company Limited, Kanagawa, Japan
| | - Yoshiyasu Takefuji
- Faculty of Data Science, Musashino University, Tokyo, Japan
- Keio University, Tokyo, Japan
| | - Fumitake Satoh
- Research and Development Department, MiZ Company Limited, Kanagawa, Japan
- MiZ Inc., Newark, CA, USA
| |
Collapse
|
16
|
Hu Y, Zhang R, Li J, Wang H, Wang M, Ren Q, Fang Y, Tian L. Association Between Gut and Nasal Microbiota and Allergic Rhinitis: A Systematic Review. J Asthma Allergy 2024; 17:633-651. [PMID: 39006241 PMCID: PMC11246088 DOI: 10.2147/jaa.s472632] [Citation(s) in RCA: 3] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/15/2024] [Accepted: 07/01/2024] [Indexed: 07/16/2024] Open
Abstract
Allergic rhinitis is a chronic non-infectious inflammation of the nasal mucosa mediated by specific IgE. Recently, the human microbiome has drawn broad interest as a potential new target for treating this condition. This paper succinctly summarizes the main findings of 17 eligible studies published by February 2024, involving 1044 allergic rhinitis patients and 954 healthy controls from 5 countries. These studies examine differences in the human microbiome across important mucosal interfaces, including the nasal and intestinal areas, between patients and controls. Overall, findings suggest variations in the gut microbiota between allergic rhinitis patients and healthy individuals, although the specific bacterial taxa that significantly changed were not always consistent across studies. Due to the limited scope of existing research and patient coverage, the relationship between the nasal microbiome and allergic rhinitis remains inconclusive. The article discusses the potential immune-regulating role of the gut microbiome in allergic rhinitis. Further well-designed clinical trials with large-scale recruitment of allergic rhinitis patients are encouraged.
Collapse
Affiliation(s)
- Yucheng Hu
- Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan, People’s Republic of China
| | - Rong Zhang
- Jiangsu Province Hospital of Chinese Medicine, Nanjing, Jiangsu, People’s Republic of China
| | - Junjie Li
- Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan, People’s Republic of China
| | - Huan Wang
- Chengdu university of Traditional Chinese Medicine, Chengdu, Sichuan, People’s Republic of China
| | - Meiya Wang
- Chengdu university of Traditional Chinese Medicine, Chengdu, Sichuan, People’s Republic of China
| | - Qiuyi Ren
- Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan, People’s Republic of China
| | - Yueqi Fang
- Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan, People’s Republic of China
| | - Li Tian
- Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan, People’s Republic of China
| |
Collapse
|
17
|
Seida I, Al Shawaf M, Mahroum N. Fecal microbiota transplantation in autoimmune diseases - An extensive paper on a pathogenetic therapy. Autoimmun Rev 2024; 23:103541. [PMID: 38593970 DOI: 10.1016/j.autrev.2024.103541] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/11/2024] [Revised: 03/31/2024] [Accepted: 04/04/2024] [Indexed: 04/11/2024]
Abstract
The role of infections in the pathogenesis of autoimmune diseases has long been recognized and reported. In addition to infectious agents, the internal composition of the "friendly" living bacteria, (microbiome) and its correlation to immune balance and dysregulation have drawn the attention of researchers for decades. Nevertheless, only recently, scientific papers regarding the potential role of transferring microbiome from healthy donor subjects to patients with autoimmune diseases has been proposed. Fecal microbiota transplantation or FMT, carries the logic of transferring microorganisms responsible for immune balance from healthy donors to individuals with immune dysregulation or more accurately for our paper, autoimmune diseases. Viewing the microbiome as a pathogenetic player allows us to consider FMT as a pathogenetic-based treatment. Promising results alongside improved outcomes have been demonstrated in patients with different autoimmune diseases following FMT. Therefore, in our current extensive review, we aimed to highlight the implication of FMT in various autoimmune diseases, such as inflammatory bowel disease, autoimmune thyroid and liver diseases, systemic lupus erythematosus, and type 1 diabetes mellitus, among others. Presenting all the aspects of FMT in more than 12 autoimmune diseases in one paper, to the best of our knowledge, is the first time presented in medical literature. Viewing FMT as such could contribute to better understanding and newer application of the model in the therapy of autoimmune diseases, indeed.
Collapse
Affiliation(s)
- Isa Seida
- International School of Medicine, Istanbul Medipol University, Istanbul, Turkey
| | - Maisam Al Shawaf
- International School of Medicine, Istanbul Medipol University, Istanbul, Turkey
| | - Naim Mahroum
- International School of Medicine, Istanbul Medipol University, Istanbul, Turkey.
| |
Collapse
|
18
|
Zhang W, Wang Y, Zhu M, Liu K, Zhang HL. Gut flora in multiple sclerosis: implications for pathogenesis and treatment. Neural Regen Res 2024; 19:1480-1488. [PMID: 38051890 PMCID: PMC10883522 DOI: 10.4103/1673-5374.387974] [Citation(s) in RCA: 5] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/04/2023] [Accepted: 09/25/2023] [Indexed: 12/07/2023] Open
Abstract
ABSTRACT Multiple sclerosis is an inflammatory disorder characterized by inflammation, demyelination, and neurodegeneration in the central nervous system. Although current first-line therapies can help manage symptoms and slow down disease progression, there is no cure for multiple sclerosis. The gut-brain axis refers to complex communications between the gut flora and the immune, nervous, and endocrine systems, which bridges the functions of the gut and the brain. Disruptions in the gut flora, termed dysbiosis, can lead to systemic inflammation, leaky gut syndrome, and increased susceptibility to infections. The pathogenesis of multiple sclerosis involves a combination of genetic and environmental factors, and gut flora may play a pivotal role in regulating immune responses related to multiple sclerosis. To develop more effective therapies for multiple sclerosis, we should further uncover the disease processes involved in multiple sclerosis and gain a better understanding of the gut-brain axis. This review provides an overview of the role of the gut flora in multiple sclerosis.
Collapse
Affiliation(s)
- Weiwei Zhang
- Department of Neurology, the First Hospital of Jilin University, Jilin University, Changchun, Jilin Province, China
| | - Ying Wang
- Department of Neurology, the First Hospital of Jilin University, Jilin University, Changchun, Jilin Province, China
| | - Mingqin Zhu
- Department of Neurology, the First Hospital of Jilin University, Jilin University, Changchun, Jilin Province, China
| | - Kangding Liu
- Department of Neurology, the First Hospital of Jilin University, Jilin University, Changchun, Jilin Province, China
| | - Hong-Liang Zhang
- Department of Life Sciences, National Natural Science Foundation of China, Beijing, China
| |
Collapse
|
19
|
Fogarty EC, Schechter MS, Lolans K, Sheahan ML, Veseli I, Moore RM, Kiefl E, Moody T, Rice PA, Yu MK, Mimee M, Chang EB, Ruscheweyh HJ, Sunagawa S, Mclellan SL, Willis AD, Comstock LE, Eren AM. A cryptic plasmid is among the most numerous genetic elements in the human gut. Cell 2024; 187:1206-1222.e16. [PMID: 38428395 PMCID: PMC10973873 DOI: 10.1016/j.cell.2024.01.039] [Citation(s) in RCA: 24] [Impact Index Per Article: 24.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2023] [Revised: 10/03/2023] [Accepted: 01/25/2024] [Indexed: 03/03/2024]
Abstract
Plasmids are extrachromosomal genetic elements that often encode fitness-enhancing features. However, many bacteria carry "cryptic" plasmids that do not confer clear beneficial functions. We identified one such cryptic plasmid, pBI143, which is ubiquitous across industrialized gut microbiomes and is 14 times as numerous as crAssphage, currently established as the most abundant extrachromosomal genetic element in the human gut. The majority of mutations in pBI143 accumulate in specific positions across thousands of metagenomes, indicating strong purifying selection. pBI143 is monoclonal in most individuals, likely due to the priority effect of the version first acquired, often from one's mother. pBI143 can transfer between Bacteroidales, and although it does not appear to impact bacterial host fitness in vivo, it can transiently acquire additional genetic content. We identified important practical applications of pBI143, including its use in identifying human fecal contamination and its potential as an alternative approach to track human colonic inflammatory states.
Collapse
Affiliation(s)
- Emily C Fogarty
- Committee on Microbiology, University of Chicago, Chicago, IL 60637, USA; Duchossois Family Institute, University of Chicago, Chicago, IL 60637, USA; Department of Medicine, University of Chicago, Chicago, IL 60637, USA.
| | - Matthew S Schechter
- Committee on Microbiology, University of Chicago, Chicago, IL 60637, USA; Duchossois Family Institute, University of Chicago, Chicago, IL 60637, USA; Department of Medicine, University of Chicago, Chicago, IL 60637, USA
| | - Karen Lolans
- Department of Medicine, University of Chicago, Chicago, IL 60637, USA
| | - Madeline L Sheahan
- Duchossois Family Institute, University of Chicago, Chicago, IL 60637, USA; Department of Microbiology, University of Chicago, Chicago, IL 60637, USA
| | - Iva Veseli
- Department of Medicine, University of Chicago, Chicago, IL 60637, USA; Graduate Program in Biophysical Sciences, University of Chicago, Chicago, IL 60637, USA
| | - Ryan M Moore
- Center for Bioinformatics and Computational Biology, University of Delaware, Newark, DE, USA
| | - Evan Kiefl
- Department of Medicine, University of Chicago, Chicago, IL 60637, USA; Graduate Program in Biophysical Sciences, University of Chicago, Chicago, IL 60637, USA
| | - Thomas Moody
- Department of Systems Biology, Columbia University, New York, NY 10032, USA
| | - Phoebe A Rice
- Committee on Microbiology, University of Chicago, Chicago, IL 60637, USA; Department of Biochemistry, University of Chicago, Chicago, IL 60637, USA
| | - Michael K Yu
- Toyota Technological Institute at Chicago, Chicago, IL 60637, USA
| | - Mark Mimee
- Committee on Microbiology, University of Chicago, Chicago, IL 60637, USA; Department of Microbiology, University of Chicago, Chicago, IL 60637, USA; Pritzker School of Molecular Engineering, The University of Chicago, Chicago, IL 60637, USA
| | - Eugene B Chang
- Department of Medicine, University of Chicago, Chicago, IL 60637, USA
| | - Hans-Joachim Ruscheweyh
- Department of Biology, Institute of Microbiology and Swiss Institute of Bioinformatics, ETH Zurich, Zurich 8093, Switzerland
| | - Shinichi Sunagawa
- Department of Biology, Institute of Microbiology and Swiss Institute of Bioinformatics, ETH Zurich, Zurich 8093, Switzerland
| | - Sandra L Mclellan
- School of Freshwater Sciences, University of Wisconsin-Milwaukee, Milwaukee, WI 53204, USA
| | - Amy D Willis
- Department of Biostatistics, University of Washington, Seattle, WA 98195, USA
| | - Laurie E Comstock
- Committee on Microbiology, University of Chicago, Chicago, IL 60637, USA; Duchossois Family Institute, University of Chicago, Chicago, IL 60637, USA; Department of Microbiology, University of Chicago, Chicago, IL 60637, USA.
| | - A Murat Eren
- Department of Medicine, University of Chicago, Chicago, IL 60637, USA; Marine Biological Laboratory, Woods Hole, MA 02543, USA; Alfred Wegener Institute Helmholtz Centre for Polar and Marine Research, 27570 Bremerhaven, Germany; Institute for Chemistry and Biology of the Marine Environment, University of Oldenburg, 26129 Oldenburg, Germany; Max Planck Institute for Marine Microbiology, 28359 Bremen, Germany; Helmholtz Institute for Functional Marine Biodiversity, 26129 Oldenburg, Germany.
| |
Collapse
|
20
|
Fang J, Xiao C, Qi Y, Hong W, Wang M. Influence of pancreaticoduodenectomy for periampullary carcinoma on intestinal microbiome and metabolites. Heliyon 2024; 10:e24393. [PMID: 38304782 PMCID: PMC10831615 DOI: 10.1016/j.heliyon.2024.e24393] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2023] [Revised: 12/17/2023] [Accepted: 01/08/2024] [Indexed: 02/03/2024] Open
Abstract
Recent growing evidence suggests a role for intestinal microbiome and metabolites in patients' postoperative recovery. Therefore, there is a need to gain insight into the impact of pancreaticoduodenectomy for periampullary carcinoma on microbiome and metabolites and the potential impact of their changes on patients' condition. Based on 16S rDNA gene sequencing and untargeted metabolomic analysis, we found that the diversity and abundance of intestinal microbiome were significantly higher in patients preoperatively than postoperatively, and the level of intestinal probiotics was significantly lower after surgery compared with preoperatively. In addition, the choline metabolism level was increased and the amino acid metabolism level was decreased after surgery. A total of 53 differential microbiome and 52 differential metabolites were detected, and the differential metabolites were mapped to approximately 60 different KEGG metabolic pathways, of which 13 KEGG metabolic pathways had a differential metabolite number greater than 5. A total of 88 colony-metabolite pairs with significant positive correlation and 69 colony-metabolite pairs with significant negative correlation were identified. Our results reveal alterations in intestinal microbiome after pancreaticoduodenectomy, suggesting its association with postoperative complications. Moreover, the elevated choline metabolism level in postoperative patients may predict their poorer prognosis. At the same time, the decreased abundance of such probiotic bacteria as Prevotella spp. in the postoperative intestine of patients will affect the amino acid metabolism of the organism to some extent.
Collapse
Affiliation(s)
| | | | - Yafeng Qi
- Department of General Surgery, 900th Hospital of Joint Logistics Support Force of People's Liberation Army, Fuzhou, Fujian, 350000, China
| | - Weixuan Hong
- Department of General Surgery, 900th Hospital of Joint Logistics Support Force of People's Liberation Army, Fuzhou, Fujian, 350000, China
| | - Meiping Wang
- Department of General Surgery, 900th Hospital of Joint Logistics Support Force of People's Liberation Army, Fuzhou, Fujian, 350000, China
| |
Collapse
|
21
|
Kadyan S, Park G, Hochuli N, Miller K, Wang B, Nagpal R. Resistant starches from dietary pulses improve neurocognitive health via gut-microbiome-brain axis in aged mice. Front Nutr 2024; 11:1322201. [PMID: 38352704 PMCID: PMC10864001 DOI: 10.3389/fnut.2024.1322201] [Citation(s) in RCA: 5] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/15/2023] [Accepted: 01/10/2024] [Indexed: 02/16/2024] Open
Abstract
Introduction Cognitive decline is a common consequence of aging. Dietary patterns that lack fibers and are high in saturated fats worsen cognitive impairment by triggering pro-inflammatory pathways and metabolic dysfunctions. Emerging evidence highlights the neurocognitive benefits of fiber-rich diets and the crucial role of gut-microbiome-brain signaling. However, the mechanisms of this diet-microbiome-brain regulation remain largely unclear. Methods Accordingly, we herein investigated the unexplored neuroprotective mechanisms of dietary pulses-derived resistant starch (RS) in improving aging-associated neurocognitive function in an aged (60-weeks old) murine model carrying a human microbiome. Results and discussion Following 20-weeks dietary regimen which included a western-style diet without (control; CTL) or with 5% w/w fortification with RS from pinto beans (PTB), black-eyed-peas (BEP), lentils (LEN), chickpeas (CKP), or inulin fiber (INU), we find that RS, particularly from LEN, ameliorate the cognitive impairments induced by western diet. Mechanistically, RS-mediated improvements in neurocognitive assessments are attributed to positive remodeling of the gut microbiome-metabolome arrays, which include increased short-chain fatty acids and reduced branched-chain amino acids levels. This microbiome-metabolite-brain signaling cascade represses neuroinflammation, cellular senescence, and serum leptin/insulin levels, while enhancing lipid metabolism through improved hepatic function. Altogether, the data demonstrate the prebiotic effects of RS in improving neurocognitive function via modulating the gut-brain axis.
Collapse
Affiliation(s)
- Saurabh Kadyan
- The Gut Biome Lab, Department of Health, Nutrition, and Food Sciences, College of Education, Health, and Human Sciences, Florida State University, Tallahassee, FL, United States
| | - Gwoncheol Park
- The Gut Biome Lab, Department of Health, Nutrition, and Food Sciences, College of Education, Health, and Human Sciences, Florida State University, Tallahassee, FL, United States
| | - Nathaniel Hochuli
- The Gut Biome Lab, Department of Health, Nutrition, and Food Sciences, College of Education, Health, and Human Sciences, Florida State University, Tallahassee, FL, United States
| | - Katelyn Miller
- The Gut Biome Lab, Department of Health, Nutrition, and Food Sciences, College of Education, Health, and Human Sciences, Florida State University, Tallahassee, FL, United States
| | - Bo Wang
- Department of Biomedical and Chemical Engineering and Sciences, Florida Institute of Technology, Melbourne, FL, United States
| | - Ravinder Nagpal
- The Gut Biome Lab, Department of Health, Nutrition, and Food Sciences, College of Education, Health, and Human Sciences, Florida State University, Tallahassee, FL, United States
| |
Collapse
|
22
|
Sun X, Jin X, Wang L, Lin Z, Feng H, Zhan C, Liu X, Cheng G. Fraxetin ameliorates symptoms of dextran sulphate sodium-induced colitis in mice. Heliyon 2024; 10:e23295. [PMID: 38163213 PMCID: PMC10755303 DOI: 10.1016/j.heliyon.2023.e23295] [Citation(s) in RCA: 3] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2023] [Revised: 11/22/2023] [Accepted: 11/30/2023] [Indexed: 01/03/2024] Open
Abstract
Ulcerative colitis (UC) is one of the primary inflammatory bowel diseases (IBDs) and causes a serious threat to human public health around the world. Currently, there are no proven safe and effective treatment options to treat UC. Fraxetin (Fxt) is a widely recognized antioxidant and anti-inflammatory legume derived from ash bark. In the present study, we investigated the protective effect and mechanism of Fxt on UC. Our results showed that Fxt significantly attenuated the body weight, colon length reduction, tissue damage, and disease activity index induced by dextran sodium sulphate (DSS). Moreover, the DSS-induced activation of the NF-κB pathway and NLRP3 inflammasomes was inhibited, and the inflammatory response was reduced. Fxt restored gut barrier function by increasing the number of goblet cells and the levels of tight junction proteins (ZO-1 and occludin). In addition, Fxt can alter the intestinal microbiota by enhancing the diversity of the microbiota, increasing the relative abundance of beneficial bacteria and inhibiting the growth of harmful bacteria. These results revealed that Fxt alleviates DSS-induced colitis by modulating the inflammatory response, enhancing epithelial barrier integrity and regulating the gut microbiota. This study may provide a scientific basis for the potential therapeutic effect of Fxt in the prevention of colitis and other related diseases.
Collapse
Affiliation(s)
- Xiuxiu Sun
- Huazhong Agricultural University, Wuhan 430070, China
| | - Xinxin Jin
- Huazhong Agricultural University, Wuhan 430070, China
| | - Lumeng Wang
- Shengming Biological Technology (Zhengzhou) Co., Ltd., Zhengzhou 450000, China
| | - Zhengdan Lin
- Huazhong Agricultural University, Wuhan 430070, China
| | - Helong Feng
- Huazhong Agricultural University, Wuhan 430070, China
| | - Cunlin Zhan
- Huazhong Agricultural University, Wuhan 430070, China
| | - Xi Liu
- Huazhong Agricultural University, Wuhan 430070, China
| | - Guofu Cheng
- Huazhong Agricultural University, Wuhan 430070, China
| |
Collapse
|
23
|
Xi D, Liu P, Feng Y, Teng Y, Liang Y, Zhou J, Deng H, Zeng G, Zong S. Fecal microbiota transplantation regulates the microbiota-gut-spinal cord axis to promote recovery after spinal cord injury. Int Immunopharmacol 2024; 126:111212. [PMID: 37979452 DOI: 10.1016/j.intimp.2023.111212] [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: 09/20/2023] [Revised: 10/31/2023] [Accepted: 11/09/2023] [Indexed: 11/20/2023]
Abstract
Spinal cord injury (SCI) is devastating for patients, and currently lacks effective treatments. Dysbiosis commonly occurs after SCI and has significant immunomodulatory effects, but its impact on recovery remains unclear. The current study investigated the effects and mechanisms of fecal microbiota transplantation (FMT) in SCI. FMT was administered in a rat model of SCI and spinal pathology, inflammatory cytokines, and gut microbiome composition were assessed. Flow cytometry identified a source of interleukin (IL)-17 in spinal cord tissues, and carboxyfluorescein succimidyl ester labeling tracked γδ T cell migration. In vitro coculture was used to analyze the regulatory mechanisms of γδ T cells. Seahorse analysis was used to profile dendritic cell (DC) metabolism. Here we show that FMT improved spinal pathology and dampened post-injury inflammation. It also corrected post-SCI dysbiosis, increasing levels of the beneficial bacterium Akkermansia. The therapeutic effects of FMT were mediated by IL-17 produced by γδ T cells. FMT regulated γδ T cells via DC-T regulatory cell interaction, and induced metabolic reprogramming in DCs. These findings suggest that FMT represents a promising therapeutic approach for SCI, with potential to target IL-17+ γδ T cells. Elucidating the interconnected pathways between microbiota, immunity, and the spinal cord may facilitate novel treatment strategies.
Collapse
Affiliation(s)
- Deshuang Xi
- Department of Spine and Osteopathy Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning 530021, Guangxi, China
| | - Pan Liu
- Department of Orthopaedics, The Third Affiliated Hospital of Xinxiang Medical University, Xinxiang 453000, He-nan, China
| | - Yanbing Feng
- Department of Spine and Osteopathy Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning 530021, Guangxi, China
| | - Yilin Teng
- Department of Spine and Osteopathy Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning 530021, Guangxi, China
| | - Yu Liang
- Department of Spine Surgery, The Second People's Hospital of Nanning, Nanning 530021, Guangxi, China
| | - Junhong Zhou
- Department of Spine and Osteopathy Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning 530021, Guangxi, China
| | - Hao Deng
- Department of Spine and Osteopathy Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning 530021, Guangxi, China
| | - Gaofeng Zeng
- College of Public Hygiene of Guangxi Medical University, Nanning 530021, Guangxi, China.
| | - Shaohui Zong
- Department of Spine and Osteopathy Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning 530021, Guangxi, China.
| |
Collapse
|
24
|
Kraimi N, Ross T, Pujo J, De Palma G. The gut microbiome in disorders of gut-brain interaction. Gut Microbes 2024; 16:2360233. [PMID: 38949979 PMCID: PMC11218806 DOI: 10.1080/19490976.2024.2360233] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/30/2024] [Accepted: 05/21/2024] [Indexed: 07/03/2024] Open
Abstract
Functional gastrointestinal disorders (FGIDs), chronic disorders characterized by either abdominal pain, altered intestinal motility, or their combination, have a worldwide prevalence of more than 40% and impose a high socioeconomic burden with a significant decline in quality of life. Recently, FGIDs have been reclassified as disorders of gut-brain interaction (DGBI), reflecting the key role of the gut-brain bidirectional communication in these disorders and their impact on psychological comorbidities. Although, during the past decades, the field of DGBIs has advanced significantly, the molecular mechanisms underlying DGBIs pathogenesis and pathophysiology, and the role of the gut microbiome in these processes are not fully understood. This review aims to discuss the latest body of literature on the complex microbiota-gut-brain interactions and their implications in the pathogenesis of DGBIs. A better understanding of the existing communication pathways between the gut microbiome and the brain holds promise in developing effective therapeutic interventions for DGBIs.
Collapse
Affiliation(s)
- Narjis Kraimi
- Farncombe Family Digestive Health Research Institute, McMaster University, Hamilton, Canada
| | - Taylor Ross
- Farncombe Family Digestive Health Research Institute, McMaster University, Hamilton, Canada
| | - Julien Pujo
- Farncombe Family Digestive Health Research Institute, McMaster University, Hamilton, Canada
| | - Giada De Palma
- Farncombe Family Digestive Health Research Institute, McMaster University, Hamilton, Canada
| |
Collapse
|
25
|
Del Negro I, Pez S, Versace S, Marziali A, Gigli GL, Tereshko Y, Valente M. Impact of Disease-Modifying Therapies on Gut-Brain Axis in Multiple Sclerosis. MEDICINA (KAUNAS, LITHUANIA) 2023; 60:6. [PMID: 38276041 PMCID: PMC10818907 DOI: 10.3390/medicina60010006] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 12/03/2023] [Revised: 12/16/2023] [Accepted: 12/18/2023] [Indexed: 01/27/2024]
Abstract
Multiple sclerosis is a chronic, autoimmune-mediated, demyelinating disease whose pathogenesis remains to be defined. In past years, in consideration of a constantly growing number of patients diagnosed with multiple sclerosis, the impacts of different environmental factors in the pathogenesis of the disease have been largely studied. Alterations in gut microbiome composition and intestinal barrier permeability have been suggested to play an essential role in the regulation of autoimmunity. Thus, increased efforts are being conducted to demonstrate the complex interplay between gut homeostasis and disease pathogenesis. Numerous results confirm that disease-modifying therapies (DMTs) used for the treatment of MS, in addition to their immunomodulatory effect, could exert an impact on the intestinal microbiota, contributing to the modulation of the immune response itself. However, to date, the direct influence of these treatments on the microbiota is still unclear. This review intends to underline the impact of DMTs on the complex system of the microbiota-gut-brain axis in patients with multiple sclerosis.
Collapse
Affiliation(s)
- Ilaria Del Negro
- Clinical Neurology Unit, Udine University Hospital, Piazzale S. Maria della Misericordia, 33100 Udine, Italy
- Department of Medical Area (DAME), University of Udine, 33100 Udine, Italy
| | - Sara Pez
- Clinical Neurology Unit, Udine University Hospital, Piazzale S. Maria della Misericordia, 33100 Udine, Italy
- Department of Medical Area (DAME), University of Udine, 33100 Udine, Italy
| | - Salvatore Versace
- Clinical Neurology Unit, Udine University Hospital, Piazzale S. Maria della Misericordia, 33100 Udine, Italy
- Department of Medical Area (DAME), University of Udine, 33100 Udine, Italy
| | - Alessandro Marziali
- Clinical Neurology Unit, Udine University Hospital, Piazzale S. Maria della Misericordia, 33100 Udine, Italy
- Department of Medical Area (DAME), University of Udine, 33100 Udine, Italy
| | - Gian Luigi Gigli
- Department of Medical Area (DAME), University of Udine, 33100 Udine, Italy
| | - Yan Tereshko
- Clinical Neurology Unit, Udine University Hospital, Piazzale S. Maria della Misericordia, 33100 Udine, Italy
- Department of Medical Area (DAME), University of Udine, 33100 Udine, Italy
| | - Mariarosaria Valente
- Clinical Neurology Unit, Udine University Hospital, Piazzale S. Maria della Misericordia, 33100 Udine, Italy
- Department of Medical Area (DAME), University of Udine, 33100 Udine, Italy
| |
Collapse
|
26
|
Ye Q, Sun S, Deng J, Chen X, Zhang J, Lin S, Du H, Gao J, Zou X, Lin X, Cai Y, Lu Z. Using 16S rDNA and metagenomic sequencing technology to analyze the fecal microbiome of children with avoidant/restrictive food intake disorder. Sci Rep 2023; 13:20253. [PMID: 37985845 PMCID: PMC10661725 DOI: 10.1038/s41598-023-47760-y] [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: 08/16/2023] [Accepted: 11/17/2023] [Indexed: 11/22/2023] Open
Abstract
To investigate the gut microbiota distribution and its functions in children with avoidant/restrictive food intake disorder (ARFID). A total of 135 children were enrolled in the study, including 102 children with ARFID and 33 healthy children. Fecal samples were analyzed to explore differences in gut microbiota composition and diversity and functional differences between the ARFID and healthy control (HC) groups via 16S rDNA and metagenomic sequencing. The gut microbiota composition and diversity in children with ARFID were different from those in heathy children, but there is no difference in the composition and diversity of gut microbiota between children at the age of 3-6 and 7-12 with ARFID. At the phylum level, the most abundant microbes in the two groups identified by 16S rDNA and metagenomic sequencing were the same. At the genus level, the abundance of Bacteroides was higher in the ARFID group (P > 0.05); however, different from the result of 16SrDNA sequencing, metagenomic sequencing showed that the abundance of Bacteroides in the ARFID group was significantly higher than that in the HC group (P = 0.041). At the species level, Escherichia coli, Streptococcus thermophilus and Lachnospira eligens were the most abundant taxa in the ARFID group, and Prevotella copri, Bifidobacterium pseudocatenulatum, and Ruminococcus gnavus were the top three microbial taxa in the HC group; there were no statistically significant differences between the abundance of these microbial taxa in the two groups. LefSe analysis indicated a greater abundance of the order Enterobacterales and its corresponding family Enterobacteriaceae, the family Bacteroidaceae and corresponding genus Bacteroides, the species Bacteroides vulgatus in ARFID group, while the abundance of the phylum Actinobacteriota and its corresponding class Actinobacteria , the order Bifidobacteriales and corresponding family Bifidobacteriaceae, the genus Bifidobacterium were enriched in the HC group. There were no statistically significant differences in the Chao1, Shannon and Simpson indices between the Y1 and Y2 groups (P = 0.1, P = 0.06, P = 0.06). At the phylum level, Bacillota, Bacteroidota, Proteobacteria and Actinobacteriota were the most abundant taxa in both groups, but there were no statistically significant differences among the abundance of these bacteria (P = 0.958, P = 0.456, P = 0.473, P = 0.065). At the genus level, Faecalibacterium was more abundant in the Y2 group than in the Y1 group, and the difference was statistically significant (P = 0.037). The KEGG annotation results showed no significant difference in gut microbiota function between children with ARFID and healthy children; however, GT26 was significantly enriched in children with ARFID based on the CAZy database. The most abundant antibiotic resistance genes in the ARFID group were the vanT, tetQ, adeF, ermF genes, and the abundance of macrolide resistance genes in the ARFID group was significantly higher than that in the HC group (P = 0.041). Compared with healthy children, children with ARFID have a different distribution of the gut microbiota and functional genes. This indicates that the gut microbiome might play an important role in the pathogenesis of ARFID.Clinical trial registration: ChiCTR2300074759.
Collapse
Affiliation(s)
- Qina Ye
- Department of Traditional Chinese Medicine, Guangzhou Women and Children Medical Center, No. 9 Jinsui Road, Guangzhou, 510623, China
- Guangzhou University of Chinese Medicine, Guangzhou, 510405, China
| | - Shaodan Sun
- Guangzhou University of Chinese Medicine, Guangzhou, 510405, China
| | - Jian Deng
- Department of Traditional Chinese Medicine, Guangzhou Women and Children Medical Center, No. 9 Jinsui Road, Guangzhou, 510623, China
| | - Xiaogang Chen
- Department of Pediatrics, The First Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, 510405, China
| | - Jing Zhang
- Department of Traditional Chinese Medicine, Guangzhou Women and Children Medical Center, No. 9 Jinsui Road, Guangzhou, 510623, China
| | - Suihua Lin
- Department of Traditional Chinese Medicine, Guangzhou Women and Children Medical Center, No. 9 Jinsui Road, Guangzhou, 510623, China
| | - Hongxuan Du
- Department of Traditional Chinese Medicine, Guangzhou Women and Children Medical Center, No. 9 Jinsui Road, Guangzhou, 510623, China
| | - Jinxiong Gao
- Department of Traditional Chinese Medicine, Guangzhou Women and Children Medical Center, No. 9 Jinsui Road, Guangzhou, 510623, China
| | - Xiaoyin Zou
- Department of Traditional Chinese Medicine, Guangzhou Women and Children Medical Center, No. 9 Jinsui Road, Guangzhou, 510623, China
| | - Xiaoling Lin
- Department of Pediatrics, The First Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, 510405, China
| | - Yawen Cai
- Department of Pediatrics, The First Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, 510405, China
| | - Zhuoming Lu
- Department of Traditional Chinese Medicine, Guangzhou Women and Children Medical Center, No. 9 Jinsui Road, Guangzhou, 510623, China.
| |
Collapse
|
27
|
Khawar MM, Ijaz S, Goyal P, Kandambige D, Sharifa M, Maslamani ANJ, Al Kutabi S, Saleh I, Albshir MM, I Kh Almadhoun MK, Soomro SN, Kumari N. The Gut-Brain Axis in Autoimmune Diseases: Emerging Insights and Therapeutic Implications. Cureus 2023; 15:e48655. [PMID: 38090441 PMCID: PMC10712442 DOI: 10.7759/cureus.48655] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 11/07/2023] [Indexed: 05/04/2025] Open
Abstract
The gut-brain axis (GBA) is a two-way communication system that is influenced by signals from the nervous system, hormones, metabolism, the immune system, and microbes. The GBA may play a key role in gastrointestinal and neurological illnesses. Signaling events from the gut can regulate brain function. As a result, mounting data point to a connection between autoimmune disorders (AIDs), both neuroinflammatory and neurodegenerative diseases, and the GBA. Clinical, epidemiological, and experimental studies have shown that a variety of neurological illnesses are linked to alterations in the intestinal environment, which are suggestive of disease-mediated inter-organ communication between the gut and the brain. This review's objective is to draw attention to the clinical and biological relationship between the gut and the brain, as well as the clinical importance of this relationship for AIDs, neurodegeneration, and neuroinflammation. We also discuss the dysbiosis in the gut microbiota that has been linked to various AIDs, and we make some assumptions about how dietary changes such as prebiotics and probiotics may be able to prevent or treat AIDs by restoring the composition of the gut microbiota and regulating metabolites.
Collapse
Affiliation(s)
| | - Sami Ijaz
- Internal Medicine, North China University of Science & Technology, Tangshan, CHN
| | - Priya Goyal
- Internal Medicine, Dayanand Medical College & Hospital, Ludhiana, IND
| | | | | | | | | | - Inam Saleh
- Pediatrics, University of Kentucky College of Medicine, Lexington, USA
| | | | | | | | - Neelam Kumari
- Internal Medicine, Jinnah Medical & Dental College, Karachi, PAK
| |
Collapse
|
28
|
Zamora-Pineda J, Kalinina O, Sperling AI, Knight KL. Mechanism of TLR4-Mediated Anti-Inflammatory Response Induced by Exopolysaccharide from the Probiotic Bacillus subtilis. JOURNAL OF IMMUNOLOGY (BALTIMORE, MD. : 1950) 2023; 211:1232-1239. [PMID: 37672039 DOI: 10.4049/jimmunol.2200855] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/21/2022] [Accepted: 08/02/2023] [Indexed: 09/07/2023]
Abstract
Intestinal inflammatory diseases affect millions of people worldwide, and one class of drugs showing promise toward treatment of several inflammatory diseases is probiotics. Numerous studies have been performed using probiotics to prevent and treat intestinal inflammatory diseases. Most of these studies used intact bacteria, and neither the active molecule nor the molecular mechanisms by which they affect immune responses are known. We have shown that the probiotic Bacillus subtilis is anti-inflammatory and can protect mice from acute colitis induced by the enteric pathogen Citrobacter rodentium. We identified and purified the active molecule, exopolysaccharide (EPS), and showed that it protects mice from C. rodentium-induced colitis by inducing anti-inflammatory M2 macrophages or inhibitory dendritic cells (DCs), both of which inhibit excessive T cell responses. We showed previously that EPS affects macrophages and DCs in a TLR4-dependent manner, and in the current study we asked how EPS induces these anti-inflammatory cells and how they function to inhibit T cells. By investigating the signaling downstream of TLR4 that leads to acquisition of inhibitory properties of macrophages and DCs, we found that EPS induces expression of the inhibitory molecule IDO in bone marrow-derived DCs, and that inhibition of T cell proliferation by IDO-expressing bone marrow-derived DCs utilizes the kynurenine/aryl hydrocarbon receptor circuit. Furthermore, unlike LPS, EPS does not induce inflammatory cytokines upon injection in vivo, directly demonstrating different outcomes induced by two different TLR4 agonists.
Collapse
Affiliation(s)
- Jesus Zamora-Pineda
- Department of Microbiology and Immunology, Loyola University Chicago, Maywood, IL
| | - Olga Kalinina
- Department of Microbiology and Immunology, Loyola University Chicago, Maywood, IL
| | - Anne I Sperling
- Pulmonary and Critical Care Division, Department of Medicine, University of Virginia, Charlottesville, VA
| | - Katherine L Knight
- Department of Microbiology and Immunology, Loyola University Chicago, Maywood, IL
| |
Collapse
|
29
|
Li X, Chen J, Zhang C, Zhang S, Shen Q, Wang B, Bao M, Xu B, Wu Q, Han N, Huang Z. Fecal Metagenomics Study Reveals That a Low-Fiber Diet Drives the Migration of Wild Asian Elephants in Xishuangbanna, China. Animals (Basel) 2023; 13:3193. [PMID: 37893918 PMCID: PMC10603651 DOI: 10.3390/ani13203193] [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: 08/26/2023] [Revised: 09/30/2023] [Accepted: 10/12/2023] [Indexed: 10/29/2023] Open
Abstract
The rare northward migration of wild Asian elephants in Xishuangbanna, China, has attracted global attention. Elephant migration is a complex ecological process, and the factors driving this long-distance migration remain elusive. In this study, fresh fecal samples were collected from both captive and wild Asian elephants, along with breastfed calves residing within the Wild Elephant Valley of Xishuangbanna. Our aim was to investigate the relationship between diet, gut microbiota, and migration patterns in Asian elephants through comprehensive metagenomic sequencing analyses. Among the breastfed Asian elephant group, Bacteroidales and Escherichia emerged as the dominant bacterial taxa, while the primary carbohydrate-active enzymes (CAZymes) enriched in this group were GH2, GH20, GH92, GH97, GH38, GH23, and GH43, aligning with their dietary source, namely breast milk. The bacterial taxa enriched in captive Asian elephants (CAEs) were mainly Butyrivibrio, Treponema, and Fibrobacter, and the enriched lignocellulose-degrading enzymes mainly included GH25, GH10, GH9, and cellulase (EC 3.2.1.4). These findings are consistent with the high-fiber diet of captive elephants. In contrast, the main bacterial taxa enriched in wild Asian elephants (WAEs) were Ruminococcus and Eubacterium, and the enriched CAZymes included GH109, GH20, GH33, GH28, GH106, and GH39. The abundance of lignocellulose-degrading bacteria and CAZyme content was low in WAEs, indicating challenges in processing high-fiber foods and explaining the low-fiber diet in this group. These findings suggest that wild elephant herds migrate in search of nutritionally suitable, low-fiber food sources.
Collapse
Affiliation(s)
- Xia Li
- Engineering Research Center of Sustainable Development and Utilization of Biomass Energy, Ministry of Education, School of Life Sciences, Yunnan Normal University, Kunming 650500, China
- Southwest United Graduate School, Kunming 650092, China
| | - Junmin Chen
- Engineering Research Center of Sustainable Development and Utilization of Biomass Energy, Ministry of Education, School of Life Sciences, Yunnan Normal University, Kunming 650500, China
- Key Laboratory of Yunnan Provincial Education Department for Plateau Characteristic Food Enzymes, Yunnan Normal University, Kunming 650500, China
| | - Chengbo Zhang
- Engineering Research Center of Sustainable Development and Utilization of Biomass Energy, Ministry of Education, School of Life Sciences, Yunnan Normal University, Kunming 650500, China
| | - Shuyin Zhang
- Engineering Research Center of Sustainable Development and Utilization of Biomass Energy, Ministry of Education, School of Life Sciences, Yunnan Normal University, Kunming 650500, China
| | - Qingzhong Shen
- Xishuangbanna National Nature Reserve Management and Protection Bureau, Jinghong 666100, China
| | - Bin Wang
- Xishuangbanna National Nature Reserve Management and Protection Bureau, Jinghong 666100, China
| | - Mingwei Bao
- Asian Elephant Provenance Breeding and Rescue Center in Xishuangbanna, Jinghong 666100, China
| | - Bo Xu
- Engineering Research Center of Sustainable Development and Utilization of Biomass Energy, Ministry of Education, School of Life Sciences, Yunnan Normal University, Kunming 650500, China
| | - Qian Wu
- Engineering Research Center of Sustainable Development and Utilization of Biomass Energy, Ministry of Education, School of Life Sciences, Yunnan Normal University, Kunming 650500, China
| | - Nanyu Han
- Engineering Research Center of Sustainable Development and Utilization of Biomass Energy, Ministry of Education, School of Life Sciences, Yunnan Normal University, Kunming 650500, China
| | - Zunxi Huang
- Engineering Research Center of Sustainable Development and Utilization of Biomass Energy, Ministry of Education, School of Life Sciences, Yunnan Normal University, Kunming 650500, China
| |
Collapse
|
30
|
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: 17] [Impact Index Per Article: 8.5] [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.
Collapse
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
| |
Collapse
|
31
|
Doyle WJ, Walters D, Shi X, Hoffman K, Magori K, Roullet JB, Ochoa-Repáraz J. Farnesol brain transcriptomics in CNS inflammatory demyelination. Clin Immunol 2023; 255:109752. [PMID: 37673223 PMCID: PMC10619994 DOI: 10.1016/j.clim.2023.109752] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/13/2023] [Revised: 08/26/2023] [Accepted: 08/30/2023] [Indexed: 09/08/2023]
Abstract
BACKGROUND Farnesol (FOL) prevents the onset of experimental autoimmune encephalomyelitis (EAE), a murine model of multiple sclerosis (MS). OBJECTIVE We examined the transcriptomic profile of the brains of EAE mice treated with daily oral FOL using next-generation sequencing (RNA-seq). METHODS Transcriptomics from whole brains of treated and untreated EAE mice at the peak of EAE was performed. RESULTS EAE-induced mice, compared to naïve, healthy mice, overall showed increased expression in pathways for immune response, as well as an increased cytokine signaling pathway, with downregulation of cellular stress proteins. FOL downregulates pro-inflammatory pathways and attenuates the immune response in EAE. FOL downregulated the expression of genes involved in misfolded protein response, MAPK activation/signaling, and pro-inflammatory response. CONCLUSION This study provides insight into the molecular impact of FOL in the brain and identifies potential therapeutic targets of the isoprenoid pathway in MS patients.
Collapse
Affiliation(s)
- William J Doyle
- Department of Biological Sciences, Boise State University, Boise, ID 83725, USA
| | - Dana Walters
- Pharmacotherapy, College of Pharmacy and Pharmaceutical Sciences, Washington State University, Spokane, WA 99202, USA
| | - Xutong Shi
- Pharmacotherapy, College of Pharmacy and Pharmaceutical Sciences, Washington State University, Spokane, WA 99202, USA
| | - Kristina Hoffman
- Department of Biological Sciences, Boise State University, Boise, ID 83725, USA
| | - Krisztian Magori
- Department of Biology, Eastern Washington University, Cheney, WA 99004, USA
| | - Jean-Baptiste Roullet
- Pharmacotherapy, College of Pharmacy and Pharmaceutical Sciences, Washington State University, Spokane, WA 99202, USA
| | - Javier Ochoa-Repáraz
- Department of Biological Sciences, Boise State University, Boise, ID 83725, USA.
| |
Collapse
|
32
|
Yadav SK, Ito K, Dhib-Jalbut S. Interaction of the Gut Microbiome and Immunity in Multiple Sclerosis: Impact of Diet and Immune Therapy. Int J Mol Sci 2023; 24:14756. [PMID: 37834203 PMCID: PMC10572709 DOI: 10.3390/ijms241914756] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2023] [Revised: 09/24/2023] [Accepted: 09/27/2023] [Indexed: 10/15/2023] Open
Abstract
The bidirectional communication between the gut and central nervous system (CNS) through microbiota is known as the microbiota-gut-brain axis. The brain, through the enteric neural innervation and the vagus nerve, influences the gut physiological activities (motility, mucin, and peptide secretion), as well as the development of the mucosal immune system. Conversely, the gut can influence the CNS via intestinal microbiota, its metabolites, and gut-homing immune cells. Growing evidence suggests that gut immunity is critically involved in gut-brain communication during health and diseases, including multiple sclerosis (MS). The gut microbiota can influence the development and function of gut immunity, and conversely, the innate and adaptive mucosal immunity can influence microbiota composition. Gut and systemic immunity, along with gut microbiota, are perturbed in MS. Diet and disease-modifying therapies (DMTs) can affect the composition of the gut microbial community, leading to changes in gut and peripheral immunity, which ultimately affects MS. A high-fat diet is highly associated with gut dysbiosis-mediated inflammation and intestinal permeability, while a high-fiber diet/short-chain fatty acids (SCFAs) can promote the development of Foxp3 Tregs and improvement in intestinal barrier function, which subsequently suppress CNS autoimmunity in the animal model of MS (experimental autoimmune encephalomyelitis or EAE). This review will address the role of gut immunity and its modulation by diet and DMTs via gut microbiota during MS pathophysiology.
Collapse
Affiliation(s)
- Sudhir Kumar Yadav
- Department of Neurology, Rutgers-Robert Wood Johnson Medical School, Piscataway, NJ 08854, USA; (S.K.Y.); (K.I.)
| | - Kouichi Ito
- Department of Neurology, Rutgers-Robert Wood Johnson Medical School, Piscataway, NJ 08854, USA; (S.K.Y.); (K.I.)
| | - Suhayl Dhib-Jalbut
- Department of Neurology, Rutgers-Robert Wood Johnson Medical School, Piscataway, NJ 08854, USA; (S.K.Y.); (K.I.)
- Rutgers New Jersey Medical School, Newark, NJ 07101, USA
| |
Collapse
|
33
|
Park JS, Gazzaniga FS, Kasper DL, Sharpe AH. Microbiota-dependent regulation of costimulatory and coinhibitory pathways via innate immune sensors and implications for immunotherapy. Exp Mol Med 2023; 55:1913-1921. [PMID: 37696895 PMCID: PMC10545783 DOI: 10.1038/s12276-023-01075-0] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/02/2023] [Revised: 07/11/2023] [Accepted: 07/19/2023] [Indexed: 09/13/2023] Open
Abstract
Our bodies are inhabited by trillions of microorganisms. The host immune system constantly interacts with the microbiota in barrier organs, including the intestines. Over decades, numerous studies have shown that our mucosal immune system is dynamically shaped by a variety of microbiota-derived signals. Elucidating the mediators of these interactions is an important step for understanding how the microbiota is linked to mucosal immune homeostasis and gut-associated diseases. Interestingly, the efficacy of cancer immunotherapies that manipulate costimulatory and coinhibitory pathways has been correlated with the gut microbiota. Moreover, adverse effects of these therapies in the gut are linked to dysregulation of the intestinal immune system. These findings suggest that costimulatory pathways in the immune system might serve as a bridge between the host immune system and the gut microbiota. Here, we review mechanisms by which commensal microorganisms signal immune cells and their potential impact on costimulation. We highlight how costimulatory pathways modulate the mucosal immune system through not only classical antigen-presenting cells but also innate lymphocytes, which are highly enriched in barrier organs. Finally, we discuss the adverse effects of immune checkpoint inhibitors in the gut and the possible relationship with the gut microbiota.
Collapse
Affiliation(s)
- Joon Seok Park
- Department of Immunology, Blavatnik Institute, Harvard Medical School, Boston, MA, 02115, USA
| | - Francesca S Gazzaniga
- Department of Pathology and Center for Cancer Research, Massachusetts General Hospital, Charlestown, MA, 02129, USA
- Department of Pathology, Harvard Medical School, Boston, MA, 02115, USA
| | - Dennis L Kasper
- Department of Immunology, Blavatnik Institute, Harvard Medical School, Boston, MA, 02115, USA
| | - Arlene H Sharpe
- Department of Immunology, Blavatnik Institute, Harvard Medical School, Boston, MA, 02115, USA.
| |
Collapse
|
34
|
Mao D, Tao B, Sheng S, Jin H, Chen W, Gao H, Deng J, Li Z, Chen F, Chan S, Qian L. Causal Effects of Gut Microbiota on Age-Related Macular Degeneration: A Mendelian Randomization Study. Invest Ophthalmol Vis Sci 2023; 64:32. [PMID: 37725382 PMCID: PMC10513115 DOI: 10.1167/iovs.64.12.32] [Citation(s) in RCA: 17] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2023] [Accepted: 08/06/2023] [Indexed: 09/21/2023] Open
Abstract
Purpose Recently, the association between gut microbiota and age-related macular degeneration (AMD) through the gut-retina axis has attracted great interest. However, the causal relationship between them has not been elucidated. Using publicly available genome-wide association study summary statistics, we conducted a two-sample Mendelian randomization (MR) analysis to examine the causal relationship between the gut microbiota and the occurrence of AMD. Methods The study used a variety of quality control techniques to select instrumental single nucleotide polymorphisms (SNPs) with strong exposure associations. We used a set of SNPs as instrumental variable that were below the genome-wide statistical significance threshold (5 × 10-8). Additionally, a separate group of SNPs below the locus-wide significance level (1 × 10-5) were selected as instrumental variables to ensure a comprehensive conclusion. Inverse variance-weighted (IVW) analysis was the primary technique we used to examine causality in order to confirm the validity of our findings. The MR-Egger intercept test, Cochran's Q test, and leave-one-out sensitivity analysis were used to evaluate the horizontal pleiotropy, heterogeneities, and stability of the genetic variants. Results IVW results showed that genus Anaerotruncus (P = 5.00 × 10-3), genus Candidatus Soleaferrea (P = 1.83 × 10-2), and genus unknown id.2071 (P = 3.12 × 10-2) were protective factors for AMD. The Eubacterium oxidoreducens group (P = 3.17 × 10-2), genus Faecalibacterium (P = 2.67 × 10-2), and genus Ruminococcaceae UCG-011 (P = 4.04 × 10-2) were risk factors of AMD. No gut microbiota (GM) taxa were found to be causally related to AMD at the phylum, class, order, and family levels (P > 0.05). The robustness of MR results were confirmed by heterogeneity and pleiotropy analysis. (P > 0.05). We also performed a bidirectional analysis, which showed that genus Anaerotruncus, genus Candidatus Soleaferrea, genus unknown id.2071 and the Eubacterium oxidoreducens group had an interaction with AMD, whereas genus Faecalibacterium showed only a unilateral unfavorable effect on AMD. Conclusions We confirmed a causal relationship between AMD and GM taxa, including the Eubacterium oxidoreducens group, Faecalibacterium, Ruminococcaceae UCG-011, Anaerotruncus, and Candidatus Soleaferrea. These strains have the potential to serve as new biomarkers, offering valuable insights into the treatment and prevention of AMD.
Collapse
Affiliation(s)
- Deshen Mao
- Department of Ophthalmology, Anqing Municipal Hospital, Anqing, China
- First Clinical Medical College, Anhui Medical University, Hefei, China
| | - Borui Tao
- First Clinical Medical College, Anhui Medical University, Hefei, China
| | - Shuyan Sheng
- First Clinical Medical College, Anhui Medical University, Hefei, China
| | - Hui Jin
- Department of Medical Imaging, Anqing First People's Hospital, Anqing, China
| | - Wenxuan Chen
- Second Clinical Medical College, Anhui Medical University, Hefei, China
| | - Huimin Gao
- Department of Pathology, Anqing Municipal Hospital, Anqing, China
| | - Jianyi Deng
- First Clinical Medical College, Anhui Medical University, Hefei, China
| | - Zhuo Li
- School of Clinical Medicine, Anhui Medical University, Hefei, China
| | - Fan Chen
- Department of Ophthalmology, Anqing Municipal Hospital, Anqing, China
| | - Shixin Chan
- Department of General Surgery, The First Affiliated Hospital of Anhui Medical University, Hefei, China
| | - Longqi Qian
- Department of Ophthalmology, Anqing Municipal Hospital, Anqing, China
| |
Collapse
|
35
|
Miyamoto K, Sujino T, Harada Y, Ashida H, Yoshimatsu Y, Yonemoto Y, Nemoto Y, Tomura M, Melhem H, Niess JH, Suzuki T, Suzuki T, Suzuki S, Koda Y, Okamoto R, Mikami Y, Teratani T, Tanaka KF, Yoshimura A, Sato T, Kanai T. The gut microbiota-induced kynurenic acid recruits GPR35-positive macrophages to promote experimental encephalitis. Cell Rep 2023; 42:113005. [PMID: 37590143 DOI: 10.1016/j.celrep.2023.113005] [Citation(s) in RCA: 15] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/17/2023] [Revised: 07/25/2023] [Accepted: 08/02/2023] [Indexed: 08/19/2023] Open
Abstract
The intricate interplay between gut microbes and the onset of experimental autoimmune encephalomyelitis (EAE) remains poorly understood. Here, we uncover remarkable similarities between CD4+ T cells in the spinal cord and their counterparts in the small intestine. Furthermore, we unveil a synergistic relationship between the microbiota, particularly enriched with the tryptophan metabolism gene EC:1.13.11.11, and intestinal cells. This symbiotic collaboration results in the biosynthesis of kynurenic acid (KYNA), which modulates the recruitment and aggregation of GPR35-positive macrophages. Subsequently, a robust T helper 17 (Th17) immune response is activated, ultimately triggering the onset of EAE. Conversely, modulating the KYNA-mediated GPR35 signaling in Cx3cr1+ macrophages leads to a remarkable amelioration of EAE. These findings shed light on the crucial role of microbial-derived tryptophan metabolites in regulating immune responses within extraintestinal tissues.
Collapse
Affiliation(s)
- Kentaro Miyamoto
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo 160-8582, Japan; Miyarisan Pharmaceutical Co., Ltd., Research Laboratory, 1-10-3, Kaminagazato, Kita-ku, Tokyo 114-0016, Japan
| | - Tomohisa Sujino
- Center for Diagnostic and Therapeutic Endoscopy, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo 160-8582, Japan.
| | - Yosuke Harada
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo 160-8582, Japan
| | - Hiroshi Ashida
- Department of Bacterial Infection and Host Response, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University (TMDU), 1-5-45, Yushima, Bunkyo-ku, Tokyo 113-8510, Japan; Medical Mycology Research Center, Chiba University, 1-8-1, Inohana, Cyuo-ku, Chiba city, Chiba 260-8673, Japan
| | - Yusuke Yoshimatsu
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo 160-8582, Japan
| | - Yuki Yonemoto
- Department of Gastroenterology and Hepatology, Tokyo Medical Dental University (TMDU), 1-5-45, Yushima, Bunkyo-ku, Tokyo 113-8510, Japan
| | - Yasuhiro Nemoto
- Department of Gastroenterology and Hepatology, Tokyo Medical Dental University (TMDU), 1-5-45, Yushima, Bunkyo-ku, Tokyo 113-8510, Japan
| | - Michio Tomura
- Laboratory of Immunology, Faculty of Pharmacy, Osaka Otani University, 3-11-1 Nshikiorikita, Tondabayshi, Osaka, 584-8584, Japan
| | - Hassan Melhem
- Department of Biomedicine, University of Basel, 4031 Basel, Switzerland
| | - Jan Hendrik Niess
- Department of Biomedicine, University of Basel, 4031 Basel, Switzerland; Clarunis-University Center for Gastrointestinal and Liver Diseases, University Hospital Basel, 4002 Basel, Switzerland
| | - Toshihiko Suzuki
- Department of Bacterial Infection and Host Response, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University (TMDU), 1-5-45, Yushima, Bunkyo-ku, Tokyo 113-8510, Japan
| | - Toru Suzuki
- Division of Brain Sciences Institute for Advanced Medical Research, Keio University School of Medicne, 35 Shinanomachi, Shinjuku-ku, Tokyo 160-8582, Japan
| | - Shohei Suzuki
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo 160-8582, Japan
| | - Yuzo Koda
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo 160-8582, Japan
| | - Ryuichi Okamoto
- Department of Gastroenterology and Hepatology, Tokyo Medical Dental University (TMDU), 1-5-45, Yushima, Bunkyo-ku, Tokyo 113-8510, Japan
| | - Yohei Mikami
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo 160-8582, Japan
| | - Toshiaki Teratani
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo 160-8582, Japan
| | - Kenji F. Tanaka
- Division of Brain Sciences Institute for Advanced Medical Research, Keio University School of Medicne, 35 Shinanomachi, Shinjuku-ku, Tokyo 160-8582, Japan
| | - Akihiko Yoshimura
- Department of Microbiology and Immunology, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo 160-8582, Japan
| | - Toshiro Sato
- Department of Organoid Medicine, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo 160-8582, Japan
| | - Takanori Kanai
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo 160-8582, Japan; AMED-CREST, Japan Agency for Medical Research and Development, 1-7-1, Otemachi, Chiyoda-ku, Tokyo 100-0004, Japan.
| |
Collapse
|
36
|
Uceda S, Echeverry-Alzate V, Reiriz-Rojas M, Martínez-Miguel E, Pérez-Curiel A, Gómez-Senent S, Beltrán-Velasco AI. Gut Microbial Metabolome and Dysbiosis in Neurodegenerative Diseases: Psychobiotics and Fecal Microbiota Transplantation as a Therapeutic Approach-A Comprehensive Narrative Review. Int J Mol Sci 2023; 24:13294. [PMID: 37686104 PMCID: PMC10487945 DOI: 10.3390/ijms241713294] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2023] [Revised: 08/22/2023] [Accepted: 08/25/2023] [Indexed: 09/10/2023] Open
Abstract
The comprehensive narrative review conducted in this study delves into the mechanisms of communication and action at the molecular level in the human organism. The review addresses the complex mechanism involved in the microbiota-gut-brain axis as well as the implications of alterations in the microbial composition of patients with neurodegenerative diseases. The pathophysiology of neurodegenerative diseases with neuronal loss or death is analyzed, as well as the mechanisms of action of the main metabolites involved in the bidirectional communication through the microbiota-gut-brain axis. In addition, interventions targeting gut microbiota restructuring through fecal microbiota transplantation and the use of psychobiotics-pre- and pro-biotics-are evaluated as an opportunity to reduce the symptomatology associated with neurodegeneration in these pathologies. This review provides valuable information and facilitates a better understanding of the neurobiological mechanisms to be addressed in the treatment of neurodegenerative diseases.
Collapse
Affiliation(s)
- Sara Uceda
- BRABE Group, Psychology Department, School of Life and Nature Sciences, Nebrija University, 28240 Madrid, Spain
| | - Víctor Echeverry-Alzate
- BRABE Group, Psychology Department, School of Life and Nature Sciences, Nebrija University, 28240 Madrid, Spain
| | - Manuel Reiriz-Rojas
- BRABE Group, Psychology Department, School of Life and Nature Sciences, Nebrija University, 28240 Madrid, Spain
| | - Esther Martínez-Miguel
- Health Department, School of Life and Nature Sciences, Nebrija University, 28240 Madrid, Spain
| | - Ana Pérez-Curiel
- Health Department, School of Life and Nature Sciences, Nebrija University, 28240 Madrid, Spain
| | - Silvia Gómez-Senent
- Health Department, School of Life and Nature Sciences, Nebrija University, 28240 Madrid, Spain
| | | |
Collapse
|
37
|
Grabska-Kobyłecka I, Szpakowski P, Król A, Książek-Winiarek D, Kobyłecki A, Głąbiński A, Nowak D. Polyphenols and Their Impact on the Prevention of Neurodegenerative Diseases and Development. Nutrients 2023; 15:3454. [PMID: 37571391 PMCID: PMC10420887 DOI: 10.3390/nu15153454] [Citation(s) in RCA: 78] [Impact Index Per Article: 39.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/09/2023] [Revised: 07/13/2023] [Accepted: 07/18/2023] [Indexed: 08/13/2023] Open
Abstract
It is well known that neurodegenerative diseases' development and progression are accelerated due to oxidative stress and inflammation, which result in impairment of mitochondrial function, cellular damage, and dysfunction of DNA repair systems. The increased consumption of antioxidants can postpone the development of these disorders and improve the quality of patients' lives who have already been diagnosed with neurodegenerative diseases. Prolonging life span in developed countries contributes to an increase in the incidence ratio of chronic age-related neurodegenerative disorders, such as PD (Parkinson's disease), AD (Alzheimer's disease), or numerous forms of age-related dementias. Dietary supplementation with neuroprotective plant-derived polyphenols might be considered an important element of healthy aging. Some polyphenols improve cognition, mood, visual functions, language, and verbal memory functions. Polyphenols bioavailability differs greatly from one compound to another and is determined by solubility, degree of polymerization, conjugation, or glycosylation resulting from chemical structure. It is still unclear which polyphenols are beneficial because their potential depends on efficient transport across the BBB (blood-brain barrier), bioavailability, and stability in the CNS (central nervous system). Polyphenols improve brain functions by having a direct impact on cells and processes in the CNS. For a direct effect, polyphenolic compounds must be able to overcome the BBB and accumulate in brain tissue. In this review, the latest achievements in studies (animal models and clinical trials) on the effect of polyphenols on brain activity and function are described. The beneficial impact of plant polyphenols on the brain may be summarized by their role in increasing brain plasticity and related cognition improvement. As reversible MAO (monoamine oxidase) inhibitors, polyphenols are mood modulators and improve neuronal self-being through an increase in dopamine, serotonin, and noradrenaline amounts in the brain tissue. After analyzing the prohealth effects of various eating patterns, it was postulated that their beneficial effects result from synergistic interactions between individual dietary components. Polyphenols act on the brain endothelial cells and improve the BBB's integrity and reduce inflammation, thus protecting the brain from additional injury during stroke or autoimmune diseases. Polyphenolic compounds are capable of lowering blood pressure and improving cerebral blood flow. Many studies have revealed that a nutritional model based on increased consumption of antioxidants has the potential to ameliorate the cognitive impairment associated with neurodegenerative disorders. Randomized clinical trials have also shown that the improvement of cognitive functions resulting from the consumption of foods rich in flavonoids is independent of age and health conditions. For therapeutic use, sufficient quantities of polyphenols must cross the BBB and reach the brain tissue in active form. An important issue in the direct action of polyphenols on the CNS is not only their penetration through the BBB, but also their brain metabolism and localization. The bioavailability of polyphenols is low. The most usual oral administration also conflicts with bioavailability. The main factors that limit this process and have an effect on therapeutic efficacy are: selective permeability across BBB, gastrointestinal transformations, poor absorption, rapid hepatic and colonic metabolism, and systemic elimination. Thus, phenolic compounds have inadequate bioavailability for human applications to have any beneficial effects. In recent years, new strategies have been attempted in order to exert cognitive benefits and neuroprotective effects. Converting polyphenols into nanostructures is one of the theories proposed to enhance their bioavailability. The following nanoscale delivery systems can be used to encapsulate polyphenols: nanocapsules, nanospheres, micelles, cyclodextrins, solid lipid nanoparticles, and liposomes. It results in great expectations for the wide-scale and effective use of polyphenols in the prevention of neurodegenerative diseases. Thus far, only natural polyphenols have been studied as neuroprotectors. Perhaps some modification of the chemical structure of a given polyphenol may increase its neuroprotective activity and transportation through the BBB. However, numerous questions should be answered before developing neuroprotective medications based on plant polyphenols.
Collapse
Affiliation(s)
- Izabela Grabska-Kobyłecka
- Department of Clinical Physiology, Medical University of Lodz, Mazowiecka 6/8 Street, 92-215 Łódź, Poland
| | - Piotr Szpakowski
- Department of Neurology and Stroke, Medical University of Lodz, Zeromskiego 113 Street, 90-549 Łódź, Poland; (P.S.); (D.K.-W.); (A.G.)
| | - Aleksandra Król
- Department of Experimental Physiology, Medical University of Lodz, Mazowiecka 6/8 Street, 92-215 Łódź, Poland;
| | - Dominika Książek-Winiarek
- Department of Neurology and Stroke, Medical University of Lodz, Zeromskiego 113 Street, 90-549 Łódź, Poland; (P.S.); (D.K.-W.); (A.G.)
| | - Andrzej Kobyłecki
- Interventional Cardiology Lab, Copernicus Hospital, Pabianicka Str. 62, 93-513 Łódź, Poland;
| | - Andrzej Głąbiński
- Department of Neurology and Stroke, Medical University of Lodz, Zeromskiego 113 Street, 90-549 Łódź, Poland; (P.S.); (D.K.-W.); (A.G.)
| | - Dariusz Nowak
- Department of Clinical Physiology, Medical University of Lodz, Mazowiecka 6/8 Street, 92-215 Łódź, Poland
| |
Collapse
|
38
|
Bugbee E, Wang AA, Gommerman JL. Under the influence: environmental factors as modulators of neuroinflammation through the IL-10/IL-10R axis. Front Immunol 2023; 14:1188750. [PMID: 37600781 PMCID: PMC10435745 DOI: 10.3389/fimmu.2023.1188750] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/17/2023] [Accepted: 07/12/2023] [Indexed: 08/22/2023] Open
Abstract
The IL-10/IL-10 receptor (IL-10R) axis plays an important role in attenuating neuroinflammation in animal models of Multiple Sclerosis (MS) and increased IL-10 has been associated with a positive response to MS disease modifying therapy. Because environmental factors play an important role in MS susceptibility and disease course, identification of environmental factors that impact the IL-10/IL-10R axis has therapeutic potential. In this review, we provide historical and updated perspectives of how IL-10R signaling impacts neuroinflammation, discuss environmental factors and intestinal microbes with known impacts on the IL-10/IL-10R axis, and provide a hypothetical model for how B cells, via their production of IL-10, may be important in conveying environmental "information" to the inflamed central nervous system.
Collapse
|
39
|
Blackmer-Raynolds L, Sampson TR. Overview of the Gut Microbiome. Semin Neurol 2023; 43:518-529. [PMID: 37562449 DOI: 10.1055/s-0043-1771463] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 08/12/2023]
Abstract
The human gastrointestinal tract is home to trillions of microorganisms-collectively referred to as the gut microbiome-that maintain a symbiotic relationship with their host. This diverse community of microbes grows and changes as we do, with developmental, lifestyle, and environmental factors all shaping microbiome community structure. Increasing evidence suggests this relationship is bidirectional, with the microbiome also influencing host physiological processes. For example, changes in the gut microbiome have been shown to alter neurodevelopment and have lifelong effects on the brain and behavior. Age-related changes in gut microbiome composition have also been linked to inflammatory changes in the brain, perhaps increasing susceptibility to neurological disease. Indeed, associations between gut dysbiosis and many age-related neurological diseases-including Parkinson's disease, Alzheimer's disease, multiple sclerosis, and amyotrophic lateral sclerosis-have been reported. Further, microbiome manipulation in animal models of disease highlights a potential role for the gut microbiome in disease development and progression. Although much remains unknown, these associations open up an exciting new world of therapeutic targets, potentially allowing for improved quality of life for a wide range of patient populations.
Collapse
Affiliation(s)
| | - Timothy R Sampson
- Department of Cell Biology, Emory University School of Medicine, Atlanta, Georgia
| |
Collapse
|
40
|
Cameron G, Nguyen T, Ciula M, Williams SJ, Godfrey DI. Glycolipids from the gut symbiont Bacteroides fragilis are agonists for natural killer T cells and induce their regulatory differentiation. Chem Sci 2023; 14:7887-7896. [PMID: 37502334 PMCID: PMC10370605 DOI: 10.1039/d3sc02124f] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/25/2023] [Accepted: 05/26/2023] [Indexed: 07/29/2023] Open
Abstract
Natural Killer T (NKT) cells are a lipid-antigen reactive T cell subset that is restricted to the antigen presenting molecule CD1d. They possess diverse functional properties that contribute to inflammatory and regulatory immune responses. The most studied lipid antigen target for these T cells is α-galactosylceramide (αGC). The commensal organism Bacteroides fragilis (B. fragilis) produces several forms of αGC, but conflicting information exists about the influence of these lipids on NKT cells. Herein, we report the total synthesis of a major form of αGC from B. fragilis (Bf αGC), and several analogues thereof. We confirm the T cell receptor (TCR)-mediated recognition of these glycolipids by mouse and human NKT cells. Despite the natural structure of Bf αGC containing lipid branching that limits potency, we demonstrate that Bf αGC drives mouse NKT cells to proliferate and differentiate into producers of the immunoregulatory cytokine, interleukin-10 (IL-10). These Bf αGC-experienced NKT cells display regulatory function by inhibiting the expansion of naïve NKT cells upon subsequent exposure to this antigen. Moreover, this regulatory activity impacts more than just NKT cells, as demonstrated by the NKT cell-mediated inhibition of antigen-stimulated mucosal-associated invariant T (MAIT) cells (a T cell subset restricted to a different antigen presenting molecule, MR1). These findings reveal that B. fragilis-derived NKT cell agonists may have broad immunoregulatory activity, providing insight into the mechanisms influencing immune tolerance to commensal bacteria and highlighting a potential means to manipulate NKT cell function for therapeutic benefit.
Collapse
Affiliation(s)
- Garth Cameron
- Department of Microbiology and Immunology, Peter Doherty Institute for Infection and Immunity, University of Melbourne Melbourne VIC 3000 Australia
| | - Tram Nguyen
- School of Chemistry, University of Melbourne Parkville VIC 3010 Australia
- Bio21 Molecular Science and Biotechnology Institute, University of Melbourne Parkville VIC 3010 Australia
| | - Marcin Ciula
- Department of Microbiology and Immunology, Peter Doherty Institute for Infection and Immunity, University of Melbourne Melbourne VIC 3000 Australia
| | - Spencer J Williams
- School of Chemistry, University of Melbourne Parkville VIC 3010 Australia
- Bio21 Molecular Science and Biotechnology Institute, University of Melbourne Parkville VIC 3010 Australia
| | - Dale I Godfrey
- Department of Microbiology and Immunology, Peter Doherty Institute for Infection and Immunity, University of Melbourne Melbourne VIC 3000 Australia
| |
Collapse
|
41
|
Iyaswamy A, Lu K, Guan XJ, Kan Y, Su C, Liu J, Jaganathan R, Vasudevan K, Paul J, Thakur A, Li M. Impact and Advances in the Role of Bacterial Extracellular Vesicles in Neurodegenerative Disease and Its Therapeutics. Biomedicines 2023; 11:2056. [PMID: 37509695 PMCID: PMC10377521 DOI: 10.3390/biomedicines11072056] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/23/2023] [Revised: 07/16/2023] [Accepted: 07/19/2023] [Indexed: 07/30/2023] Open
Abstract
Bacterial Extracellular Vesicles (BEVs) possess the capability of intracellular interactions with other cells, and, hence, can be utilized as an efficient cargo for worldwide delivery of therapeutic substances such as monoclonal antibodies, proteins, plasmids, siRNA, and small molecules for the treatment of neurodegenerative diseases (NDs). BEVs additionally possess a remarkable capacity for delivering these therapeutics across the blood-brain barrier to treat Alzheimer's disease (AD). This review summarizes the role and advancement of BEVs for NDs, AD, and their treatment. Additionally, it investigates the critical BEV networks in the microbiome-gut-brain axis, their defensive and offensive roles in NDs, and their interaction with NDs. Furthermore, the part of BEVs in the neuroimmune system and their interference with ND, as well as the risk factors made by BEVs in the autophagy-lysosomal pathway and their potential outcomes on ND, are all discussed. To conclude, this review aims to gain a better understanding of the credentials of BEVs in NDs and possibly discover new therapeutic strategies.
Collapse
Affiliation(s)
- Ashok Iyaswamy
- Mr. & Mrs. Ko Chi-Ming Centre for Parkinson's Disease Research, School of Chinese Medicine, Hong Kong Baptist University, Hong Kong SAR, China
- Department of Biochemistry, Karpagam Academy of Higher Education, Coimbatore 641021, India
| | - Kejia Lu
- Mr. & Mrs. Ko Chi-Ming Centre for Parkinson's Disease Research, School of Chinese Medicine, Hong Kong Baptist University, Hong Kong SAR, China
| | - Xin-Jie Guan
- Mr. & Mrs. Ko Chi-Ming Centre for Parkinson's Disease Research, School of Chinese Medicine, Hong Kong Baptist University, Hong Kong SAR, China
| | - Yuxuan Kan
- Mr. & Mrs. Ko Chi-Ming Centre for Parkinson's Disease Research, School of Chinese Medicine, Hong Kong Baptist University, Hong Kong SAR, China
| | - Chengfu Su
- Mr. & Mrs. Ko Chi-Ming Centre for Parkinson's Disease Research, School of Chinese Medicine, Hong Kong Baptist University, Hong Kong SAR, China
| | - Jia Liu
- Mr. & Mrs. Ko Chi-Ming Centre for Parkinson's Disease Research, School of Chinese Medicine, Hong Kong Baptist University, Hong Kong SAR, China
| | - Ravindran Jaganathan
- Preclinical Department, Faculty of Medicine, Royal College of Medicine Perak, Universiti Kuala Lumpur, Ipoh 30450, Malaysia
| | | | - Jeyakumari Paul
- Department of Physiology, Dr. ALM PG Institute of Basic Medical Sciences, University of Madras, Chennai 600005, India
| | - Abhimanyu Thakur
- Pritzker School of Molecular Engineering, Ben May Department for Cancer Research, University of Chicago, Chicago, IL 60637, USA
| | - Min Li
- Mr. & Mrs. Ko Chi-Ming Centre for Parkinson's Disease Research, School of Chinese Medicine, Hong Kong Baptist University, Hong Kong SAR, China
| |
Collapse
|
42
|
Li M, Li M, Dai Y, Li D, Yu H, Liu J, Gao H, Zhong Y, Huang M, Lin J, Xie Y, Guo Z, Chen X. 16S rRNA gene sequencing reveals the correlation between the gut microbiota and the susceptibility to pathological scars. Front Microbiol 2023; 14:1215884. [PMID: 37434704 PMCID: PMC10332274 DOI: 10.3389/fmicb.2023.1215884] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/02/2023] [Accepted: 06/01/2023] [Indexed: 07/13/2023] Open
Abstract
The gut microbiome profile in patients with pathological scars remains rarely known, especially those patients who are susceptible to pathological scars. Previous studies demonstrated that gut microbial dysbiosis can promote the development of a series of diseases via the interaction between gut microbiota and host. The current study aimed to explore the gut microbiota of patients who are prone to suffer from pathological scars. 35 patients with pathological scars (PS group) and 40 patients with normal scars (NS group) were recruited for collection of fecal samples to sequence the 16S ribosomal RNA (16S rRNA) V3-V4 region of gut microbiota. Alpha diversity of gut microbiota showed a significant difference between NS group and PS group, and beta diversity indicated that the composition of gut microbiota in NS and PS participants was different, which implied that dysbiosis exhibits in patients who are susceptible to pathological scars. Based on phylum, genus, species levels, we demonstrated that the changing in some gut microbiota (Firmicutes; Bacteroides; Escherichia coli, etc.) may contribute to the occurrence or development of pathological scars. Moreover, the interaction network of gut microbiota in NS and PS group clearly revealed the different interaction model of each group. Our study has preliminary confirmed that dysbiosis exhibits in patients who are susceptible to pathological scars, and provide a new insight regarding the role of the gut microbiome in PS development and progression.
Collapse
Affiliation(s)
- Ming Li
- Department of Plastic Surgery and Regenerative Medicine, Fujian Medical University Union Hospital, Fuzhou, China
- Department of Plastic Surgery and Regenerative Medicine Institute, Fujian Medical University, Fuzhou, China
- Engineering Research Center of Tissue and Organ Regeneration, Fujian Province University, Fuzhou, China
| | - Minghao Li
- Department of Plastic Surgery and Regenerative Medicine, Fujian Medical University Union Hospital, Fuzhou, China
- Department of Plastic Surgery and Regenerative Medicine Institute, Fujian Medical University, Fuzhou, China
- Engineering Research Center of Tissue and Organ Regeneration, Fujian Province University, Fuzhou, China
| | - Yingting Dai
- Department of Plastic Surgery and Regenerative Medicine, Fujian Medical University Union Hospital, Fuzhou, China
- Department of Plastic Surgery and Regenerative Medicine Institute, Fujian Medical University, Fuzhou, China
- Engineering Research Center of Tissue and Organ Regeneration, Fujian Province University, Fuzhou, China
| | - Dang Li
- Nursing Department of Fujian Medical University Union Hospital, Fuzhou, China
| | - Han Yu
- Department of Dermatology, Pingtan Comprehensive Experimental Area Hospital, Fuzhou, China
| | - Jian Liu
- Fuzhou MineButy Clinics, Fuzhou, China
| | - Hangqi Gao
- Department of Plastic Surgery and Regenerative Medicine, Fujian Medical University Union Hospital, Fuzhou, China
- Department of Plastic Surgery and Regenerative Medicine Institute, Fujian Medical University, Fuzhou, China
- Engineering Research Center of Tissue and Organ Regeneration, Fujian Province University, Fuzhou, China
| | - Yi Zhong
- Department of Plastic Surgery and Regenerative Medicine, Fujian Medical University Union Hospital, Fuzhou, China
- Department of Plastic Surgery and Regenerative Medicine Institute, Fujian Medical University, Fuzhou, China
- Engineering Research Center of Tissue and Organ Regeneration, Fujian Province University, Fuzhou, China
| | - Mingquan Huang
- Department of Plastic Surgery and Regenerative Medicine, Fujian Medical University Union Hospital, Fuzhou, China
- Department of Plastic Surgery and Regenerative Medicine Institute, Fujian Medical University, Fuzhou, China
- Engineering Research Center of Tissue and Organ Regeneration, Fujian Province University, Fuzhou, China
| | - Jing Lin
- Department of Plastic Surgery and Regenerative Medicine, Fujian Medical University Union Hospital, Fuzhou, China
- Department of Plastic Surgery and Regenerative Medicine Institute, Fujian Medical University, Fuzhou, China
- Engineering Research Center of Tissue and Organ Regeneration, Fujian Province University, Fuzhou, China
| | - Yide Xie
- Department of Plastic Surgery and Regenerative Medicine, Fujian Medical University Union Hospital, Fuzhou, China
- Department of Plastic Surgery and Regenerative Medicine Institute, Fujian Medical University, Fuzhou, China
- Engineering Research Center of Tissue and Organ Regeneration, Fujian Province University, Fuzhou, China
| | - Zhihui Guo
- Department of Plastic Surgery and Regenerative Medicine, Fujian Medical University Union Hospital, Fuzhou, China
- Department of Plastic Surgery and Regenerative Medicine Institute, Fujian Medical University, Fuzhou, China
- Engineering Research Center of Tissue and Organ Regeneration, Fujian Province University, Fuzhou, China
| | - Xiaosong Chen
- Department of Plastic Surgery and Regenerative Medicine, Fujian Medical University Union Hospital, Fuzhou, China
- Department of Plastic Surgery and Regenerative Medicine Institute, Fujian Medical University, Fuzhou, China
- Engineering Research Center of Tissue and Organ Regeneration, Fujian Province University, Fuzhou, China
| |
Collapse
|
43
|
Thapa HB, Ebenberger SP, Schild S. The Two Faces of Bacterial Membrane Vesicles: Pathophysiological Roles and Therapeutic Opportunities. Antibiotics (Basel) 2023; 12:1045. [PMID: 37370364 PMCID: PMC10295235 DOI: 10.3390/antibiotics12061045] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2023] [Revised: 06/07/2023] [Accepted: 06/12/2023] [Indexed: 06/29/2023] Open
Abstract
Bacterial membrane vesicles (MVs) are nanosized lipid particles secreted by lysis or blebbing mechanisms from Gram-negative and -positive bacteria. It is becoming increasingly evident that MVs can promote antimicrobial resistance but also provide versatile opportunities for therapeutic exploitation. As non-living facsimiles of parent bacteria, MVs can carry multiple bioactive molecules such as proteins, lipids, nucleic acids, and metabolites, which enable them to participate in intra- and interspecific communication. Although energetically costly, the release of MVs seems beneficial for bacterial fitness, especially for pathogens. In this review, we briefly discuss the current understanding of diverse MV biogenesis routes affecting MV cargo. We comprehensively highlight the physiological functions of MVs derived from human pathogens covering in vivo adaptation, colonization fitness, and effector delivery. Emphasis is given to recent findings suggesting a vicious cycle of MV biogenesis, pathophysiological function, and antibiotic therapy. We also summarize potential therapeutical applications, such as immunotherapy, vaccination, targeted delivery, and antimicrobial potency, including their experimental validation. This comparative overview identifies common and unique strategies for MV modification used along diverse applications. Thus, the review summarizes timely aspects of MV biology in a so far unprecedented combination ranging from beneficial function for bacterial pathogen survival to future medical applications.
Collapse
Affiliation(s)
- Himadri B. Thapa
- Institute of Molecular Biosciences, University of Graz, Humboldtstrasse 50, 8010 Graz, Austria
| | - Stephan P. Ebenberger
- Institute of Molecular Biosciences, University of Graz, Humboldtstrasse 50, 8010 Graz, Austria
| | - Stefan Schild
- Institute of Molecular Biosciences, University of Graz, Humboldtstrasse 50, 8010 Graz, Austria
- BioTechMed Graz, 8010 Graz, Austria
- Field of Excellence Biohealth, University of Graz, 8010 Graz, Austria
| |
Collapse
|
44
|
Zhou JY, Glendenning LM, Cavanaugh JM, McNeer SK, Goodman WA, Cobb BA. Intestinal Tr1 Cells Confer Protection against Colitis in the Absence of Foxp3+ Regulatory T Cell-Derived IL-10. Immunohorizons 2023; 7:456-466. [PMID: 37314833 PMCID: PMC10580124 DOI: 10.4049/immunohorizons.2200071] [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: 05/12/2023] [Accepted: 05/16/2023] [Indexed: 06/15/2023] Open
Abstract
The intestinal mucosa is continually exposed to diverse microbial and dietary Ags, requiring coordinated efforts by specialized populations of regulatory T cells (Tregs) to maintain homeostasis. Suppressive mechanisms used by intestinal Tregs include the secretion of anti-inflammatory cytokines such as IL-10 and TGF-β. Defects in IL-10 signaling are associated with severe infantile enterocolitis in humans, and mice deficient in IL-10 or its receptors develop spontaneous colitis. To determine the requirement of Foxp3+ Treg-specific IL-10 for protection against colitis, we generated Foxp3-specific IL-10 knockout (KO) mice (IL-10 conditional KO [cKO] mice). Colonic Foxp3+ Tregs isolated from IL-10cKO mice showed impaired ex vivo suppressive function, although IL-10cKO mice maintained normal body weights and developed only mild inflammation over 30 wk of age (in contrast to severe colitis in global IL-10KO mice). Protection from colitis in IL-10cKO mice was associated with an expanded population of IL-10-producing type 1 Tregs (Tr1, CD4+Foxp3-) in the colonic lamina propria that produced more IL-10 on a per-cell basis compared with wild-type intestinal Tr1 cells. Collectively, our findings reveal a role for Tr1 cells in the gut, as they expand to fill a tolerogenic niche in conditions of suboptimal Foxp3+ Treg-mediated suppression and provide functional protection against experimental colitis.
Collapse
Affiliation(s)
- Julie Y. Zhou
- Department of Pathology, Case Western Reserve University School of Medicine, Cleveland, OH
| | - Leandre M. Glendenning
- Department of Pathology, Case Western Reserve University School of Medicine, Cleveland, OH
| | - Jill M. Cavanaugh
- Department of Pathology, Case Western Reserve University School of Medicine, Cleveland, OH
| | - Sarah K. McNeer
- Department of Pathology, Case Western Reserve University School of Medicine, Cleveland, OH
| | - Wendy A. Goodman
- Department of Pathology, Case Western Reserve University School of Medicine, Cleveland, OH
| | - Brian A. Cobb
- Department of Pathology, Case Western Reserve University School of Medicine, Cleveland, OH
| |
Collapse
|
45
|
Bronzini M, Maglione A, Rosso R, Matta M, Masuzzo F, Rolla S, Clerico M. Feeding the gut microbiome: impact on multiple sclerosis. Front Immunol 2023; 14:1176016. [PMID: 37304278 PMCID: PMC10248010 DOI: 10.3389/fimmu.2023.1176016] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2023] [Accepted: 05/02/2023] [Indexed: 06/13/2023] Open
Abstract
Multiple sclerosis (MS) is a multifactorial neurological disease characterized by chronic inflammation and immune-driven demyelination of the central nervous system (CNS). The rising number of MS cases in the last decade could be partially attributed to environmental changes, among which the alteration of the gut microbiome driven by novel dietary habits is now of particular interest. The intent of this review is to describe how diet can impact the development and course of MS by feeding the gut microbiome. We discuss the role of nutrition and the gut microbiota in MS disease, describing preclinical studies on experimental autoimmune encephalomyelitis (EAE) and clinical studies on dietary interventions in MS, with particular attention to gut metabolites-immune system interactions. Possible tools that target the gut microbiome in MS, such as the use of probiotics, prebiotics and postbiotics, are analyzed as well. Finally, we discuss the open questions and the prospects of these microbiome-targeted therapies for people with MS and for future research.
Collapse
Affiliation(s)
- Matteo Bronzini
- Department of Clinical and Biological Sciences, University of Turin, Orbassano, Italy
| | - Alessandro Maglione
- Department of Clinical and Biological Sciences, University of Turin, Orbassano, Italy
| | - Rachele Rosso
- Department of Clinical and Biological Sciences, University of Turin, Orbassano, Italy
| | - Manuela Matta
- San Luigi Gonzaga University Hospital, Orbassano, Italy
| | | | - Simona Rolla
- Department of Clinical and Biological Sciences, University of Turin, Orbassano, Italy
| | - Marinella Clerico
- Department of Clinical and Biological Sciences, University of Turin, Orbassano, Italy
- San Luigi Gonzaga University Hospital, Orbassano, Italy
| |
Collapse
|
46
|
Wang J, He L, Wang S, Zhao H, Chen J, Dong Y, Yasen S, Wang L, Zou H. Therapeutic effect of the total saponin from Panax Japonicus on experimental autoimmune encephalomyelitis by attenuating inflammation and regulating gut microbiota in mice. JOURNAL OF ETHNOPHARMACOLOGY 2023:116681. [PMID: 37230280 DOI: 10.1016/j.jep.2023.116681] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/19/2023] [Revised: 05/18/2023] [Accepted: 05/22/2023] [Indexed: 05/27/2023]
Abstract
ETHNOPHARMACOLOGICAL RELEVANCE Rhizomes of Panax japonicus (RPJ), a traditional herbal medicine, was used for treating arthritis and physical weakness in China from the Ming dynasty. Triterpene saponins are the main bioactive components of RPJ. In this work, for the first time, we evaluate the therapeutic effect of the total saponin from RPJ (TSPJ) on experimental autoimmune encephalomyelitis (EAE) mice induced by myelin oligodendrocyte glycoprotein (MOG) 35-55, a commonly used animal model of Multiple sclerosis (MS). AIM OF THE STUDY To evaluate the therapeutic effect of TSPJ on EAE and explored its possible underlying mechanisms. MATERIALS AND METHODS EAE was induced by MOG 35-55. Mice were administrated with TSPJ (36.5 mg/kg, 73 mg/kg) and prednisone acetate (positive control) orally once daily up to 28 days postimmunization, and their neurological deficit was scored. Hematoxylin and Eosin (HE), Luxol Fast Blue (LFB), and transmission electron microscopy (TEM) were carried out to evaluate the EAE-induced pathological changes in the brain and spinal cord. IL-17a and Foxp3 levels in central nervous system(CNS)were evaluated by immunohistochemical staining. The changes in IL-1β, IL-6, and TNF-α levels in serum and CNS were measured with ELISA. Quantitative reverse transcription PCR (qRT-PCR) was used to access mRNA expression in CNS of the above indices. The percentages of Th1, Th2, Th17and Treg cells in spleen were determined by Flow Cytometry (FCM). Furthermore, 16S rDNA sequencing was used to detect the intestinal flora of mice in each group. In vitro studies, lipopolysaccharides (LPS)-induced BV2 microglia cells were used and the expression of TLR4, MyD88, p65, and p-p65 in cells was detected by Western blot. RESULTS TSPJ treatment significantly alleviated neurological impairment caused by EAE. Histological examination confirmed the protective effects of TSPJ on myelin sheath and the reduction of inflammatory cell infiltration in the brain and spinal cord of EAE mice. TSPJ notably downregulated the ratio of IL-17a/Foxp3 at protein and mRNA levels in CNS, as well as Th17/Treg and Th1/Th2 cell ratios in the spleen of EAE mice. The levels of TNF-α, IL-6, and IL-1β in CNS and peripheral serum also decreased post-TSPJ treatment. In vitro, TSPJ suppressed LPS-induced production of inflammatory factors in BV2 cells via TLR4-MyD88-NF-κB signaling pathway. More importantly, TSPJ interventions altered the composition of gut microbiota and restored the ratio of Firmicutes to Bacteroidetes in EAE mice. Furthermore, Spearman's correlation analysis revealed that a relationship existed between statistically significantly altered genera and CNS inflammatory indices. CONCLUSION Our results demonstrated TSPJ had therapeutic effects on EAE. Its anti-neuroinflammation property in EAE was related to modulating gut microbiota and inhibiting TLR4-MyD88-NF-κB signaling pathway. Our study indicated that TSPJ may be a potential candidate for the treatment of MS.
Collapse
Affiliation(s)
- Jing Wang
- School of Traditional Chinese Medicine, Capital Medical University, Beijing, 100069, China
| | - Liying He
- School of Traditional Chinese Medicine, Capital Medical University, Beijing, 100069, China
| | - Siyuan Wang
- School of Traditional Chinese Medicine, Capital Medical University, Beijing, 100069, China.
| | - Hui Zhao
- School of Traditional Chinese Medicine, Capital Medical University, Beijing, 100069, China.
| | - Jie Chen
- School of Traditional Chinese Medicine, Capital Medical University, Beijing, 100069, China.
| | - Yixin Dong
- School of Traditional Chinese Medicine, Capital Medical University, Beijing, 100069, China.
| | - Subinuer Yasen
- School of Traditional Chinese Medicine, Capital Medical University, Beijing, 100069, China.
| | - Lei Wang
- School of Traditional Chinese Medicine, Capital Medical University, Beijing, 100069, China.
| | - Haiyan Zou
- School of Traditional Chinese Medicine, Capital Medical University, Beijing, 100069, China.
| |
Collapse
|
47
|
Hoffman K, Brownell Z, Doyle WJ, Ochoa-Repáraz J. The immunomodulatory roles of the gut microbiome in autoimmune diseases of the central nervous system: Multiple sclerosis as a model. J Autoimmun 2023; 137:102957. [PMID: 36435700 PMCID: PMC10203067 DOI: 10.1016/j.jaut.2022.102957] [Citation(s) in RCA: 11] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/10/2022] [Accepted: 11/14/2022] [Indexed: 11/24/2022]
Abstract
The gut-associated lymphoid tissue is a primary activation site for immune responses to infection and immunomodulation. Experimental evidence using animal disease models suggests that specific gut microbes significantly regulate inflammation and immunoregulatory pathways. Furthermore, recent clinical findings indicate that gut microbes' composition, collectively named gut microbiota, is altered under disease state. This review focuses on the functional mechanisms by which gut microbes promote immunomodulatory responses that could be relevant in balancing inflammation associated with autoimmunity in the central nervous system. We also propose therapeutic interventions that target the composition of the gut microbiota as immunomodulatory mechanisms to control neuroinflammation.
Collapse
Affiliation(s)
- Kristina Hoffman
- Department of Biological Sciences, Boise State University, Boise, ID, 83725, USA
| | - Zackariah Brownell
- Department of Biological Sciences, Arizona State University, Tempe, AZ, 85281, USA
| | - William J Doyle
- Department of Biological Sciences, Boise State University, Boise, ID, 83725, USA
| | - Javier Ochoa-Repáraz
- Department of Biological Sciences, Boise State University, Boise, ID, 83725, USA.
| |
Collapse
|
48
|
Fiyouzi T, Pelaez-Prestel HF, Reyes-Manzanas R, Lafuente EM, Reche PA. Enhancing Regulatory T Cells to Treat Inflammatory and Autoimmune Diseases. Int J Mol Sci 2023; 24:ijms24097797. [PMID: 37175505 PMCID: PMC10177847 DOI: 10.3390/ijms24097797] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2023] [Revised: 04/19/2023] [Accepted: 04/21/2023] [Indexed: 05/15/2023] Open
Abstract
Regulatory T cells (Tregs) control immune responses and are essential to maintain immune homeostasis and self-tolerance. Hence, it is no coincidence that autoimmune and chronic inflammatory disorders are associated with defects in Tregs. These diseases have currently no cure and are treated with palliative drugs such as immunosuppressant and immunomodulatory agents. Thereby, there is a great interest in developing medical interventions against these diseases based on enhancing Treg cell function and numbers. Here, we give an overview of Treg cell ontogeny and function, paying particular attention to mucosal Tregs. We review some notable approaches to enhance immunomodulation by Tregs with therapeutic purposes including adoptive Treg cell transfer therapy and discuss relevant clinical trials for inflammatory bowel disease. We next introduce ways to expand mucosal Tregs in vivo using microbiota and dietary products that have been the focus of clinical trials in various autoimmune and chronic-inflammatory diseases.
Collapse
Affiliation(s)
- Tara Fiyouzi
- Laboratory of Immunomedicine, Faculty of Medicine, University Complutense of Madrid, Ave Complutense S/N, 28040 Madrid, Spain
| | - Hector F Pelaez-Prestel
- Laboratory of Immunomedicine, Faculty of Medicine, University Complutense of Madrid, Ave Complutense S/N, 28040 Madrid, Spain
| | - Raquel Reyes-Manzanas
- Laboratory of Immunomedicine, Faculty of Medicine, University Complutense of Madrid, Ave Complutense S/N, 28040 Madrid, Spain
| | - Esther M Lafuente
- Laboratory of Immunomedicine, Faculty of Medicine, University Complutense of Madrid, Ave Complutense S/N, 28040 Madrid, Spain
| | - Pedro A Reche
- Laboratory of Immunomedicine, Faculty of Medicine, University Complutense of Madrid, Ave Complutense S/N, 28040 Madrid, Spain
| |
Collapse
|
49
|
Fogarty EC, Schechter MS, Lolans K, Sheahan ML, Veseli I, Moore R, Kiefl E, Moody T, Rice PA, Yu MK, Mimee M, Chang EB, Mclellan SL, Willis AD, Comstock LE, Eren AM. A highly conserved and globally prevalent cryptic plasmid is among the most numerous mobile genetic elements in the human gut. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2023:2023.03.25.534219. [PMID: 36993556 PMCID: PMC10055365 DOI: 10.1101/2023.03.25.534219] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 04/13/2023]
Abstract
Plasmids are extrachromosomal genetic elements that often encode fitness enhancing features. However, many bacteria carry 'cryptic' plasmids that do not confer clear beneficial functions. We identified one such cryptic plasmid, pBI143, which is ubiquitous across industrialized gut microbiomes, and is 14 times as numerous as crAssphage, currently established as the most abundant genetic element in the human gut. The majority of mutations in pBI143 accumulate in specific positions across thousands of metagenomes, indicating strong purifying selection. pBI143 is monoclonal in most individuals, likely due to the priority effect of the version first acquired, often from one's mother. pBI143 can transfer between Bacteroidales and although it does not appear to impact bacterial host fitness in vivo, can transiently acquire additional genetic content. We identified important practical applications of pBI143, including its use in identifying human fecal contamination and its potential as an inexpensive alternative for detecting human colonic inflammatory states.
Collapse
Affiliation(s)
- Emily C Fogarty
- Committee on Microbiology, University of Chicago, Chicago, IL 60637, USA
- Duchossois Family Institute, University of Chicago, Chicago, IL 60637, USA
- Department of Medicine, University of Chicago, Chicago, IL 60637, USA
| | - Matthew S Schechter
- Committee on Microbiology, University of Chicago, Chicago, IL 60637, USA
- Duchossois Family Institute, University of Chicago, Chicago, IL 60637, USA
- Department of Medicine, University of Chicago, Chicago, IL 60637, USA
| | - Karen Lolans
- Department of Medicine, University of Chicago, Chicago, IL 60637, USA
| | - Madeline L. Sheahan
- Duchossois Family Institute, University of Chicago, Chicago, IL 60637, USA
- Department of Microbiology, University of Chicago, Chicago, IL, 60637, USA
| | - Iva Veseli
- Department of Medicine, University of Chicago, Chicago, IL 60637, USA
- Graduate Program in Biophysical Sciences, University of Chicago, Chicago, IL 60637, USA
| | - Ryan Moore
- Center for Bioinformatics and Computational Biology, University of Delaware, Newark, DE, USA
| | - Evan Kiefl
- Department of Medicine, University of Chicago, Chicago, IL 60637, USA
- Graduate Program in Biophysical Sciences, University of Chicago, Chicago, IL 60637, USA
| | - Thomas Moody
- Department of Systems Biology, Columbia University, New York, NY, 10032 USA
| | - Phoebe A Rice
- Committee on Microbiology, University of Chicago, Chicago, IL 60637, USA
- Department of Biochemistry, University of Chicago, Chicago, IL, 60637, USA
| | | | - Mark Mimee
- Committee on Microbiology, University of Chicago, Chicago, IL 60637, USA
- Department of Microbiology, University of Chicago, Chicago, IL, 60637, USA
- Pritzker School of Molecular Engineering, The University of Chicago, Chicago, IL 60637, USA
| | - Eugene B Chang
- Department of Medicine, University of Chicago, Chicago, IL 60637, USA
| | - Sandra L Mclellan
- School of Freshwater Sciences, University of Wisconsin-Milwaukee, Milwaukee, WI, 53204, USA
| | - Amy D Willis
- Department of Biostatistics, University of Washington, Seattle, WA, 98195, USA
| | - Laurie E Comstock
- Duchossois Family Institute, University of Chicago, Chicago, IL 60637, USA
- Department of Microbiology, University of Chicago, Chicago, IL, 60637, USA
| | - A Murat Eren
- Marine Biological Laboratory, Woods Hole, MA, 02543, USA
- Alfred Wegener Institute, Helmholtz Centre for Polar and Marine Research, 27570 Bremerhaven, Germany
- Institute for Chemistry and Biology of the Marine Environment, University of Oldenburg, 26129 Oldenburg, Germany
- Helmholtz Institute for Functional Marine Biodiversity, 26129 Oldenburg, Germany
| |
Collapse
|
50
|
Hashemi B, Abdollahi M, Abbaspour-Aghdam S, Hazrati A, Malekpour K, Meshgi S, Kafil HS, Ghazi F, Yousefi M, Roshangar L, Ahmadi M. The effect of probiotics on immune responses and their therapeutic application: A new treatment option for multiple sclerosis. Biomed Pharmacother 2023; 159:114195. [PMID: 36630847 DOI: 10.1016/j.biopha.2022.114195] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/26/2022] [Revised: 12/10/2022] [Accepted: 12/28/2022] [Indexed: 01/12/2023] Open
Abstract
Multiple sclerosis (MS) is known as a chronic inflammatory disease (CID) that affects the central nervous system and leads to nerve demyelination. However, the exact cause of MS is unknown, but immune system regulation and inhibiting the function of inflammatory pathways may have a beneficial effect on controlling and improving the disease. Studies show that probiotics can alter the gut microbiome, thereby improving and affecting the immune system and inflammatory responses in patients with MS. The results show that probiotics have a good effect on the recovery of patients with MS in humans and animals. The present study investigated the effect of probiotics and possible therapeutic mechanisms of probiotics on immune cells and inflammatory cytokines. This review article showed that probiotics could improve immune cells and inflammatory cytokines in patients with MS and can play an effective role in disease management and control.
Collapse
Affiliation(s)
- Behnam Hashemi
- Department of Bacteriology, Faculty of Medical Science, Tarbiat Modares University, Tehran, Iran
| | - Maryam Abdollahi
- Department of Bacteriology, Faculty of Medical Science, Tarbiat Modares University, Tehran, Iran
| | - Sanaz Abbaspour-Aghdam
- Department of Clinical Biochemistry and Applied Cell Sciences, Faculty of Medicine, Urmia University of Medical Sciences, Urmia, Iran
| | - Ali Hazrati
- Department of Immunology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Kosar Malekpour
- Department of Immunology, School of Medicine, Iran University of Medical Sciences, Tehran, Iran
| | - Shahla Meshgi
- Cardiovascular Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Hossein Samadi Kafil
- Drug Applied Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Farhood Ghazi
- Stem Cell Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Mehdi Yousefi
- Stem Cell Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Leila Roshangar
- Stem Cell Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Majid Ahmadi
- Stem Cell Research Center, Tabriz University of Medical Sciences, Tabriz, Iran.
| |
Collapse
|