|
1
|
An C, Jiang C, Pei W, Li A, Wang M, Wang Y, Wang H, Zuo L. Intestinal epithelial cells in health and disease. Tissue Barriers 2025:2504744. [PMID: 40401816 DOI: 10.1080/21688370.2025.2504744] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/25/2024] [Revised: 04/23/2025] [Accepted: 05/06/2025] [Indexed: 05/23/2025] Open
Abstract
This comprehensive review delves into the pivotal role of intestinal epithelial cells in the context of various diseases. It provides an in-depth analysis of the diverse types and functions of these cells, explores the influence of multiple signaling pathways on their differentiation, and elucidates their critical roles in a spectrum of diseases. The significance of the gastrointestinal tract in maintaining overall health is extremely important and cannot be exaggerated. This complex and elongated organ acts as a crucial link between the internal and external environments, making it vulnerable to various harmful influences. Preserving the normal structure and function of the gut is essential for well-being. Intestinal epithelial cells serve as the primary defense mechanism within the gastrointestinal tract and play a crucial role in preventing harmful substances from infiltrating the body. As the main components of the digestive system, they not only participate in the absorption and secretion of nutrients and the maintenance of barrier function but also play a pivotal role in immune defense. Therefore, the health of intestinal epithelial cells is of vital importance for overall health.
Collapse
Affiliation(s)
- Chenchen An
- Laboratory of Molecular Biology, Department of Biochemistry, School of Basic Medical Science, Anhui Medical University, Hefei, China
- Innovation and Entrepreneurship Laboratory for college students, Anhui Medical University, Hefei, China
| | - Chonggui Jiang
- Laboratory of Molecular Biology, Department of Biochemistry, School of Basic Medical Science, Anhui Medical University, Hefei, China
- Innovation and Entrepreneurship Laboratory for college students, Anhui Medical University, Hefei, China
| | - Wangxiang Pei
- Laboratory of Molecular Biology, Department of Biochemistry, School of Basic Medical Science, Anhui Medical University, Hefei, China
- Innovation and Entrepreneurship Laboratory for college students, Anhui Medical University, Hefei, China
| | - Ao Li
- Innovation and Entrepreneurship Laboratory for college students, Anhui Medical University, Hefei, China
- The 904th Hospital of PLA, Medical School of Anhui Medical University, Wuxi, China
| | - Minghui Wang
- Innovation and Entrepreneurship Laboratory for college students, Anhui Medical University, Hefei, China
- The First College of Clinical Medicine, Anhui Medical University, Hefei, China
| | - Yufei Wang
- Innovation and Entrepreneurship Laboratory for college students, Anhui Medical University, Hefei, China
- The First College of Clinical Medicine, Anhui Medical University, Hefei, China
| | - Hua Wang
- Inflammation and Immune- Mediated Diseases Laboratory of Anhui Province, Anhui Medical University, Hefei, China
- Department of Oncology, the First Affiliated Hospital of Anhui Medical University, Hefei, China
| | - Li Zuo
- Laboratory of Molecular Biology, Department of Biochemistry, School of Basic Medical Science, Anhui Medical University, Hefei, China
- Innovation and Entrepreneurship Laboratory for college students, Anhui Medical University, Hefei, China
| |
Collapse
|
|
2
|
Creighton RL, Hughes SM, Hladik F, Gornalusse GG. The intestinal interferon system and specialized enterocytes as putative drivers of HIV latency. Front Immunol 2025; 16:1589752. [PMID: 40438119 PMCID: PMC12116432 DOI: 10.3389/fimmu.2025.1589752] [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: 03/07/2025] [Accepted: 04/23/2025] [Indexed: 06/01/2025] Open
Abstract
The barrier to HIV cure is the HIV reservoir, which is composed of latently infected CD4+ T cells and myeloid cells that carry stably integrated and replication-competent provirus. The gastrointestinal tract (GIT) contains a substantial part of the HIV reservoir and its immunophysiology could be especially conducive for HIV persistence and reactivation. However, the exact cellular microenvironment and molecular mechanisms that govern the renewal of provirus-harboring cells and proviral reactivation in the GIT remain unclear. In this review, we outline the evidence supporting an overarching hypothesis that interferon activity driven by specialized enterocytes creates a microenvironment that fosters proliferation of latently infected CD4+ T cells and sporadic HIV reactivation from these cells. First, we describe unique immunologic features of the gastrointestinal associated lymphoid tissue (GALT), specifically highlighting IFN activity in specialized enterocytes and potential interactions between these cells and neighboring HIV susceptible cells. Then, we will describe dysregulation of IFN signaling in HIV infection and how IFN dysregulation in the GALT may contribute to the persistence and reactivation of the latent HIV reservoir. Finally, we will speculate on the clinical implications of this hypothesis for HIV cure strategies and outline the next steps.
Collapse
Affiliation(s)
- Rachel L. Creighton
- Department of Obstetrics and Gynecology, School of Medicine, University of Washington, Seattle, WA, United States
- Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Center, Seattle, WA, United States
| | - Sean M. Hughes
- Department of Obstetrics and Gynecology, School of Medicine, University of Washington, Seattle, WA, United States
- Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Center, Seattle, WA, United States
| | - Florian Hladik
- Department of Obstetrics and Gynecology, School of Medicine, University of Washington, Seattle, WA, United States
- Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Center, Seattle, WA, United States
- Department of Medicine, Division of Allergy and Infectious Diseases, University of Washington, Seattle, WA, United States
| | - Germán G. Gornalusse
- Department of Obstetrics and Gynecology, School of Medicine, University of Washington, Seattle, WA, United States
- Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Center, Seattle, WA, United States
- Department of Global Health, Schools of Medicine and Public Health, University of Washington, Seattle, WA, United States
| |
Collapse
|
|
3
|
Scott TA, Baker KS, Trotter C, Jenkins C, Mostowy S, Hawkey J, Schmidt H, Holt KE, Thomson NR, Baker S. Shigella sonnei: epidemiology, evolution, pathogenesis, resistance and host interactions. Nat Rev Microbiol 2025; 23:303-317. [PMID: 39604656 DOI: 10.1038/s41579-024-01126-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 10/30/2024] [Indexed: 11/29/2024]
Abstract
Shigella sonnei is a major cause of diarrhoea globally and is increasing in prevalence relative to other Shigella because of multiple demographic and environmental influences. This single-serotype species has traditionally received less attention in comparison to Shigella flexneri and Shigella dysenteriae, which were more common in low-income countries and more tractable in the laboratory. In recent years, we have learned that Shigella are highly complex and highly susceptible to environmental change, as exemplified by epidemiological trends and increasing relevance of S. sonnei. Ultimately, methods, tools and data generated from decades of detailed research into S. flexneri have been used to gain new insights into the epidemiology, microbiology and pathogenesis of S. sonnei. In parallel, widespread adoption of genomic surveillance has yielded insights into antimicrobial resistance, evolution and organism transmission. In this Review, we provide an overview of current knowledge of S. sonnei, highlighting recent insights into this globally disseminated antimicrobial-resistant pathogen and assessing how novel data may impact future vaccine development and implementation.
Collapse
Affiliation(s)
- Timothy A Scott
- Cambridge Institute for Therapeutic Immunology and Infectious Disease, Jeffrey Cheah Biomedical Centre, Department of Medicine, Cambridge Biomedical Campus, University of Cambridge, Cambridge, UK.
| | - Kate S Baker
- Department of Clinical Microbiology, Immunology and Infection, University of Liverpool, Liverpool, UK
- Department of Genetics, University of Cambridge, Cambridge, UK
| | - Caroline Trotter
- Department of Veterinary Medicine, University of Cambridge, Cambridge, UK
- Department of Pathology, University of Cambridge, Cambridge, UK
| | | | - Serge Mostowy
- Department of Infection Biology, Faculty of Infectious and Tropical Diseases, London School of Hygiene & Tropical Medicine, London, UK
| | - Jane Hawkey
- Department of Infectious Diseases, School of Translational Medicine, Monash University, Melbourne, Victoria, Australia
| | - Hayden Schmidt
- Neutralizing Antibody Center, International AIDS Vaccine Initiative, San Diego, CA, USA
| | - Kathryn E Holt
- Department of Infection Biology, Faculty of Infectious and Tropical Diseases, London School of Hygiene & Tropical Medicine, London, UK
- Department of Infectious Diseases, School of Translational Medicine, Monash University, Melbourne, Victoria, Australia
| | - Nicholas R Thomson
- Department of Infection Biology, Faculty of Infectious and Tropical Diseases, London School of Hygiene & Tropical Medicine, London, UK
- Wellcome Sanger Institute, Wellcome Genome Campus, Cambridge, UK
| | - Stephen Baker
- Cambridge Institute for Therapeutic Immunology and Infectious Disease, Jeffrey Cheah Biomedical Centre, Department of Medicine, Cambridge Biomedical Campus, University of Cambridge, Cambridge, UK.
- International AIDS Vaccine Initiative, London, UK.
| |
Collapse
|
|
4
|
Ding G, Yang X, Li Y, Wang Y, Du Y, Wang M, Ye R, Wang J, Zhang Y, Chen Y, Zhang Y. Gut microbiota regulates gut homeostasis, mucosal immunity and influences immune-related diseases. Mol Cell Biochem 2025; 480:1969-1981. [PMID: 39060829 DOI: 10.1007/s11010-024-05077-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/25/2024] [Accepted: 07/20/2024] [Indexed: 07/28/2024]
Abstract
The intestinal microbiome constitutes a sophisticated and massive ecosystem pivotal for maintaining gastrointestinal equilibrium and mucosal immunity via diverse pathways. The gut microbiota is continuously reshaped by multiple environmental factors, thereby influencing overall wellbeing or predisposing individuals to disease state. Many observations reveal an altered microbiome composition in individuals with autoimmune conditions, coupled with shifts in metabolic profiles, which has spurred ongoing development of therapeutic interventions targeting the microbiome. This review delineates the microbial consortia of the intestine, their role in sustaining gastrointestinal stability, the association between the microbiome and immune-mediated pathologies, and therapeutic modalities focused on microbiome modulation. We emphasize the entire role of the intestinal microbiome in human health and recommend microbiome modulation as a viable strategy for disease prophylaxis and management. However, the application of gut microbiota modification for the treatment of immune-related diseases, such as fecal microbiota transplantation and probiotics, remain quite challenging. Therefore, more research is needed into the role and mechanisms of these therapeutics.
Collapse
Affiliation(s)
- Guoao Ding
- School of Biological and Food Engineering, Hefei Normal University, Hefei, 230061, China
- Department of Life Science, Anhui University, Hefei, 230061, China
| | - Xuezhi Yang
- Institute of Clinical Pharmacology, Key Laboratory of Anti-Inflammatory and Immune Medicine, Anhui Collaborative Innovation Center of Anti-Inflammatory and Immune Medicine, Ministry of Education, Anhui Medical University, Hefei, 230032, China
| | - Ying Li
- School of Biological and Food Engineering, Hefei Normal University, Hefei, 230061, China
| | - Ying Wang
- School of Biological and Food Engineering, Hefei Normal University, Hefei, 230061, China
| | - Yujie Du
- School of Biological and Food Engineering, Hefei Normal University, Hefei, 230061, China
| | - Meng Wang
- School of Biological and Food Engineering, Hefei Normal University, Hefei, 230061, China
| | - Ruxin Ye
- School of Biological and Food Engineering, Hefei Normal University, Hefei, 230061, China
| | - Jingjing Wang
- School of Biological and Food Engineering, Hefei Normal University, Hefei, 230061, China
| | - Yongkang Zhang
- School of Biological and Food Engineering, Hefei Normal University, Hefei, 230061, China
| | - Yajun Chen
- School of Biological and Food Engineering, Hefei Normal University, Hefei, 230061, China
| | - Yan Zhang
- School of Biological and Food Engineering, Hefei Normal University, Hefei, 230061, China.
- Department of Life Science, Anhui University, Hefei, 230061, China.
- Institute of Clinical Pharmacology, Key Laboratory of Anti-Inflammatory and Immune Medicine, Anhui Collaborative Innovation Center of Anti-Inflammatory and Immune Medicine, Ministry of Education, Anhui Medical University, Hefei, 230032, China.
| |
Collapse
|
|
5
|
Sharan K, Brandt C, Yusuf MA, Singh P, Halder N, Edwards ME, Mangu SVVSR, Das A, Mishra A, Kumar SS, Sharma A, Gupta A, Liu XS, Guo EX, Monani UR, Ponnalagu D, Ivanov II, Lal G, Clare S, Dougan G, Yadav VK. Rapid and relaying deleterious effects of a gastrointestinal pathogen, Citrobacter rodentium, on bone, an extra-intestinal organ. iScience 2025; 28:111802. [PMID: 39967874 PMCID: PMC11834125 DOI: 10.1016/j.isci.2025.111802] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/05/2021] [Revised: 08/04/2024] [Accepted: 01/10/2025] [Indexed: 02/20/2025] Open
Abstract
Enteropathogenic infections cause pathophysiological changes in the host but their effects beyond the gastrointestinal tract are undefined. Here, using Citrobacter rodentium infection in mouse, which mimics human diarrheal enteropathogenic Escherichia coli, we show that gastrointestinal infection negatively affects bone remodeling, leading to compromised bone architecture. Transmission of infection through fecal-oral route from Citrobacter rodentium-infected to non-infected mice caused bone loss in non-infected cage mates. Mice with B cell deficiency (Igh6-/- mice) failed to clear C. rodentium infection and exhibited more severe and long-term bone loss compared to WT mice. Unbiased cytokine profiling showed an increase in circulating tumor necrosis factor α (TNFα) levels following Citrobacter rodentium infection, and immunoneutralization of TNFα prevented infection-induced bone loss completely in WT and immunocompromised mice. These findings reveal rapid, relaying, and modifiable effects of enteropathogenic infections on an extraintestinal organ-bone, and provide insights into the mechanism(s) through which these infections affect extraintestinal organ homeostasis.
Collapse
Affiliation(s)
- Kunal Sharan
- Mouse Genetics Project, Wellcome Sanger Institute, Hinxton, Saffron Walden, UK
- Department of Molecular Nutrition, CSIR-CFTRI, Mysore, Karnataka, India
| | - Cordelia Brandt
- Host-Pathogen Interaction Group, Wellcome Sanger Institute, Hinxton, Saffron Walden, UK
| | - Mohd Aslam Yusuf
- Department of Bioengineering, Integral University, Lucknow, Uttar Pradesh, India
| | - Parminder Singh
- National Institute of Immunology, New Delhi, New Delhi, India
| | - Namrita Halder
- National Centre for Cell Science, Pune, Maharastra, India
| | - Madeline E. Edwards
- Department of Microbiology and Immunology, Columbia University, New York, NY, USA
| | - SVVS Ravi Mangu
- Department of Molecular Nutrition, CSIR-CFTRI, Mysore, Karnataka, India
| | - Abhilipsa Das
- Department of Molecular Nutrition, CSIR-CFTRI, Mysore, Karnataka, India
| | - Amrita Mishra
- National Centre for Cell Science, Pune, Maharastra, India
| | - Shashi S. Kumar
- Center for Motor Neuron Biology & Disease, Columbia University, New York, NY, USA
- Department of Neurology, Columbia University, New York, NY, USA
| | - Amita Sharma
- Pediatric Kidney Foundation, New Delhi, New Delhi, India
| | - Alka Gupta
- Reproductive Biology Laboratory, National Institute of Immunology, New Delhi, New Delhi, India
| | - Xiaowei S. Liu
- Department of Orthopaedic Surgery, University of Pennsylvania, Philadelphia, PA, USA
| | - Edward X. Guo
- Bone Biomechanics Laboratory, Columbia University, New York, NY, USA
| | - Umrao R. Monani
- Center for Motor Neuron Biology & Disease, Columbia University, New York, NY, USA
- Department of Neurology, Columbia University, New York, NY, USA
- Department of Pathology & Cell Biology, Columbia University, New York, NY, USA
| | | | - Ivaylo I. Ivanov
- Department of Microbiology and Immunology, Columbia University, New York, NY, USA
| | - Girdhari Lal
- National Centre for Cell Science, Pune, Maharastra, India
| | - Simon Clare
- Host-Pathogen Interaction Group, Wellcome Sanger Institute, Hinxton, Saffron Walden, UK
| | - Gordon Dougan
- Host-Pathogen Interaction Group, Wellcome Sanger Institute, Hinxton, Saffron Walden, UK
- Department of Medicine, University of Cambridge, Cambridge, Cambridgeshire, UK
- Centre for Translational Stem Cell Biology, Hong Kong, China
| | - Vijay K. Yadav
- Mouse Genetics Project, Wellcome Sanger Institute, Hinxton, Saffron Walden, UK
- National Institute of Immunology, New Delhi, New Delhi, India
- Department of Genetics and Development, Columbia University, New York, NY, USA
- Healthy Longevity Program, Department of Pathology, Immunology and Laboratory Medicine, Rutgers University, Newark, NJ, USA
- Center for Cell Signaling, Rutgers University, Newark, NJ, USA
- Center for Immunity and Inflammation, Rutgers University, Newark, NJ, USA
| |
Collapse
|
|
6
|
Abankwah JK, Wang Y, Wang J, Ogbe SE, Pozzo LD, Chu X, Bian Y. Gut aging: A wane from the normal to repercussion and gerotherapeutic strategies. Heliyon 2024; 10:e37883. [PMID: 39381110 PMCID: PMC11456882 DOI: 10.1016/j.heliyon.2024.e37883] [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: 06/01/2024] [Revised: 08/01/2024] [Accepted: 09/11/2024] [Indexed: 10/10/2024] Open
Abstract
Globally, age-related diseases represent a significant public health concern among the elderly population. In aging, healthy organs and tissues undergo structural and functional changes that put the aged adults at risk of diseases. Some of the age-related diseases include cancer, atherosclerosis, brain disorders, muscle atrophy (sarcopenia), gastrointestinal (GIT) disorders, etc. In organs, a decline in stem cell function is the starting point of many conditions and is extremely important in GIT disorder development. Many studies have established that aging affects stem cells and their surrounding supportive niche components. Although there is a significant advancement in treating intestinal aging, the rising elderly population coupled with a higher occurrence of chronic gut ailments necessitates more effective therapeutic approaches to preserve gut health. Notable therapeutic strategies such as Western medicine, traditional Chinese medicine, and other health-promotion interventions have been reported in several studies to hold promise in mitigating age-related gut disorders. This review highlights findings across various facets of gut aging with a focus on aging-associated changes of intestinal stem cells and their niche components, thus a deviation from the normal to repercussion, as well as essential therapeutic strategies to mitigate intestinal aging.
Collapse
Affiliation(s)
- Joseph K. Abankwah
- School of Integrative Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin 301617, China
| | - Ying Wang
- School of Integrative Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin 301617, China
| | - Jida Wang
- School of Integrative Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin 301617, China
| | - Susan Enechojo Ogbe
- School of Integrative Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin 301617, China
| | - Lisa Dal Pozzo
- School of Integrative Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin 301617, China
| | - XiaoQian Chu
- School of Integrative Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin 301617, China
| | - YuHong Bian
- School of Integrative Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin 301617, China
| |
Collapse
|
|
7
|
Karmele EP, Moldoveanu AL, Kaymak I, Jugder BE, Ursin RL, Bednar KJ, Corridoni D, Ort T. Single cell RNA-sequencing profiling to improve the translation between human IBD and in vivo models. Front Immunol 2023; 14:1291990. [PMID: 38179052 PMCID: PMC10766350 DOI: 10.3389/fimmu.2023.1291990] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/10/2023] [Accepted: 11/29/2023] [Indexed: 01/06/2024] Open
Abstract
Inflammatory bowel disease (IBD) is an umbrella term for two conditions (Crohn's Disease and Ulcerative Colitis) that is characterized by chronic inflammation of the gastrointestinal tract. The use of pre-clinical animal models has been invaluable for the understanding of potential disease mechanisms. However, despite promising results of numerous therapeutics in mouse colitis models, many of these therapies did not show clinical benefits in patients with IBD. Single cell RNA-sequencing (scRNA-seq) has recently revolutionized our understanding of complex interactions between the immune system, stromal cells, and epithelial cells by mapping novel cell subpopulations and their remodeling during disease. This technology has not been widely applied to pre-clinical models of IBD. ScRNA-seq profiling of murine models may provide an opportunity to increase the translatability into the clinic, and to choose the most appropriate model to test hypotheses and novel therapeutics. In this review, we have summarized some of the key findings at the single cell transcriptomic level in IBD, how specific signatures have been functionally validated in vivo, and highlighted the similarities and differences between scRNA-seq findings in human IBD and experimental mouse models. In each section of this review, we highlight the importance of utilizing this technology to find the most suitable or translational models of IBD based on the cellular therapeutic target.
Collapse
Affiliation(s)
- Erik P. Karmele
- Bioscience Immunology, Research and Early Development, Respiratory and Immunology, Biopharmaceuticals R&D, AstraZeneca, Gaithersburg, MD, United States
| | - Ana Laura Moldoveanu
- Bioscience Immunology, Research and Early Development, Respiratory and Immunology, Biopharmaceuticals R&D, AstraZeneca, Cambridge, United Kingdom
| | - Irem Kaymak
- Bioscience Immunology, Research and Early Development, Respiratory and Immunology, Biopharmaceuticals R&D, AstraZeneca, Cambridge, United Kingdom
| | - Bat-Erdene Jugder
- Bioscience Immunology, Research and Early Development, Respiratory and Immunology, Biopharmaceuticals R&D, AstraZeneca, Waltham, MA, United States
| | - Rebecca L. Ursin
- Bioscience Immunology, Research and Early Development, Respiratory and Immunology, Biopharmaceuticals R&D, AstraZeneca, Waltham, MA, United States
| | - Kyle J. Bednar
- Bioscience Immunology, Research and Early Development, Respiratory and Immunology, Biopharmaceuticals R&D, AstraZeneca, Gaithersburg, MD, United States
| | - Daniele Corridoni
- Bioscience Immunology, Research and Early Development, Respiratory and Immunology, Biopharmaceuticals R&D, AstraZeneca, Cambridge, United Kingdom
| | - Tatiana Ort
- Bioscience Immunology, Research and Early Development, Respiratory and Immunology, Biopharmaceuticals R&D, AstraZeneca, Gaithersburg, MD, United States
| |
Collapse
|
|
8
|
Kim N, Ju IG, Jeon SH, Lee Y, Jung MJ, Gee MS, Cho JS, Inn KS, Garrett-Sinha LA, Oh MS, Lee JK. Inhibition of microfold cells ameliorates early pathological phenotypes by modulating microglial functions in Alzheimer's disease mouse model. J Neuroinflammation 2023; 20:282. [PMID: 38012646 PMCID: PMC10680211 DOI: 10.1186/s12974-023-02966-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/21/2023] [Accepted: 11/21/2023] [Indexed: 11/29/2023] Open
Abstract
BACKGROUND The gut microbiota has recently attracted attention as a pathogenic factor in Alzheimer's disease (AD). Microfold (M) cells, which play a crucial role in the gut immune response against external antigens, are also exploited for the entry of pathogenic bacteria and proteins into the body. However, whether changes in M cells can affect the gut environments and consequently change brain pathologies in AD remains unknown. METHODS Five familial AD (5xFAD) and 5xFAD-derived fecal microbiota transplanted (5xFAD-FMT) naïve mice were used to investigate the changes of M cells in the AD environment. Next, to establish the effect of M cell depletion on AD environments, 5xFAD mice and Spib knockout mice were bred, and behavioral and histological analyses were performed when M cell-depleted 5xFAD mice were six or nine months of age. RESULTS In this study, we found that M cell numbers were increased in the colons of 5xFAD and 5xFAD-FMT mice compared to those of wild-type (WT) and WT-FMT mice. Moreover, the level of total bacteria infiltrating the colons increased in the AD-mimicked mice. The levels of M cell-related genes and that of infiltrating bacteria showed a significant correlation. The genetic inhibition of M cells (Spib knockout) in 5xFAD mice changed the composition of the gut microbiota, along with decreasing proinflammatory cytokine levels in the colons. M cell depletion ameliorated AD symptoms including amyloid-β accumulation, microglial dysfunction, neuroinflammation, and memory impairment. Similarly, 5xFAD-FMT did not induce AD-like pathologies, such as memory impairment and excessive neuroinflammation in Spib-/- mice. CONCLUSION Therefore, our findings provide evidence that the inhibiting M cells can prevent AD progression, with therapeutic implications.
Collapse
Affiliation(s)
- Namkwon Kim
- Department of Life and Nanopharmaceutical Sciences, Graduate School, Kyung Hee University, Seoul, Republic of Korea
- Department of Pharmacy, College of Pharmacy, Kyung Hee University, Seoul, Republic of Korea
| | - In Gyoung Ju
- Kyung Hee East-West Pharmaceutical Research Institute, Kyung Hee University, Seoul, Republic of Korea
- Department of Oriental Pharmaceutical Science, College of Pharmacy, Kyung Hee University, Seoul, Republic of Korea
| | - Seung Ho Jeon
- Department of Pharmacy, College of Pharmacy, Kyung Hee University, Seoul, Republic of Korea
| | - Yeongae Lee
- Department of Pharmacy, College of Pharmacy, Kyung Hee University, Seoul, Republic of Korea
| | - Min-Ji Jung
- Department of Pharmacy, College of Pharmacy, Kyung Hee University, Seoul, Republic of Korea
| | - Min Sung Gee
- Department of Pharmacy, College of Pharmacy, Kyung Hee University, Seoul, Republic of Korea
| | - Jae Seok Cho
- Department of Pharmacy, College of Pharmacy, Kyung Hee University, Seoul, Republic of Korea
| | - Kyung-Soo Inn
- Department of Pharmaceutical Science, College of Pharmacy, Kyung Hee University, Seoul, Republic of Korea
| | - Lee Ann Garrett-Sinha
- Department of Biochemistry, State University of New York at Buffalo, Buffalo, NY, USA
| | - Myung Sook Oh
- Department of Life and Nanopharmaceutical Sciences, Graduate School, Kyung Hee University, Seoul, Republic of Korea.
- Kyung Hee East-West Pharmaceutical Research Institute, Kyung Hee University, Seoul, Republic of Korea.
- Department of Oriental Pharmaceutical Science, College of Pharmacy, Kyung Hee University, Seoul, Republic of Korea.
| | - Jong Kil Lee
- Department of Pharmacy, College of Pharmacy, Kyung Hee University, Seoul, Republic of Korea.
- Kyung Hee East-West Pharmaceutical Research Institute, Kyung Hee University, Seoul, Republic of Korea.
| |
Collapse
|
|
9
|
He G, Wang X, Liu W, Li Y, Shao Y, Liu W, Liang X, Bao X. Chemical constituents, pharmacological effects, toxicology, processing and compatibility of Fuzi (lateral root of Aconitum carmichaelii Debx): A review. JOURNAL OF ETHNOPHARMACOLOGY 2023; 307:116160. [PMID: 36773791 DOI: 10.1016/j.jep.2023.116160] [Citation(s) in RCA: 27] [Impact Index Per Article: 13.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/09/2022] [Revised: 12/23/2022] [Accepted: 01/08/2023] [Indexed: 06/18/2023]
Abstract
ETHNOPHARMACOLOGICAL RELEVANCE The lateral root of Aconitum carmichaelii Debx is known as Fuzi in Chinese. It is traditionally valued and used for dispelling cold, relieving pain effects, restoring 'Yang,' and treating shock despite its high toxicity. This review aims to provide comprehensive information on the chemical composition, pharmacological research, preparation, and compatibility of Fuzi to help reduce its toxicity and increase its efficiency, based on the scientific literature. In addition, this review will establish a new foundation for further studies on Fuzi. MATERIALS AND METHODS A systematic review of the literature on Fuzi was performed using several resources, namely classic books on Chinese herbal medicine and various scientific databases, such as PubMed, the Web of Science, and the China Knowledge Resource Integrated databases. RESULTS Fuzi extracts contain diester-type alkaloids, monoester-type alkaloids, other types of alkaloids, and non-alkaloids types, and have various pharmacological activities, such as strong heart effect, effect on blood vessels, and antidepressant, anti-diabetes, anti-inflammatory, pain-relieving, antitumor, immunomodulatory, and other therapeutic effects. However, these extracts can also lead to various toxicities such as cardiotoxicity, neurotoxicity, reproductive toxicity, hepatotoxicity, and embryonic toxicity. In vivo and in vitro experiments have demonstrated that different processing methods and suitable compatibility with other herbs can effectively reduce the toxicities and increase the efficiency of Fuzi. CONCLUSION The therapeutic potential of Fuzi has been demonstrated in conditions, such as heart failure, various pains, inflammation, and tumors, which is attributed to the diester-type alkaloids, monoester-type alkaloids, other types of alkaloids, and non-alkaloid types. In contrast, they are also toxic components. Proper processing and suitable compatibility can effectively reduce toxicity and increase the efficiency of Fuzi. Thus more pharmacological and toxicological mechanisms on main active compounds are necessary to be explored.
Collapse
Affiliation(s)
- Guannan He
- Shandong University of Traditional Chinese Medicine, Jinan, China
| | - Xiaoxin Wang
- Shandong University of Traditional Chinese Medicine, Jinan, China
| | - Weiran Liu
- Shandong University of Traditional Chinese Medicine, Jinan, China
| | - Yuling Li
- Shandong University of Traditional Chinese Medicine, Jinan, China
| | - Yumeng Shao
- Shandong University of Traditional Chinese Medicine, Jinan, China
| | - Weidong Liu
- Shandong University of Traditional Chinese Medicine, Jinan, China
| | - Xiaodong Liang
- Shandong University of Traditional Chinese Medicine, Jinan, China.
| | - Xia Bao
- Shandong University of Traditional Chinese Medicine, Jinan, China
| |
Collapse
|
|
10
|
Tucker JS, Cho J, Albrecht TM, Ferrell JL, D’Orazio SEF. Egress of Listeria monocytogenes from Mesenteric Lymph Nodes Depends on Intracellular Replication and Cell-to-Cell Spread. Infect Immun 2023; 91:e0006423. [PMID: 36916918 PMCID: PMC10112146 DOI: 10.1128/iai.00064-23] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/15/2023] [Accepted: 02/20/2023] [Indexed: 03/15/2023] Open
Abstract
The mesenteric lymph nodes (MLN) function as a barrier to systemic spread for both commensal and pathogenic bacteria in the gut. Listeria monocytogenes, a facultative intracellular foodborne pathogen, readily overcomes this barrier and spreads into the bloodstream, causing life-threatening systemic infections. We show here that intracellular replication protected L. monocytogenes from clearance by monocytes and neutrophils and promoted colonization of the small intestine-draining MLN (sMLN) but was not required for dissemination to the colon-draining MLN (cMLN). Intestinal tissue had enough free lipoate to support LplA2-dependent extracellular growth of L. monocytogenes, but exogenous lipoate in the MLN was severely limited, and so the bacteria could replicate only inside cells, where they used LplA1 to scavenge lipoate from host peptides. When foodborne infection was manipulated to allow ΔlplA1 L. monocytogenes to colonize the MLN to the same extent as wild-type bacteria, the mutant was still never recovered in the spleen or liver of any animal. We found that intracellular replication in the MLN promoted actin-based motility and cell-to-cell spread of L. monocytogenes and that rapid efficient exit from the MLN was actA dependent. We conclude that intracellular replication of L. monocytogenes in intestinal tissues is not essential and serves primarily to amplify bacterial burdens above a critical threshold needed to efficiently colonize the cMLN. In contrast, intracellular replication in the MLN is absolutely required for further systemic spread and serves primarily to promote ActA-mediated cell-to-cell spread.
Collapse
Affiliation(s)
- Jamila S. Tucker
- Department of Microbiology, Immunology, and Molecular Genetics, University of Kentucky, Lexington, Kentucky, USA
| | - Jooyoung Cho
- Department of Microbiology, Immunology, and Molecular Genetics, University of Kentucky, Lexington, Kentucky, USA
| | - Taylor M. Albrecht
- Department of Microbiology, Immunology, and Molecular Genetics, University of Kentucky, Lexington, Kentucky, USA
| | - Jessica L. Ferrell
- Department of Microbiology, Immunology, and Molecular Genetics, University of Kentucky, Lexington, Kentucky, USA
| | - Sarah E. F. D’Orazio
- Department of Microbiology, Immunology, and Molecular Genetics, University of Kentucky, Lexington, Kentucky, USA
| |
Collapse
|
|
11
|
Hsu NY, Nayar S, Gettler K, Talware S, Giri M, Alter I, Argmann C, Sabic K, Thin TH, Ko HBM, Werner R, Tastad C, Stappenbeck T, Azabdaftari A, Uhlig HH, Chuang LS, Cho JH. NOX1 is essential for TNFα-induced intestinal epithelial ROS secretion and inhibits M cell signatures. Gut 2023; 72:654-662. [PMID: 36191961 PMCID: PMC9998338 DOI: 10.1136/gutjnl-2021-326305] [Citation(s) in RCA: 32] [Impact Index Per Article: 16.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/12/2021] [Accepted: 08/20/2022] [Indexed: 12/08/2022]
Abstract
OBJECTIVE Loss-of-function mutations in genes generating reactive oxygen species (ROS), such as NOX1, are associated with IBD. Mechanisms whereby loss of ROS drive IBD are incompletely defined. DESIGN ROS measurements and single-cell transcriptomics were performed on colonoids stratified by NOX1 genotype and TNFα stimulation. Clustering of epithelial cells from human UC (inflamed and uninflamed) scRNASeq was performed. Validation of M cell induction was performed by immunohistochemistry using UEA1 (ulex europaeus agglutin-1 lectin) and in vivo with DSS injury. RESULTS TNFα induces ROS production more in NOX1-WT versus NOX1-deficient murine colonoids under a range of Wnt-mediated and Notch-mediated conditions. scRNASeq from inflamed and uninflamed human colitis versus TNFα stimulated, in vitro colonoids defines substantially shared, induced transcription factors; NOX1-deficient colonoids express substantially lower levels of STAT3 (signal transducer and activator of transcription 3), CEBPD (CCAAT enhancer-binding protein delta), DNMT1 (DNA methyltransferase) and HIF1A (hypoxia-inducible factor) baseline. Subclustering unexpectedly showed marked TNFα-mediated induction of M cells (sentinel cells overlying lymphoid aggregates) in NOX1-deficient colonoids. M cell induction by UEA1 staining is rescued with H2O2 and paraquat, defining extra- and intracellular ROS roles in maintenance of LGR5+ stem cells. DSS injury demonstrated GP2 (glycoprotein-2), basal lymphoplasmacytosis and UEA1 induction in NOX1-deficiency. Principal components analyses of M cell genes and decreased DNMT1 RNA velocity correlate with UC inflammation. CONCLUSIONS NOX1 deficiency plus TNFα stimulation contribute to colitis through dysregulation of the stem cell niche and altered cell differentiation, enhancing basal lymphoplasmacytosis. Our findings prioritise ROS modulation for future therapies.
Collapse
Affiliation(s)
- Nai-Yun Hsu
- Department of Pathology, Molecular and Cell Based Medicine, Icahn School of Medicine at Mount Sinai, New York, New York, USA
| | - Shikha Nayar
- The Charles Bronfman Institute for Personalized Medicine, Icahn School of Medicine at Mount Sinai, New York, New York, USA
| | - Kyle Gettler
- Department of Pathology, Molecular and Cell Based Medicine, Icahn School of Medicine at Mount Sinai, New York, New York, USA
| | - Sayali Talware
- Division of Gastroenterology, Icahn School of Medicine at Mount Sinai Department of Medicine, New York, New York, USA
- The Icahn Genomic Institute, Icahn School of Medicine at Mount Sinai, New York, New York, USA
| | - Mamta Giri
- The Charles Bronfman Institute for Personalized Medicine, Icahn School of Medicine at Mount Sinai, New York, New York, USA
| | - Isaac Alter
- The Charles Bronfman Institute for Personalized Medicine, Icahn School of Medicine at Mount Sinai, New York, New York, USA
| | - Carmen Argmann
- Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, New York, USA
| | - Ksenija Sabic
- Department of Pathology, Molecular and Cell Based Medicine, Icahn School of Medicine at Mount Sinai, New York, New York, USA
| | - Tin Htwe Thin
- Department of Pathology, Molecular and Cell Based Medicine, Icahn School of Medicine at Mount Sinai, New York, New York, USA
| | - Huai-Bin Mabel Ko
- Department of Pathology and Cell Biology, Columbia University Medical Center, New York, New York, USA
| | - Robert Werner
- Department of Pathology, Molecular and Cell Based Medicine, Icahn School of Medicine at Mount Sinai, New York, New York, USA
| | - Christopher Tastad
- Department of Pathology, Molecular and Cell Based Medicine, Icahn School of Medicine at Mount Sinai, New York, New York, USA
| | - Thaddeus Stappenbeck
- Department of Inflammation and Immunity, Lerner Research Institute, Cleveland, Ohio, USA
| | - Aline Azabdaftari
- Translational Gastroenterology Unit, University of Oxford, Oxford, UK
| | - Holm H Uhlig
- Translational Gastroenterology Unit, University of Oxford, Oxford, UK
| | - Ling-Shiang Chuang
- Department of Pathology, Molecular and Cell Based Medicine, Icahn School of Medicine at Mount Sinai, New York, New York, USA
- The Charles Bronfman Institute for Personalized Medicine, Icahn School of Medicine at Mount Sinai, New York, New York, USA
| | - Judy H Cho
- Department of Pathology, Molecular and Cell Based Medicine, Icahn School of Medicine at Mount Sinai, New York, New York, USA
- The Charles Bronfman Institute for Personalized Medicine, Icahn School of Medicine at Mount Sinai, New York, New York, USA
| |
Collapse
|
|
12
|
Maddipatla SC, Kolachala VL, Venkateswaran S, Dodd AF, Pelia RS, Geem D, Yin H, Sun Y, Xu C, Mo A, Kosters A, Yang J, Matthews JD, Ghosn E, Kugathasan S, Qiu P. Assessing Cellular and Transcriptional Diversity of Ileal Mucosa Among Treatment-Naïve and Treated Crohn's Disease. Inflamm Bowel Dis 2023; 29:274-285. [PMID: 36206201 PMCID: PMC9890215 DOI: 10.1093/ibd/izac201] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/11/2022] [Indexed: 02/04/2023]
Abstract
BACKGROUND Crohn's disease is a lifelong disease characterized by chronic inflammation of the gastrointestinal tract. Defining the cellular and transcriptional composition of the mucosa at different stages of disease progression is needed for personalized therapy in Crohn's. METHODS Ileal biopsies were obtained from (1) control subjects (n = 6), (2) treatment-naïve patients (n = 7), and (3) established (n = 14) Crohn's patients along with remission (n = 3) and refractory (n = 11) treatment groups. The biopsies processed using 10x Genomics single cell 5' yielded 139 906 cells. Gene expression count matrices of all samples were analyzed by reciprocal principal component integration, followed by clustering analysis. Manual annotations of the clusters were performed using canonical gene markers. Cell type proportions, differential expression analysis, and gene ontology enrichment were carried out for each cell type. RESULTS We identified 3 cellular compartments with 9 epithelial, 1 stromal, and 5 immune cell subtypes. We observed differences in the cellular composition between control, treatment-naïve, and established groups, with the significant changes in the epithelial subtypes of the treatment-naïve patients, including microfold, tuft, goblet, enterocyte,s and BEST4+ cells. Surprisingly, fewer changes in the composition of the immune compartment were observed; however, gene expression in the epithelial and immune compartment was different between Crohn's phenotypes, indicating changes in cellular activity. CONCLUSIONS Our study identified cellular and transcriptional signatures associated with treatment-naïve Crohn's disease that collectively point to dysfunction of the intestinal barrier with an increase in inflammatory cellular activity. Our analysis also highlights the heterogeneity among patients within the same disease phenotype, shining a new light on personalized treatment responses and strategies.
Collapse
Affiliation(s)
- Sushma Chowdary Maddipatla
- Division of Pediatric Gastroenterology, Department of Pediatrics and Pediatric Research Institute, Children’s Healthcare of Atlanta, Emory University School of Medicine, Atlanta, GA, USA
| | - Vasantha L Kolachala
- Division of Pediatric Gastroenterology, Department of Pediatrics and Pediatric Research Institute, Children’s Healthcare of Atlanta, Emory University School of Medicine, Atlanta, GA, USA
| | - Suresh Venkateswaran
- Division of Pediatric Gastroenterology, Department of Pediatrics and Pediatric Research Institute, Children’s Healthcare of Atlanta, Emory University School of Medicine, Atlanta, GA, USA
| | - Anne F Dodd
- Division of Pediatric Gastroenterology, Department of Pediatrics and Pediatric Research Institute, Children’s Healthcare of Atlanta, Emory University School of Medicine, Atlanta, GA, USA
| | - Ranjit Singh Pelia
- Division of Pediatric Gastroenterology, Department of Pediatrics and Pediatric Research Institute, Children’s Healthcare of Atlanta, Emory University School of Medicine, Atlanta, GA, USA
| | - Duke Geem
- Division of Pediatric Gastroenterology, Department of Pediatrics and Pediatric Research Institute, Children’s Healthcare of Atlanta, Emory University School of Medicine, Atlanta, GA, USA
| | - Hong Yin
- Department of Pathology, Children’s Healthcare of Atlanta, Emory University, Atlanta, GA, USA
| | - Yutong Sun
- School of Electrical and Computer Engineering, Georgia Institute of Technology, Atlanta, GA, USA
| | - Congmin Xu
- Department of Biomedical Engineering, Georgia Institute of Technology and Emory University, Atlanta, GA, USA
| | - Angela Mo
- School of Biological Sciences, Georgia Institute of Technology, Atlanta, GA, USA
| | - Astrid Kosters
- Lowance Center for Human Immunology, Division of Immunology and Rheumatology, Department of Medicine, Emory University School of Medicine, Atlanta, GA, USA
| | - Junkai Yang
- Lowance Center for Human Immunology, Division of Immunology and Rheumatology, Department of Medicine, Emory University School of Medicine, Atlanta, GA, USA
| | - Jason D Matthews
- Division of Pediatric Gastroenterology, Department of Pediatrics and Pediatric Research Institute, Children’s Healthcare of Atlanta, Emory University School of Medicine, Atlanta, GA, USA
| | - Eliver Ghosn
- Emory Vaccine Center, Lowance Center for Human Immunology, Departments of Medicine and Pediatrics, Emory University School of Medicine, Atlanta, GA, USA
| | - Subra Kugathasan
- Division of Pediatric Gastroenterology, Department of Pediatrics and Pediatric Research Institute, Children’s Healthcare of Atlanta, Emory University School of Medicine, Atlanta, GA, USA
- Genetics and Molecular Biology Program, Emory University School of Medicine, Atlanta, GA, USAand
- Department of Human Genetics, Emory University, Atlanta, GA, USA
| | - Peng Qiu
- Department of Biomedical Engineering, Georgia Institute of Technology and Emory University, Atlanta, GA, USA
| |
Collapse
|
|
13
|
Grasset EK, Alenghat T. Good intentions gone wrong: The B cell block to epithelial repair. Immunity 2022; 55:2222-2224. [PMID: 36516815 PMCID: PMC11008460 DOI: 10.1016/j.immuni.2022.11.011] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
Cellular dynamics that influence mucosal healing are not well understood. In this issue of Immunity, Frede, Czarnewski, Monasterio et al. find that B cells accumulate in the colon following intestinal injury. These B cells impair epithelial repair by hindering local stromal-epithelial interactions.
Collapse
Affiliation(s)
- Emilie K Grasset
- Department of Medicine, Division of Clinical Immunology, Icahn School of Medicine at Mount Sinai, New York, NY, USA; Drukier Institute for Children's Health and Department of Pediatrics, Division of Gastroenterology, Hepatology, and Nutrition, Weill Cornell Medicine, Cornell University, New York, NY, USA
| | - Theresa Alenghat
- Division of Immunobiology and Center for Inflammation and Tolerance, Cincinnati Children's Hospital Medical Center and the University of Cincinnati College of Medicine, Cincinnati, OH, USA.
| |
Collapse
|
|
14
|
Wang B, Shen J. NF-κB Inducing Kinase Regulates Intestinal Immunity and Homeostasis. Front Immunol 2022; 13:895636. [PMID: 35833111 PMCID: PMC9271571 DOI: 10.3389/fimmu.2022.895636] [Citation(s) in RCA: 22] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/14/2022] [Accepted: 05/31/2022] [Indexed: 11/22/2022] Open
Abstract
Intestinal immunity and homeostasis are maintained through the regulation of cytokine trafficking, microbiota, necrosis and apoptosis. Intestinal immunity and homeostasis participate in host defenses and inflammatory responses locally or systemically through the gut-organ axis. NF-κB functions as a crucial transcription factor mediating the expression of proteins related to the immune responses. The activation of NF-κB involves two major pathways: canonical and non-canonical. The canonical pathway has been extensively studied and reviewed. Here, we present the current knowledge of NIK, a pivotal mediator of the non-canonical NF-κB pathway and its role in intestinal immunity and homeostasis. This review also discusses the novel role of NIK signaling in the pathogenesis and treatment of inflammatory bowel disease.
Collapse
Affiliation(s)
- Bingran Wang
- Division of Gastroenterology and Hepatology, Key Laboratory of Gastroenterology and Hepatology, Ministry of Health, Inflammatory Bowel Disease Research Center, Renji Hospital, School of Medicine, Shanghai Institute of Digestive Disease, Shanghai Jiao Tong University, Shanghai, China
- Ottawa-Shanghai Joint School of Medicine, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Jun Shen
- Division of Gastroenterology and Hepatology, Key Laboratory of Gastroenterology and Hepatology, Ministry of Health, Inflammatory Bowel Disease Research Center, Renji Hospital, School of Medicine, Shanghai Institute of Digestive Disease, Shanghai Jiao Tong University, Shanghai, China
- Ottawa-Shanghai Joint School of Medicine, Shanghai Jiao Tong University School of Medicine, Shanghai, China
- *Correspondence: Jun Shen,
| |
Collapse
|
|
15
|
Serigado JM, Foulke-Abel J, Hines WC, Hanson JA, In J, Kovbasnjuk O. Ulcerative Colitis: Novel Epithelial Insights Provided by Single Cell RNA Sequencing. Front Med (Lausanne) 2022; 9:868508. [PMID: 35530046 PMCID: PMC9068527 DOI: 10.3389/fmed.2022.868508] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/02/2022] [Accepted: 03/14/2022] [Indexed: 12/22/2022] Open
Abstract
Ulcerative Colitis (UC) is a chronic inflammatory disease of the intestinal tract for which a definitive etiology is yet unknown. Both genetic and environmental factors have been implicated in the development of UC. Recently, single cell RNA sequencing (scRNA-seq) technology revealed cell subpopulations contributing to the pathogenesis of UC and brought new insight into the pathways that connect genome to pathology. This review describes key scRNA-seq findings in two major studies by Broad Institute and University of Oxford, investigating the transcriptomic landscape of epithelial cells in UC. We focus on five major findings: (1) the identification of BEST4 + cells, (2) colonic microfold (M) cells, (3) detailed comparison of the transcriptomes of goblet cells, and (4) colonocytes and (5) stem cells in health and disease. In analyzing the two studies, we identify the commonalities and differences in methodologies, results, and conclusions, offering possible explanations, and validated several cell cluster markers. In systematizing the results, we hope to offer a framework that the broad scientific GI community and GI clinicians can use to replicate or corroborate the extensive new findings that RNA-seq offers.
Collapse
Affiliation(s)
- Joao M. Serigado
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, University of New Mexico Health Sciences Center, Albuquerque, NM, United States
| | - Jennifer Foulke-Abel
- Division of Gastroenterology and Hepatology, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, United States
| | - William C. Hines
- Department of Biochemistry and Molecular Biology, University of New Mexico Health Sciences Center, Albuquerque, NM, United States
| | - Joshua A Hanson
- Department of Pathology, University of New Mexico Health Sciences Center, Albuquerque, NM, United States
| | - Julie In
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, University of New Mexico Health Sciences Center, Albuquerque, NM, United States
- Division of Gastroenterology and Hepatology, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, United States
| | - Olga Kovbasnjuk
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, University of New Mexico Health Sciences Center, Albuquerque, NM, United States
- Department of Microbiology and Immunology, University of Maryland School of Medicine, Baltimore, MD, United States
- *Correspondence: Olga Kovbasnjuk,
| |
Collapse
|
|
16
|
Guo Y, Xu Y, Lin X, Zhen Z, Yi F, Guan H, Shi Q, Sun W, Yang A, Dong X, Wang J. Creutzfeldt-Jakob Disease: Alterations of Gut Microbiota. Front Neurol 2022; 13:832599. [PMID: 35493823 PMCID: PMC9051076 DOI: 10.3389/fneur.2022.832599] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/10/2021] [Accepted: 02/18/2022] [Indexed: 12/03/2022] Open
Abstract
Introduction Human gut dysbiosis has been implicated with the onset of many neurodegenerative disorders. However, the current data focused on the gut microbiota of patients with Creutzfeldt-Jakob disease (CJD) are still lacking. In our study, we explored the gut microbiota alteration in patients with CJD. Method We performed 16S ribosomal RNA MiSeq sequencing in stool samples of patients with CJD and controls. Functional analysis of the gut microbiota between these two groups was based on Kyoto Encyclopedia of Genes and Genomes and Phylogenetic Investigation of Communities by Reconstruction of Unobserved States 2. Clinical rating scales were used to evaluate the association between cognitive impairment and gut microbiota alteration. Result We identified a significant alteration in both the structure and the richness of the CJD group. Function analysis revealed that the gut microbiota of patients with CJD enriched in immune signaling molecule interactions and xenobiotics biodegradation. MoCA and survival times were found to be associated with gut microbiota in patients with CJD. Conclusion We demonstrated an altered gut microbiota in patients with CJD, which was associated with the cognitive impairment and the survival time of these patients.
Collapse
Affiliation(s)
- Yanjun Guo
- Department of Neurology, Beijing Tongren Hospital, Capital Medical University, Beijing, China
| | - Yichen Xu
- Department of Neurosurgery, Beijing Tiantan Hospital, Capital Medical University, Beijing, China
| | - Xue Lin
- Department of Neurology, Beijing Tongren Hospital, Capital Medical University, Beijing, China
| | - Zhen Zhen
- Department of Neurology, Beijing Tongren Hospital, Capital Medical University, Beijing, China
| | - Fang Yi
- Department of Neurology, Lishilu Outpatient, Central Medical Branch of PLA General Hospital, Beijing, China
| | - Hongzhi Guan
- Department of Neurology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, Beijing, China
| | - Qi Shi
- State Key Laboratory for Infectious Disease Prevention and Control, National Institute for Viral Disease Control and Prevention, Chinese Center for Disease Control and Prevention, Beijing, China
| | - Wenjie Sun
- Department of Hematology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, Beijing, China
| | - Anchao Yang
- Department of Neurosurgery, Beijing Tiantan Hospital, Capital Medical University, Beijing, China
| | - Xiaoping Dong
- State Key Laboratory for Infectious Disease Prevention and Control, National Institute for Viral Disease Control and Prevention, Chinese Center for Disease Control and Prevention, Beijing, China
| | - Jiawei Wang
- Department of Neurology, Beijing Tongren Hospital, Capital Medical University, Beijing, China
| |
Collapse
|
|
17
|
Li Y, Yang S, Huang X, Yang N, Wang C, Zhao J, Jing Z, Willems L, Liu G. MyD88 Mediates Colitis- and RANKL-Induced Microfold Cell Differentiation. Vet Sci 2021; 9:vetsci9010006. [PMID: 35051090 PMCID: PMC8779303 DOI: 10.3390/vetsci9010006] [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: 11/09/2021] [Revised: 12/18/2021] [Accepted: 12/20/2021] [Indexed: 11/16/2022] Open
Abstract
Intestinal microfold (M) cells are critical for sampling antigens in the gut and initiating the intestinal mucosal immune response. In this study, we found that the oral administration of dextran sulfate sodium (DSS) and Salmonella infection induced colitis. In the process, the expression levels of M cell differentiation-related genes were synchronized with the kinetics of pro-inflammatory cytokines. Compared to wild-type (WT) mice, MyD88-/- mice exhibited significantly lower expression levels of M cell differentiation-related genes. However, DSS induced colitis in MyD88-/- mice but failed to promote the transcription of M cell differentiation related genes. Furthermore, the receptor activator of the Nuclear Factor-κB ligand (RANKL) upregulated the transcription of M cell differentiation related genes in murine intestinal organoids prepared from both WT and MyD88-/- mice. Meanwhile, fewer changes in M cell differentiation related genes were found in MyD88-/- mice as compared to WT mice. Hence, we concluded that myeloid differentiation factor 88 (MyD88) is an essential molecule for colitis- and RANKL-related differentiation of M cells.
Collapse
Affiliation(s)
- Yang Li
- State Key Laboratory of Veterinary Etiological Biology, Lanzhou Veterinary Research Institute, Chinese Academy of Agricultural Science, Lanzhou 730046, China; (Y.L.); (S.Y.); (X.H.); (N.Y.); (C.W.); (J.Z.); (Z.J.)
- Molecular and Cellular Epigenetics (GIGA), University of Liege, 4000 Liege, Belgium;
| | - Shanshan Yang
- State Key Laboratory of Veterinary Etiological Biology, Lanzhou Veterinary Research Institute, Chinese Academy of Agricultural Science, Lanzhou 730046, China; (Y.L.); (S.Y.); (X.H.); (N.Y.); (C.W.); (J.Z.); (Z.J.)
- Cell Biology and Immunology Group, Wageningen University and Research, P.O. Box 9101, 6700 HB Wageningen, The Netherlands
| | - Xin Huang
- State Key Laboratory of Veterinary Etiological Biology, Lanzhou Veterinary Research Institute, Chinese Academy of Agricultural Science, Lanzhou 730046, China; (Y.L.); (S.Y.); (X.H.); (N.Y.); (C.W.); (J.Z.); (Z.J.)
| | - Ning Yang
- State Key Laboratory of Veterinary Etiological Biology, Lanzhou Veterinary Research Institute, Chinese Academy of Agricultural Science, Lanzhou 730046, China; (Y.L.); (S.Y.); (X.H.); (N.Y.); (C.W.); (J.Z.); (Z.J.)
- Molecular and Cellular Epigenetics (GIGA), University of Liege, 4000 Liege, Belgium;
| | - Caiying Wang
- State Key Laboratory of Veterinary Etiological Biology, Lanzhou Veterinary Research Institute, Chinese Academy of Agricultural Science, Lanzhou 730046, China; (Y.L.); (S.Y.); (X.H.); (N.Y.); (C.W.); (J.Z.); (Z.J.)
- Cell Biology and Immunology Group, Wageningen University and Research, P.O. Box 9101, 6700 HB Wageningen, The Netherlands
| | - Jing Zhao
- State Key Laboratory of Veterinary Etiological Biology, Lanzhou Veterinary Research Institute, Chinese Academy of Agricultural Science, Lanzhou 730046, China; (Y.L.); (S.Y.); (X.H.); (N.Y.); (C.W.); (J.Z.); (Z.J.)
| | - Zhizhong Jing
- State Key Laboratory of Veterinary Etiological Biology, Lanzhou Veterinary Research Institute, Chinese Academy of Agricultural Science, Lanzhou 730046, China; (Y.L.); (S.Y.); (X.H.); (N.Y.); (C.W.); (J.Z.); (Z.J.)
| | - Luc Willems
- Molecular and Cellular Epigenetics (GIGA), University of Liege, 4000 Liege, Belgium;
| | - Guangliang Liu
- State Key Laboratory of Veterinary Etiological Biology, Lanzhou Veterinary Research Institute, Chinese Academy of Agricultural Science, Lanzhou 730046, China; (Y.L.); (S.Y.); (X.H.); (N.Y.); (C.W.); (J.Z.); (Z.J.)
- Correspondence: ; Tel.: +86-(931)834-2682; Fax: +86-(931)834-0977
| |
Collapse
|
|
18
|
Chevalier G, Laveissière A, Desachy G, Barnich N, Sivignon A, Maresca M, Nicoletti C, Di Pasquale E, Martinez-Medina M, Simpson KW, Yajnik V, Sokol H, Plassais J, Strozzi F, Cervino A, Morra R, Bonny C. Blockage of bacterial FimH prevents mucosal inflammation associated with Crohn's disease. MICROBIOME 2021; 9:176. [PMID: 34425887 PMCID: PMC8383459 DOI: 10.1186/s40168-021-01135-5] [Citation(s) in RCA: 32] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/27/2021] [Accepted: 07/01/2021] [Indexed: 05/14/2023]
Abstract
BACKGROUND An Escherichia coli (E. coli) pathotype with invasive properties, first reported by Darfeuille-Michaud and termed adherent-invasive E. coli (AIEC), was shown to be prevalent in up to half the individuals with Crohn's Disease (CD), suggesting that these bacteria could be involved in the pathophysiology of CD. Among the genes related to AIEC pathogenicity, fim has the potential to generate an inflammatory reaction from the intestinal epithelial cells and macrophages, as it interacts with TLR4, inducing the production of inflammatory cytokines independently of LPS. Therefore, targeting the bacterial adhesion of FimH-expressing bacteria seems a promising therapeutic approach, consisting of disarming bacteria without killing them, representing a selective strategy to suppress a potentially critical trigger of intestinal inflammation, without disturbing the intestinal microbiota. RESULTS We analyzed the metagenomic composition of the gut microbiome of 358 patients with CD from two different cohorts and characterized the presence of FimH-expressing bacteria. To assess the pathogenic role of FimH, we used human intestinal explants and tested a specific FimH blocker to prevent bacterial adhesion and associated inflammation. We observed a significant and disease activity-dependent enrichment of Enterobacteriaceae in the gut microbiome of patients with CD. Bacterial FimH expression was functionally confirmed in ileal biopsies from 65% of the patients with CD. Using human intestinal explants, we further show that FimH is essential for adhesion and to trigger inflammation. Finally, a specific FimH-blocker, TAK-018, inhibits bacterial adhesion to the intestinal epithelium and prevents inflammation, thus preserving mucosal integrity. CONCLUSIONS We propose that TAK-018, which is safe and well tolerated in humans, is a promising candidate for the treatment of CD and in particular in preventing its recurrence. Video abstract.
Collapse
Affiliation(s)
| | | | | | - Nicolas Barnich
- Université Clermont Auvergne, Inserm U1071, M2iSH, USC-INRA 2018, F-63000, Clermont-Ferrand, France
| | - Adeline Sivignon
- Université Clermont Auvergne, Inserm U1071, M2iSH, USC-INRA 2018, F-63000, Clermont-Ferrand, France
| | - Marc Maresca
- Aix Marseille Université, CNRS, Centrale Marseille, iSm2, Marseille, France
| | - Cendrine Nicoletti
- Aix Marseille Université, CNRS, Centrale Marseille, iSm2, Marseille, France
| | - Eric Di Pasquale
- Aix-Marseille Université, CNRS, INP, Institut de Neurophysiopathologie, Marseille, France
| | | | | | - Vijay Yajnik
- GI Therapeutic Area Unit, Takeda Pharmaceuticals, Cambridge, MA, 02139, USA
| | - Harry Sokol
- Gastroenterology Department, Sorbonne Université, INSERM, Centre de Recherche Saint-Antoine, CRSA, AP-HP, Saint Antoine Hospital, 75012, Paris, France
- INRA, UMR1319 Micalis & AgroParisTech, Jouy en Josas, France
- Paris Center for Microbiome Medicine (PaCeMM) FHU, AP-HP, Paris, France
| | | | | | | | - Rachel Morra
- Enterome, 94-96 Avenue Ledru-Rollin, 75011, Paris, France
| | | |
Collapse
|
|
19
|
Chikina A, Matic Vignjevic D. At the right time in the right place: How do luminal gradients position the microbiota along the gut? Cells Dev 2021; 168:203712. [PMID: 34174490 DOI: 10.1016/j.cdev.2021.203712] [Citation(s) in RCA: 25] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/18/2021] [Revised: 06/16/2021] [Accepted: 06/21/2021] [Indexed: 01/02/2023]
Abstract
The gastrointestinal system is highly compartmentalized, where individual segments perform separate tasks to achieve common physiological goals. The gut luminal content, chyme, changes its chemical and physical properties as it passes through different intestinal segments. Together, the chyme composition, mucus, pH and oxygen gradients along the gut create a variety of highly distinct ecological niches that form, maintain and reinforce the symbiosis with the particular microbiota. Hosting different microbiota members at specific locations creates one of the most complex and sophisticated gradient - gradient of the local ecosystems that live and interact with each other, providing advantages and challenges to the host and creating our microbial self. Here, we discuss how intestinal luminal gradients are created and maintained in homeostasis, their role in a correct microbiota positioning, and their change upon inflammation and cancer.
Collapse
Affiliation(s)
- Aleksandra Chikina
- Institut Curie, PSL Research University, CNRS UMR 144, F-75005 Paris, France.
| | | |
Collapse
|
|
20
|
Alterations in gut microbiota linked to provenance, sex, and chronic wasting disease in white-tailed deer (Odocoileus virginianus). Sci Rep 2021; 11:13218. [PMID: 34168170 PMCID: PMC8225879 DOI: 10.1038/s41598-021-89896-9] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/11/2021] [Accepted: 05/04/2021] [Indexed: 01/04/2023] Open
Abstract
Chronic wasting disease (CWD) is a fatal, contagious, neurodegenerative prion disease affecting both free-ranging and captive cervid species. CWD is spread via direct or indirect contact or oral ingestion of prions. In the gastrointestinal tract, prions enter the body through microfold cells (M-cells), and the abundance of these cells can be influenced by the gut microbiota. To explore potential links between the gut microbiota and CWD, we collected fecal samples from farmed and free-ranging white-tailed deer (Odocoileus virginianus) around the Midwest, USA. Farmed deer originated from farms that were depopulated due to CWD. Free-ranging deer were sampled during annual deer harvests. All farmed deer were tested for CWD via ELISA and IHC, and we used 16S rRNA gene sequencing to characterize the gut microbiota. We report significant differences in gut microbiota by provenance (Farm 1, Farm 2, Free-ranging), sex, and CWD status. CWD-positive deer from Farm 1 and 2 had increased abundances of Akkermansia, Lachnospireacea UCG-010, and RF39 taxa. Overall, differences by provenance and sex appear to be driven by diet, while differences by CWD status may be linked to CWD pathogenesis.
Collapse
|
|
21
|
Li QX, Guo YX, Hua RX, Shang HW, Li LS, Xu JD. New insight into function and dysfunction of gut microfold cells. Shijie Huaren Xiaohua Zazhi 2021; 29:197-203. [DOI: 10.11569/wcjd.v29.i4.197] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
Microfold cells (M cells), derived from intestinal crypt Lgr5+ stem cells, are distributed in gut-associated lymphoid tissue (GALT), nasopharyngeal-associated lymphoid tissue (NALT), and bronchial-associated lymphoid tissue (BALT). The basement membrane of mature M cells protrudes upward, showing a "pocket-like" shape. M cell differentiation is mainly regulated by two pathways, one is the non-canonical NF-κB pathway, and the other is the canonical NF-κB pathway. The differentiation and maturation of M cells are closely related to RANKL and S100A4. M cells can not only transport antigens and trigger an immune response, but also are the gateway for various pathogens to invade the body. The occurrence and development of tuberculosis, prion disease, and Crohn's disease are closely related to M cells.
Collapse
Affiliation(s)
- Qiu-Xuan Li
- Clinical Medicine of "5+3" Program, Capital Medical University, Beijing 100069, China
| | - Yue-Xin Guo
- Clinical Medicine of "5+3" Program, Capital Medical University, Beijing 100069, China
| | - Rong-Xuan Hua
- Clinical Medicine of "5+3" Program, Capital Medical University, Beijing 100069, China
| | - Hong-Wei Shang
- Morphological Experiment Center, School of Basic Medical Sciences, Capital Medical University, Beijing 100069, China
| | - Li-Sheng Li
- Functional Experiment Center, School of Basic Medical Sciences, Capital Medical University, Beijing 100069, China
| | - Jing-Dong Xu
- Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Capital Medical University, Beijing 100069, China
| |
Collapse
|
|
22
|
Rochereau N, Roblin X, Michaud E, Gayet R, Chanut B, Jospin F, Corthésy B, Paul S. NOD2 deficiency increases retrograde transport of secretory IgA complexes in Crohn's disease. Nat Commun 2021; 12:261. [PMID: 33431850 PMCID: PMC7801705 DOI: 10.1038/s41467-020-20348-0] [Citation(s) in RCA: 35] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/20/2019] [Accepted: 10/23/2020] [Indexed: 02/07/2023] Open
Abstract
Intestinal microfold cells are the primary pathway for translocation of secretory IgA (SIgA)-pathogen complexes to gut-associated lymphoid tissue. Uptake of SIgA/commensals complexes is important for priming adaptive immunity in the mucosa. This study aims to explore the effect of SIgA retrograde transport of immune complexes in Crohn's disease (CD). Here we report a significant increase of SIgA transport in CD patients with NOD2-mutation compared to CD patients without NOD2 mutation and/or healthy individuals. NOD2 has an effect in the IgA transport through human and mouse M cells by downregulating Dectin-1 and Siglec-5 expression, two receptors involved in retrograde transport. These findings define a mechanism of NOD2-mediated regulation of mucosal responses to intestinal microbiota, which is involved in CD intestinal inflammation and dysbiosis.
Collapse
Affiliation(s)
- Nicolas Rochereau
- GIMAP/EA3064, Université de Lyon, CIC 1408 Vaccinology, F42023, Saint-Etienne, France.
| | - Xavier Roblin
- GIMAP/EA3064, Université de Lyon, CIC 1408 Vaccinology, F42023, Saint-Etienne, France
| | - Eva Michaud
- GIMAP/EA3064, Université de Lyon, CIC 1408 Vaccinology, F42023, Saint-Etienne, France
| | - Rémi Gayet
- GIMAP/EA3064, Université de Lyon, CIC 1408 Vaccinology, F42023, Saint-Etienne, France
| | - Blandine Chanut
- GIMAP/EA3064, Université de Lyon, CIC 1408 Vaccinology, F42023, Saint-Etienne, France
| | - Fabienne Jospin
- GIMAP/EA3064, Université de Lyon, CIC 1408 Vaccinology, F42023, Saint-Etienne, France
| | - Blaise Corthésy
- R&D Laboratory of the Division of Immunology and Allergy, CHUV, Centre des Laboratoires d'Epalinges, 1066, Epalinges, Switzerland
| | - Stéphane Paul
- GIMAP/EA3064, Université de Lyon, CIC 1408 Vaccinology, F42023, Saint-Etienne, France
| |
Collapse
|
|
23
|
Mabbott NA, Bradford BM, Pal R, Young R, Donaldson DS. The Effects of Immune System Modulation on Prion Disease Susceptibility and Pathogenesis. Int J Mol Sci 2020; 21:E7299. [PMID: 33023255 PMCID: PMC7582561 DOI: 10.3390/ijms21197299] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/09/2020] [Revised: 09/25/2020] [Accepted: 09/29/2020] [Indexed: 12/17/2022] Open
Abstract
Prion diseases are a unique group of infectious chronic neurodegenerative disorders to which there are no cures. Although prion infections do not stimulate adaptive immune responses in infected individuals, the actions of certain immune cell populations can have a significant impact on disease pathogenesis. After infection, the targeting of peripherally-acquired prions to specific immune cells in the secondary lymphoid organs (SLO), such as the lymph nodes and spleen, is essential for the efficient transmission of disease to the brain. Once the prions reach the brain, interactions with other immune cell populations can provide either host protection or accelerate the neurodegeneration. In this review, we provide a detailed account of how factors such as inflammation, ageing and pathogen co-infection can affect prion disease pathogenesis and susceptibility. For example, we discuss how changes to the abundance, function and activation status of specific immune cell populations can affect the transmission of prion diseases by peripheral routes. We also describe how the effects of systemic inflammation on certain glial cell subsets in the brains of infected individuals can accelerate the neurodegeneration. A detailed understanding of the factors that affect prion disease transmission and pathogenesis is essential for the development of novel intervention strategies.
Collapse
Affiliation(s)
- Neil A. Mabbott
- The Roslin Institute & Royal (Dick) School of Veterinary Studies, University of Edinburgh, Easter Bush, Midlothian EH25 9RG, UK; (B.M.B.); (R.P.); (R.Y.); (D.S.D.)
| | | | | | | | | |
Collapse
|
|
24
|
Ding S, Song Y, Brulois KF, Pan J, Co JY, Ren L, Feng N, Yasukawa LL, Sánchez-Tacuba L, Wosen JE, Mellins ED, Monack DM, Amieva MR, Kuo CJ, Butcher EC, Greenberg HB. Retinoic Acid and Lymphotoxin Signaling Promote Differentiation of Human Intestinal M Cells. Gastroenterology 2020; 159:214-226.e1. [PMID: 32247021 PMCID: PMC7569531 DOI: 10.1053/j.gastro.2020.03.053] [Citation(s) in RCA: 31] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/17/2019] [Revised: 03/12/2020] [Accepted: 03/20/2020] [Indexed: 01/11/2023]
Abstract
BACKGROUND & AIMS Intestinal microfold (M) cells are a unique subset of intestinal epithelial cells in the Peyer's patches that regulate mucosal immunity, serving as portals for sampling and uptake of luminal antigens. The inability to efficiently develop human M cells in cell culture has impeded studies of the intestinal immune system. We aimed to identify signaling pathways required for differentiation of human M cells and establish a robust culture system using human ileum enteroids. METHODS We analyzed transcriptome data from mouse Peyer's patches to identify cell populations in close proximity to M cells. We used the human enteroid system to determine which cytokines were required to induce M-cell differentiation. We performed transcriptome, immunofluorescence, scanning electron microscope, and transcytosis experiments to validate the development of phenotypic and functional human M cells. RESULTS A combination of retinoic acid and lymphotoxin induced differentiation of glycoprotein 2-positive human M cells, which lack apical microvilli structure. Upregulated expression of innate immune-related genes within M cells correlated with a lack of viral antigens after rotavirus infection. Human M cells, developed in the enteroid system, internalized and transported enteric viruses, such as rotavirus and reovirus, across the intestinal epithelium barrier in the enteroids. CONCLUSIONS We identified signaling pathways required for differentiation of intestinal M cells, and used this information to create a robust culture method to develop human M cells with capacity for internalization and transport of viruses. Studies of this model might increase our understanding of antigen presentation and the systemic entry of enteric pathogens in the human intestine.
Collapse
Affiliation(s)
- Siyuan Ding
- Department of Molecular Microbiology, Washington University School of Medicine, St Louis, Missouri.
| | - Yanhua Song
- Palo Alto Veterans Institute of Research, VA Palo Alto Health Care System, Palo Alto, CA 94304, USA,Department of Medicine, Division of Gastroenterology and Hepatology, Stanford University, Stanford, CA 94305, USA,Department of Microbiology and Immunology, Stanford University, Stanford, CA 94305, USA,Institute of Veterinary Medicine, Jiangsu Academy of Agricultural Sciences, Nanjing, 210014, China
| | - Kevin F. Brulois
- Palo Alto Veterans Institute of Research, VA Palo Alto Health Care System, Palo Alto, CA 94304, USA,Department of Pathology, Stanford University, Stanford, CA 94305, USA
| | - Junliang Pan
- Palo Alto Veterans Institute of Research, VA Palo Alto Health Care System, Palo Alto, CA 94304, USA,Department of Pathology, Stanford University, Stanford, CA 94305, USA
| | - Julia Y. Co
- Department of Microbiology and Immunology, Stanford University, Stanford, CA 94305, USA,Department of Pediatrics, Stanford University, Stanford, CA 94305, USA
| | - Lili Ren
- School of Pharmaceutical Sciences, Nanjing Tech University, Nanjing, 211816, China
| | - Ningguo Feng
- Palo Alto Veterans Institute of Research, VA Palo Alto Health Care System, Palo Alto, CA 94304, USA,Department of Medicine, Division of Gastroenterology and Hepatology, Stanford University, Stanford, CA 94305, USA,Department of Microbiology and Immunology, Stanford University, Stanford, CA 94305, USA
| | - Linda L. Yasukawa
- Palo Alto Veterans Institute of Research, VA Palo Alto Health Care System, Palo Alto, CA 94304, USA,Department of Medicine, Division of Gastroenterology and Hepatology, Stanford University, Stanford, CA 94305, USA,Department of Microbiology and Immunology, Stanford University, Stanford, CA 94305, USA
| | - Liliana Sánchez-Tacuba
- Palo Alto Veterans Institute of Research, VA Palo Alto Health Care System, Palo Alto, CA 94304, USA,Department of Medicine, Division of Gastroenterology and Hepatology, Stanford University, Stanford, CA 94305, USA,Department of Microbiology and Immunology, Stanford University, Stanford, CA 94305, USA
| | - Jonathan E. Wosen
- Department of Pediatrics, Stanford University, Stanford, CA 94305, USA
| | | | - Denise M. Monack
- Department of Microbiology and Immunology, Stanford University, Stanford, CA 94305, USA
| | - Manuel R. Amieva
- Department of Microbiology and Immunology, Stanford University, Stanford, CA 94305, USA,Department of Pediatrics, Stanford University, Stanford, CA 94305, USA
| | - Calvin J. Kuo
- Department of Medicine, Division of Hematology, Stanford University, Stanford, CA 94305, USA
| | - Eugene C. Butcher
- Palo Alto Veterans Institute of Research, VA Palo Alto Health Care System, Palo Alto, CA 94304, USA,Department of Pathology, Stanford University, Stanford, CA 94305, USA
| | - Harry B. Greenberg
- Palo Alto Veterans Institute of Research, VA Palo Alto Health Care System, Palo Alto, CA 94304, USA,Department of Medicine, Division of Gastroenterology and Hepatology, Stanford University, Stanford, CA 94305, USA,Department of Microbiology and Immunology, Stanford University, Stanford, CA 94305, USA
| |
Collapse
|
|
25
|
Lipopolysaccharide derived alginate coated Hepatitis B antigen loaded chitosan nanoparticles for oral mucosal immunization. Int J Biol Macromol 2020; 154:466-476. [DOI: 10.1016/j.ijbiomac.2020.03.124] [Citation(s) in RCA: 22] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/12/2019] [Revised: 03/13/2020] [Accepted: 03/14/2020] [Indexed: 02/08/2023]
|
|
26
|
Nigro G, Arena ET, Sachse M, Moya-Nilges M, Marteyn BS, Sansonetti PJ, Campbell-Valois FX. Mapping of Shigella flexneri's tissue distribution and type III secretion apparatus activity during infection of the large intestine of guinea pigs. Pathog Dis 2020; 77:5580288. [PMID: 31578543 PMCID: PMC6920510 DOI: 10.1093/femspd/ftz054] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/04/2019] [Accepted: 09/30/2019] [Indexed: 12/12/2022] Open
Abstract
Shigella spp. are bacterial pathogens that invade the human colonic mucosa using a type III secretion apparatus (T3SA), a proteinaceous device activated upon contact with host cells. Active T3SAs translocate proteins that carve the intracellular niche of Shigella spp. Nevertheless, the activation state of the T3SA has not been addressed in vivo. Here, we used a green fluorescent protein transcription-based secretion activity reporter (TSAR) to provide a spatio-temporal description of S. flexneri T3SAs activity in the colon of Guinea pigs. First, we observed that early mucus release is triggered in the vicinity of luminal bacteria with inactive T3SA. Subsequent mucosal invasion showed bacteria with active T3SA associated with the brush border, eventually penetrating into epithelial cells. From 2 to 8 h post-challenge, the infection foci expanded, and these intracellular bacteria displayed homogeneously high-secreting activity, while extracellular foci within the lamina propria featured bacteria with low secretion activity. We also found evidence that within lamina propria macrophages, bacteria reside in vacuoles instead of accessing the cytosol. Finally, bacteria were cleared from tissues between 8 and 24 h post-challenge, highlighting the hit-and-run colonization strategy of Shigella. This study demonstrates how genetically encoded reporters can contribute to deciphering pathogenesis in vivo.
Collapse
Affiliation(s)
- Giulia Nigro
- Unité de Pathogénie Microbienne Moléculaire, Institut Pasteur, INSERM U1202, 24-28 rue du Docteur-Roux, 75015 Paris, France
| | - Ellen T Arena
- Unité de Pathogénie Microbienne Moléculaire, Institut Pasteur, INSERM U1202, 24-28 rue du Docteur-Roux, 75015 Paris, France.,Laboratory for Optical and Computational Instrumentation, University of Wisconsin-Madison, Laboratory for Optical and Computational Instrumentation, 271 Animal Sciences, 1675 Observatory Drive, Madison, WI 53706, USA
| | - Martin Sachse
- Ultrastructural Bioimaging unit, Institut Pasteur, 24-28 rue du Docteur-Roux, 75015 Paris, France
| | - Maryse Moya-Nilges
- Ultrastructural Bioimaging unit, Institut Pasteur, 24-28 rue du Docteur-Roux, 75015 Paris, France
| | - Benoit S Marteyn
- Unité de Pathogénie Microbienne Moléculaire, Institut Pasteur, INSERM U1202, 24-28 rue du Docteur-Roux, 75015 Paris, France.,Architecture et Réactivité de l'ARN, Université de Strasbourg, CNRS UPR9002, 2 Allée Konrad Roentgen, 67084 Strasbourg, France.,Unité Pathogenèse des Infections Vasculaires, Institut Pasteur, 24-28 rue du Docteur-Roux, 75015 Paris, France
| | - Philippe J Sansonetti
- Unité de Pathogénie Microbienne Moléculaire, Institut Pasteur, INSERM U1202, 24-28 rue du Docteur-Roux, 75015 Paris, France.,Chaire de Microbiologie et Maladies Infectieuses, Collège de France, 11 Place Marcelin Berthelot, 75231 Paris, France
| | - F-X Campbell-Valois
- Unité de Pathogénie Microbienne Moléculaire, Institut Pasteur, INSERM U1202, 24-28 rue du Docteur-Roux, 75015 Paris, France.,The Host-Microbe Interactions Laboratory, Department of Chemistry and Biomolecular Sciences, University of Ottawa, 150 Louis-Pasteur private, Ottawa, ON, K1N 6N5, Canada.,Department of Biochemistry, Microbiology and Immunology, University of Ottawa, 451 Smyth Rd, Ottawa, ON, K1N 6N5, Canada
| |
Collapse
|
|
27
|
Kobayashi N, Takahashi D, Takano S, Kimura S, Hase K. The Roles of Peyer's Patches and Microfold Cells in the Gut Immune System: Relevance to Autoimmune Diseases. Front Immunol 2019; 10:2345. [PMID: 31649668 PMCID: PMC6794464 DOI: 10.3389/fimmu.2019.02345] [Citation(s) in RCA: 128] [Impact Index Per Article: 21.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/20/2019] [Accepted: 09/17/2019] [Indexed: 02/06/2023] Open
Abstract
Microfold (M) cells are located in the epithelium covering mucosa-associated lymphoid tissues, such as the Peyer's patches (PPs) of the small intestine. M cells actively transport luminal antigens to the underlying lymphoid follicles to initiate an immune response. The molecular machinery of M-cell differentiation and function has been vigorously investigated over the last decade. Studies have shed light on the role of M cells in the mucosal immune system and have revealed that antigen uptake by M cells contributes to not only mucosal but also systemic immune responses. However, M-cell studies usually focus on infectious diseases; the contribution of M cells to autoimmune diseases has remained largely unexplored. Accumulating evidence suggests that dysbiosis of the intestinal microbiota is implicated in multiple systemic diseases, including autoimmune diseases. This implies that the uptake of microorganisms by M cells in PPs may play a role in the pathogenesis of autoimmune diseases. We provide an outline of the current understanding of M-cell biology and subsequently discuss the potential contribution of M cells and PPs to the induction of systemic autoimmunity, beyond the mucosal immune response.
Collapse
Affiliation(s)
- Nobuhide Kobayashi
- Division of Biochemistry, Faculty of Pharmacy and Graduate School of Pharmaceutical Science, Keio University, Tokyo, Japan.,Department of Bacteriology, Graduate School of Medical Sciences, Kanazawa University, Kanazawa, Japan
| | - Daisuke Takahashi
- Division of Biochemistry, Faculty of Pharmacy and Graduate School of Pharmaceutical Science, Keio University, Tokyo, Japan
| | - Shunsuke Takano
- Division of Biochemistry, Faculty of Pharmacy and Graduate School of Pharmaceutical Science, Keio University, Tokyo, Japan
| | - Shunsuke Kimura
- Division of Biochemistry, Faculty of Pharmacy and Graduate School of Pharmaceutical Science, Keio University, Tokyo, Japan
| | - Koji Hase
- Division of Biochemistry, Faculty of Pharmacy and Graduate School of Pharmaceutical Science, Keio University, Tokyo, Japan.,International Research and Development Center for Mucosal Vaccines, The Institute of Medical Science, The University of Tokyo (IMSUT), Tokyo, Japan
| |
Collapse
|
|
28
|
Loktionov A. Eosinophils in the gastrointestinal tract and their role in the pathogenesis of major colorectal disorders. World J Gastroenterol 2019; 25:3503-3526. [PMID: 31367153 PMCID: PMC6658389 DOI: 10.3748/wjg.v25.i27.3503] [Citation(s) in RCA: 62] [Impact Index Per Article: 10.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/06/2019] [Revised: 05/22/2019] [Accepted: 05/31/2019] [Indexed: 02/06/2023] Open
Abstract
Eosinophils are currently regarded as versatile mobile cells controlling and regulating multiple biological pathways and responses in health and disease. These cells store in their specific granules numerous biologically active substances (cytotoxic cationic proteins, cytokines, growth factors, chemokines, enzymes) ready for rapid release. The human gut is the main destination of eosinophils that are produced and matured in the bone marrow and then transferred to target tissues through the circulation. In health the most important functions of gut-residing eosinophils comprise their participation in the maintenance of the protective mucosal barrier and interactions with other immune cells in providing immunity to microbiota of the gut lumen. Eosinophils are closely involved in the development of inflammatory bowel disease (IBD), when their cytotoxic granule proteins cause damage to host tissues. However, their roles in Crohn's disease and ulcerative colitis appear to follow different immune response patterns. Eosinophils in IBD are especially important in altering the structure and protective functions of the mucosal barrier and modulating massive neutrophil influx to the lamina propria followed by transepithelial migration to colorectal mucus. IBD-associated inflammatory process involving eosinophils then appears to expand to the mucus overlaying the internal gut surface. The author hypothesises that immune responses within colorectal mucus as well as ETosis exerted by both neutrophils and eosinophils on the both sides of the colonic epithelial barrier act as additional pathogenetic factors in IBD. Literature analysis also shows an association between elevated eosinophil levels and better colorectal cancer (CRC) prognosis, but mechanisms behind this effect remain to be elucidated. In conclusion, the author emphasises the importance of investigating colorectal mucus in IBD and CRC patients as a previously unexplored milieu of disease-related inflammatory responses.
Collapse
|
|
29
|
Dillon A, Lo DD. M Cells: Intelligent Engineering of Mucosal Immune Surveillance. Front Immunol 2019; 10:1499. [PMID: 31312204 PMCID: PMC6614372 DOI: 10.3389/fimmu.2019.01499] [Citation(s) in RCA: 120] [Impact Index Per Article: 20.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/20/2019] [Accepted: 06/14/2019] [Indexed: 12/25/2022] Open
Abstract
M cells are specialized intestinal epithelial cells that provide the main machinery for sampling luminal microbes for mucosal immune surveillance. M cells are usually found in the epithelium overlying organized mucosal lymphoid tissues, but studies have identified multiple distinct lineages of M cells that are produced under different conditions, including intestinal inflammation. Among these lineages there is a common morphology that helps explain the efficiency of M cells in capturing luminal bacteria and viruses; in addition, M cells recruit novel cellular mechanisms to transport the particles across the mucosal barrier into the lamina propria, a process known as transcytosis. These specializations used by M cells point to a novel engineering of cellular machinery to selectively capture and transport microbial particles of interest. Because of the ability of M cells to effectively violate the mucosal barrier, the circumstances of M cell induction have important consequences. Normal immune surveillance insures that transcytosed bacteria are captured by underlying myeloid/dendritic cells; in contrast, inflammation can induce development of new M cells not accompanied by organized lymphoid tissues, resulting in bacterial transcytosis with the potential to amplify inflammatory disease. In this review, we will discuss our own perspectives on the life history of M cells and also raise a few questions regarding unique aspects of their biology among epithelia.
Collapse
Affiliation(s)
- Andrea Dillon
- Division of Biomedical Sciences, School of Medicine, University of California, Riverside, Riverside, CA, United States
| | - David D Lo
- Division of Biomedical Sciences, School of Medicine, University of California, Riverside, Riverside, CA, United States
| |
Collapse
|
|
30
|
Effect of co-infection with a small intestine-restricted helminth pathogen on oral prion disease pathogenesis in mice. Sci Rep 2019; 9:6674. [PMID: 31040320 PMCID: PMC6491469 DOI: 10.1038/s41598-019-42900-9] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/13/2019] [Accepted: 04/11/2019] [Indexed: 11/24/2022] Open
Abstract
The early replication of some orally-acquired prion strains upon stromal-derived follicular dendritic cells (FDC) within the small intestinal Peyer’s patches is essential to establish host infection, and for the disease to efficiently spread to the brain. Factors that influence the early accumulation of prions in Peyer’s patches can directly influence disease pathogenesis. The host’s immune response to a gastrointestinal helminth infection can alter susceptibility to co-infection with certain pathogenic bacteria and viruses. Here we used the natural mouse small intestine-restricted helminth pathogen Heligmosomoides polygyrus to test the hypothesis that pathology specifically within the small intestine caused by a helminth co-infection would influence oral prion disease pathogenesis. When mice were co-infected with prions on d 8 after H. polygyrus infection the early accumulation of prions within Peyer’s patches was reduced and survival times significantly extended. Natural prion susceptible hosts such as sheep, deer and cattle are regularly exposed to gastrointestinal helminth parasites. Our data suggest that co-infections with small intestine-restricted helminth pathogens may be important factors that influence oral prion disease pathogenesis.
Collapse
|
|
31
|
Ramakrishnan SK, Zhang H, Ma X, Jung I, Schwartz AJ, Triner D, Devenport SN, Das NK, Xue X, Zeng MY, Hu Y, Mortensen RM, Greenson JK, Cascalho M, Wobus CE, Colacino JA, Nunez G, Rui L, Shah YM. Intestinal non-canonical NFκB signaling shapes the local and systemic immune response. Nat Commun 2019; 10:660. [PMID: 30737385 PMCID: PMC6368617 DOI: 10.1038/s41467-019-08581-8] [Citation(s) in RCA: 69] [Impact Index Per Article: 11.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/20/2018] [Accepted: 01/21/2019] [Indexed: 12/13/2022] Open
Abstract
Microfold cells (M-cells) are specialized cells of the intestine that sample luminal microbiota and dietary antigens to educate the immune cells of the intestinal lymphoid follicles. The function of M-cells in systemic inflammatory responses are still unclear. Here we show that epithelial non-canonical NFkB signaling mediated by NFkB-inducing kinase (NIK) is highly active in intestinal lymphoid follicles, and is required for M-cell maintenance. Intestinal NIK signaling modulates M-cell differentiation and elicits both local and systemic IL-17A and IgA production. Importantly, intestinal NIK signaling is active in mouse models of colitis and patients with inflammatory bowel diseases; meanwhile, constitutive NIK signaling increases the susceptibility to inflammatory injury by inducing ectopic M-cell differentiation and a chronic increase of IL-17A. Our work thus defines an important function of non-canonical NFkB and M-cells in immune homeostasis, inflammation and polymicrobial sepsis.
Collapse
Affiliation(s)
| | - Huabing Zhang
- Department of Molecular & Integrative Physiology, University of Michigan, Michigan, MI, 48109, USA
| | - Xiaoya Ma
- Department of Molecular & Integrative Physiology, University of Michigan, Michigan, MI, 48109, USA
| | - Inkyung Jung
- Department of Molecular & Integrative Physiology, University of Michigan, Michigan, MI, 48109, USA
| | - Andrew J Schwartz
- Department of Molecular & Integrative Physiology, University of Michigan, Michigan, MI, 48109, USA
| | - Daniel Triner
- Department of Molecular & Integrative Physiology, University of Michigan, Michigan, MI, 48109, USA
| | - Samantha N Devenport
- Department of Molecular & Integrative Physiology, University of Michigan, Michigan, MI, 48109, USA
| | - Nupur K Das
- Department of Molecular & Integrative Physiology, University of Michigan, Michigan, MI, 48109, USA
| | - Xiang Xue
- Department of Molecular & Integrative Physiology, University of Michigan, Michigan, MI, 48109, USA
| | - Melody Y Zeng
- Department of Pathology, University of Michigan, Ann Arbor, MI, 48109, USA
- Internal Medicine, University of Michigan, Ann Arbor, MI, 48109, USA
| | - Yinling Hu
- Cancer and Inflammation Program, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Frederick, MD, 21702, USA
| | - Richard M Mortensen
- Department of Molecular & Integrative Physiology, University of Michigan, Michigan, MI, 48109, USA
| | - Joel K Greenson
- Department of Pathology, University of Michigan, Ann Arbor, MI, 48109, USA
| | - Marilia Cascalho
- Transplantation Biology, University of Michigan, Ann Arbor, MI, 48109, USA
- Department of Surgery, University of Michigan, Ann Arbor, MI, 48109, USA
- Department of Microbiology and Immunology, University of Michigan, Ann Arbor, MI, 48109, USA
| | - Christiane E Wobus
- Department of Microbiology and Immunology, University of Michigan, Ann Arbor, MI, 48109, USA
| | - Justin A Colacino
- Department of Environmental Health Sciences, University of Michigan, Ann Arbor, MI, 48109, USA
- Department of Nutritional Sciences, University of Michigan, Ann Arbor, MI, 48109, USA
| | - Gabriel Nunez
- Department of Pathology, University of Michigan, Ann Arbor, MI, 48109, USA
- Comprehensive Cancer Center, University of Michigan, Ann Arbor, MI, 48109, USA
| | - Liangyou Rui
- Department of Molecular & Integrative Physiology, University of Michigan, Michigan, MI, 48109, USA
- Internal Medicine, University of Michigan, Ann Arbor, MI, 48109, USA
| | - Yatrik M Shah
- Department of Molecular & Integrative Physiology, University of Michigan, Michigan, MI, 48109, USA.
- Internal Medicine, University of Michigan, Ann Arbor, MI, 48109, USA.
| |
Collapse
|
|
32
|
Górski A, Jończyk-Matysiak E, Łusiak-Szelachowska M, Międzybrodzki R, Weber-Dąbrowska B, Borysowski J. Bacteriophages targeting intestinal epithelial cells: a potential novel form of immunotherapy. Cell Mol Life Sci 2018; 75:589-595. [PMID: 29164271 PMCID: PMC5769817 DOI: 10.1007/s00018-017-2715-6] [Citation(s) in RCA: 26] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/20/2017] [Revised: 11/07/2017] [Accepted: 11/15/2017] [Indexed: 02/07/2023]
Abstract
In addition to their established role as a physical barrier to invading pathogens and other harmful agents, intestinal epithelial cells (IEC) are actively involved in local immune reactions. In the past years, evidence has accumulated suggesting the role of IEC in the immunopathology of intestinal inflammatory disorders (IBD). Recent advances in research on bacteriophages strongly suggest that-in addition to their established antibacterial activity-they have immunomodulating properties that are potentially useful in the clinic. We suggest that these immunomodulating phage activities targeting IEC may open novel treatment perspectives in disorders of the alimentary tract, particularly IBD.
Collapse
Affiliation(s)
- Andrzej Górski
- Bacteriophage Laboratory, Hirszfeld Institute of Immunology and Experimental Therapy, Polish Academy of Sciences (HIIET PAS), 53-114, Wrocław, Poland.
- Department of Clinical Immunology, Transplantation Institute, Medical University of Warsaw, 02-006, Warsaw, Poland.
| | - Ewa Jończyk-Matysiak
- Bacteriophage Laboratory, Hirszfeld Institute of Immunology and Experimental Therapy, Polish Academy of Sciences (HIIET PAS), 53-114, Wrocław, Poland
| | - Marzanna Łusiak-Szelachowska
- Bacteriophage Laboratory, Hirszfeld Institute of Immunology and Experimental Therapy, Polish Academy of Sciences (HIIET PAS), 53-114, Wrocław, Poland
| | - Ryszard Międzybrodzki
- Bacteriophage Laboratory, Hirszfeld Institute of Immunology and Experimental Therapy, Polish Academy of Sciences (HIIET PAS), 53-114, Wrocław, Poland
- Department of Clinical Immunology, Transplantation Institute, Medical University of Warsaw, 02-006, Warsaw, Poland
| | - Beata Weber-Dąbrowska
- Bacteriophage Laboratory, Hirszfeld Institute of Immunology and Experimental Therapy, Polish Academy of Sciences (HIIET PAS), 53-114, Wrocław, Poland
| | - Jan Borysowski
- Department of Clinical Immunology, Transplantation Institute, Medical University of Warsaw, 02-006, Warsaw, Poland
| |
Collapse
|
|
33
|
Mabbott NA. How do PrP Sc Prions Spread between Host Species, and within Hosts? Pathogens 2017; 6:pathogens6040060. [PMID: 29186791 PMCID: PMC5750584 DOI: 10.3390/pathogens6040060] [Citation(s) in RCA: 25] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/02/2017] [Revised: 11/16/2017] [Accepted: 11/21/2017] [Indexed: 12/22/2022] Open
Abstract
Prion diseases are sub-acute neurodegenerative diseases that affect humans and some domestic and free-ranging animals. Infectious prion agents are considered to comprise solely of abnormally folded isoforms of the cellular prion protein known as PrPSc. Pathology during prion disease is restricted to the central nervous system where it causes extensive neurodegeneration and ultimately leads to the death of the host. The first half of this review provides a thorough account of our understanding of the various ways in which PrPSc prions may spread between individuals within a population, both horizontally and vertically. Many natural prion diseases are acquired peripherally, such as by oral exposure, lesions to skin or mucous membranes, and possibly also via the nasal cavity. Following peripheral exposure, some prions accumulate to high levels within the secondary lymphoid organs as they make their journey from the site of infection to the brain, a process termed neuroinvasion. The replication of PrPSc prions within secondary lymphoid organs is important for their efficient spread to the brain. The second half of this review describes the key tissues, cells and molecules which are involved in the propagation of PrPSc prions from peripheral sites of exposure (such as the lumen of the intestine) to the brain. This section also considers how additional factors such as inflammation and aging might influence prion disease susceptibility.
Collapse
Affiliation(s)
- Neil A Mabbott
- The Roslin Institute & Royal (Dick) School of Veterinary Sciences, University of Edinburgh, Easter Bush, Midlothian EH25 9RG, UK
| |
Collapse
|
|
34
|
Targeted deletion of RANKL in M cell inducer cells by the Col6a1-Cre driver. Biochem Biophys Res Commun 2017; 493:437-443. [DOI: 10.1016/j.bbrc.2017.09.004] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/16/2017] [Accepted: 09/02/2017] [Indexed: 12/23/2022]
|
|
35
|
Vigilance or Subversion? Constitutive and Inducible M Cells in Mucosal Tissues. Trends Immunol 2017; 39:185-195. [PMID: 28958392 DOI: 10.1016/j.it.2017.09.002] [Citation(s) in RCA: 25] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/27/2017] [Revised: 09/01/2017] [Accepted: 09/07/2017] [Indexed: 02/08/2023]
Abstract
Microfold (M) cells are epithelial cells present in mucosal tissues and specialized for the capture of luminal microparticles and their delivery to underlying immune cells; thus, they are crucial participants in mucosal immune surveillance. Multiple phenotypic subsets of M cells have now been described, all sharing a unique apical morphology that provides clues to their ability to capture microbial particles. The existence of diverse M cell phenotypes, especially inflammation-inducible M cells, provides an intriguing puzzle: some variants may augment luminal surveillance to boost mucosal immunity, while others may promote microbial access to tissues. Here, I consider the unique induction requirements of each M cell subset and functional differences, highlighting the potentially distinct consequences in mucosal immunity.
Collapse
|
|
36
|
Zhang L, Song J, Bai T, Qian W, Hou XH. Stress induces more serious barrier dysfunction in follicle-associated epithelium than villus epithelium involving mast cells and protease-activated receptor-2. Sci Rep 2017; 7:4950. [PMID: 28694438 PMCID: PMC5503989 DOI: 10.1038/s41598-017-05064-y] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/16/2017] [Accepted: 05/23/2017] [Indexed: 02/08/2023] Open
Abstract
Psychological stress has been associated with intestinal epithelial hyperpermeability, the basic process in various functional and organic bowel diseases. In the present study, we aimed to clarify the differences and underlining mechanisms in stress-induced barrier disruption in functionally and structurally distinct epitheliums, including the villus epithelium (VE) and follicle-associated epithelium (FAE), a specialized epithelium overlaid the domes of Peyer's lymphoid follicles. Employing an Ussing Chamber system, the epithelial permeability was assessed in rats following water avoidance stress (WAS) in vivo and in mucosa tissues exposed to corticotropin-releasing factor (CRF) ex vivo. Decreased transepithelial resistance (TER) and increased paracellular and transcellular macromolecular permeability in colon, ileal VE and FAE had been observed in WAS rats and in CRF-exposed mucosa. Especially, the barrier dysfunction was more serious in the FAE. Moreover, WAS upregulated the expression of mast cell tryptase and protease-activated receptor-2 (PAR2), which positively correlated with epithelial conductance. Mast cell stabilizer cromolyn sodium obviously alleviated the barrier disruption induced by WAS in vivo and CRF in vitro. Serine protease inhibitor aprotinin and FUT-175, and selective PAR2 antagonist ENMD-1068 effectively inhibited the CRF-induced FAE hyperpermeability. Altogether, it concluded that the FAE was more susceptible to stress, and the mast cells and PAR2 signaling played crucial roles in this process.
Collapse
Affiliation(s)
- Lei Zhang
- Division of Gastroenterology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China
| | - Jun Song
- Division of Gastroenterology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China
| | - Tao Bai
- Division of Gastroenterology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China
| | - Wei Qian
- Division of Gastroenterology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China
| | - Xiao-Hua Hou
- Division of Gastroenterology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China.
| |
Collapse
|
|
37
|
Parnell EA, Walch EM, Lo DD. Inducible Colonic M Cells Are Dependent on TNFR2 but Not Ltβr, Identifying Distinct Signalling Requirements for Constitutive Versus Inducible M Cells. J Crohns Colitis 2017; 11:751-760. [PMID: 27932454 PMCID: PMC5881705 DOI: 10.1093/ecco-jcc/jjw212] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/16/2016] [Accepted: 11/16/2016] [Indexed: 02/08/2023]
Abstract
BACKGROUND AND AIMS M cells associated with organised lymphoid tissues such as intestinal Peyer's patches provide surveillance of the intestinal lumen. Inflammation or infection in the colon can induce an M cell population associated with lymphoid infiltrates; paradoxically, induction is dependent on the inflammatory cytokine tumour necrosis factor [TNF]-α. Anti-TNFα blockade is an important therapeutic in inflammatory bowel disease, so understanding the effects of TNFα signalling is important in refining therapeutics. METHODS To dissect pro-inflammatory signals from M cell inductive signals, we used confocal microscopy image analysis to assess requirements for specific cytokine receptor signals using TNF receptor 1 [TNFR1] and 2 [TNFR2] knockouts [ko] back-crossed to the PGRP-S-dsRed transgene; separate groups were treated with soluble lymphotoxin β receptor [sLTβR] to block LTβR signalling. All groups were treated with dextran sodium sulphate [DSS] to induce colitis. RESULTS Deficiency of TNFR1 or TNFR2 did not prevent DSS-induced inflammation nor induction of stromal cell expression of receptor activator of nuclear factor kappa-B ligand [RANKL], but absence of TNFR2 prevented M cell induction. LTβR blockade had no effect on M cell induction, but it appeared to reduce RANKL induction below adjacent M cells. CONCLUSIONS TNFR2 is required for inflammation-inducible M cells, indicating that constitutive versus inflammation-inducible M cells depend on different triggers. The inducible M cell dependence on TNFR2 suggests that this specific subset is dependent on TNFα in addition to a presumed requirement for RANKL. Since inducible M cell function will influence immune responses, selective blockade of TNFα may affect colonic inflammation.
Collapse
Affiliation(s)
- Erinn A. Parnell
- Division of Biomedical Sciences, University of California Riverside School of Medicine,Riverside, CA, USA.
| | - Erin M. Walch
- Division of Biomedical Sciences, University of California Riverside School of Medicine,Riverside, CA, USA.
| | - David D. Lo
- Division of Biomedical Sciences, University of California Riverside School of Medicine,Riverside, CA, USA.
| |
Collapse
|
|
38
|
Shawki A, McCole DF. Mechanisms of Intestinal Epithelial Barrier Dysfunction by Adherent-Invasive Escherichia coli. Cell Mol Gastroenterol Hepatol 2017; 3:41-50. [PMID: 28174756 PMCID: PMC5247418 DOI: 10.1016/j.jcmgh.2016.10.004] [Citation(s) in RCA: 83] [Impact Index Per Article: 10.4] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/12/2016] [Accepted: 10/14/2016] [Indexed: 12/12/2022]
Abstract
Pathobiont expansion, such as that of adherent-invasive Escherichia coli (AIEC), is an emerging factor associated with inflammatory bowel disease. The intestinal epithelial barrier is the first line of defense against these pathogens. Inflammation plays a critical role in altering the epithelial barrier and is a major factor involved in promoting the expansion and pathogenesis of AIEC. AIEC in turn can exacerbate intestinal epithelial barrier dysfunction by targeting multiple elements of the barrier. One critical element of the epithelial barrier is the tight junction. Increasing evidence suggests that AIEC may selectively target protein components of tight junctions, leading to increased barrier permeability. This may represent one mechanism by which AIEC could contribute to the development of inflammatory bowel disease. This review article discusses potential mechanisms by which AIEC can disrupt epithelial tight junction function and intestinal barrier function.
Collapse
Key Words
- AIEC, adherent-invasive Escherichia coli
- AJ, adherens junction
- AJC, apical junctional complex
- BP, bacterial peptidoglycans
- CD, Crohn’s disease
- CEACAM6, carcinoembryonic antigen–related cell-adhesion molecule
- IBD, inflammatory bowel disease
- IEC, intestinal epithelial cell
- IFN, interferon
- IL, interleukin
- Inflammatory Bowel Disease
- Intestinal Permeability
- JAM-A, junctional adhesion molecule-A
- LPF, long polar fimbriae
- MLC, myosin light chain
- MLCK, myosin light chain kinase
- NF-κB, nuclear factor-κB
- NOD2, nucleotide-binding oligomerization domain 2
- PDZ, PSD95-DlgA-zonula occludens-1 homology domain
- TJ, tight junction
- TNF, tumor necrosis factor
- Tight Junctions
- UC, ulcerative colitis
- ZO, zonula occludens
Collapse
Affiliation(s)
| | - Declan F. McCole
- Division of Biomedical Sciences, University of California Riverside, Riverside, California
| |
Collapse
|
|
39
|
Donaldson DS, Sehgal A, Rios D, Williams IR, Mabbott NA. Increased Abundance of M Cells in the Gut Epithelium Dramatically Enhances Oral Prion Disease Susceptibility. PLoS Pathog 2016; 12:e1006075. [PMID: 27973593 PMCID: PMC5156364 DOI: 10.1371/journal.ppat.1006075] [Citation(s) in RCA: 36] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/07/2016] [Accepted: 11/17/2016] [Indexed: 02/07/2023] Open
Abstract
Many natural prion diseases of humans and animals are considered to be acquired through oral consumption of contaminated food or pasture. Determining the route by which prions establish host infection will identify the important factors that influence oral prion disease susceptibility and to which intervention strategies can be developed. After exposure, the early accumulation and replication of prions within small intestinal Peyer's patches is essential for the efficient spread of disease to the brain. To replicate within Peyer's patches, the prions must first cross the gut epithelium. M cells are specialised epithelial cells within the epithelia covering Peyer's patches that transcytose particulate antigens and microorganisms. M cell-development is dependent upon RANKL-RANK-signalling, and mice in which RANK is deleted only in the gut epithelium completely lack M cells. In the specific absence of M cells in these mice, the accumulation of prions within Peyer's patches and the spread of disease to the brain was blocked, demonstrating a critical role for M cells in the initial transfer of prions across the gut epithelium in order to establish host infection. Since pathogens, inflammatory stimuli and aging can modify M cell-density in the gut, these factors may also influence oral prion disease susceptibility. Mice were therefore treated with RANKL to enhance M cell density in the gut. We show that prion uptake from the gut lumen was enhanced in RANKL-treated mice, resulting in shortened survival times and increased disease susceptibility, equivalent to a 10-fold higher infectious titre of prions. Together these data demonstrate that M cells are the critical gatekeepers of oral prion infection, whose density in the gut epithelium directly limits or enhances disease susceptibility. Our data suggest that factors which alter M cell-density in the gut epithelium may be important risk factors which influence host susceptibility to orally acquired prion diseases.
Collapse
Affiliation(s)
- David S. Donaldson
- The Roslin Institute & Royal (Dick) School of Veterinary Sciences, University of Edinburgh, United Kingdom
| | - Anuj Sehgal
- The Roslin Institute & Royal (Dick) School of Veterinary Sciences, University of Edinburgh, United Kingdom
| | - Daniel Rios
- Dept. Pathology, Emory University School of Medicine, Atlanta, Georgia, United States of America
| | - Ifor R. Williams
- Dept. Pathology, Emory University School of Medicine, Atlanta, Georgia, United States of America
| | - Neil A. Mabbott
- The Roslin Institute & Royal (Dick) School of Veterinary Sciences, University of Edinburgh, United Kingdom
- * E-mail:
| |
Collapse
|