1
|
Parekh Z, Xiao J, Mani A, Evans Q, Phung C, Barba HA, Xie B, Sidebottom AM, Sundararajan A, Lin H, Ramaswamy R, Dao D, Gonnah R, Yehia M, Hariprasad SM, D'Souza M, Sulakhe D, Chang EB, Skondra D. Fecal Microbial Profiles and Short-Chain Fatty Acid/Bile Acid Metabolomics in Patients With Age-Related Macular Degeneration: A Pilot Study. Invest Ophthalmol Vis Sci 2025; 66:21. [PMID: 40202735 PMCID: PMC11993127 DOI: 10.1167/iovs.66.4.21] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/11/2024] [Accepted: 02/25/2025] [Indexed: 04/10/2025] Open
Abstract
Purpose Age-related macular degeneration (AMD) is a multifactorial disease, and studies have implicated the role of gut microbiota in its pathogenesis. However, characterization of microbiome dysbiosis and associated microbial-derived metabolomic profiles across AMD stages remains unknown. In this pilot study, we explored how gut microbiome composition and gut-derived metabolites differ in AMD. Methods Our pilot study analyzed fasted stool samples that were collected from 22 patients at a tertiary academic center. Subjects were classified as control, intermediate AMD, or advanced AMD based on clinical presentation. 16S rRNA amplicon sequencing and standard chromatography-mass spectrometry methods were used to identify bacterial taxonomy composition and abundance of short-chain fatty acids (SCFAs) and bile acids (BAs), respectively. Genetic testing was used to investigate the frequency of 14 high-risk single nucleotide polymorphisms (SNPs) associated with AMD in the AMD cohort. Results Forty-three differentially abundant genera were present among the control, intermediate, and advanced groups. Taxa with known roles in immunologic pathways, such as Desulfovibrionales (q = 0.10) and Terrisporobacter (q = 1.16e-03), were in greater abundance in advanced AMD patients compared to intermediate. Advanced AMD patients had decreased abundance of 12 SCFAs, including acetate (P = 0.002), butyrate (P = 0.04), and propionate (P = 0.01), along with 12 BAs, including taurocholic acid (P = 0.02) and tauroursodeoxycholic acid (P = 0.04). Frequencies of high-risk SNPs were not significantly different between the intermediate and advanced AMD groups. Conclusions This pilot study identifies distinct gut microbiome compositions and metabolomic profiles associated with AMD and its stages, providing preliminary evidence of a potential link between gut microbiota and AMD pathogenesis. To validate these findings and elucidate the underlying mechanisms, future research with larger cohorts and more comprehensive sampling is strongly recommended.
Collapse
Affiliation(s)
- Zaid Parekh
- Pritzker School of Medicine, The University of Chicago, Chicago, Illinois, United States
| | - Jason Xiao
- Pritzker School of Medicine, The University of Chicago, Chicago, Illinois, United States
| | - Amir Mani
- Department of Ophthalmology and Visual Science, The University of Chicago, Chicago, Illinois, United States
| | - Quadis Evans
- Department of Ophthalmology and Visual Science, The University of Chicago, Chicago, Illinois, United States
| | - Christopher Phung
- Pritzker School of Medicine, The University of Chicago, Chicago, Illinois, United States
| | - Hugo A. Barba
- Department of Ophthalmology and Visual Science, The University of Chicago, Chicago, Illinois, United States
| | - Bingqing Xie
- Department of Medicine, The University of Chicago, Chicago, Illinois, United States
| | - Ashley M. Sidebottom
- Duchossois Family Institute, The University of Chicago, Chicago, Illinois, United States
| | - Anitha Sundararajan
- Duchossois Family Institute, The University of Chicago, Chicago, Illinois, United States
| | - Huaiying Lin
- Duchossois Family Institute, The University of Chicago, Chicago, Illinois, United States
| | - Ramanujam Ramaswamy
- Duchossois Family Institute, The University of Chicago, Chicago, Illinois, United States
| | - David Dao
- Department of Ophthalmology and Visual Science, The University of Chicago, Chicago, Illinois, United States
| | - Reem Gonnah
- Department of Ophthalmology and Visual Science, The University of Chicago, Chicago, Illinois, United States
| | - Madeleine Yehia
- Department of Ophthalmology and Visual Science, The University of Chicago, Chicago, Illinois, United States
| | - Seenu M. Hariprasad
- Department of Ophthalmology and Visual Science, The University of Chicago, Chicago, Illinois, United States
| | - Mark D'Souza
- Duchossois Family Institute, The University of Chicago, Chicago, Illinois, United States
| | - Dinanath Sulakhe
- Duchossois Family Institute, The University of Chicago, Chicago, Illinois, United States
| | - Eugene B. Chang
- Department of Medicine, The University of Chicago, Chicago, Illinois, United States
- Duchossois Family Institute, The University of Chicago, Chicago, Illinois, United States
| | - Dimitra Skondra
- Department of Ophthalmology and Visual Science, The University of Chicago, Chicago, Illinois, United States
| |
Collapse
|
2
|
Zong Y, Tong X, Chong WP. Th17 Response in Uveitis: A Double-Edged Sword in Ocular Inflammation and Immune Regulation. Clin Rev Allergy Immunol 2025; 68:26. [PMID: 40072803 PMCID: PMC11903535 DOI: 10.1007/s12016-025-09038-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 02/24/2025] [Indexed: 03/14/2025]
Abstract
Uveitis involves a complex interplay of immune cell infiltration and cytokine imbalances, with Th17 cells playing a central role in this process. Th17 cells contribute to disease pathogenesis by promoting inflammation, recruiting additional immune cells, and directly damaging retinal tissues. This review discusses the current knowledge on therapeutic strategies targeting Th17-related cytokines, including cytokine blockade, small molecule inhibitors, and immunomodulatory approaches. Traditionally, Th17-related cytokines have been viewed as pro-inflammatory agents in uveitis. However, emerging research has highlighted the capacity of the Th17 response to express immunoregulatory cytokines, notably IL-10, IL-24, and TGF-β. This suggest that the Th17 response may have a dualistic role that includes immune suppression. In this review, we will discuss this paradoxical nature of Th17 cells in immune regulation and inflammation that they can both promote and mitigate uveitis. We expected that a deeper understanding of these mechanisms is imperative for the innovation of novel therapeutics that could consider the dual role of Th17 response in the pathogenesis of uveitis. By finely tuning the Th17 response to preserve retinal integrity and function, these new treatments could bring significant benefits to patients with uveitis. This review aims to shed light on the complexities of the Th17 response in uveitis and its implications for future therapeutic strategies.
Collapse
Affiliation(s)
- Yuan Zong
- School of Chinese Medicine, Hong Kong Baptist University, Hong Kong, China
- Institute for Research and Continuing Education, Hong Kong Baptist University, Shenzhen, China
| | - Xue Tong
- School of Chinese Medicine, Hong Kong Baptist University, Hong Kong, China
| | - Wai Po Chong
- School of Chinese Medicine, Hong Kong Baptist University, Hong Kong, China.
- Institute for Research and Continuing Education, Hong Kong Baptist University, Shenzhen, China.
| |
Collapse
|
3
|
Luo L, Tang X, Xu J, Bao Y, Hu X, Zhong X. The causal effects of inflammatory bowel disease on its ocular manifestations: A Mendelian randomization study. PLoS One 2025; 20:e0316437. [PMID: 40072972 PMCID: PMC11902285 DOI: 10.1371/journal.pone.0316437] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/03/2024] [Accepted: 12/10/2024] [Indexed: 03/14/2025] Open
Abstract
BACKGROUND Observational studies have shown that ocular manifestations of inflammatory bowel disease (IBD) are common extraintinal manifestations, among which iridocyclitis, scleritis and episcleritis are the most common. However, whether there is a causal relationship between the two is unclear. The purpose of this study was to evaluate the causality of IBD on ocular manifestations using the mendelian randomization (MR) analysis. METHODS We performed a two-sample MR analysis with public genome-wide association studies (GWAS) data. Eligible instrumental variables (IVs) were selected according to the three assumptions of MR analysis. The inverse-variance weighted (IVW) method was the main method. Complementary methods included the MR-Egger regression, the Weighted Median, the Weighted Mode and MR pleiotropy residual sum and outlier (MR-PRESSO) methods. RESULTS After false discovery rate (FDR) correction, genetically predicted IBD (IVW OR = 1.184, 95% CI: 1.125-1.247, P_FDR < 0.001), Crohn's disease (CD, IVW OR = 1.082, 95% CI: 1.033-1.133, P_FDR = 0.007) and ulcerative colitis (UC, IVW OR = 1.192, 95% CI: 1.114-1.275, P_FDR < 0.001) were associated with an increased risk of iridocyclitis. Moreover, IBD (IVW OR = 1.128, 95% CI: 1.064-1.196, P_FDR = 0.001), CD (IVW OR = 1.077, 95% CI: 1.026-1.131, P_FDR = 0.019) and UC (IVW OR = 1.153, 95% CI: 1.069-1.243, P_FDR = 0.003) were associated with a higher risk of uveitis (uveitis includes iridocyclitis). Further sensitivity analyses validated the robustness of the above associations. However, IBD and its subtypes were not associated with scleritis, episcleritis, optic neuritis and corneal disease. Results of complementary methods were generally consistent with those of the IVW method. CONCLUSIONS Our study revealed genetically predicted associations of IBD, CD and UC on iridocyclitis and uveitis in European populations. However, IBD, CD, and UC are not causally related to scleritis, external scleritis, optic neuritis, and corneal disease.
Collapse
Affiliation(s)
- Lian Luo
- Department of Gastroenterology, The Affiliated Hospital of Southwest Medical University, Luzhou, China
- Nuclear Medicine and Molecular Imaging Key Laboratory of Sichuan Province, Luzhou, China
| | - Xiaowei Tang
- Department of Gastroenterology, The Affiliated Hospital of Southwest Medical University, Luzhou, China
- Nuclear Medicine and Molecular Imaging Key Laboratory of Sichuan Province, Luzhou, China
| | - Jia Xu
- Department of Gastroenterology, The Affiliated Hospital of Southwest Medical University, Luzhou, China
- Nuclear Medicine and Molecular Imaging Key Laboratory of Sichuan Province, Luzhou, China
| | - Yuxi Bao
- Department of Gastroenterology, The Affiliated Hospital of Southwest Medical University, Luzhou, China
| | - Xinyue Hu
- Department of Gastroenterology, The Affiliated Hospital of Southwest Medical University, Luzhou, China
| | - Xiaolin Zhong
- Department of Gastroenterology, The Affiliated Hospital of Southwest Medical University, Luzhou, China
| |
Collapse
|
4
|
Zhang Y, Jing Y, He J, Dong R, Li T, Li F, Zheng X, Liu G, Jia R, Xu J, Wu F, Jia C, Song J, Zhang L, Zhou P, Wang H, Yao Z, Liu Q, Yu Y, Zhou J. Bile acid receptor FXR promotes intestinal epithelial ferroptosis and subsequent ILC3 dysfunction in neonatal necrotizing enterocolitis. Immunity 2025; 58:683-700.e10. [PMID: 40023163 DOI: 10.1016/j.immuni.2025.02.003] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/21/2024] [Revised: 11/14/2024] [Accepted: 02/04/2025] [Indexed: 03/04/2025]
Abstract
Necrotizing enterocolitis (NEC) is a common pediatric emergency primarily afflicting preterm infants, yet its mechanisms remain to be fully understood. Here, we report that plasma fibroblast growth factor (FGF)19, a target of farnesoid X receptor (FXR), was positively correlated with the clinical parameters of NEC. NEC patients and the NEC murine model displayed abundant FXR in intestinal epithelial cells (IECs), which was restricted by microbiota-derived short-chain fatty acids (SCFAs) under homeostasis. Genetic deficiency of FXR in IECs caused remission of NEC. Mechanistically, FXR facilitated ferroptosis of IECs via targeting acyl-coenzyme A synthetase long-chain family member 4 (Acsl4). Lipid peroxides released by ferroptotic IECs suppressed interleukin (IL)-22 secretion from type 3 innate lymphoid cells (ILC3s), thereby exacerbating NEC. Intestinal FXR antagonist, ACSL4 inhibitor, and ferroptosis inhibitor ameliorated murine NEC. Furthermore, the elevated lipid peroxides in NEC patients were positively correlated with FGF19 and disease parameters. These observations demonstrate the therapeutic value of targeting intestinal FXR and ferroptosis in NEC treatment.
Collapse
MESH Headings
- Animals
- Ferroptosis/immunology
- Humans
- Enterocolitis, Necrotizing/metabolism
- Enterocolitis, Necrotizing/immunology
- Enterocolitis, Necrotizing/pathology
- Mice
- Receptors, Cytoplasmic and Nuclear/metabolism
- Receptors, Cytoplasmic and Nuclear/genetics
- Intestinal Mucosa/metabolism
- Intestinal Mucosa/immunology
- Intestinal Mucosa/pathology
- Infant, Newborn
- Lymphocytes/immunology
- Lymphocytes/metabolism
- Fibroblast Growth Factors/blood
- Fibroblast Growth Factors/metabolism
- Disease Models, Animal
- Mice, Inbred C57BL
- Coenzyme A Ligases/metabolism
- Mice, Knockout
- Female
- Male
- Immunity, Innate
Collapse
Affiliation(s)
- Yuxin Zhang
- Tianjin Institute of Immunology, Department of Immunology, School of Basic Medical Sciences, Tianjin Medical University, Key Laboratory of Immune Microenvironment and Disease (Ministry of Education), The Province and Ministry Co-sponsored Collaborative Innovation Center for Medical Epigenetics, International Joint Laboratory of Ocular Diseases (Ministry of Education), State Key Laboratory of Experimental Hematology, Tianjin 300070, China
| | - Yuchao Jing
- Tianjin Institute of Immunology, Department of Immunology, School of Basic Medical Sciences, Tianjin Medical University, Key Laboratory of Immune Microenvironment and Disease (Ministry of Education), The Province and Ministry Co-sponsored Collaborative Innovation Center for Medical Epigenetics, International Joint Laboratory of Ocular Diseases (Ministry of Education), State Key Laboratory of Experimental Hematology, Tianjin 300070, China; Department of Immunology, Basic Medical College, Changzhi 046000, China
| | - Juan He
- Provincial Key Laboratory of Research in Structure Birth Defect Disease and Department of Pediatric Surgery, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, Guangzhou 510623, China
| | - Rui Dong
- Tianjin Institute of Immunology, Department of Immunology, School of Basic Medical Sciences, Tianjin Medical University, Key Laboratory of Immune Microenvironment and Disease (Ministry of Education), The Province and Ministry Co-sponsored Collaborative Innovation Center for Medical Epigenetics, International Joint Laboratory of Ocular Diseases (Ministry of Education), State Key Laboratory of Experimental Hematology, Tianjin 300070, China
| | - Tongyang Li
- Tianjin Institute of Immunology, Department of Immunology, School of Basic Medical Sciences, Tianjin Medical University, Key Laboratory of Immune Microenvironment and Disease (Ministry of Education), The Province and Ministry Co-sponsored Collaborative Innovation Center for Medical Epigenetics, International Joint Laboratory of Ocular Diseases (Ministry of Education), State Key Laboratory of Experimental Hematology, Tianjin 300070, China
| | - Fang Li
- Department of Central Laboratory, Changzhi Medical College, Changzhi 046000, China
| | - Xiaoqing Zheng
- Laboratory of Immunity, Inflammation & Cancer, Department of Oncology, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, China
| | - Gaoyu Liu
- Laboratory of Immunity, Inflammation & Cancer, Department of Oncology, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, China
| | - Ran Jia
- Department of Clinical Laboratory, Children's Hospital of Fudan University, National Children's Medical Center, Shanghai 201102, China
| | - Jin Xu
- Department of Clinical Laboratory, Children's Hospital of Fudan University, National Children's Medical Center, Shanghai 201102, China
| | - Fan Wu
- Department of Neonatology, Guangzhou Key Laboratory of Neonatal Intestinal Diseases, The Third Affiliated Hospital of Guangzhou Medical University, Guangzhou 510150, Guangdong, China
| | - Chunhong Jia
- Department of Neonatology, Guangzhou Key Laboratory of Neonatal Intestinal Diseases, The Third Affiliated Hospital of Guangzhou Medical University, Guangzhou 510150, Guangdong, China
| | - Jin Song
- Department of Pediatric Surgery Maternal and Child Health Care of Changzhi, Changzhi 046011, China
| | - Lijuan Zhang
- Tianjin Institute of Immunology, Department of Immunology, School of Basic Medical Sciences, Tianjin Medical University, Key Laboratory of Immune Microenvironment and Disease (Ministry of Education), The Province and Ministry Co-sponsored Collaborative Innovation Center for Medical Epigenetics, International Joint Laboratory of Ocular Diseases (Ministry of Education), State Key Laboratory of Experimental Hematology, Tianjin 300070, China
| | - Pan Zhou
- Tianjin Institute of Immunology, Department of Immunology, School of Basic Medical Sciences, Tianjin Medical University, Key Laboratory of Immune Microenvironment and Disease (Ministry of Education), The Province and Ministry Co-sponsored Collaborative Innovation Center for Medical Epigenetics, International Joint Laboratory of Ocular Diseases (Ministry of Education), State Key Laboratory of Experimental Hematology, Tianjin 300070, China
| | - Haitao Wang
- Department of Oncology, The Second Hospital of Tianjin Medical University, Tianjin Key Laboratory of Precision Medicine for Sex Hormones and Diseases, Tianjin 300211, China
| | - Zhi Yao
- Tianjin Institute of Immunology, Department of Immunology, School of Basic Medical Sciences, Tianjin Medical University, Key Laboratory of Immune Microenvironment and Disease (Ministry of Education), The Province and Ministry Co-sponsored Collaborative Innovation Center for Medical Epigenetics, International Joint Laboratory of Ocular Diseases (Ministry of Education), State Key Laboratory of Experimental Hematology, Tianjin 300070, China
| | - Qiang Liu
- Tianjin Institute of Immunology, Department of Immunology, School of Basic Medical Sciences, Tianjin Medical University, Key Laboratory of Immune Microenvironment and Disease (Ministry of Education), The Province and Ministry Co-sponsored Collaborative Innovation Center for Medical Epigenetics, International Joint Laboratory of Ocular Diseases (Ministry of Education), State Key Laboratory of Experimental Hematology, Tianjin 300070, China; Department of Neurology, Tianjin Neurological Institute, Tianjin Medical University General Hospital, Tianjin 300050, China
| | - Ying Yu
- Tianjin Institute of Immunology, Department of Immunology, School of Basic Medical Sciences, Tianjin Medical University, Key Laboratory of Immune Microenvironment and Disease (Ministry of Education), The Province and Ministry Co-sponsored Collaborative Innovation Center for Medical Epigenetics, International Joint Laboratory of Ocular Diseases (Ministry of Education), State Key Laboratory of Experimental Hematology, Tianjin 300070, China; Department of Pharmacology, Tianjin Key Laboratory of Inflammatory Biology, School of Basic Medical Sciences, Tianjin Medical University, Tianjin 300070, China
| | - Jie Zhou
- Tianjin Institute of Immunology, Department of Immunology, School of Basic Medical Sciences, Tianjin Medical University, Key Laboratory of Immune Microenvironment and Disease (Ministry of Education), The Province and Ministry Co-sponsored Collaborative Innovation Center for Medical Epigenetics, International Joint Laboratory of Ocular Diseases (Ministry of Education), State Key Laboratory of Experimental Hematology, Tianjin 300070, China; Laboratory of Immunity, Inflammation & Cancer, Department of Oncology, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, China.
| |
Collapse
|
5
|
Liu R, Zhang J, Chen S, Xiao Y, Hu J, Zhou Z, Xie L. Intestinal mucosal immunity and type 1 diabetes: Non-negligible communication between gut and pancreas. Diabetes Obes Metab 2025; 27:1045-1064. [PMID: 39618164 PMCID: PMC11802406 DOI: 10.1111/dom.16101] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/28/2024] [Revised: 11/16/2024] [Accepted: 11/18/2024] [Indexed: 02/08/2025]
Abstract
Type 1 diabetes (T1D) is a chronic autoimmune disease characterized by T cell-mediated pancreatic β cell loss, resulting in lifelong absolute insulin deficiency and hyperglycaemia. Environmental factors are recognized as a key contributor to the development of T1D, with the gut serving as a primary interface for environmental stimuli. Recent studies have revealed that the alterations in the intestinal microenvironment profoundly affect host immune responses, contributing to the aetiology and pathogenesis of T1D. However, the dominant intestinal immune cells and the underlying mechanisms remain incompletely elucidated. In this review, we provide an overview of the possible mechanisms of the intestinal mucosal system that underpin the pathogenesis of T1D, shedding light on the roles of both non-classical and classical immune cells in T1D. Our goal is to gain insights into how modulating these immune components may hold potential implications for T1D prevention and provide novel perspectives for immune-mediated therapy.
Collapse
Affiliation(s)
- Ruonan Liu
- National Clinical Research Center for Metabolic Diseases, Key Laboratory of Diabetes Immunology (Central South University), Ministry of Education, and Department of Metabolism and EndocrinologyThe Second Xiangya Hospital of Central South UniversityChangshaChina
| | - Jing Zhang
- National Clinical Research Center for Metabolic Diseases, Key Laboratory of Diabetes Immunology (Central South University), Ministry of Education, and Department of Metabolism and EndocrinologyThe Second Xiangya Hospital of Central South UniversityChangshaChina
| | - Si Chen
- State Key Laboratory of Developmental Biology of Freshwater Fish, College of Life ScienceHunan Normal UniversityChangshaChina
| | - Yang Xiao
- National Clinical Research Center for Metabolic Diseases, Key Laboratory of Diabetes Immunology (Central South University), Ministry of Education, and Department of Metabolism and EndocrinologyThe Second Xiangya Hospital of Central South UniversityChangshaChina
| | - Jingyi Hu
- National Clinical Research Center for Metabolic Diseases, Key Laboratory of Diabetes Immunology (Central South University), Ministry of Education, and Department of Metabolism and EndocrinologyThe Second Xiangya Hospital of Central South UniversityChangshaChina
| | - Zhiguang Zhou
- National Clinical Research Center for Metabolic Diseases, Key Laboratory of Diabetes Immunology (Central South University), Ministry of Education, and Department of Metabolism and EndocrinologyThe Second Xiangya Hospital of Central South UniversityChangshaChina
| | - Lingxiang Xie
- National Clinical Research Center for Metabolic Diseases, Key Laboratory of Diabetes Immunology (Central South University), Ministry of Education, and Department of Metabolism and EndocrinologyThe Second Xiangya Hospital of Central South UniversityChangshaChina
| |
Collapse
|
6
|
Wang Y, Wang J, Liu G, Yi X, Wu J, Cao H, Zhang L, Zhou P, Fan Y, Yu Y, Liu Q, Yao Z, Wang H, Zhou J. NRP1 instructs IL-17-producing ILC3s to drive colitis progression. Cell Mol Immunol 2025; 22:161-175. [PMID: 39741194 PMCID: PMC11782674 DOI: 10.1038/s41423-024-01246-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/08/2024] [Accepted: 11/27/2024] [Indexed: 01/02/2025] Open
Abstract
Group 3 innate lymphoid cells (ILC3s) control tissue homeostasis and orchestrate mucosal inflammation; however, the precise mechanisms governing ILC3 activity are fully understood. Here, we identified the transmembrane protein neuropilin-1 (NRP1) as a positive regulator of interleukin (IL)-17-producing ILC3s in the intestine. NRP1 was markedly upregulated in intestinal mucosal biopsies from patients with inflammatory bowel disease (IBD) compared with healthy controls. Genetic deficiency of NRP1 reduces the frequency of ILC3s in the gut and impairs their production of IL-17A in an NF-κB signaling-dependent and cell-intrinsic manner. The diminished IL-17A production in ILC3s altered the composition of the microbiota and improved the outcome of dextran sodium sulfate (DSS)-induced colitis. Furthermore, pharmacological inhibition of NRP1 with EG00229 alleviated the severity of colitis. These observations demonstrated the critical role of NRP1 in the control of intestinal ILC3s, suggesting that NRP1 is a potential therapeutic target for IBD.
Collapse
Affiliation(s)
- Ying Wang
- Department of oncology, The Second Hospital of Tianjin Medical University; Tianjin Key Laboratory of Precision Medicine for Sex Hormones and Diseases; Tianjin Institute of Immunology, Department of Immunology, School of Basic Medical Sciences, Tianjin Medical University, Tianjin, China
- Key Laboratory of Immune Microenvironment and Disease (Ministry of Education), The Province and Ministry Co-sponsored Collaborative Innovation Center for Medical Epigenetics, International Joint Laboratory of Ocular Diseases (Ministry of Education), State Key Laboratory of Experimental Hematology, Tianjin, China
- Key Laboratory for Major Obstetric Diseases of Guangdong Province, Center of Reproductive Medicine, The Third Affiliated Hospital of Guangzhou Medical University, Guangzhou, China
| | - Jianye Wang
- Department of oncology, The Second Hospital of Tianjin Medical University; Tianjin Key Laboratory of Precision Medicine for Sex Hormones and Diseases; Tianjin Institute of Immunology, Department of Immunology, School of Basic Medical Sciences, Tianjin Medical University, Tianjin, China
- Key Laboratory of Immune Microenvironment and Disease (Ministry of Education), The Province and Ministry Co-sponsored Collaborative Innovation Center for Medical Epigenetics, International Joint Laboratory of Ocular Diseases (Ministry of Education), State Key Laboratory of Experimental Hematology, Tianjin, China
| | - Gaoyu Liu
- Department of oncology, The Second Hospital of Tianjin Medical University; Tianjin Key Laboratory of Precision Medicine for Sex Hormones and Diseases; Tianjin Institute of Immunology, Department of Immunology, School of Basic Medical Sciences, Tianjin Medical University, Tianjin, China
- Key Laboratory of Immune Microenvironment and Disease (Ministry of Education), The Province and Ministry Co-sponsored Collaborative Innovation Center for Medical Epigenetics, International Joint Laboratory of Ocular Diseases (Ministry of Education), State Key Laboratory of Experimental Hematology, Tianjin, China
- Division of Hematology/Oncology, Department of Pediatrics, The Seventh Affiliated Hospital, Sun Yat-sen University, Shenzhen, China
| | - Xianfu Yi
- Department of Bioinformatics, School of Basic Medical Sciences, Tianjin Medical University, Tianjin, China
| | - Jingyi Wu
- Department of Gastroenterology and Hepatology, General Hospital, Tianjin Medical University, Tianjin, China
| | - Hailong Cao
- Department of Gastroenterology and Hepatology, General Hospital, Tianjin Medical University, Tianjin, China
| | - Lijuan Zhang
- Department of oncology, The Second Hospital of Tianjin Medical University; Tianjin Key Laboratory of Precision Medicine for Sex Hormones and Diseases; Tianjin Institute of Immunology, Department of Immunology, School of Basic Medical Sciences, Tianjin Medical University, Tianjin, China
- Key Laboratory of Immune Microenvironment and Disease (Ministry of Education), The Province and Ministry Co-sponsored Collaborative Innovation Center for Medical Epigenetics, International Joint Laboratory of Ocular Diseases (Ministry of Education), State Key Laboratory of Experimental Hematology, Tianjin, China
| | - Pan Zhou
- Department of oncology, The Second Hospital of Tianjin Medical University; Tianjin Key Laboratory of Precision Medicine for Sex Hormones and Diseases; Tianjin Institute of Immunology, Department of Immunology, School of Basic Medical Sciences, Tianjin Medical University, Tianjin, China
- Key Laboratory of Immune Microenvironment and Disease (Ministry of Education), The Province and Ministry Co-sponsored Collaborative Innovation Center for Medical Epigenetics, International Joint Laboratory of Ocular Diseases (Ministry of Education), State Key Laboratory of Experimental Hematology, Tianjin, China
| | - Yong Fan
- Key Laboratory for Major Obstetric Diseases of Guangdong Province, Center of Reproductive Medicine, The Third Affiliated Hospital of Guangzhou Medical University, Guangzhou, China
| | - Ying Yu
- Department of Pharmacology, Tianjin Key Laboratory of Inflammatory Biology, School of Basic Medical Sciences, Tianjin Medical University, Tianjin, China
| | - Qiang Liu
- Department of Neurology, Tianjin Neurological Institute, Tianjin Institute of Immunology, Tianjin Medical University General Hospital, Tianjin, China
| | - Zhi Yao
- Department of oncology, The Second Hospital of Tianjin Medical University; Tianjin Key Laboratory of Precision Medicine for Sex Hormones and Diseases; Tianjin Institute of Immunology, Department of Immunology, School of Basic Medical Sciences, Tianjin Medical University, Tianjin, China
- Key Laboratory of Immune Microenvironment and Disease (Ministry of Education), The Province and Ministry Co-sponsored Collaborative Innovation Center for Medical Epigenetics, International Joint Laboratory of Ocular Diseases (Ministry of Education), State Key Laboratory of Experimental Hematology, Tianjin, China
| | - Haitao Wang
- Department of oncology, The Second Hospital of Tianjin Medical University; Tianjin Key Laboratory of Precision Medicine for Sex Hormones and Diseases; Tianjin Institute of Immunology, Department of Immunology, School of Basic Medical Sciences, Tianjin Medical University, Tianjin, China.
| | - Jie Zhou
- Department of oncology, The Second Hospital of Tianjin Medical University; Tianjin Key Laboratory of Precision Medicine for Sex Hormones and Diseases; Tianjin Institute of Immunology, Department of Immunology, School of Basic Medical Sciences, Tianjin Medical University, Tianjin, China.
- Key Laboratory of Immune Microenvironment and Disease (Ministry of Education), The Province and Ministry Co-sponsored Collaborative Innovation Center for Medical Epigenetics, International Joint Laboratory of Ocular Diseases (Ministry of Education), State Key Laboratory of Experimental Hematology, Tianjin, China.
| |
Collapse
|
7
|
Samalia PD, Solanki J, Kam J, Angelo L, Niederer RL. From Dysbiosis to Disease: The Microbiome's Influence on Uveitis Pathogenesis. Microorganisms 2025; 13:271. [PMID: 40005638 PMCID: PMC11857511 DOI: 10.3390/microorganisms13020271] [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: 12/17/2024] [Revised: 01/12/2025] [Accepted: 01/17/2025] [Indexed: 02/27/2025] Open
Abstract
The microbiome, comprising the diverse microbial communities inhabiting the human body, has emerged as a critical factor in regulating immune function and inflammation. The relationship between the microbiome and uveitis represents a promising frontier in ophthalmological research, with the microbiome increasingly implicated in disease onset and progression. Research has predominantly focused on the gut microbiome, with animal studies providing evidence that dysbiosis is a key factor in autoimmunity. As the understanding of the microbiome increases, so does the potential for developing innovative treatments that leverage the microbiome's impact on immune and inflammatory processes. Future research will be crucial for deciphering the complexities of the interaction between the microbiome and immune system and for creating effective microbiome-based therapies for those with uveitis. Incorporating microbiome research into clinical practice could transform how uveitis is managed, leading to better and more individualized approaches for management. This review discusses the current understanding of the microbiome-uveitis axis, the promise of microbiome-based diagnostics and therapeutics, and the critical need for large-scale, longitudinal studies. Unlocking the potential of microbiome-targeted approaches may revolutionize the management of uveitis and other inflammatory diseases.
Collapse
Affiliation(s)
- Priya D. Samalia
- Health New Zealand Auckland, Auckland 1051, New Zealand
- Department of Medicine, University of Otago, Dunedin 9016, New Zealand
| | | | - Joseph Kam
- Health New Zealand Auckland, Auckland 1051, New Zealand
- Department of Ophthalmology, University of Auckland, Auckland 1010, New Zealand
| | - Lize Angelo
- Department of Ophthalmology, University of Auckland, Auckland 1010, New Zealand
| | - Rachael L. Niederer
- Health New Zealand Auckland, Auckland 1051, New Zealand
- Department of Ophthalmology, University of Auckland, Auckland 1010, New Zealand
| |
Collapse
|
8
|
Unzueta-Medina JA, González-Chávez SA, Salas-Leiva JS, Silva-Sánchez SE, Pacheco-Tena C. Differential Composition and Structure of the Microbiota from Active and Inactive Stages of HLA-B27-associated Uveitis by Paired Fecal Metagenomes. Ocul Immunol Inflamm 2025; 33:56-64. [PMID: 38709227 DOI: 10.1080/09273948.2024.2346818] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/26/2023] [Revised: 04/17/2024] [Accepted: 04/19/2024] [Indexed: 05/07/2024]
Abstract
PURPOSE To compare the diversities and abundances of bacterial taxa in the microbiome of patients with HLA B27-positive acute anterior uveitis (AAU) in the active and inactive phases. METHODS An observational descriptive prospective and comparative study was conducted in ten HLA-B27-positive AAU patients (44.6 ± 13.4 years). The microbiome of the stool samples obtained in the active and inactive stages was analyzed by sequencing the V3 region of the 16S rRNA gene. RESULTS The differences in the bacteria profile between active and inactive stages in each individual were confirmed (p < 0.0001). Ten OTUs were found exclusively in the active phase of 90% of the individuals, suggesting a proinflammatory association. Blautia OUT_4 and Faecalibacterium OUT_2 abundances showed a direct relationship between abundance and severity of ocular inflammation. Two OTUs were exclusive of the inactive stage, suggesting an anti-inflammatory role. CONCLUSION The metagenomic profile of the fecal microbiota differs in the acute phase of the AAU compared to when the inflammation subsides, despite being the same individual and a short time-lapse. AAU is a fertile field for studying the connection between subtle rapid changes in microbiota and their systemic consequences.
Collapse
Affiliation(s)
- José Antonio Unzueta-Medina
- Laboratorio PABIOM, Facultad de Medicina y Ciencias Biomédicas, Universidad Autónoma de Chihuahua, Chihuahua, México
| | - Susana Aideé González-Chávez
- Laboratorio PABIOM, Facultad de Medicina y Ciencias Biomédicas, Universidad Autónoma de Chihuahua, Chihuahua, México
| | - Joan Sebastian Salas-Leiva
- Departamento de medio ambiente y energía, CONAHCyT, Centro de Investigación en Materiales Avanzados, Chihuahua, México
| | - Sandra Estela Silva-Sánchez
- Laboratorio PABIOM, Facultad de Medicina y Ciencias Biomédicas, Universidad Autónoma de Chihuahua, Chihuahua, México
| | - César Pacheco-Tena
- Laboratorio PABIOM, Facultad de Medicina y Ciencias Biomédicas, Universidad Autónoma de Chihuahua, Chihuahua, México
| |
Collapse
|
9
|
Chang YH, Yeh YM, Lee CC, Chiu CH, Chen HC, Hsueh YJ, Lee CW, Lien R, Chu SM, Chiang MC, Kang EYC, Chen KJ, Wang NK, Liu L, Hwang YS, Lai CC, Wu WC. Neonatal gut microbiota profile and the association with retinopathy of prematurity in preterm infants. Clin Exp Ophthalmol 2025; 53:54-66. [PMID: 39322810 DOI: 10.1111/ceo.14441] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/18/2024] [Revised: 09/03/2024] [Accepted: 09/07/2024] [Indexed: 09/27/2024]
Abstract
BACKGROUND To explore the role of gut microbiota in preterm infants at high risk of developing retinopathy of prematurity (ROP). METHODS Preterm infants with gestational age (GA) < 32 weeks and/or birth weight (BW) < 1500 g born between 2020 and 2021 were prospectively enrolled. Their faecal samples were collected and analysed at different postnatal ages of life using 16S rRNA gene sequencing on the Miseq platform. The main outcome measures were the microbial diversity, taxonomy, relative abundance, bacterial predicted functional analysis, and their associations with different ROP groups. Subgroup analyses were performed by matching their GA and BW across different ROP groups. RESULTS A total of 268 stool samples were collected from 110 preterm infants, including 13 with type 1 ROP, 44 with type 2 or mild ROP, and 53 without ROP. Type 1 ROP showed no significant difference in microbial diversity up to 8 postnatal weeks (p = 0.057), while type 2 and no ROP groups displayed increased diversity (p = 0.0015 and p = 0.049, respectively). Bifidobacterium genera was notably less abundant in type 1 ROP group at first postnatal week (p = 0.022) and remained low in subsequent weeks. Predicted functional analysis revealed enriched pathways in membrane transport, carbohydrate metabolism, amino acid metabolism, and replication and repair. CONCLUSIONS Reduced gut microbial diversity may be associated with ROP development in high-risk preterm infants. Further research is needed to comprehend how early-life Bifidobacterium reduction affects metabolism and how targeting microbiome may help for ROP prevention and management.
Collapse
Affiliation(s)
- Yin-Hsi Chang
- Department of Ophthalmology, Chang Gung Memorial Hospital, Linkou Medical Center, Taoyuan, Taiwan
- College of Medicine, Chang Gung University, Taoyuan, Taiwan
| | - Yuan-Ming Yeh
- Genomic Medicine Core Laboratory, Chang Gung Memorial Hospital, Linkou Medical Center, Taoyuan, Taiwan
- Graduate Institute of Health Industry Technology, Chang Gung University of Science and Technology, Taoyuan, Taiwan
| | - Chien-Chung Lee
- College of Medicine, Chang Gung University, Taoyuan, Taiwan
- Division of Neonatology, Department of Pediatrics, Chang Gung Memorial Hospital, Taoyuan, Taiwan
| | - Cheng-Hsun Chiu
- College of Medicine, Chang Gung University, Taoyuan, Taiwan
- Molecular Infectious Disease Research Center, Chang Gung Memorial Hospital, Taoyuan, Taiwan
- Division of Pediatric Infectious Diseases, Department of Pediatrics, Chang Gung Memorial Hospital, Taoyuan, Taiwan
| | - Hung-Chi Chen
- Department of Ophthalmology, Chang Gung Memorial Hospital, Linkou Medical Center, Taoyuan, Taiwan
- College of Medicine, Chang Gung University, Taoyuan, Taiwan
| | - Yi-Jen Hsueh
- Department of Ophthalmology, Chang Gung Memorial Hospital, Linkou Medical Center, Taoyuan, Taiwan
- Center for Tissue Engineering, Chang Gung Memorial Hospital, Linkou Medical Center, Taoyuan, Taiwan
| | - Chia-Wen Lee
- Department of Ophthalmology, Chang Gung Memorial Hospital, Linkou Medical Center, Taoyuan, Taiwan
| | - Reyin Lien
- College of Medicine, Chang Gung University, Taoyuan, Taiwan
- Division of Neonatology, Department of Pediatrics, Chang Gung Memorial Hospital, Taoyuan, Taiwan
| | - Shih-Ming Chu
- College of Medicine, Chang Gung University, Taoyuan, Taiwan
- Division of Neonatology, Department of Pediatrics, Chang Gung Memorial Hospital, Taoyuan, Taiwan
| | - Ming-Chou Chiang
- College of Medicine, Chang Gung University, Taoyuan, Taiwan
- Division of Neonatology, Department of Pediatrics, Chang Gung Memorial Hospital, Taoyuan, Taiwan
| | - Eugene Yu-Chuan Kang
- Department of Ophthalmology, Chang Gung Memorial Hospital, Linkou Medical Center, Taoyuan, Taiwan
- College of Medicine, Chang Gung University, Taoyuan, Taiwan
| | - Kuan-Jen Chen
- Department of Ophthalmology, Chang Gung Memorial Hospital, Linkou Medical Center, Taoyuan, Taiwan
- College of Medicine, Chang Gung University, Taoyuan, Taiwan
| | - Nan-Kai Wang
- Department of Ophthalmology, Chang Gung Memorial Hospital, Linkou Medical Center, Taoyuan, Taiwan
- College of Medicine, Chang Gung University, Taoyuan, Taiwan
- Department of Ophthalmology, Edward S. Harkness Eye Institute, Columbia University Irving Medical Center, Columbia University, New York, New York, USA
| | - Laura Liu
- Department of Ophthalmology, Chang Gung Memorial Hospital, Linkou Medical Center, Taoyuan, Taiwan
- School of Traditional Chinese Medicine, Chang Gung University, Taoyuan, Taiwan
| | - Yih-Shiou Hwang
- Department of Ophthalmology, Chang Gung Memorial Hospital, Linkou Medical Center, Taoyuan, Taiwan
- College of Medicine, Chang Gung University, Taoyuan, Taiwan
| | - Chi-Chun Lai
- College of Medicine, Chang Gung University, Taoyuan, Taiwan
- Department of Ophthalmology, Chang Gung Memorial Hospital, Keelung, Taiwan
| | - Wei-Chi Wu
- Department of Ophthalmology, Chang Gung Memorial Hospital, Linkou Medical Center, Taoyuan, Taiwan
- College of Medicine, Chang Gung University, Taoyuan, Taiwan
| |
Collapse
|
10
|
Richardson H, Yoon G, Moussa G, Kumar A, Harvey P. Ocular Manifestations of IBD: Pathophysiology, Epidemiology, and Iatrogenic Associations of Emerging Treatment Strategies. Biomedicines 2024; 12:2856. [PMID: 39767762 PMCID: PMC11673599 DOI: 10.3390/biomedicines12122856] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/20/2024] [Revised: 12/10/2024] [Accepted: 12/12/2024] [Indexed: 01/11/2025] Open
Abstract
Inflammatory bowel disease (IBD) is a complex, multisystemic disease and is associated with ocular pathology in 4-12% of patients. In general, ocular disease affects Crohn's patients more frequently than those with ulcerative colitis. Episcleritis and uveitis are the most common presentations, with episcleritis often correlating with IBD flares, whereas uveitis presents independently of IBD activity and, in some cases, may even alert clinicians to a new diagnosis of IBD. Corneal EIMs encompass a range of pathologies, such as the common and benign keratoconjunctivitis sicca (dry eye disease), which nevertheless causes significant patient discomfort, and the rarer condition of peripheral ulcerative keratitis, which warrants urgent review due to the risk of corneal perforation. Alongside EIMs, clinicians should also be aware of the iatrogenic consequences to the eye following treatment of IBD. Corticosteroids may cause cataracts, glaucoma, and-indirectly via hyperglycaemia-diabetic retinopathy. Methotrexate is irritating to ocular tissues and may cause conjunctivitis and blepharitis. Biologic medications, such as anti-TNFα agents, overlap in their use as treatment of both IBD and uveitis, and yet in some patients may also increase the risk of acute uveitis flares, as well as opportunistic, sight-threatening infections. With integrated care between gastroenterology and ophthalmology, patient outcomes can be improved by facilitating earlier detection and management of ocular disease. This narrative review summarises the ocular extraintestinal manifestations of IBD, including pathophysiology, epidemiology, and current treatment strategies.
Collapse
Affiliation(s)
- Holly Richardson
- Department of Undergraduate Medical Education, The Royal Wolverhampton NHS Trust, Wolverhampton WV10 0QP, UK
| | - Giho Yoon
- Department of Undergraduate Medical Education, The Royal Wolverhampton NHS Trust, Wolverhampton WV10 0QP, UK
| | - George Moussa
- Manchester Royal Eye Hospital, Manchester M13 9WL, UK;
| | - Aditi Kumar
- Department of Gastroenterology, The Royal Wolverhampton NHS Trust, Wolverhampton WV10 0QP, UK;
| | - Philip Harvey
- Department of Gastroenterology, The Royal Wolverhampton NHS Trust, Wolverhampton WV10 0QP, UK;
| |
Collapse
|
11
|
Xie X, Ren W, Zhou W, Zhang X, Deng X, Wang X, Wu Y, Lu Q. Genetic prediction of the effect of gut microbiota on uveitis via blood metabolites: A mediated Mendelian randomization investigation. Medicine (Baltimore) 2024; 103:e40922. [PMID: 39686482 PMCID: PMC11651470 DOI: 10.1097/md.0000000000040922] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/21/2024] [Accepted: 11/12/2024] [Indexed: 12/18/2024] Open
Abstract
The gut microbiota (GM) may be associated with uveitis. However, the causal relationship between the GM and uveitis and whether blood metabolites act as mediators of the GM remain unclear. We extracted the GM, blood metabolites, and uveitis data from genome-wide association study (GWAS) summary data. We used Mendelian randomization (MR) to investigate the causal relationships among GM, blood metabolites, and uveitis. The primary statistical method used was the inverse variance weighted (IVW) method. In addition, we used 2-sample MR, bidirectional MR, 2-step method and multiple MR to explore whether blood metabolites were mediators of the association between the GM and uveitis. After removing confounding factors, the abundances of the order Bacillales and the genus Holdemanella are risk factors for uveitis, and the abundances of Peptococcus and Ruminococcaceae UCG010 are protective factors. The inverse analysis revealed that uveitis affected 6 GM taxa - 4 positively and 2 negatively. In addition, N-methyl proline and 2-hydroxy sebacate were identified as risk factors for uveitis, and N-formy1 phenylalanine, 1-ribosyl-imidazole acetate, 1-palmitoyl-2-arachidonoyl-GPE (16:0/20:4) and alpha-ketoglutarate/pyruvate were identified as protective factors for uveitis. Finally, there was a causal association between 3 GM taxa and 6 blood metabolites, with 6 positive and 2 negative effects. N-methylproline possessed the greatest mediated effect (9.41%) between Ruminococcaceae UCG010 and uveitis. These results provide new insights into the pathogenesis of uveitis and offer a new approach to uveitis prevention and treatment from GM and blood metabolites perspective.
Collapse
Affiliation(s)
- Xiaodong Xie
- The Affiliated Peoples Hospital of Ningbo University, Ningbo, Zhejiang, China
- School of Ophthalmology and Optometry, Wenzhou Medical University, Wenzhou, Zhejiang, China
| | - Weina Ren
- The Affiliated Peoples Hospital of Ningbo University, Ningbo, Zhejiang, China
| | - Weiping Zhou
- The Affiliated Peoples Hospital of Ningbo University, Ningbo, Zhejiang, China
| | - Xixi Zhang
- The Affiliated Peoples Hospital of Ningbo University, Ningbo, Zhejiang, China
- School of Ophthalmology and Optometry, Wenzhou Medical University, Wenzhou, Zhejiang, China
| | - Xiaoyu Deng
- The Affiliated Peoples Hospital of Ningbo University, Ningbo, Zhejiang, China
- School of Ophthalmology and Optometry, Wenzhou Medical University, Wenzhou, Zhejiang, China
| | - Xinyi Wang
- The Affiliated Peoples Hospital of Ningbo University, Ningbo, Zhejiang, China
| | - Yufei Wu
- The Affiliated Peoples Hospital of Ningbo University, Ningbo, Zhejiang, China
- School of Ophthalmology and Optometry, Wenzhou Medical University, Wenzhou, Zhejiang, China
| | - Qinkang Lu
- The Affiliated Peoples Hospital of Ningbo University, Ningbo, Zhejiang, China
- School of Ophthalmology and Optometry, Wenzhou Medical University, Wenzhou, Zhejiang, China
| |
Collapse
|
12
|
Wu M, Fletcher EL, Chinnery HR, Downie LE, Mueller SN. Redefining our vision: an updated guide to the ocular immune system. Nat Rev Immunol 2024; 24:896-911. [PMID: 39215057 DOI: 10.1038/s41577-024-01064-y] [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: 07/01/2024] [Indexed: 09/04/2024]
Abstract
Balanced immune responses in the eyes are crucial to preserve vision. The ocular immune system has long been considered distinct, owing to the so-called 'immune privilege' of its component tissues. More recently, intravital imaging and transcriptomic techniques have reshaped scientific understanding of the ocular immune landscape, such as revealing the specialization of immune cell populations in the various tissues of the eye. As knowledge of the phenotypes of corneal and retinal immune cells has evolved, links to both the systemic immune system, and the central and peripheral nervous systems, have been identified. Using intravital imaging, T cells have recently been found to reside in, and actively patrol, the healthy human cornea. Disease-associated retinal microglia with links to retinal degeneration have also been identified. This Review provides an updated guide to the ocular immune system, highlighting current knowledge of the immune cells that are present in steady-state and specific diseased ocular tissues, as well as evidence for their relationship to systemic disease. In addition, we discuss emerging intravital imaging techniques that can be used to visualize immune cell morphology and dynamics in living human eyes and how these could be applied to advance understanding of the human immune system.
Collapse
Affiliation(s)
- Mengliang Wu
- Department of Optometry and Vision Sciences, The University of Melbourne, Carlton, Victoria, Australia
- Department of Microbiology and Immunology, The University of Melbourne, at The Peter Doherty Institute for Infection and Immunity, Melbourne, Victoria, Australia
| | - Erica L Fletcher
- Department of Anatomy and Physiology, The University of Melbourne, Carlton, Victoria, Australia
| | - Holly R Chinnery
- Department of Optometry and Vision Sciences, The University of Melbourne, Carlton, Victoria, Australia.
- Lions Eye Institute, Nedlands, Western Australia, Australia.
- Optometry, The University of Western Australia, Crawley, Western Australia, Australia.
| | - Laura E Downie
- Department of Optometry and Vision Sciences, The University of Melbourne, Carlton, Victoria, Australia.
| | - Scott N Mueller
- Department of Microbiology and Immunology, The University of Melbourne, at The Peter Doherty Institute for Infection and Immunity, Melbourne, Victoria, Australia.
| |
Collapse
|
13
|
Wang Y, Gao S, Cao F, Yang H, Lei F, Hou S. Ocular immune-related diseases: molecular mechanisms and therapy. MedComm (Beijing) 2024; 5:e70021. [PMID: 39611043 PMCID: PMC11604294 DOI: 10.1002/mco2.70021] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/29/2024] [Revised: 10/05/2024] [Accepted: 10/31/2024] [Indexed: 11/30/2024] Open
Abstract
Ocular immune-related diseases, represent a spectrum of conditions driven by immune system dysregulation, include but not limit to uveitis, diabetic retinopathy, age-related macular degeneration, Graves' ophthalmopathy, etc. The molecular and cellular mechanisms underlying these diseases are typically dysfunctioned immune responses targeting ocular tissues, resulting in inflammation and tissue damage. Recent advances have further elucidated the pivotal role of different immune responses in the development, progression, as well as management of various ocular immune diseases. However, there is currently a relative lack of connection between the cellular mechanisms and treatments of several immune-related ocular diseases. In this review, we discuss recent findings related to the immunopathogenesis of above-mentioned diseases. In particular, we summarize the different types of immune cells, inflammatory mediators, and associated signaling pathways that are involved in the pathophysiology of above-mentioned ophthalmopathies. Furthermore, we also discuss the future directions of utilizing anti-inflammatory regime in the management of these diseases. This will facilitate a better understanding of the pathogenesis of immune-related ocular diseases and provide new insights for future treatment approaches.
Collapse
Affiliation(s)
- Yakun Wang
- The First Affiliated Hospital of Chongqing Medical UniversityChongqingChina
- Beijing Institute of OphthalmologyBeijing Tongren Eye CenterBeijing Tongren Hospital, Beijing Ophthalmology & Visual Sciences Key Laboratory, Capital Medical UniversityBeijingChina
| | - Shangze Gao
- Beijing Institute of OphthalmologyBeijing Tongren Eye CenterBeijing Tongren Hospital, Beijing Ophthalmology & Visual Sciences Key Laboratory, Capital Medical UniversityBeijingChina
| | - Fan Cao
- Beijing Institute of OphthalmologyBeijing Tongren Eye CenterBeijing Tongren Hospital, Beijing Ophthalmology & Visual Sciences Key Laboratory, Capital Medical UniversityBeijingChina
| | - Hui Yang
- Beijing Institute of OphthalmologyBeijing Tongren Eye CenterBeijing Tongren Hospital, Beijing Ophthalmology & Visual Sciences Key Laboratory, Capital Medical UniversityBeijingChina
| | - Fengyang Lei
- Beijing Institute of OphthalmologyBeijing Tongren Eye CenterBeijing Tongren Hospital, Beijing Ophthalmology & Visual Sciences Key Laboratory, Capital Medical UniversityBeijingChina
| | - Shengping Hou
- Beijing Institute of OphthalmologyBeijing Tongren Eye CenterBeijing Tongren Hospital, Beijing Ophthalmology & Visual Sciences Key Laboratory, Capital Medical UniversityBeijingChina
| |
Collapse
|
14
|
Trojacka E, Izdebska J, Szaflik J, Przybek-Skrzypecka J. The Ocular Microbiome: Micro-Steps Towards Macro-Shift in Targeted Treatment? A Comprehensive Review. Microorganisms 2024; 12:2232. [PMID: 39597621 PMCID: PMC11596073 DOI: 10.3390/microorganisms12112232] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/24/2024] [Revised: 10/14/2024] [Accepted: 11/01/2024] [Indexed: 11/29/2024] Open
Abstract
A healthy ocular surface is inhabited by microorganisms that constitute the ocular microbiome. The core of the ocular microbiome is still a subject of debate. Numerous culture-dependent and gene sequencing studies have revealed the composition of the ocular microbiome. There was a confirmed correlation between the ocular microbiome and ocular surface homeostasis as well as between ocular dysbiosis and pathologies such as blepharitis, microbial keratitis, and conjunctivitis. However, the role of the ocular microbiome in the pathogenesis and treatment of ocular surface diseases remains unclear. This article reviews available data on the ocular microbiome and microbiota, their role in maintaining ocular homeostasis, and the impact of dysbiosis on several ophthalmic disorders. Moreover, we aimed to discuss potential treatment targets within the ocular microbiota.
Collapse
Affiliation(s)
- Ewelina Trojacka
- SPKSO Ophthalmic University Hospital in Warsaw, 03-709 Warsaw, Poland; (E.T.); (J.I.); (J.S.)
| | - Justyna Izdebska
- SPKSO Ophthalmic University Hospital in Warsaw, 03-709 Warsaw, Poland; (E.T.); (J.I.); (J.S.)
- Department of Ophthalmology, Medical University of Warsaw, 03-709 Warsaw, Poland
| | - Jacek Szaflik
- SPKSO Ophthalmic University Hospital in Warsaw, 03-709 Warsaw, Poland; (E.T.); (J.I.); (J.S.)
- Department of Ophthalmology, Medical University of Warsaw, 03-709 Warsaw, Poland
| | - J. Przybek-Skrzypecka
- SPKSO Ophthalmic University Hospital in Warsaw, 03-709 Warsaw, Poland; (E.T.); (J.I.); (J.S.)
- Department of Ophthalmology, Medical University of Warsaw, 03-709 Warsaw, Poland
| |
Collapse
|
15
|
Layús BI, Gómez MA, Cazorla SI, Rodriguez AV. A Postbiotic Formulation of Lactiplantibacillus plantarum CRL 759 Attenuates Endotoxin Induced Uveitis. Ocul Immunol Inflamm 2024; 32:1973-1982. [PMID: 38335476 DOI: 10.1080/09273948.2024.2310173] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/13/2023] [Revised: 01/17/2024] [Accepted: 01/21/2024] [Indexed: 02/12/2024]
Abstract
PURPOSE To evaluate the anti-inflammatory activity of a cell-free supernatant from Lactiplantibacillus plantarum CRL 759, in phosphate buffer modified according to Sorensen called POF-759. METHODS The activity of POF-759 administered by means of eye drops was evaluated on animals subcutaneously injected with the lipopolysaccharide animals in which uveitis was induced by a subcutaneous injection of lipopolysaccharide (EIU). Clinical signs of ocular inflammation, cytokines and proteins were examined in the aqueous humor. Additionally, cellular infiltration was evaluated by histopathological analysis. RESULTS The new postbiotic administered locally decreases signs of ocular damage, the number of infiltrating cells in the anterior and posterior chambers, the proinflammatory mediators and the proteins in the aqueous humor on mice with EIU. CONCLUSIONS Our results provide an impetus to relieve ocular inflammation and to identify and develop preventive and therapeutic approaches, to avoid deterioration and to maintain healthy eyes on inflammatory processes.
Collapse
Affiliation(s)
- Bárbara Ivana Layús
- Centro de Referencia para Lactobacilos (CERELA-CONICET), San Miguel de Tucumán, Argentina
| | - María Alejandra Gómez
- Servicio de Oftalomolgía, Hospital Ángel C. Padilla, San Miguel de Tucumán, Argentina
| | - Silvia Inés Cazorla
- Centro de Referencia para Lactobacilos (CERELA-CONICET), San Miguel de Tucumán, Argentina
- Cátedra de Inmunología, Facultad de Bioquímica, Química y Farmacia, Universidad Nacional de Tucumán, San Miguel de Tucumán, Argentina
| | - Ana Virginia Rodriguez
- Centro de Referencia para Lactobacilos (CERELA-CONICET), San Miguel de Tucumán, Argentina
| |
Collapse
|
16
|
Ullah Z, Tao Y, Mehmood A, Huang J. The Role of Gut Microbiota in the Pathogenesis of Glaucoma: Evidence from Bibliometric Analysis and Comprehensive Review. Bioengineering (Basel) 2024; 11:1063. [PMID: 39593723 PMCID: PMC11591249 DOI: 10.3390/bioengineering11111063] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/13/2024] [Revised: 10/08/2024] [Accepted: 10/19/2024] [Indexed: 11/28/2024] Open
Abstract
The relationship between gut microbiota and glaucoma has garnered significant interest, with emerging evidence suggesting that gut dysbiosis, inflammation, and immune mechanisms may contribute to glaucoma pathogenesis. Understanding these interactions through the gut-retina axis offers new insights into disease progression and potential therapeutic options. This study combines bibliometric analysis and literature review to evaluate research trends and key research areas related to gut microbiota's role in glaucoma. Our data were collected from the Web of Science Core Collection (WoSCC) and included the English original articles and reviews published between 1 January 2008, and 6 August 2024. Visual and statistical analyses were conducted using VOSviewer and CiteSpace. The analyses comprised 810 citations from leading journals, representing contributions from 23 countries/regions, 111 institutions, 40 journals, and 321 authors. Among the countries and regions involved, the USA and China were the leading contributors, publishing the most articles and being major research hubs. The Experimental Eye Research and Investigative Ophthalmology & Visual Science were the top journals in citation and co-citations that produced high-quality publications. The top 10 highly cited articles were published in high-ranking, top-quartile journals. The frequently occurring keywords were "glaucoma", "microbiota", "gut microbiota", "inflammation", "gut-retina axis", and "probiotics". Our study highlights the growing interest in the association between gut microbiota and glaucoma. It summarizes the possible ways gut microbiota dysbiosis, systemic and neuroinflammation, and autoimmune mechanisms contribute to glaucomatous pathogenesis. Future research should focus on mechanistic studies to elucidate the pathways linking gut microbiota to glaucoma development and progression.
Collapse
Affiliation(s)
- Zakir Ullah
- Department of Anatomy and Neurobiology, School of Basic Medical Sciences, Central South University, Changsha 410017, China; (Z.U.); (Y.T.)
- Taiwan International Graduate Program in Interdisciplinary Neuroscience, National Cheng Kung University and Academia Sinica, Taipei 115014, Taiwan
| | - Yuanyuan Tao
- Department of Anatomy and Neurobiology, School of Basic Medical Sciences, Central South University, Changsha 410017, China; (Z.U.); (Y.T.)
| | - Amina Mehmood
- Department of Microbiology and Immunology, College of Medicine, National Cheng Kung University, Tainan 701401, Taiwan;
| | - Jufang Huang
- Department of Anatomy and Neurobiology, School of Basic Medical Sciences, Central South University, Changsha 410017, China; (Z.U.); (Y.T.)
| |
Collapse
|
17
|
Zhao Y, Qiu P, Shen T. Gut microbiota and eye diseases: A review. Medicine (Baltimore) 2024; 103:e39866. [PMID: 39331938 PMCID: PMC11441905 DOI: 10.1097/md.0000000000039866] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/12/2024] [Accepted: 09/06/2024] [Indexed: 09/29/2024] Open
Abstract
Recent studies reveal that alterations in gut microbiota play a significant role in the progression of various diseases, including those affecting the eyes. The association between gut microbiota and eye health is an emerging focus of research. This review seeks to summarize the connection between the gut microbiome and specific eye conditions, such as ocular surface diseases, funduscopic disorders and immune-mediated eye diseases. Gut microbiota may influence these conditions by regulating the immune system or altering metabolites, thereby contributing to disease development. Strategies like probiotics, antibiotics, dietary modifications, and fecal transplants show promise in addressing these issues. This review examines how the gut microbiome may be linked to the pathogenesis of eye diseases, providing fresh therapeutic perspectives for ophthalmology.
Collapse
Affiliation(s)
- Yue Zhao
- School of Public Health, Hangzhou Medical College, Hangzhou, China
| | - Peijin Qiu
- Eye Center, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China
| | - Ting Shen
- Eye Center, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China
| |
Collapse
|
18
|
Haghshenas L, Banihashemi S, Malekzadegan Y, Catanzaro R, Moghadam Ahmadi A, Marotta F. Microbiome as an endocrine organ and its relationship with eye diseases: Effective factors and new targeted approaches. World J Gastrointest Pathophysiol 2024; 15:96446. [PMID: 39355345 PMCID: PMC11440246 DOI: 10.4291/wjgp.v15.i5.96446] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/07/2024] [Revised: 09/04/2024] [Accepted: 09/13/2024] [Indexed: 09/20/2024] Open
Abstract
Microbiome is an endocrine organ that refers to both the complicated biological system of microbial species that colonize our bodies and their genomes and surroundings. Recent studies confirm the connection between the microbiome and eye diseases, which are involved in the pathogenesis of eye diseases, including age-related macular disorders, diabetic retinopathy, glaucoma, retinitis pigmentosa, dry eye, and uveitis. The aim of this review is to investigate the microbiome in relation to eye health. First, a brief introduction of the characteristics of the gut microorganisms terms of composition and work, the role of dysbiosis, the gut microbiome and the eye microbiome in the progression of eye illnesses are highlighted, then the relationship among the microbiome and the function of the immune system and eye diseases, the role of inflammation and aging and the immune system, It has been reviewed and finally, the control and treatment goals of microbiome and eye diseases, the role of food factors and supplements, biotherapy and antibiotics in relation to microbiome and eye health have been reviewed.
Collapse
Affiliation(s)
- Leila Haghshenas
- Department of Clinical Bioinformatics, Harvard Medical School, Boston, MA 02115, United States
| | - Sara Banihashemi
- Department of Bioscience, School of Science and Technology, Nottingham Trend University, Nottingham NG1 4FQ, United Kingdom
| | - Yalda Malekzadegan
- Department of Microbiology, Saveh University of Medical Sciences, Saveh 3919676651, Iran
| | - Roberto Catanzaro
- Department of Clinical and Experimental Medicine, University of Catania, Catania 95123, Catania, Italy
| | - Amir Moghadam Ahmadi
- Department of Neuroimmunology, Thomas Jefferson University Hospital, Philadelphia, PA 19107, United States
| | - Francesco Marotta
- Department of Human Nutrition and Food Sciences, Texas Women University, Milano 20154, Italy
| |
Collapse
|
19
|
Sepulveda M, Rasic M, Lei YM, Kwan M, Chen L, Chen Y, Perkins D, Alegre ML. Coordinated elimination of bacterial taxa optimally attenuates alloimmunity and prolongs allograft survival. Am J Transplant 2024; 24:1573-1582. [PMID: 38519004 PMCID: PMC11390333 DOI: 10.1016/j.ajt.2024.03.020] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/10/2024] [Revised: 02/27/2024] [Accepted: 03/14/2024] [Indexed: 03/24/2024]
Abstract
This study aimed to dissect the relationship between specific gut commensal bacterial subgroups, their functional metabolic pathways, and their impact on skin allograft outcome and alloimmunity. We previously showed that oral broad-spectrum antibiotic (Abx) pretreatment in mice delayed skin, heart, and lung allograft rejection and dampened alloimmune responses. Here, rationally designed Abx combinations targeting major bacterial groups were used to elucidate their individual contribution to modulating alloimmune responses. Abx cocktails targeting intestinal gram-negative, gram-positive, or anaerobic/gram-positive bacteria by oral gavage, all delayed skin allograft rejection, and reduced alloreactive T cell priming to different extents. Notably, the most pronounced extension of skin allograft survival and attenuation of alloimmunity were achieved when all gut bacterial groups were simultaneously targeted. These results suggest a model in which the strength of the alloimmune response is additively tuned up by gut microbial diversity. Shotgun metagenomic sequencing enabled strain-level resolution and identified a shared commensal, Parabacteroides distasonis, as the most enriched following all Abx treatments. Oral administration of P.distasonis to mice harboring a diverse microbiota significantly prolonged skin allograft survival, identifying a probiotic with therapeutic benefit in transplantation.
Collapse
Affiliation(s)
- Martin Sepulveda
- Section of Rheumatology, Department of Medicine, University of Chicago, Chicago, Illinois, USA
| | - Mladen Rasic
- Department of Medicine, University of Illinois at Chicago, Chicago, Illinois, USA
| | - Yuk Man Lei
- Section of Rheumatology, Department of Medicine, University of Chicago, Chicago, Illinois, USA
| | - Montserrat Kwan
- Section of Rheumatology, Department of Medicine, University of Chicago, Chicago, Illinois, USA
| | - Luqiu Chen
- Section of Rheumatology, Department of Medicine, University of Chicago, Chicago, Illinois, USA
| | - Yang Chen
- Department of Medicine, University of Illinois at Chicago, Chicago, Illinois, USA
| | - David Perkins
- Department of Nephrology, University of Illinois at Chicago, Chicago, Illinois, USA
| | - Maria-Luisa Alegre
- Section of Rheumatology, Department of Medicine, University of Chicago, Chicago, Illinois, USA.
| |
Collapse
|
20
|
Yang Z, Tian D, Zhao X, Luo Y, Chen Y. The gut-retina axis: Uncovering the role of autoimmunity in glaucoma development. Heliyon 2024; 10:e35516. [PMID: 39170439 PMCID: PMC11336731 DOI: 10.1016/j.heliyon.2024.e35516] [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: 04/10/2024] [Revised: 07/27/2024] [Accepted: 07/30/2024] [Indexed: 08/23/2024] Open
Abstract
Glaucoma, a leading cause of irreversible blindness worldwide, is characterized by progressive loss of retinal ganglion cells (RGCs) and optic nerve damage. While elevated intraocular pressure (IOP) is the only known modifiable risk factor, normal-tension glaucoma (NTG) challenges this notion, suggesting other mechanisms beyond IOP may contribute to its development. Emerging evidence support the hypothesis that glaucoma may be an autoimmune disease. This review summarizes evidence for this hypothesis, focusing on the gut-retina axis. We discuss how antigens of gut bacterial prime peripheral T cells to breach the blood-retina barrier (BRB) and initiate cross-reactivity with ocular tissues via molecular mimicry, resulting in autoimmune RGC damage. Understanding these mechanisms may uncover new diagnostic biomarkers and therapeutic strategies targeting immune pathways alongside conventional IOP-lowering treatments.
Collapse
Affiliation(s)
- Zuyi Yang
- Eight-year Medical Doctor Program, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Dianzhe Tian
- Eight-year Medical Doctor Program, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Xinyu Zhao
- Department of Ophthalmology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, Beijing, 100730, China
- Key Lab of Ocular Fundus Diseases, Chinese Academy of Medical Sciences, Beijing, 100730, China
| | - Yunping Luo
- Department of Immunology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences, School of Basic Medicine, Peking Union Medical College, Beijing, China
- Collaborative Innovation Center for Biotherapy, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences, School of Basic Medicine, Peking Union Medical College, Beijing, China
| | - Youxin Chen
- Department of Ophthalmology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, Beijing, 100730, China
- Key Lab of Ocular Fundus Diseases, Chinese Academy of Medical Sciences, Beijing, 100730, China
| |
Collapse
|
21
|
Lima Barrientos J, Rojas Huerta A, Perez Mendoza A, Abreu Lopez BA, Salolin Vargas VP, Garcia Gonzalez OY, Saldaña Ruiz MA, Diarte E, Torijano Sarria AJ. The Relationship Between Gut Microbiome and Ophthalmologic Diseases: A Comprehensive Review. Cureus 2024; 16:e66808. [PMID: 39280427 PMCID: PMC11392598 DOI: 10.7759/cureus.66808] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 08/13/2024] [Indexed: 09/18/2024] Open
Abstract
The gut microbiome has been studied in recent years due to its association with various pathological pathways involved in different diseases, caused by its structure, function, and diversity alteration. The knowledge of this mechanism has generated interest in the investigation of its relationship with ophthalmologic diseases. Recent studies infer the existence of a gut-eye microbiota axis, influenced by the intestinal barrier, the blood-retina barrier, and the immune privilege of the eye. A common denominator among ophthalmologic diseases that have been related to this axis is inflammation, which is perpetuated by dysbiosis, causing an alteration of the intestinal barrier leading to increased permeability and, in turn, the release of components such as lipopolysaccharides (LPS), trimethylamine oxide (TMAO), and bacterial translocation. Some theories explain that depending on how the microbiome is composed, a different type of T cells will be activated, while others say that some bacteria can pre-activate T cells that mimic ocular structures and intestinal permeability that allow leakage of metabolites into the circulation. In addition, therapies such as probiotics, diet, and fecal microbiota transplantation (FMT) have been shown to favor the presence of a balanced population of microorganisms that limit inflammation and, in turn, generate a beneficial effect in these eye pathologies. This review aims to analyze how the intestinal microbiome influences various ocular pathologies based on microbial composition and pathological mechanisms, which may provide a better understanding of the diseases and their therapeutic potential.
Collapse
Affiliation(s)
| | - Anahi Rojas Huerta
- General Practice, Benemérita Universidad Autónoma de Puebla, Puebla, MEX
| | | | | | | | | | | | - Edna Diarte
- Medicine, Universidad Autónoma de Sinaloa, Culiacan, MEX
| | | |
Collapse
|
22
|
Morandi SC, Herzog EL, Munk M, Kreuzer M, Largiadèr CR, Wolf S, Zinkernagel M, Zysset-Burri DC. The gut microbiome and HLA-B27-associated anterior uveitis: a case-control study. J Neuroinflammation 2024; 21:120. [PMID: 38715051 PMCID: PMC11077820 DOI: 10.1186/s12974-024-03109-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/20/2023] [Accepted: 04/22/2024] [Indexed: 05/12/2024] Open
Abstract
BACKGROUND The human gut microbiome (GM) is involved in inflammation and immune response regulation. Dysbiosis, an imbalance in this ecosystem, facilitates pathogenic invasion, disrupts immune equilibrium, and potentially triggers diseases including various human leucocyte antigen (HLA)-B27-associated autoinflammatory and autoimmune diseases such as inflammatory bowel disease (IBD) and spondyloarthropathy (SpA). This study assesses compositional and functional alterations of the GM in patients with HLA-B27-associated non-infectious anterior uveitis (AU) compared to healthy controls. METHODS The gut metagenomes of 20 patients with HLA-B27-associated non-infectious AU, 21 age- and sex-matched HLA-B27-negative controls, and 6 HLA-B27-positive healthy controls without a history of AU were sequenced using the Illumina NovaSeq 6000 platform for whole metagenome shotgun sequencing. To identify taxonomic and functional features with significantly different relative abundances between groups and to identify associations with clinical metadata, the multivariate association by linear models (MaAsLin) R package was applied. RESULTS Significantly higher levels of the Eubacterium ramulus species were found in HLA-B27-negative controls (p = 0.0085, Mann-Whitney U-test). No significant differences in microbial composition were observed at all other taxonomic levels. Functionally, the lipid IVA biosynthesis pathway was upregulated in patients (p < 0.0001, Mann-Whitney U-test). A subgroup analysis comparing patients with an active non-infectious AU to their age- and sex-matched HLA-B27-negative controls, showed an increase of the species Phocaeicola vulgatus in active AU (p = 0.0530, Mann-Whitney U-test). An additional analysis comparing AU patients to age- and sex-matched HLA-B27-positive controls, showed an increase of the species Bacteroides caccae in controls (p = 0.0022, Mann-Whitney U-test). CONCLUSION In our cohort, non-infectious AU development is associated with compositional and functional alterations of the GM. Further research is needed to assess the causality of these associations, offering potentially novel therapeutic strategies.
Collapse
Affiliation(s)
- Sophia C Morandi
- Department of Ophthalmology, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland.
- Department for BioMedical Research, University of Bern, Bern, Switzerland.
| | - Elio L Herzog
- Department of Ophthalmology, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland
- Graduate School for Cellular and Biomedical Sciences, University of Bern, Bern, Switzerland
| | - Marion Munk
- Department of Ophthalmology, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland
| | - Marco Kreuzer
- Department for BioMedical Research, University of Bern, Bern, Switzerland
- Interfaculty Bioinformatics Unit, University of Bern, Bern, Switzerland
| | - Carlo R Largiadèr
- Department of Clinical Chemistry, Bern University Hospital, Inselspital, University of Bern, Bern, Switzerland
| | - Sebastian Wolf
- Department of Ophthalmology, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland
- Department for BioMedical Research, University of Bern, Bern, Switzerland
| | - Martin Zinkernagel
- Department of Ophthalmology, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland
- Department for BioMedical Research, University of Bern, Bern, Switzerland
| | - Denise C Zysset-Burri
- Department of Ophthalmology, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland
- Department for BioMedical Research, University of Bern, Bern, Switzerland
| |
Collapse
|
23
|
Bordbar A, Manches O, Nowatzky J. Biology of HLA class I associated inflammatory diseases. Best Pract Res Clin Rheumatol 2024; 38:101977. [PMID: 39085016 PMCID: PMC11441793 DOI: 10.1016/j.berh.2024.101977] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/04/2024] [Revised: 07/15/2024] [Accepted: 07/15/2024] [Indexed: 08/02/2024]
Abstract
Human leukocyte antigen (HLA) class I association is a well-established feature of common and uncommon inflammatory diseases, but it is unknown whether it impacts the pathogenesis of these disorders. The "arthritogenic peptide" hypothesis proposed initially for HLA-B27-associated ankylosing spondylitis (AS) seems the most intuitive to serve as a model for other HLA class I-associated diseases, but evidence supporting it has been scarce. Recent technological advances and the discovery of epistatic relationships between disease-associated HLA class I and endoplasmic reticulum aminopeptidase (ERAP) coding variants have led to the generation of new data and conceptual approaches to the problem requiring its re-examination. Continued success in these endeavors holds promise to resolve a Gordian Knot in human immunobiology. It may ultimately benefit patients by enabling the development of new therapies and precision tools for assessing disease risk and predicting treatment responses.
Collapse
Affiliation(s)
- Ali Bordbar
- New York University Grossman School of Medicine, Department of Medicine, New York, NY, USA
| | - Olivier Manches
- New York University Grossman School of Medicine, Department of Medicine, New York, NY, USA
| | - Johannes Nowatzky
- New York University Grossman School of Medicine, Department of Medicine, New York, NY, USA; New York University Grossman School of Medicine, Department of Pathology, USA; New York University Grossman School of Medicine, Department of Medicine Division of Rheumatology, NYU Langone Ocular Rheumatology Program, New York, NY, USA; New York University Grossman School of Medicine, Department of Medicine, Division of Rheumatology, NYU Langone Center for Behçet's Disease, New York, NY, USA.
| |
Collapse
|
24
|
Peng S, Li JJ, Song W, Li Y, Zeng L, Liang Q, Wen X, Shang H, Liu K, Peng P, Xue W, Zou B, Yang L, Liang J, Zhang Z, Guo S, Chen T, Li W, Jin M, Xing XB, Wan P, Liu C, Lin H, Wei H, Lee RWJ, Zhang F, Wei L. CRB1-associated retinal degeneration is dependent on bacterial translocation from the gut. Cell 2024; 187:1387-1401.e13. [PMID: 38412859 DOI: 10.1016/j.cell.2024.01.040] [Citation(s) in RCA: 5] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/10/2021] [Revised: 07/07/2023] [Accepted: 01/25/2024] [Indexed: 02/29/2024]
Abstract
The Crumbs homolog 1 (CRB1) gene is associated with retinal degeneration, most commonly Leber congenital amaurosis (LCA) and retinitis pigmentosa (RP). Here, we demonstrate that murine retinas bearing the Rd8 mutation of Crb1 are characterized by the presence of intralesional bacteria. While normal CRB1 expression was enriched in the apical junctional complexes of retinal pigment epithelium and colonic enterocytes, Crb1 mutations dampened its expression at both sites. Consequent impairment of the outer blood retinal barrier and colonic intestinal epithelial barrier in Rd8 mice led to the translocation of intestinal bacteria from the lower gastrointestinal (GI) tract to the retina, resulting in secondary retinal degeneration. Either the depletion of bacteria systemically or the reintroduction of normal Crb1 expression colonically rescued Rd8-mutation-associated retinal degeneration without reversing the retinal barrier breach. Our data elucidate the pathogenesis of Crb1-mutation-associated retinal degenerations and suggest that antimicrobial agents have the potential to treat this devastating blinding disease.
Collapse
Affiliation(s)
- Shanzhen Peng
- State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangzhou 510060, China
| | - Jing Jing Li
- State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangzhou 510060, China
| | - Wanying Song
- State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangzhou 510060, China
| | - Ye Li
- State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangzhou 510060, China
| | - Lei Zeng
- State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangzhou 510060, China
| | - Qiaoxing Liang
- State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangzhou 510060, China
| | - Xiaofeng Wen
- School of Pharmaceutical Sciences, Southern Medical University, Guangzhou 510000, China
| | - Haitao Shang
- Precision Medicine Institute, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou 510080, China
| | - Keli Liu
- State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangzhou 510060, China
| | - Peiyao Peng
- State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangzhou 510060, China
| | - Wei Xue
- State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangzhou 510060, China
| | - Bin Zou
- State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangzhou 510060, China
| | - Liu Yang
- State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangzhou 510060, China
| | - Juanran Liang
- State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangzhou 510060, China
| | - Zhihui Zhang
- State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangzhou 510060, China; Tianjin Medical University Eye Hospital, Eye Institute & School of Optometry and Ophthalmology, Tianjin 300384, China
| | - Shixin Guo
- State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangzhou 510060, China
| | - Tingting Chen
- State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangzhou 510060, China
| | - Wenxuan Li
- State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangzhou 510060, China; Department of Biostatistics, Yale School of Public Health, New Haven, CT 06510, USA
| | - Ming Jin
- Department of Ophthalmology, China-Japan Friendship Hospital, Beijing 10029, China
| | - Xiang-Bin Xing
- Department of Gastroenterology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou 510000, China
| | - Pengxia Wan
- Department of Ophthalmology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou 510000, China
| | - Chunqiao Liu
- State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangzhou 510060, China
| | - Haotian Lin
- State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangzhou 510060, China
| | - Hong Wei
- Precision Medicine Institute, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou 510080, China.
| | - Richard W J Lee
- UCL Institute of Ophthalmology and Moorfields Eye Hospital NHS Foundation Trust, London, UK.
| | - Feng Zhang
- State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangzhou 510060, China.
| | - Lai Wei
- State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangzhou 510060, China; Guangdong Provincial Key Laboratory of Allergy & Clinical Immunology, The Second Affiliated Hospital, Guangzhou Medical University, Guangzhou 510260, China; The First Affiliated Hospital, Department of Ophthalmology, University of South China, Hengyang 421001, Hunan, China.
| |
Collapse
|
25
|
Fukui C, Yamana S, Xue Y, Shirane M, Tsutsui H, Asahara K, Yoshitomi K, Ito T, Lestari T, Hasegawa E, Yawata N, Takeda A, Sonoda KH, Shibata K. Functions of mucosal associated invariant T cells in eye diseases. Front Immunol 2024; 15:1341180. [PMID: 38440736 PMCID: PMC10911089 DOI: 10.3389/fimmu.2024.1341180] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/20/2023] [Accepted: 01/29/2024] [Indexed: 03/06/2024] Open
Abstract
Mucosal-associated invariant T (MAIT) cells are a unique subset of T cells that recognizes metabolites derived from the vitamin B2 biosynthetic pathway. Since the identification of cognate antigens for MAIT cells, knowledge of the functions of MAIT cells in cancer, autoimmunity, and infectious diseases has been rapidly expanding. Recently, MAIT cells have been found to contribute to visual protection against autoimmunity in the eye. The protective functions of MAIT cells are induced by T-cell receptor (TCR)-mediated activation. However, the underlying mechanisms remain unclear. Thus, this mini-review aims to discuss our findings and the complexity of MAIT cell-mediated immune regulation in the eye.
Collapse
Affiliation(s)
- Chihiro Fukui
- Department of Ophthalmology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Satoshi Yamana
- Department of Ophthalmology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Yanqi Xue
- Department of Ophthalmology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Mariko Shirane
- Department of Ophthalmology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Hiroki Tsutsui
- Department of Ophthalmology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Kenichiro Asahara
- Department of Ophthalmology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Keiko Yoshitomi
- Department of Ophthalmology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Takako Ito
- Department of Ophthalmology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Tantri Lestari
- Department of Ophthalmology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Eiichi Hasegawa
- Department of Ophthalmology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Nobuyo Yawata
- Department of Ocular Pathology and Imaging Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Atsunobu Takeda
- Department of Ophthalmology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Koh-Hei Sonoda
- Department of Ophthalmology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Kensuke Shibata
- Department of Ocular Pathology and Imaging Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
- Department of Microbiology and Immunology, Graduate School of Medicine, Yamaguchi University, Ube, Japan
- Department of Molecular Immunology, Research Institute for Microbial Diseases, Osaka University, Suita, Japan
| |
Collapse
|
26
|
Sun C, Zhu D, Zhu Q, He Z, Lou Y, Chen D. The significance of gut microbiota in the etiology of autoimmune hepatitis: a narrative review. Front Cell Infect Microbiol 2024; 14:1337223. [PMID: 38404291 PMCID: PMC10884129 DOI: 10.3389/fcimb.2024.1337223] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/12/2023] [Accepted: 01/04/2024] [Indexed: 02/27/2024] Open
Abstract
Autoimmune hepatitis (AIH) is a chronic inflammatory disease of the liver that is mediated by autoimmunity and has complex pathogenesis. Its prevalence has increased globally. Since the liver is the first organ to be exposed to harmful substances, such as gut-derived intestinal microbiota and its metabolites, gut health is closely related to liver health, and the "liver-gut axis" allows abnormalities in the gut microbiota to influence the development of liver-related diseases such as AIH. Changes in the composition of the intestinal microbiota and its resultant disruption of the intestinal barrier and microbial transport are involved in multiple ways in the disruption of immune homeostasis and inflammation, thereby influencing the development of AIH. In terms of the mechanisms involved in immune, the gut microbiota or its metabolites, which is decreased in secondary bile acids, short-chain fatty acids (SCFAs), and polyamines, and increased in lipopolysaccharide (LPS), branched-chain amino acids (BCAA), tryptophan metabolite, amino acid, and bile acid, can disrupt immune homeostasis by activating various immune cells and immune-related signaling pathways, resulting in aberrant activation of the immune system. Clarifying this mechanism has significant clinical implications for the treatment of AIH with drugs that target intestinal microbiota and related signaling pathways. Therefore, this narrative review summarizes the progress in exploring the involvement of gut microbiota in the pathogenesis of AIH, with the aim of helping to improve the precise targeting of therapeutic treatments against AIH for the benefit of clinical AIH treatment.
Collapse
Affiliation(s)
- Chen Sun
- Clinical Research Center, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Dongzi Zhu
- Department of General Surgery, Shanghai Ninth People’s Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Qi Zhu
- Department of General Surgery, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Zeping He
- Department of General Surgery, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Yichao Lou
- Department of General Surgery, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Desheng Chen
- Department of General Surgery, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| |
Collapse
|
27
|
Avendaño-Monje CL, Cordero-Coma M, Mauriz JL, Calleja-Antolín S, Fonollosa A, Garrote Llordén A, Martin García-Sancho J, Sánchez-Salazar MI, Ruiz de Morales JG. Anti-retinal Antibodies in Sarcoidosis. Ocul Immunol Inflamm 2024; 32:141-147. [PMID: 36240484 DOI: 10.1080/09273948.2022.2129693] [Citation(s) in RCA: 4] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/02/2022] [Accepted: 09/20/2022] [Indexed: 10/17/2022]
Abstract
PURPOSE To measure, characterize, and evaluate the clinical significance of anti-retinal antibodies in patients with sarcoid uveitis. SUBJECTS/METHODS Prospective study of anti-retinal antibodies in 45 patients with biopsy-proven sarcoidosis (25 with and 20 without uveitis). Results were compared with patients with confirmed infectious uveitis (n = 40) and non-infectious uveitis (n = 40). RESULTS Among sarcoidosis patients, anti-retinal antibodies were positive in 23/25 patients with uveitis and in 15/20 without uveitis [P = ns]. The most common antigens recognized were carbonic anhydrase II (14/23) and α-enolase (6/23). Anti-carbonic anhydrase II autoantibodies were infrequently detected in sarcoidosis patients without uveitis (2 out 15, P < .001), in patients with infectious uveitis (1 out 18, P < .001), and in patients with non-infectious uveitis (8 out 37, P < .001). CONCLUSIONS Anti-retinal antibodies recognizing carbonic anhydrase II are common in sarcoid uveitis. Although not fully sensitive and specific, they might be a useful non-invasive diagnostic tool for the diagnosis of sarcoid uveitis.
Collapse
Affiliation(s)
- Carmen L Avendaño-Monje
- Immunology Service and Uveitis Unit, University Hospital of León, León, Spain
- Instituto de Biomedicina (IBIOMED), University of León, León, Spain
| | - Miguel Cordero-Coma
- Instituto de Biomedicina (IBIOMED), University of León, León, Spain
- Ophthalmology Service and Uveitis Unit, University Hospital of León, León, Spain
| | - José L Mauriz
- Instituto de Biomedicina (IBIOMED), University of León, León, Spain
| | | | - Alex Fonollosa
- Ophthalmology Service, Cruces University Hospital, Barakaldo, Spain
| | - Ana Garrote Llordén
- Ophthalmology Service and Uveitis Unit, University Hospital of León, León, Spain
| | | | | | - José G Ruiz de Morales
- Immunology Service and Uveitis Unit, University Hospital of León, León, Spain
- Instituto de Biomedicina (IBIOMED), University of León, León, Spain
- Immunology Service, University Hospital of León, Altos de Nava S/N, León, Spain
| |
Collapse
|
28
|
Yin M, Smith JA, Chou M, Chan J, Jittayasothorn Y, Gould DB, Caspi RR, Anderson MS, DeFranco AL. Tracking the role of Aire in immune tolerance to the eye with a TCR transgenic mouse model. Proc Natl Acad Sci U S A 2024; 121:e2311487121. [PMID: 38261611 PMCID: PMC10835137 DOI: 10.1073/pnas.2311487121] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/06/2023] [Accepted: 12/04/2023] [Indexed: 01/25/2024] Open
Abstract
Roughly one-half of mice with partial defects in two immune tolerance pathways (AireGW/+Lyn-/- mice) spontaneously develop severe damage to their retinas due to T cell reactivity to Aire-regulated interphotoreceptor retinoid-binding protein (IRBP). Single-cell T cell receptor (TCR) sequencing of CD4+ T cells specific for a predominate epitope of IRBP showed a remarkable diversity of autoantigen-specific TCRs with greater clonal expansions in mice with disease. TCR transgenic mice made with an expanded IRBP-specific TCR (P2.U2) of intermediate affinity exhibited strong but incomplete negative selection of thymocytes. This negative selection was absent in IRBP-/- mice and greatly defective in AireGW/+ mice. Most P2.U2+/- mice and all P2.U.2+/-AireGW/+ mice rapidly developed inflammation of the retina and adjacent uvea (uveitis). Aire-dependent IRBP expression in the thymus also promoted Treg differentiation, but the niche for this fate determination was small, suggesting differences in antigen presentation leading to negative selection vs. thymic Treg differentiation and a stronger role for negative selection in preventing autoimmune disease in the retina.
Collapse
Affiliation(s)
- Mianmian Yin
- Department of Microbiology and Immunology, University of California, San Francisco, San Francisco, CA94143
| | - Jennifer A. Smith
- Diabetes Center, University of California, San Francisco, San Francisco, CA94143
| | - Marissa Chou
- Department of Microbiology and Immunology, University of California, San Francisco, San Francisco, CA94143
| | - Jackie Chan
- Department of Microbiology and Immunology, University of California, San Francisco, San Francisco, CA94143
| | | | - Douglas B. Gould
- Department of Ophthalmology, Institute for Human Genetics, University of California, San Francisco, San Francisco, CA94143
- Department of Anatomy, Cardiovascular Research Institute, Bakar Aging Research Institute, and Institute for Human Genetics, University of California, San Francisco, San Francisco, CA94143
| | - Rachel R. Caspi
- Laboratory of Immunology, National Eye Institute, NIH, Bethesda, MD20892-1857
| | - Mark S. Anderson
- Diabetes Center, University of California, San Francisco, San Francisco, CA94143
- Department of Medicine, University of California, San Francisco, San Francisco, CA94143
| | - Anthony L. DeFranco
- Department of Microbiology and Immunology, University of California, San Francisco, San Francisco, CA94143
| |
Collapse
|
29
|
Migliorisi G, Vella G, Dal Buono A, Gabbiadini R, Busacca A, Loy L, Bezzio C, Vinciguerra P, Armuzzi A. Ophthalmological Manifestations in Inflammatory Bowel Diseases: Keep an Eye on It. Cells 2024; 13:142. [PMID: 38247834 PMCID: PMC10814681 DOI: 10.3390/cells13020142] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2023] [Revised: 12/31/2023] [Accepted: 01/09/2024] [Indexed: 01/23/2024] Open
Abstract
BACKGROUND AND AIMS Inflammatory bowel diseases (IBD) are multifactorial chronic inflammatory disorders affecting the gastrointestinal tract. However, a broad spectrum of extraintestinal manifestations (EIMs) is associated with IBD, affecting several organs and systems, such as the skin, musculoskeletal and hepatobiliary systems, and, not least, the eye. Approximately 10% of IBD patients can develop ocular EIMs (O-EIMs) with a higher prevalence in Crohn's disease (CD). Eye-redness, photophobia, pain, and blurred vision are the common symptoms, with a wide rate of severity and clinical impact on the quality of life. This narrative review aims to summarize the prevalence, pathogenesis, and current evidence-based management of O-EIMs, underlying the importance of a holistic approach and specialties collaboration for a prompt diagnosis and treatment. METHODS PubMed was searched up to December 2023 to identify relevant studies investigating the pathogenesis, epidemiology, and treatment of O-EIMs in IBD patients. RESULTS The mechanisms underlying O-EIMs are partially unknown, encompassing immune dysregulation, shared antigens between the eye and the gut, genetic predisposition, and systemic inflammation driven by high levels of interleukins and cytokines in IBD patients. The complexity of O-EIMs' pathogenesis reflects in the management of these conditions, varying from topical and systemic steroids to immunomodulatory molecules and biologic therapy, such as anti-tumor necrosis factor (TNF)-alpha. A multidisciplinary approach is the backbone of the management of O-EIMs.
Collapse
Affiliation(s)
- Giulia Migliorisi
- IBD Center, IRCCS Humanitas Research Hospital, Via Manzoni 56, Rozzano, 20089 Milan, Italy; (G.M.); (A.D.B.); (R.G.); (A.B.); (L.L.); (C.B.)
- Department of Biomedical Sciences, Humanitas University, Via Rita Levi Montalcini 4, Pieve Emanuele, 20072 Milan, Italy;
| | - Giovanna Vella
- Department of Ophtalmology, IRCCS Humanitas Research Hospital, Via Manzoni 56, Rozzano, 20089 Milan, Italy;
| | - Arianna Dal Buono
- IBD Center, IRCCS Humanitas Research Hospital, Via Manzoni 56, Rozzano, 20089 Milan, Italy; (G.M.); (A.D.B.); (R.G.); (A.B.); (L.L.); (C.B.)
| | - Roberto Gabbiadini
- IBD Center, IRCCS Humanitas Research Hospital, Via Manzoni 56, Rozzano, 20089 Milan, Italy; (G.M.); (A.D.B.); (R.G.); (A.B.); (L.L.); (C.B.)
| | - Anita Busacca
- IBD Center, IRCCS Humanitas Research Hospital, Via Manzoni 56, Rozzano, 20089 Milan, Italy; (G.M.); (A.D.B.); (R.G.); (A.B.); (L.L.); (C.B.)
| | - Laura Loy
- IBD Center, IRCCS Humanitas Research Hospital, Via Manzoni 56, Rozzano, 20089 Milan, Italy; (G.M.); (A.D.B.); (R.G.); (A.B.); (L.L.); (C.B.)
| | - Cristina Bezzio
- IBD Center, IRCCS Humanitas Research Hospital, Via Manzoni 56, Rozzano, 20089 Milan, Italy; (G.M.); (A.D.B.); (R.G.); (A.B.); (L.L.); (C.B.)
- Department of Biomedical Sciences, Humanitas University, Via Rita Levi Montalcini 4, Pieve Emanuele, 20072 Milan, Italy;
| | - Paolo Vinciguerra
- Department of Biomedical Sciences, Humanitas University, Via Rita Levi Montalcini 4, Pieve Emanuele, 20072 Milan, Italy;
- Department of Ophtalmology, IRCCS Humanitas Research Hospital, Via Manzoni 56, Rozzano, 20089 Milan, Italy;
| | - Alessandro Armuzzi
- IBD Center, IRCCS Humanitas Research Hospital, Via Manzoni 56, Rozzano, 20089 Milan, Italy; (G.M.); (A.D.B.); (R.G.); (A.B.); (L.L.); (C.B.)
- Department of Biomedical Sciences, Humanitas University, Via Rita Levi Montalcini 4, Pieve Emanuele, 20072 Milan, Italy;
| |
Collapse
|
30
|
Galván-Peña S, Zhu Y, Hanna BS, Mathis D, Benoist C. A dynamic atlas of immunocyte migration from the gut. Sci Immunol 2024; 9:eadi0672. [PMID: 38181094 PMCID: PMC10964343 DOI: 10.1126/sciimmunol.adi0672] [Citation(s) in RCA: 17] [Impact Index Per Article: 17.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2023] [Accepted: 12/06/2023] [Indexed: 01/07/2024]
Abstract
Dysbiosis in the gut microbiota affects several systemic diseases, possibly by driving the migration of perturbed intestinal immunocytes to extraintestinal tissues. Combining Kaede photoconvertible mice and single-cell genomics, we generated a detailed map of migratory trajectories from the colon, at baseline, and in several models of intestinal and extraintestinal inflammation. All lineages emigrated from the colon in an S1P-dependent manner. B lymphocytes represented the largest contingent, with the unexpected circulation of nonexperienced follicular B cells, which carried a gut-imprinted transcriptomic signature. T cell emigration included distinct groups of RORγ+ and IEL-like CD160+ subsets. Gut inflammation curtailed emigration, except for dendritic cells disseminating to lymph nodes. Colon-emigrating cells distributed differentially to distinct sites of extraintestinal models of inflammation (psoriasis-like skin, arthritic synovium, and tumors). Thus, specific cellular trails originating in the gut and influenced by microbiota may shape peripheral immunity in varied ways.
Collapse
Affiliation(s)
| | - Yangyang Zhu
- Department of Immunology, Harvard Medical School, Boston, MA, USA
| | - Bola S. Hanna
- Department of Immunology, Harvard Medical School, Boston, MA, USA
| | - Diane Mathis
- Department of Immunology, Harvard Medical School, Boston, MA, USA
| | | |
Collapse
|
31
|
Parthasarathy R, Wakefield D, Santiago FS, Kaakoush NO, Tedla N. Horizontal gene transfer and endogenous retroviruses as mechanisms for molecular mimicry. THE LANCET. MICROBE 2024; 5:e4-e5. [PMID: 37883987 DOI: 10.1016/s2666-5247(23)00316-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/06/2023] [Revised: 09/26/2023] [Accepted: 09/26/2023] [Indexed: 10/28/2023]
Affiliation(s)
- Rohit Parthasarathy
- School of Biomedical Sciences, Faculty of Medicine and Health, University of New South Wales, Sydney, NSW 2052, Australia
| | - Denis Wakefield
- School of Biomedical Sciences, Faculty of Medicine and Health, University of New South Wales, Sydney, NSW 2052, Australia
| | - Fernando S Santiago
- School of Biomedical Sciences, Faculty of Medicine and Health, University of New South Wales, Sydney, NSW 2052, Australia
| | - Nadeem O Kaakoush
- School of Biomedical Sciences, Faculty of Medicine and Health, University of New South Wales, Sydney, NSW 2052, Australia.
| | - Nicodemus Tedla
- School of Biomedical Sciences, Faculty of Medicine and Health, University of New South Wales, Sydney, NSW 2052, Australia.
| |
Collapse
|
32
|
Xu H, Yi X, Cui Z, Li H, Zhu L, Zhang L, Chen J, Fan X, Zhou P, Li MJ, Yu Y, Liu Q, Huang D, Yao Z, Zhou J. Maternal antibiotic exposure enhances ILC2 activation in neonates via downregulation of IFN1 signaling. Nat Commun 2023; 14:8332. [PMID: 38097561 PMCID: PMC10721923 DOI: 10.1038/s41467-023-43903-x] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/26/2023] [Accepted: 11/23/2023] [Indexed: 12/17/2023] Open
Abstract
Microbiota have an important function in shaping and priming neonatal immunity, although the cellular and molecular mechanisms underlying these effects remain obscure. Here we report that prenatal antibiotic exposure causes significant elevation of group 2 innate lymphoid cells (ILC2s) in neonatal lungs, in both cell numbers and functionality. Downregulation of type 1 interferon signaling in ILC2s due to diminished production of microbiota-derived butyrate represents the underlying mechanism. Mice lacking butyrate receptor GPR41 (Gpr41-/-) or type 1 interferon receptor IFNAR1 (Ifnar1-/-) recapitulate the phenotype of neonatal ILC2s upon maternal antibiotic exposure. Furthermore, prenatal antibiotic exposure induces epigenetic changes in ILC2s and has a long-lasting deteriorative effect on allergic airway inflammation in adult offspring. Prenatal supplementation of butyrate ameliorates airway inflammation in adult mice born to antibiotic-exposed dams. These observations demonstrate an essential role for the microbiota in the control of type 2 innate immunity at the neonatal stage, which suggests a therapeutic window for treating asthma in early life.
Collapse
Affiliation(s)
- Haixu Xu
- Department of Immunology, Tianjin Institute of Immunology, Key Laboratory of Immune Microenvironment and Disease of the Ministry of Education, State Key Laboratory of Experimental Hematology, School of Basic Medical Sciences, Tianjin Medical University, Tianjin, 300070, China
| | - Xianfu Yi
- Department of Bioinformatics, School of Basic Medical Sciences, Tianjin Medical University, Tianjin, 300070, China
| | - Zhaohai Cui
- Department of Immunology, Tianjin Institute of Immunology, Key Laboratory of Immune Microenvironment and Disease of the Ministry of Education, State Key Laboratory of Experimental Hematology, School of Basic Medical Sciences, Tianjin Medical University, Tianjin, 300070, China
| | - Hui Li
- Department of Immunology, Tianjin Institute of Immunology, Key Laboratory of Immune Microenvironment and Disease of the Ministry of Education, State Key Laboratory of Experimental Hematology, School of Basic Medical Sciences, Tianjin Medical University, Tianjin, 300070, China
| | - Lin Zhu
- Department of Immunology, Tianjin Institute of Immunology, Key Laboratory of Immune Microenvironment and Disease of the Ministry of Education, State Key Laboratory of Experimental Hematology, School of Basic Medical Sciences, Tianjin Medical University, Tianjin, 300070, China
| | - Lijuan Zhang
- Department of Immunology, Tianjin Institute of Immunology, Key Laboratory of Immune Microenvironment and Disease of the Ministry of Education, State Key Laboratory of Experimental Hematology, School of Basic Medical Sciences, Tianjin Medical University, Tianjin, 300070, China
| | - JiaLe Chen
- Department of Immunology, Tianjin Institute of Immunology, Key Laboratory of Immune Microenvironment and Disease of the Ministry of Education, State Key Laboratory of Experimental Hematology, School of Basic Medical Sciences, Tianjin Medical University, Tianjin, 300070, China
| | - Xutong Fan
- Department of Bioinformatics, School of Basic Medical Sciences, Tianjin Medical University, Tianjin, 300070, China
| | - Pan Zhou
- Department of Immunology, Tianjin Institute of Immunology, Key Laboratory of Immune Microenvironment and Disease of the Ministry of Education, State Key Laboratory of Experimental Hematology, School of Basic Medical Sciences, Tianjin Medical University, Tianjin, 300070, China
| | - Mulin Jun Li
- Department of Bioinformatics, School of Basic Medical Sciences, Tianjin Medical University, Tianjin, 300070, China
| | - Ying Yu
- Department of Pharmacology, School of Basic Medical Sciences, Tianjin Medical University, Tianjin, 300070, China
| | - Qiang Liu
- Department of Neurology, Institute of Neuroimmunology, Tianjin Medical University General Hospital, Tianjin, 300052, China
| | - Dandan Huang
- Department of Pharmacology, School of Basic Medical Sciences, Tianjin Medical University, Tianjin, 300070, China.
| | - Zhi Yao
- Department of Immunology, Tianjin Institute of Immunology, Key Laboratory of Immune Microenvironment and Disease of the Ministry of Education, State Key Laboratory of Experimental Hematology, School of Basic Medical Sciences, Tianjin Medical University, Tianjin, 300070, China.
| | - Jie Zhou
- Department of Immunology, Tianjin Institute of Immunology, Key Laboratory of Immune Microenvironment and Disease of the Ministry of Education, State Key Laboratory of Experimental Hematology, School of Basic Medical Sciences, Tianjin Medical University, Tianjin, 300070, China.
- Department of Neonatology, Guangzhou Key Laboratory of Neonatal Intestinal Diseases, the Third Affiliated Hospital of Guangzhou Medical University, Guangzhou, 510150, China.
| |
Collapse
|
33
|
Tie Y, Huang Y, Chen R, Li L, Chen M, Zhang S. Current insights on the roles of gut microbiota in inflammatory bowel disease-associated extra-intestinal manifestations: pathophysiology and therapeutic targets. Gut Microbes 2023; 15:2265028. [PMID: 37822139 PMCID: PMC10572083 DOI: 10.1080/19490976.2023.2265028] [Citation(s) in RCA: 15] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/15/2023] [Accepted: 09/26/2023] [Indexed: 10/13/2023] Open
Abstract
Inflammatory bowel disease (IBD) is a chronic, recurrent inflammatory disease of the gastrointestinal tract. In addition to digestive symptoms, patients with IBD may also develop extra-intestinal manifestations (EIMs), the etiology of which remains undefined. The gut microbiota has been reported to exert a critical role in the pathogenesis of IBD, with a similar pattern of gut dysbiosis observed between patients with IBD and those with EIMs. Therefore, it is hypothesized that the gut microbiota is also involved in the pathogenesis of EIMs. The potential mechanisms are presented in this review, including: 1) impaired gut barrier: dysbiosis induces pore formation in the intestinal epithelium, and activates pattern recognition receptors to promote local inflammation; 2) microbial translocation: intestinal pathogens, antigens, and toxins translocate via the impaired gut barrier into extra-intestinal sites; 3) molecular mimicry: certain microbial antigens share similar epitopes with self-antigens, inducing inflammatory responses targeting extra-intestinal tissues; 4) microbiota-related metabolites: dysbiosis results in the dysregulation of microbiota-related metabolites, which could modulate the differentiation of lymphocytes and cytokine production; 5) immunocytes and cytokines: immunocytes are over-activated and pro-inflammatory cytokines are excessively released. Additionally, we summarize microbiota-related therapies, including probiotics, prebiotics, postbiotics, antibiotics, and fecal microbiota transplantation, to promote better clinical management of IBD-associated EIMs.
Collapse
Affiliation(s)
- Yizhe Tie
- Department of Gastroenterology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| | - Yongle Huang
- Department of Gastroenterology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
- Department of Clinical Medicine, Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou, China
| | - Rirong Chen
- Department of Gastroenterology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| | - Li Li
- Department of Gastroenterology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| | - Minhu Chen
- Department of Gastroenterology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| | - Shenghong Zhang
- Department of Gastroenterology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| |
Collapse
|
34
|
Zhang JY, Xiao J, Xie B, Barba H, Boachie-Mensah M, Shah RN, Nadeem U, Spedale M, Dylla N, Lin H, Sidebottom AM, D'Souza M, Theriault B, Sulakhe D, Chang EB, Skondra D. Oral Metformin Inhibits Choroidal Neovascularization by Modulating the Gut-Retina Axis. Invest Ophthalmol Vis Sci 2023; 64:21. [PMID: 38108689 PMCID: PMC10732090 DOI: 10.1167/iovs.64.15.21] [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: 01/19/2023] [Accepted: 11/09/2023] [Indexed: 12/19/2023] Open
Abstract
Purpose Emerging data indicate that metformin may prevent the development of age-related macular degeneration (AMD). Whereas the underlying mechanisms of metformin's anti-aging properties remain undetermined, one proposed avenue is the gut microbiome. Using the laser-induced choroidal neovascularization (CNV) model, we investigate the effects of oral metformin on CNV, retinal pigment epithelium (RPE)/choroid transcriptome, and gut microbiota. Methods Specific pathogen free (SPF) male mice were treated via daily oral gavage of metformin 300 mg/kg or vehicle. Male mice were selected to minimize sex-specific differences to laser induction and response to metformin. Laser-induced CNV size and macrophage/microglial infiltration were assessed by isolectin and Iba1 immunostaining. High-throughput RNA-seq of the RPE/choroid was performed using Illumina. Fecal pellets were analyzed for gut microbiota composition/pathways with 16S rRNA sequencing/shotgun metagenomics, as well as microbial-derived metabolites, including small-chain fatty acids and bile acids. Investigation was repeated in metformin-treated germ-free (GF) mice and antibiotic-treated/GF mice receiving fecal microbiota transplantation (FMT) from metformin-treated SPF mice. Results Metformin treatment reduced CNV size (P < 0.01) and decreased Iba1+ macrophage/microglial infiltration (P < 0.005). One hundred forty-five differentially expressed genes were identified in the metformin-treated group (P < 0.05) with a downregulation in pro-angiogenic genes Tie1, Pgf, and Gata2. Furthermore, metformin altered the gut microbiome in favor of Bifidobacterium and Akkermansia, with a significant increase in fecal levels of butyrate, succinate, and cholic acid. Metformin did not suppress CNV in GF mice but colonization of microbiome-depleted mice with metformin-derived FMT suppressed CNV. Conclusions These data suggest that oral metformin suppresses CNV, the hallmark lesion of advanced neovascular AMD, via gut microbiome modulation.
Collapse
Affiliation(s)
- Jason Y. Zhang
- Pritzker School of Medicine, University of Chicago, Chicago, Illinois, United States
| | - Jason Xiao
- Pritzker School of Medicine, University of Chicago, Chicago, Illinois, United States
| | - Bingqing Xie
- Department of Medicine, University of Chicago, Chicago, Illinois, United States
| | - Hugo Barba
- Department of Ophthalmology and Visual Science, University of Chicago, Chicago, Illinois, United States
| | | | - Rohan N. Shah
- Pritzker School of Medicine, University of Chicago, Chicago, Illinois, United States
| | - Urooba Nadeem
- Department of Pathology, University of Chicago, Chicago, Illinois, United States
| | - Melanie Spedale
- Animal Resources Center, University of Chicago, University of Chicago, Chicago, Illinois, United States
| | - Nicholas Dylla
- Duchossois Family Institute, University of Chicago, Chicago, Illinois, United States
| | - Huaiying Lin
- Duchossois Family Institute, University of Chicago, Chicago, Illinois, United States
| | - Ashley M. Sidebottom
- Duchossois Family Institute, University of Chicago, Chicago, Illinois, United States
| | - Mark D'Souza
- Duchossois Family Institute, University of Chicago, Chicago, Illinois, United States
| | - Betty Theriault
- Animal Resources Center, University of Chicago, University of Chicago, Chicago, Illinois, United States
- Department of Surgery, University of Chicago, Chicago, Illinois, United States
| | - Dinanath Sulakhe
- Duchossois Family Institute, University of Chicago, Chicago, Illinois, United States
| | - Eugene B. Chang
- Department of Medicine, University of Chicago, Chicago, Illinois, United States
- Duchossois Family Institute, University of Chicago, Chicago, Illinois, United States
| | - Dimitra Skondra
- Department of Ophthalmology and Visual Science, University of Chicago, Chicago, Illinois, United States
| |
Collapse
|
35
|
Wu S, Zhang X, Hu C, Zhong Y, Chen J, Chong WP. CD8 + T cells reduce neuroretina inflammation in mouse by regulating autoreactive Th1 and Th17 cells through IFN-γ. Eur J Immunol 2023; 53:e2350574. [PMID: 37689974 DOI: 10.1002/eji.202350574] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/24/2023] [Revised: 08/08/2023] [Accepted: 09/08/2023] [Indexed: 09/11/2023]
Abstract
Various regulatory CD8+ T-cell subsets have been proposed for immune tolerance and have been implicated in controlling autoimmune diseases. However, their phenotypic identities and suppression mechanisms are not yet understood. This study found that coculture of T-cell receptor (TCR)- or interferon (IFN)-β-activated CD8+ T cells significantly suppressed the cytokine production of Th1 and Th17 cells. By experimenting with the experimental autoimmune uveitis (EAU), we found that adoptive transfer of TCR or IFN-β-activated CD8+ T cells significantly lessened disease development in an IFN-γ-dependent manner with a decreased uveitogenic Th1 and Th17 response. Interestingly, after adoptive transfer into the EAU mice, the IFN-γ+ CD8+ T cells were recruited more efficiently into the secondary lymphoid organs during the disease-priming phase. This recruitment depends on the IFN-γ-inducible chemokine receptor CXCR3; knocking out CXCR3 abolishes the protective effect of CD8+ T cells in EAU. In conclusion, we identified the critical role of IFN-γ for CD8+ T cells to inhibit Th1 and Th17 responses and ameliorate EAU. CXCR3 is necessary to recruit IFN-γ+ CD8+ T cells to the secondary lymphoid organ for the regulation of autoreactive Th1 and Th17 cells.
Collapse
Affiliation(s)
- Sihan Wu
- State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangzhou, China
| | - Xuan Zhang
- State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangzhou, China
| | - Cuiping Hu
- State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangzhou, China
| | - Yajie Zhong
- State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangzhou, China
| | - Jun Chen
- State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangzhou, China
| | - Wai Po Chong
- State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangzhou, China
- School of Chinese Medicine, Hong Kong Baptist University, Hong Kong SAR, China
| |
Collapse
|
36
|
Ji N, Wang F, Wang M, Zhang W, Liu H, Su J. Engineered bacterial extracellular vesicles for central nervous system diseases. J Control Release 2023; 364:46-60. [PMID: 37866404 DOI: 10.1016/j.jconrel.2023.10.027] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/10/2023] [Revised: 10/17/2023] [Accepted: 10/18/2023] [Indexed: 10/24/2023]
Abstract
The prevalence of central nervous system (CNS) diseases is on the rise as the population ages. The presence of various obstacles, particularly the blood-brain barrier (BBB), poses a challenge for drug delivery to the CNS. An expanding body of study suggests that gut microbiota (GM) plays an important role in CNS diseases. The communication between GM and CNS diseases has received increasing attention. Accumulating evidence indicates that the GM can modulate host signaling pathways to regulate distant organ functions by delivering bioactive substances to host cells via bacterial extracellular vesicles (BEVs). BEVs have emerged as a promising platform for the treatment of CNS diseases due to their nanostructure, ability to penetrate the BBB, as well as their low toxicity, high biocompatibility, ease of modification and large-scale culture. Here, we discuss the biogenesis, internalization mechanism and engineering modification methods of BEVs. We then focus on the use and potential role of BEVs in the treatment of CNS diseases. Finally, we outline the main challenges and future prospects for the application of BEVs in CNS diseases. We hope that the comprehensive understanding of the BEVs-based gut-brain axis will provide new insights into the treatment of CNS diseases.
Collapse
Affiliation(s)
- Ning Ji
- Institute of Translational Medicine, Shanghai University, Shanghai 200444, China; Organoid Research Center, Shanghai University, Shanghai 200444, China; National Center for Translational Medicine (Shanghai) SHU Branch, Shanghai University, Shanghai 200444, China
| | - Fuxiao Wang
- Institute of Translational Medicine, Shanghai University, Shanghai 200444, China; Organoid Research Center, Shanghai University, Shanghai 200444, China; National Center for Translational Medicine (Shanghai) SHU Branch, Shanghai University, Shanghai 200444, China
| | - Miaomiao Wang
- Department of Rehabilitation Medicine, Shanghai Zhongye Hospital, Shanghai 200941, China
| | - Wencai Zhang
- Department of Orthopedics, The First Affiliated Hospital of Jinan University, Guangdong, Guangzhou 510630, China.
| | - Han Liu
- Institute of Translational Medicine, Shanghai University, Shanghai 200444, China; Organoid Research Center, Shanghai University, Shanghai 200444, China; National Center for Translational Medicine (Shanghai) SHU Branch, Shanghai University, Shanghai 200444, China.
| | - Jiacan Su
- Institute of Translational Medicine, Shanghai University, Shanghai 200444, China; Organoid Research Center, Shanghai University, Shanghai 200444, China; National Center for Translational Medicine (Shanghai) SHU Branch, Shanghai University, Shanghai 200444, China; Department of Orthopedics, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200092, China.
| |
Collapse
|
37
|
Li C, Lu P. Association of Gut Microbiota with Age-Related Macular Degeneration and Glaucoma: A Bidirectional Mendelian Randomization Study. Nutrients 2023; 15:4646. [PMID: 37960299 PMCID: PMC10650403 DOI: 10.3390/nu15214646] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/01/2023] [Revised: 10/26/2023] [Accepted: 10/29/2023] [Indexed: 11/15/2023] Open
Abstract
The objective of this study was to examine the correlation between gut microbiota and both age-related macular degeneration (AMD) and glaucoma. Mendelian randomization studies were conducted utilizing the data sourced from the genome-wide association study (GWAS) database for the gut microbiome, AMD, and glaucoma. Single nucleotide polymorphism (SNP) estimates were summarized through five Mendelian randomization (MR) methods. We utilized Cochran's Q statistic to evaluate the heterogeneity of the instrumental variables (IVs). Additionally, we employed a "leave-one-out" approach to verify the stability of our findings. Inverse variance weighted (IVW) suggests that Eubacterium (oxidoreducens group) and Parabacteroides had a protective effect on AMD. Both weighted median and IVW suggest that Lachnospiraceae (NK4A136 group) and Ruminococcaceae (UCG009) had a protective effect on AMD. However, both weighted median and IVW suggest that Dorea had a risk effect on AMD. Similarly, The IVW of Eubacterium (ventriosum group) showed a risk effect on AMD. The weighted median of Eubacterium (nodatum group), Lachnospiraceae (NC2004 group), and Roseburia had a risk effect on glaucoma. IVW suggested that Ruminococcaceae (UCG004) had a risk effect on glaucoma. Reverse MR analysis found a causal link between Eubacterium (nodatum group) and glaucoma. No causal relationships were found between AMD or glaucoma and the other mentioned bacterial groups. No significant heterogeneity or evidence of horizontal pleiotropy was detected. This study found that certain gut bacteria had protective effects on AMD, while others may be risk factors for AMD or glaucoma. Likewise, reverse MR found that glaucoma led to an increased abundance of certain gut bacteria. Further trials are needed to clarify the specific mechanisms involved.
Collapse
Affiliation(s)
| | - Peirong Lu
- The First Affiliated Hospital of Soochow University, Pinghai Road 899, Suzhou 215005, China;
| |
Collapse
|
38
|
Zhong Z, Su G, Yang P. Risk factors, clinical features and treatment of Behçet's disease uveitis. Prog Retin Eye Res 2023; 97:101216. [PMID: 37734442 DOI: 10.1016/j.preteyeres.2023.101216] [Citation(s) in RCA: 20] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/21/2023] [Revised: 09/09/2023] [Accepted: 09/15/2023] [Indexed: 09/23/2023]
Abstract
Behçet's disease is a systemic vasculitis frequently associated with intraocular inflammation. Recent findings identified independent clinical clusters in Behçet's disease, each involving distinct combinations of affected organs. Ocular Behçet's disease, mainly manifested as uveitis, is characterized as an independent cluster with a low likelihood of association with other system involvements, such as intestinal, cardiovascular, or central nervous system. A prevailing theory suggests that the pathogenesis of the disease is multifactorial, where a variety of genetic and infectious agents may interact with each other to cause the disease. Among sporadic cases, the human leukocyte antigen (HLA) genes, including HLA-B51, HLA-A26, HLA-B15, and HLA-B5701, have been found to be a key component conferring genetic susceptibility. Outside the HLA region, a set of susceptibility variants are identified, closely related to interleukin (IL)-23/IL-17 pathway, tumor necrosis factor (TNF) signaling, and pattern recognition receptor systems. Microbial infections, such as Streptococcus sanguinis, Mycobacterium tuberculosis, and Herpes simplex virus (HSV), are linked to play the triggering of disease in immunogenetically predisposed individuals. Clinically, due to the notable relapsing-remitting course of ocular Behçet's disease, the prevention of recurrent attack would be the primary treatment goal. Combination of corticosteroids and immunomodulatory drugs, such as anti-TNF agents, interferon, and conventional immunosuppressants (e.g. cyclosporine, azathioprine), have been the mainstream regimen for the disease. Future research may focus on comparing the effectiveness of immunomodulatory drugs and identifying the most suitable subgroups for a specific drug on the basis of the knowledge of the molecular heterogeneity of the disease.
Collapse
Affiliation(s)
- Zhenyu Zhong
- The First Affiliated Hospital of Chongqing Medical University, Chongqing Key Laboratory of Ophthalmology, Chongqing Eye Institute, Chongqing Branch (Municipality Division) of National Clinical Research Center for Ocular Diseases, Chongqing, China
| | - Guannan Su
- The First Affiliated Hospital of Chongqing Medical University, Chongqing Key Laboratory of Ophthalmology, Chongqing Eye Institute, Chongqing Branch (Municipality Division) of National Clinical Research Center for Ocular Diseases, Chongqing, China
| | - Peizeng Yang
- The First Affiliated Hospital of Chongqing Medical University, Chongqing Key Laboratory of Ophthalmology, Chongqing Eye Institute, Chongqing Branch (Municipality Division) of National Clinical Research Center for Ocular Diseases, Chongqing, China.
| |
Collapse
|
39
|
Janetos TM, Zakaria N, Goldstein DA. The Microbiome and Uveitis: A Narrative Review. THE AMERICAN JOURNAL OF PATHOLOGY 2023; 193:1638-1647. [PMID: 37024044 DOI: 10.1016/j.ajpath.2023.03.004] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/04/2022] [Revised: 03/11/2023] [Accepted: 03/22/2023] [Indexed: 04/07/2023]
Abstract
The human intestinal microbiome is composed of hundreds of species and has recently been recognized as an important source of immune homeostasis. While dysbiosis, an altered microbiome from the normal core microbiome, has been associated with both intestinal and extraintestinal autoimmune disorders, including uveitis, causality has been difficult to establish. There are four proposed mechanisms of how the gut microbiome may influence the development of uveitis: molecular mimicry, imbalance of regulatory and effector T cells, increased intestinal permeability, and loss of intestinal metabolites. This review summarizes current literature on both animal and human studies that establish the link between dysbiosis and the development of uveitis, as well as provides evidence for the above mechanisms. Current studies provide valuable mechanistic insights as well as identify potential therapeutic targets. However, study limitations and the wide variability in the intestinal microbiome among populations and diseases make a specific targeted therapy difficult to establish. Further longitudinal clinical studies are required to identify any potential therapeutic that targets the intestinal microbiome.
Collapse
Affiliation(s)
- Timothy M Janetos
- Department of Ophthalmology, Northwestern University Feinberg School of Medicine, Chicago, Illinois.
| | - Nancy Zakaria
- Department of Ophthalmology, Northwestern University Feinberg School of Medicine, Chicago, Illinois; Department of Ophthalmology, Faculty of Medicine, Alexandria University, Alexandria, Arab Republic of Egypt
| | - Debra A Goldstein
- Department of Ophthalmology, Northwestern University Feinberg School of Medicine, Chicago, Illinois
| |
Collapse
|
40
|
Salvador R, Horai R, Zhang A, Jittayasothorn Y, Tang J, Gupta A, Nagarajan V, Caspi RR. Too Much of a Good Thing: Extended Duration of Gut Microbiota Depletion Reverses Protection From Experimental Autoimmune Uveitis. Invest Ophthalmol Vis Sci 2023; 64:43. [PMID: 38019490 PMCID: PMC10691388 DOI: 10.1167/iovs.64.14.43] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/25/2023] [Accepted: 11/06/2023] [Indexed: 11/30/2023] Open
Abstract
Purpose Using the model of experimental autoimmune uveitis (EAU) induced by immunization with a retinal antigen, two studies have reported contradictory results on disease development following oral antibiotic treatment (ABX). We showed that long-term ABX did not affect EAU, but another study showed that short-term ABX was protective. We therefore studied the effects of ABX on EAU, gut microbiota, and host immune responses as a function of treatment duration. Methods EAU-susceptible mice were treated orally with broad-spectrum antibiotics starting at least 10 weeks (long-term) or 1 week (short-term) before immunization until termination of the experiment. Gut microbiota were characterized by 16S amplicon sequencing, and host gut immune elements were studied phenotypically and functionally. Results Long-term ABX had no effect, whereas short-term ABX delayed EAU, as previously reported by us and others, respectively. Microbial sequencing revealed progressive reduction of gut microbiota that showed some differences in the two ABX groups. Interestingly, duration of ABX was associated with a gradual disappearance of the CD4+ and CD4+CD8+ subset of gut intraepithelial lymphocytes (IELs). This IEL subset is microbiota dependent and is absent in germ-free mice. Relative abundance of Lactobacillus reuteri correlated with the frequencies of CD4+CD8+ IELs. IELs suppressed antigen-specific activation of autoreactive T cells in culture. Conclusions Gut microbiota may play dual roles in uveitis development: They promote EAU development but also help maintain IEL populations that have regulatory function against autoreactive T cells. We propose that the progressive loss of this population during long-term ABX reverses the EAU-ameliorating effects of microbiota depletion.
Collapse
Affiliation(s)
- Ryan Salvador
- Laboratory of Immunology, National Eye Institute, National Institutes of Health, Bethesda, Maryland, United States
| | - Reiko Horai
- Laboratory of Immunology, National Eye Institute, National Institutes of Health, Bethesda, Maryland, United States
| | - Amy Zhang
- Laboratory of Immunology, National Eye Institute, National Institutes of Health, Bethesda, Maryland, United States
| | - Yingyos Jittayasothorn
- Laboratory of Immunology, National Eye Institute, National Institutes of Health, Bethesda, Maryland, United States
| | - Jihong Tang
- Laboratory of Immunology, National Eye Institute, National Institutes of Health, Bethesda, Maryland, United States
| | - Akriti Gupta
- Laboratory of Immunology, National Eye Institute, National Institutes of Health, Bethesda, Maryland, United States
| | - Vijayaraj Nagarajan
- Laboratory of Immunology, National Eye Institute, National Institutes of Health, Bethesda, Maryland, United States
| | - Rachel R. Caspi
- Laboratory of Immunology, National Eye Institute, National Institutes of Health, Bethesda, Maryland, United States
| |
Collapse
|
41
|
Simpson RC, Shanahan ER, Scolyer RA, Long GV. Towards modulating the gut microbiota to enhance the efficacy of immune-checkpoint inhibitors. Nat Rev Clin Oncol 2023; 20:697-715. [PMID: 37488231 DOI: 10.1038/s41571-023-00803-9] [Citation(s) in RCA: 49] [Impact Index Per Article: 24.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 07/04/2023] [Indexed: 07/26/2023]
Abstract
The gut microbiota modulates immune processes both locally and systemically. This includes whether and how the immune system reacts to emerging tumours, whether antitumour immune responses are reactivated during treatment with immune-checkpoint inhibitors (ICIs), and whether unintended destructive immune pathologies accompany such treatment. Advances over the past decade have established that the gut microbiota is a promising target and that modulation of the microbiota might overcome resistance to ICIs and/or improve the safety of treatment. However, the specific mechanisms through which the microbiota modulates antitumour immunity remain unclear. Understanding the biology underpinning microbial associations with clinical outcomes in patients receiving ICIs, as well as the landscape of a 'healthy' microbiota would provide a critical foundation to facilitate opportunities to effectively manipulate the microbiota and thus improve patient outcomes. In this Review, we explore the role of diet and the gut microbiota in shaping immune responses during treatment with ICIs and highlight the key challenges in attempting to leverage the gut microbiome as a practical tool for the clinical management of patients with cancer.
Collapse
Affiliation(s)
- Rebecca C Simpson
- Melanoma Institute Australia, The University of Sydney, Sydney, New South Wales, Australia
- Sydney Medical School, Faculty of Medicine and Health, The University of Sydney, Sydney, New South Wales, Australia
- Charles Perkins Centre, The University of Sydney, Sydney, New South Wales, Australia
| | - Erin R Shanahan
- Charles Perkins Centre, The University of Sydney, Sydney, New South Wales, Australia
- School of Life and Environmental Sciences, Faculty of Science, The University of Sydney, Sydney, New South Wales, Australia
| | - Richard A Scolyer
- Melanoma Institute Australia, The University of Sydney, Sydney, New South Wales, Australia
- Sydney Medical School, Faculty of Medicine and Health, The University of Sydney, Sydney, New South Wales, Australia
- Charles Perkins Centre, The University of Sydney, Sydney, New South Wales, Australia
- Tissue Pathology and Diagnostic Oncology, Royal Prince Alfred Hospital and NSW Health Pathology, Sydney, New South Wales, Australia
| | - Georgina V Long
- Melanoma Institute Australia, The University of Sydney, Sydney, New South Wales, Australia.
- Sydney Medical School, Faculty of Medicine and Health, The University of Sydney, Sydney, New South Wales, Australia.
- Charles Perkins Centre, The University of Sydney, Sydney, New South Wales, Australia.
- Department of Medical Oncology, Royal North Shore and Mater Hospitals, Sydney, New South Wales, Australia.
| |
Collapse
|
42
|
Russell MW, Muste JC, Kuo BL, Wu AK, Singh RP. Clinical trials targeting the gut-microbiome to effect ocular health: a systematic review. Eye (Lond) 2023; 37:2877-2885. [PMID: 36918627 PMCID: PMC10516887 DOI: 10.1038/s41433-023-02462-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/25/2022] [Revised: 11/21/2022] [Accepted: 02/21/2023] [Indexed: 03/16/2023] Open
Abstract
Clinical trials targeting the gut microbiome to mitigate ocular disease are now on the horizon. A review of clinical data thus far is essential to determine future directions in this novel promising field. This review examines recent clinical trials that support the plausibility of a gut-eye axis, and may form the basis of novel clinical interventions. PubMed was queried for English language clinical studies examining the relationships between gut microbiota and ocular pathology. 25 studies were extracted from 828 candidate publications, which suggest that gut imbalance is associated with ocular pathology. Of these, only four interventional studies exist which suggest probiotic supplementation or fecal microbiota transplant can reduce symptoms of chalazion or uveitis. The gut-eye axis appears to hold clinical relevance, but current data is limited in sample size and design. Further investigation via longitudinal clinical trials may be warranted.
Collapse
Affiliation(s)
- Matthew W Russell
- Center for Ophthalmic Bioinformatics, Cole Eye Institute, Cleveland Clinic, Cleveland, OH, USA
- Cleveland Clinic Lerner College of Medicine, Cleveland, OH, USA
| | - Justin C Muste
- Center for Ophthalmic Bioinformatics, Cole Eye Institute, Cleveland Clinic, Cleveland, OH, USA
| | - Blanche L Kuo
- Center for Ophthalmic Bioinformatics, Cole Eye Institute, Cleveland Clinic, Cleveland, OH, USA
- Case Western Reserve University School of Medicine, Cleveland, OH, USA
| | - Anna K Wu
- Center for Ophthalmic Bioinformatics, Cole Eye Institute, Cleveland Clinic, Cleveland, OH, USA
- Case Western Reserve University School of Medicine, Cleveland, OH, USA
| | - Rishi P Singh
- Center for Ophthalmic Bioinformatics, Cole Eye Institute, Cleveland Clinic, Cleveland, OH, USA.
| |
Collapse
|
43
|
Wildner G, Bansal R, Ayyadurai N, Thurau S, Basu S. Pathogenesis of Bacterial Uveitis. Ocul Immunol Inflamm 2023; 31:1396-1404. [PMID: 36622856 DOI: 10.1080/09273948.2022.2155842] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/13/2022] [Revised: 09/02/2022] [Accepted: 12/02/2022] [Indexed: 01/10/2023]
Abstract
PURPOSE To describe the pathogenesis and the general immune mechanisms of the most frequent causes of bacterial uveitis. METHODOLOGY Narrative review. RESULTS Both extra- and intracellular bacteria can induce uveitis, whereas intracellular bacteria are generally transported into the inner eye via cells of the innate immune system, mainly macrophages. Systemic adaptive immunity is usually induced before the bacteria are localized to the inner eye, and once T and B cells have detected the pathogens behind the blood-eye barriers they elicit an acute and/or chronic inflammatory response deteriorating visual acuity that can severely affect the non-regenerating, intraocular tissues. CONCLUSIONS An understanding of pathogenic mechanisms, and its correlation with clinical and imaging features, can facilitate early recognition of microbial factors and institution of appropriate therapy.
Collapse
Affiliation(s)
- Gerhild Wildner
- Department of Ophthalmology, University Hospital, LMU, Munich, Germany
| | - Reema Bansal
- Advanced Eye Centre, Post Graduate Institute of Medical Education and Research, Chandigarh, India
| | - Nikitha Ayyadurai
- Advanced Eye Centre, Post Graduate Institute of Medical Education and Research, Chandigarh, India
| | - Stephan Thurau
- Department of Ophthalmology, University Hospital, LMU, Munich, Germany
| | - Soumyava Basu
- Prof Brien Holden Eye Research Center, LV Prasad Eye Institute, Hyderabad, India
| |
Collapse
|
44
|
Mao D, Tao B, Sheng S, Jin H, Chen W, Gao H, Deng J, Li Z, Chen F, Chan S, Qian L. Causal Effects of Gut Microbiota on Age-Related Macular Degeneration: A Mendelian Randomization Study. Invest Ophthalmol Vis Sci 2023; 64:32. [PMID: 37725382 PMCID: PMC10513115 DOI: 10.1167/iovs.64.12.32] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2023] [Accepted: 08/06/2023] [Indexed: 09/21/2023] Open
Abstract
Purpose Recently, the association between gut microbiota and age-related macular degeneration (AMD) through the gut-retina axis has attracted great interest. However, the causal relationship between them has not been elucidated. Using publicly available genome-wide association study summary statistics, we conducted a two-sample Mendelian randomization (MR) analysis to examine the causal relationship between the gut microbiota and the occurrence of AMD. Methods The study used a variety of quality control techniques to select instrumental single nucleotide polymorphisms (SNPs) with strong exposure associations. We used a set of SNPs as instrumental variable that were below the genome-wide statistical significance threshold (5 × 10-8). Additionally, a separate group of SNPs below the locus-wide significance level (1 × 10-5) were selected as instrumental variables to ensure a comprehensive conclusion. Inverse variance-weighted (IVW) analysis was the primary technique we used to examine causality in order to confirm the validity of our findings. The MR-Egger intercept test, Cochran's Q test, and leave-one-out sensitivity analysis were used to evaluate the horizontal pleiotropy, heterogeneities, and stability of the genetic variants. Results IVW results showed that genus Anaerotruncus (P = 5.00 × 10-3), genus Candidatus Soleaferrea (P = 1.83 × 10-2), and genus unknown id.2071 (P = 3.12 × 10-2) were protective factors for AMD. The Eubacterium oxidoreducens group (P = 3.17 × 10-2), genus Faecalibacterium (P = 2.67 × 10-2), and genus Ruminococcaceae UCG-011 (P = 4.04 × 10-2) were risk factors of AMD. No gut microbiota (GM) taxa were found to be causally related to AMD at the phylum, class, order, and family levels (P > 0.05). The robustness of MR results were confirmed by heterogeneity and pleiotropy analysis. (P > 0.05). We also performed a bidirectional analysis, which showed that genus Anaerotruncus, genus Candidatus Soleaferrea, genus unknown id.2071 and the Eubacterium oxidoreducens group had an interaction with AMD, whereas genus Faecalibacterium showed only a unilateral unfavorable effect on AMD. Conclusions We confirmed a causal relationship between AMD and GM taxa, including the Eubacterium oxidoreducens group, Faecalibacterium, Ruminococcaceae UCG-011, Anaerotruncus, and Candidatus Soleaferrea. These strains have the potential to serve as new biomarkers, offering valuable insights into the treatment and prevention of AMD.
Collapse
Affiliation(s)
- Deshen Mao
- Department of Ophthalmology, Anqing Municipal Hospital, Anqing, China
- First Clinical Medical College, Anhui Medical University, Hefei, China
| | - Borui Tao
- First Clinical Medical College, Anhui Medical University, Hefei, China
| | - Shuyan Sheng
- First Clinical Medical College, Anhui Medical University, Hefei, China
| | - Hui Jin
- Department of Medical Imaging, Anqing First People's Hospital, Anqing, China
| | - Wenxuan Chen
- Second Clinical Medical College, Anhui Medical University, Hefei, China
| | - Huimin Gao
- Department of Pathology, Anqing Municipal Hospital, Anqing, China
| | - Jianyi Deng
- First Clinical Medical College, Anhui Medical University, Hefei, China
| | - Zhuo Li
- School of Clinical Medicine, Anhui Medical University, Hefei, China
| | - Fan Chen
- Department of Ophthalmology, Anqing Municipal Hospital, Anqing, China
| | - Shixin Chan
- Department of General Surgery, The First Affiliated Hospital of Anhui Medical University, Hefei, China
| | - Longqi Qian
- Department of Ophthalmology, Anqing Municipal Hospital, Anqing, China
| |
Collapse
|
45
|
Fu X, Tan H, Huang L, Chen W, Ren X, Chen D. Gut microbiota and eye diseases: a bibliometric study and visualization analysis. Front Cell Infect Microbiol 2023; 13:1225859. [PMID: 37621873 PMCID: PMC10445766 DOI: 10.3389/fcimb.2023.1225859] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2023] [Accepted: 07/17/2023] [Indexed: 08/26/2023] Open
Abstract
Introduction Recently the role of gut microbial dysbiosis in many ocular disorders, including but not limited to uveitis, age-related macular degeneration (AMD), diabetic retinopathy (DR), dry eye, keratitis and orbitopathy is a hot research topic in the field. Targeting gut microbiota to treat these diseases has become an unstoppable trend. Bibliometric study and visualization analysis have become essential methods for literature analysis in the medical research field. We aim to depict this area's research hotspots and future directions by bibliometric software and methods. Methods We search all the related publications from the Web of Science Core Collection. Then, CiteSpace was applied to analyze and visualize the country distributions, dual-map overlay of journals, keyword bursts, and co-cited references. VOSviewer was employed to identify authors, co-cited authors, journals and co-cited journals and display the keyword co-occurrence networks. Results A total of 284 relevant publications were identified from 2009 to 2023. The number of studies has been small in the first five years and has grown steadily since 2016. These studies were completed by 1,376 authors from 41 countries worldwide, with the United States in the lead. Lin P has published the most papers while Horai R is the most co-cited author. The top journal and co-cited journal are both Investigative Ophthalmology & Visual Science. In the keyword co-occurrence network, except gut microbiota, inflammation becomes the keyword with the highest frequency. Co-citation analyses reveal that gut dysbiosis is involved in common immune- and inflammation-mediated eye diseases, including uveitis, diabetic retinopathy, age-related macular degeneration, dry eye, and Graves' orbitopathy, and the study of microbiomes is no longer limited to the bacterial populations. Therapeutic strategies that target the gut microbiota, such as probiotics, healthy diet patterns, and fecal microbial transplantation, are effective and critical to future research. Conclusions In conclusion, the bibliometric analysis displays the research hotspots and developmental directions of the involvement of gut microbiota in the pathogenesis and treatment of some ocular diseases. It provides an overview of this field's dynamic evolution and structural relationships.
Collapse
Affiliation(s)
- Xiangyu Fu
- Department of Ophthalmology, West China Hospital, Sichuan University, Chengdu, China
- Research Laboratory of Ophthalmology and Vision Sciences, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, China
| | - Haishan Tan
- Department of Ophthalmology, West China Hospital, Sichuan University, Chengdu, China
- Research Laboratory of Ophthalmology and Vision Sciences, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, China
| | - Ling Huang
- Department of Ophthalmology, West China Hospital, Sichuan University, Chengdu, China
- Research Laboratory of Ophthalmology and Vision Sciences, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, China
| | - Wenyue Chen
- Department of Ophthalmology, West China Hospital, Sichuan University, Chengdu, China
- Research Laboratory of Ophthalmology and Vision Sciences, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, China
| | - Xiang Ren
- Department of Ophthalmology, West China Hospital, Sichuan University, Chengdu, China
- Research Laboratory of Ophthalmology and Vision Sciences, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, China
| | - Danian Chen
- Department of Ophthalmology, West China Hospital, Sichuan University, Chengdu, China
- Research Laboratory of Ophthalmology and Vision Sciences, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, China
| |
Collapse
|
46
|
He C, Xiu W, Chen Q, Peng K, Zhu X, Wang Z, Xu X, Chen Y, Zhang G, Fu J, Dong Q, Wu X, Li A, Liu D, Gao Y, Wang J, Wang Z, Deng B, Shuai P, Gao C, Chen Y, Yu L, Lu F. Gut-licensed β7 + CD4 + T cells contribute to progressive retinal ganglion cell damage in glaucoma. Sci Transl Med 2023; 15:eadg1656. [PMID: 37531415 DOI: 10.1126/scitranslmed.adg1656] [Citation(s) in RCA: 16] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/06/2022] [Accepted: 07/14/2023] [Indexed: 08/04/2023]
Abstract
Glaucoma is the leading cause of irreversible blindness. Currently, most therapeutic strategies aim to reduce elevated intraocular pressure (EIOP), but this does not always halt disease progression. Evidence suggests a role for T cells in glaucoma pathogenesis, but the underlying mechanisms remain largely unknown. Here, we found that the percentage of circulating CD4+ T cells expressing a gut-homing integrin β7 was increased in patients with glaucoma and was associated with disease stage. In an EIOP-triggered glaucoma mouse model, β7+ CD4+ T cells infiltrated the retina in the progressive phase of glaucoma via eliciting retinal endothelial cell expression of mucosal vascular addressin cell adhesion molecule 1 (MAdCAM-1). MAdCAM-1 was minimally detected in retinas of healthy mice, and neutralization with an MAdCAM-1 antibody ameliorated retinal ganglion cell (RGC) loss and glial activity in mice with glaucoma. We furthermore found that EIOP-induced β7+ CD4+ T cells homed to the gut during the acute phase of glaucoma, which was essential for progressive RGC damage in diseased mice. Gut-homing β7+ CD4+ T cells underwent transcriptional reprogramming, showing up-regulated pathways enriched in autoimmune diseases, bacteria responses, mucosal immunity, and glial activity. Gut-homing β7+ CD4+ T cells gained the competence to induce retinal MAdCAM-1 expression and to cross the blood-retina barrier. Together, our study reveals a role of gut-licensed β7+ CD4+ T cells and MAdCAM-1 in RGC degeneration and emphasizes the importance of the "gut-retina" axis in glaucoma.
Collapse
Affiliation(s)
- Chong He
- Clinical Immunology Translational Medicine Key Laboratory of Sichuan Province, Sichuan Provincial People's Hospital, University of Electronic Science and Technology of China, Chengdu, China
- Medico-Engineering Cooperation on Applied Medicine Research Center, University of Electronic Science and Technology of China, Chengdu, China
| | - Wenbo Xiu
- Clinical Immunology Translational Medicine Key Laboratory of Sichuan Province, Sichuan Provincial People's Hospital, University of Electronic Science and Technology of China, Chengdu, China
| | - Qinyuan Chen
- Clinical Immunology Translational Medicine Key Laboratory of Sichuan Province, Sichuan Provincial People's Hospital, University of Electronic Science and Technology of China, Chengdu, China
| | - Kun Peng
- Health Management Center, Sichuan Provincial People's Hospital, University of Electronic Science and Technology of China, Chengdu, China
| | - Xiong Zhu
- Clinical Immunology Translational Medicine Key Laboratory of Sichuan Province, Sichuan Provincial People's Hospital, University of Electronic Science and Technology of China, Chengdu, China
- Department of Prenatal Diagnosis, Chengdu Women's and Children's Central Hospital, School of Medicine, University of Electronic Science and Technology of China, Chengdu, China
| | - Zuo Wang
- Clinical Immunology Translational Medicine Key Laboratory of Sichuan Province, Sichuan Provincial People's Hospital, University of Electronic Science and Technology of China, Chengdu, China
- Department of Clinical Laboratory, Sichuan Cancer Hospital and Institute, Sichuan Cancer Center, School of Medicine, University of Electronic Science and Technology of China, Chengdu, China
| | - Xiang Xu
- Clinical Immunology Translational Medicine Key Laboratory of Sichuan Province, Sichuan Provincial People's Hospital, University of Electronic Science and Technology of China, Chengdu, China
| | - Yang Chen
- Clinical Immunology Translational Medicine Key Laboratory of Sichuan Province, Sichuan Provincial People's Hospital, University of Electronic Science and Technology of China, Chengdu, China
| | - Gao Zhang
- Clinical Immunology Translational Medicine Key Laboratory of Sichuan Province, Sichuan Provincial People's Hospital, University of Electronic Science and Technology of China, Chengdu, China
| | - Jing Fu
- Clinical Immunology Translational Medicine Key Laboratory of Sichuan Province, Sichuan Provincial People's Hospital, University of Electronic Science and Technology of China, Chengdu, China
| | - Qiwei Dong
- Clinical Immunology Translational Medicine Key Laboratory of Sichuan Province, Sichuan Provincial People's Hospital, University of Electronic Science and Technology of China, Chengdu, China
| | - Xiaoqiong Wu
- Department of Ophthalmology, Luzhou Meternal and Child Health Hospital, Luzhou, China
| | - An Li
- Clinical Immunology Translational Medicine Key Laboratory of Sichuan Province, Sichuan Provincial People's Hospital, University of Electronic Science and Technology of China, Chengdu, China
| | - Donghua Liu
- Health Management Center, Sichuan Provincial People's Hospital, University of Electronic Science and Technology of China, Chengdu, China
| | - Yanping Gao
- Clinical Immunology Translational Medicine Key Laboratory of Sichuan Province, Sichuan Provincial People's Hospital, University of Electronic Science and Technology of China, Chengdu, China
| | - Jinxia Wang
- Clinical Immunology Translational Medicine Key Laboratory of Sichuan Province, Sichuan Provincial People's Hospital, University of Electronic Science and Technology of China, Chengdu, China
| | - Zhao Wang
- Medico-Engineering Cooperation on Applied Medicine Research Center, University of Electronic Science and Technology of China, Chengdu, China
- School of Electronic Science and Engineering, University of Electronic Science and Technology of China, Chengdu, China
| | - Bolin Deng
- Department of Ophthalmology, Sichuan Provincial People's Hospital, University of Electronic Science and Technology of China, Chengdu, China
| | - Ping Shuai
- Health Management Center, Sichuan Provincial People's Hospital, University of Electronic Science and Technology of China, Chengdu, China
| | - Caiping Gao
- Department of Gastroenterology, Sichuan Provincial People's Hospital, University of Electronic Science and Technology of China, Chengdu, China
| | - Yilian Chen
- Department of Ophthalmology, Sichuan Provincial People's Hospital, University of Electronic Science and Technology of China, Chengdu, China
| | - Ling Yu
- Department of Ophthalmology, Daping Hospital, Army Medical Center, Army Medical University, Chongqing, China
| | - Fang Lu
- Clinical Immunology Translational Medicine Key Laboratory of Sichuan Province, Sichuan Provincial People's Hospital, University of Electronic Science and Technology of China, Chengdu, China
- Medico-Engineering Cooperation on Applied Medicine Research Center, University of Electronic Science and Technology of China, Chengdu, China
- Health Management Center, Sichuan Provincial People's Hospital, University of Electronic Science and Technology of China, Chengdu, China
| |
Collapse
|
47
|
Nakamura YK, Metea C, Llorenç V, Karstens L, Balter A, Lin P. A diet rich in fermentable fiber promotes robust changes in the intestinal microbiota, mitigates intestinal permeability, and attenuates autoimmune uveitis. Sci Rep 2023; 13:10806. [PMID: 37402809 DOI: 10.1038/s41598-023-37062-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/22/2022] [Accepted: 06/15/2023] [Indexed: 07/06/2023] Open
Abstract
Therapeutic approaches for noninfectious uveitis have expanded greatly over the past 10 years, but are limited by potential side effects and limited efficacy. Thus, therapeutic approaches that include less toxic, potentially preventative strategies to manage noninfectious uveitis are essential areas of study. Diets rich in fermentable fiber are potentially preventative in various conditions such as metabolic syndrome and type 1 diabetes. We studied the effects of various fermentable dietary fibers in an inducible model of experimental autoimmune uveitis (EAU) and found that they differentially modulated uveitis severity. A high pectin diet was the most protective, reducing clinical disease severity through the induction of regulatory T lymphocytes and the suppression of Th1 and Th17 lymphocytes at peak ocular inflammation in either intestinal or extra-intestinal lymphoid tissues. The high pectin diet also promoted intestinal homeostasis as shown by changes in intestinal morphology and gene expression, as well as intestinal permeability. Pectin-induced modulation of intestinal bacteria appeared to be associated with protective changes in immunophenotype in the intestinal tract, and correlated with reduced uveitis severity. In summary, our current findings support the potential for dietary intervention as a strategy to mitigate noninfectious uveitis severity.
Collapse
Affiliation(s)
- Yukiko K Nakamura
- Casey Eye Institute, Oregon Health and Science University, Portland, OR, USA
| | - Christina Metea
- Casey Eye Institute, Oregon Health and Science University, Portland, OR, USA
| | - Victor Llorenç
- Casey Eye Institute, Oregon Health and Science University, Portland, OR, USA
- Clinic Institute of Ophthalmology, Clinic Hospital of Barcelona, Barcelona, Spain
| | - Lisa Karstens
- Departments of Medical Informatics and Clinical Epidemiology, Oregon Health and Science University, Portland, OR, USA
| | - Ariel Balter
- Casey Eye Institute, Oregon Health and Science University, Portland, OR, USA
| | - Phoebe Lin
- Casey Eye Institute, Oregon Health and Science University, Portland, OR, USA.
- Cole Eye Institute, Cleveland Clinic Foundation, Cleveland, OH, USA.
| |
Collapse
|
48
|
Zhang Y, Chen R, Zhang D, Qi S, Liu Y. Metabolite interactions between host and microbiota during health and disease: Which feeds the other? Biomed Pharmacother 2023; 160:114295. [PMID: 36709600 DOI: 10.1016/j.biopha.2023.114295] [Citation(s) in RCA: 36] [Impact Index Per Article: 18.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/14/2022] [Revised: 01/20/2023] [Accepted: 01/20/2023] [Indexed: 01/30/2023] Open
Abstract
Metabolites produced by the host and microbiota play a crucial role in how human bodies develop and remain healthy. Most of these metabolites are produced by microbiota and hosts in the digestive tract. Metabolites in the gut have important roles in energy metabolism, cellular communication, and host immunity, among other physiological activities. Although numerous host metabolites, such as free fatty acids, amino acids, and vitamins, are found in the intestine, metabolites generated by gut microbiota are equally vital for intestinal homeostasis. Furthermore, microbiota in the gut is the sole source of some metabolites, including short-chain fatty acids (SCFAs). Metabolites produced by microbiota, such as neurotransmitters and hormones, may modulate and significantly affect host metabolism. The gut microbiota is becoming recognized as a second endocrine system. A variety of chronic inflammatory disorders have been linked to aberrant host-microbiota interplays, but the precise mechanisms underpinning these disturbances and how they might lead to diseases remain to be fully elucidated. Microbiome-modulated metabolites are promising targets for new drug discovery due to their endocrine function in various complex disorders. In humans, metabolotherapy for the prevention or treatment of various disorders will be possible if we better understand the metabolic preferences of bacteria and the host in specific tissues and organs. Better disease treatments may be possible with the help of novel complementary therapies that target host or bacterial metabolism. The metabolites, their physiological consequences, and functional mechanisms of the host-microbiota interplays will be highlighted, summarized, and discussed in this overview.
Collapse
Affiliation(s)
- Yan Zhang
- Department of Anethesiology, China-Japan Union Hospital of Jilin University, Changchun 130033, People's Republic of China.
| | - Rui Chen
- Department of Pediatrics, China-Japan Union Hospital of Jilin University, Changchun 130033, People's Republic of China.
| | - DuoDuo Zhang
- Department of Thoracic Surgery, The First Hospital of Jilin University, Changchun, Jilin Province 130021, People's Republic of China.
| | - Shuang Qi
- Department of Anethesiology, China-Japan Union Hospital of Jilin University, Changchun 130033, People's Republic of China.
| | - Yan Liu
- Department of Hand and Foot Surgery, China-Japan Union Hospital of Jilin University, Changchun 130033, People's Republic of China.
| |
Collapse
|
49
|
Kumar N, Sahoo NK, Mehan S, Verma B. The importance of gut-brain axis and use of probiotics as a treatment strategy for multiple sclerosis. Mult Scler Relat Disord 2023; 71:104547. [PMID: 36805171 DOI: 10.1016/j.msard.2023.104547] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/09/2022] [Revised: 01/16/2023] [Accepted: 01/31/2023] [Indexed: 02/05/2023]
Abstract
It has been shown that the dysbiosis of the gut's microbes substantially impacts CNS illnesses, including Alzheimer's, Parkinson's, autism, and autoimmune diseases like multiple sclerosis (MS). MS is a CNS-affected autoimmune demyelination condition. Through a two-way communication pathway known as the gut-brain axis, gut microbes communicate with the CNS. When there is a disruption in the gut microbiome, cytokines and other immune cells are secreted, which affects the BBB and gastrointestinal permeability. Recent research using animal models has revealed that the gut microbiota may greatly influence the pathophysiology of EAE/MS. Any change in the gut might increase inflammatory cytokinesand affect the quantity of SCFAs, and other metabolites that cause neuroinflammation and demyelination. In- vivo and in-vitro studies have concluded that probiotics affect the immune system and can be utilized to treat gastrointestinal dysbiosis. Any alteration in the gut microbial composition caused by probiotic intake may serve as a preventive and treatment strategy for MS. The major goal of this review is to emphasize an overview of recent research on the function of gut microbiota in the onset of MS and how probiotics have a substantial impact on gastrointestinal disruption in MS and other neuro disorders. It will be easier to develop new therapeutic approaches, particularly probiotic-based supplements, for treating multiple sclerosis (MS) if we know the link between the gut and CNS.
Collapse
Affiliation(s)
- Nitish Kumar
- SRM Modinagar College of Pharmacy, SRM Institute of Science and Technology (Deemed to be University), Delhi-NCR Campus, Modinagar, Ghaziabad, Uttar Pradesh 201204, India.
| | - Nalini Kanta Sahoo
- SRM Modinagar College of Pharmacy, SRM Institute of Science and Technology (Deemed to be University), Delhi-NCR Campus, Modinagar, Ghaziabad, Uttar Pradesh 201204, India
| | - Sidharth Mehan
- Division of Neuroscience, Department of Pharmacology, ISF College of Pharmacy, (An Autonomous College), Moga, Punjab 142001, India
| | - Bharti Verma
- SRM Modinagar College of Pharmacy, SRM Institute of Science and Technology (Deemed to be University), Delhi-NCR Campus, Modinagar, Ghaziabad, Uttar Pradesh 201204, India
| |
Collapse
|
50
|
Khadka S, Omura S, Sato F, Tsunoda I. Adjuvant Injections Altered the Ileal and Fecal Microbiota Differently with Changes in Immunoglobulin Isotypes and Antimycobacterial Antibody Responses. Int J Mol Sci 2023; 24:2818. [PMID: 36769136 PMCID: PMC9917480 DOI: 10.3390/ijms24032818] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/28/2022] [Revised: 01/28/2023] [Accepted: 01/30/2023] [Indexed: 02/05/2023] Open
Abstract
Alterations in the gut microbiota, "dysbiosis," have been reported in autoimmune diseases, including multiple sclerosis (MS), and their animal models. Although the animal models were induced by injections of autoantigens with adjuvants, including complete Freund's adjuvant (CFA) and pertussis toxin (PT), the effects of adjuvant injections on the microbiota are largely unknown. We aimed to clarify whether adjuvant injections could affect the microbiota in the ileum and feces. Using 16S rRNA sequencing, we found decreased alpha diversities of the gut microbiota in mice injected with CFA and PT, compared with naïve mice. Overall, microbial profiles visualized by principal component analysis demonstrated dysbiosis in feces, but not in the ileum, of adjuvant-injected mice, where the genera Lachnospiraceae NK4A136 group and Alistipes contributed to dysbiosis. When we compared the relative abundances of individual bacteria, we found changes in 16 bacterial genera in feces and seven genera in the ileum of adjuvant-injected mice, in which increased serum levels of antibody against mycobacteria (a component of CFA) and total IgG2c were correlated with the genus Facklamia. On the other hand, increased IgG1 and IgA concentrations were correlated with the genus Atopostipes. Therefore, adjuvant injections alone could alter the overall microbial profiles (i.e., microbiota) and individual bacterial abundances with altered antibody responses; dysbiosis in animal models could be partly due to adjuvant injections.
Collapse
Affiliation(s)
| | | | | | - Ikuo Tsunoda
- Department of Microbiology, Kindai University Faculty of Medicine, Osaka 589-8511, Japan
| |
Collapse
|