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Chen N, Wu J, Sun D, Kaplan HJ, Shao H. Mice deficient of G-protein coupled receptor 3 (GPR3) developed severe experimental autoimmune uveitis (EAU) through increased effector T cell activities. JOURNAL OF IMMUNOLOGY (BALTIMORE, MD. : 1950) 2025:vkaf099. [PMID: 40381994 DOI: 10.1093/jimmun/vkaf099] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/24/2024] [Accepted: 03/27/2025] [Indexed: 05/20/2025]
Abstract
We discovered a protective role of G protein-coupled receptor 3 (GPR3) in a mouse model of T cell-mediated autoimmune uveitis. GPR3 is an orphan receptor that maintains Gs-coupling and cyclic AMP production without an exogenous ligand. Consequently, GPR3 deficient (GPR3KO) mice were more susceptible to developing experimental autoimmune uveitis (EAU) induced by immunization with interphotoreceptor retinoid-binding protein (IRBP) or by adoptive transfer of IRBP-specific T cells than their wild type (WT) littermates. T cells isolated from IRBP-immunized GPR3KO mice demonstrated an increase in proliferation and inflammatory cytokine production in response to the specific IRBP antigen and a relatively high resistance to activation-induced T cell death compared to T cells isolated from immunized WT mice. Moreover, a major tight junction protein such as ZO-1 was reduced in GPR3 deficient retina with severe uveitis after IRBP-specific T cells were transferred. Taken together, our findings suggest that constitutively active GPR3 inhibits T cell mediated retinal inflammation.
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Affiliation(s)
- Nu Chen
- Department of Ophthalmology and Visual Sciences, Kentucky Lions Eye Center, University of Louisville, School of Medicine, Louisville, KY, United States
- Present address: Tianjin Eye Hospital, Tianjin, P. R. China
| | - Jun Wu
- Department of Ophthalmology and Visual Sciences, Kentucky Lions Eye Center, University of Louisville, School of Medicine, Louisville, KY, United States
- Present address: Department of Ophthalmology, Huaian First Hospital, Nanjing Medical University, Huaian, P. R. China
| | - Deming Sun
- Doheny Eye Institute & Department Ophthalmology, David Geffen School of Medicine/UCLA, Los Angeles, CA, United States
| | - Henry J Kaplan
- Department of Ophthalmology and Biochemistry & Molecular Biology, St Louis University School of Medicine, St Louis, MO, United States
| | - Hui Shao
- Department of Ophthalmology and Visual Sciences, Kentucky Lions Eye Center, University of Louisville, School of Medicine, Louisville, KY, United States
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Schiavone N, Isoldi G, Calcagno S, Rovida E, Antiga E, De Almeida CV, Lulli M. Exploring the Gut Microbiota-Retina Axis: Implications for Health and Disease. Microorganisms 2025; 13:1101. [PMID: 40431274 PMCID: PMC12113749 DOI: 10.3390/microorganisms13051101] [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: 03/30/2025] [Revised: 05/07/2025] [Accepted: 05/08/2025] [Indexed: 05/29/2025] Open
Abstract
The gut microbiota represents a rich and adaptive microbial network inhabiting the gastrointestinal tract, performing key functions in nutrient processing, immune response modulation, intestinal wall protection, and microbial defense. Its composition remains highly personalized and responsive to external influences, including lifestyle patterns, physical activity, body composition, and nutritional intake. The interactions of the gut microbiota with bodily systems are conventionally interpreted as broad systemic impacts on organ balance. Yet, emerging research-exemplified by the gut microbiota-brain axis-suggests the potential existence of more targeted and direct communication mechanisms. Dysbiosis, characterized by microbial ecosystem disturbance, generates multiple metabolic compounds capable of entering systemic circulation and reaching distant tissues, notably including ocular structures. This microbial imbalance has been associated with both systemic and localized conditions linked to eye disorders. Accumulating scientific evidence now supports the concept of a gut-retina axis, underscoring the significant role of microbiota disruption in generating various retinal pathologies. This review comprehensively investigates gut microbiota composition, functional dynamics, and dysbiosis-induced alterations, with specific focus on retinal interactions in age-related macular degeneration, diabetic retinopathy, glaucoma, and retinal artery occlusion. Moreover, the review explores microbiota-targeted therapeutic strategies, including precision nutritional interventions and microbial transplantation, as potential modulators of retinal disease progression.
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Affiliation(s)
- Nicola Schiavone
- Department of Experimental and Clinical Biomedical Sciences “Mario Serio”, Section of Experimental Pathology and Oncology, University of Florence, 50134 Florence, Italy; (N.S.); (G.I.); (S.C.); (E.R.)
| | - Giulia Isoldi
- Department of Experimental and Clinical Biomedical Sciences “Mario Serio”, Section of Experimental Pathology and Oncology, University of Florence, 50134 Florence, Italy; (N.S.); (G.I.); (S.C.); (E.R.)
| | - Sara Calcagno
- Department of Experimental and Clinical Biomedical Sciences “Mario Serio”, Section of Experimental Pathology and Oncology, University of Florence, 50134 Florence, Italy; (N.S.); (G.I.); (S.C.); (E.R.)
| | - Elisabetta Rovida
- Department of Experimental and Clinical Biomedical Sciences “Mario Serio”, Section of Experimental Pathology and Oncology, University of Florence, 50134 Florence, Italy; (N.S.); (G.I.); (S.C.); (E.R.)
| | - Emiliano Antiga
- Department of Health Sciences, Section of Dermatology, University of Florence, 50139 Florence, Italy;
| | - Carolina Vieira De Almeida
- Department of Experimental and Clinical Biomedical Sciences “Mario Serio”, Section of Experimental Pathology and Oncology, University of Florence, 50134 Florence, Italy; (N.S.); (G.I.); (S.C.); (E.R.)
- Press Start SRL Società Benefit, 50134 Florence, Italy
| | - Matteo Lulli
- Department of Experimental and Clinical Biomedical Sciences “Mario Serio”, Section of Experimental Pathology and Oncology, University of Florence, 50134 Florence, Italy; (N.S.); (G.I.); (S.C.); (E.R.)
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Liu S, Liu J, Xiang J, Yan R, Li S, Fan Q, Lu L, Wu J, Xue Y, Fu T, Liu J, Li Z. Restorative Effects of Short-Chain Fatty Acids on Corneal Homeostasis Disrupted by Antibiotic-Induced Gut Dysbiosis. THE AMERICAN JOURNAL OF PATHOLOGY 2025; 195:770-796. [PMID: 39732390 DOI: 10.1016/j.ajpath.2024.11.010] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/26/2024] [Revised: 11/02/2024] [Accepted: 11/14/2024] [Indexed: 12/30/2024]
Abstract
The gut microbiota plays a crucial regulatory role in various physiological processes, yet its impact on corneal homeostasis remains insufficiently understood. Here, the effects of antibiotic-induced gut dysbiosis (AIGD) and germ-free conditions were investigated on circadian gene expression, barrier integrity, nerve density, and immune cell activity in the corneas of mice. Both AIGD and germ-free conditions significantly disrupted the overall transcriptomic profile and circadian transcriptomic oscillations in the cornea, as indicated by RNA sequencing. These molecular disturbances were accompanied by a reduction in corneal epithelial thickness, nerve density, corneal sensitivity, and compromised barrier function. Notably, supplementation with short-chain fatty acids (SCFAs) significantly restored corneal integrity in AIGD mice. Further single-cell sequencing revealed that SCFA receptors G-protein-coupled receptor 109A (Hcar2), olfactory receptor 78 (Olfr78), and G-protein-coupled receptor 43 (Ffar2) are expressed in corneal epithelial basal cells, embryonically derived macrophages, perivascular cells, and γδ T cells, respectively. In conclusion, this study demonstrated that the gut microbiota plays a critical role in corneal physiology by regulating circadian gene expression and maintaining barrier function. These findings enhance our understanding of the gut-eye axis, highlighting the cornea as a target for microbiota-derived metabolic signals and underlining the potential therapeutic value of SCFAs in treating corneal dysfunction.
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Affiliation(s)
- Sijing Liu
- International Ocular Surface Research Center, Key Laboratory for Regenerative Medicine, Institute of Ophthalmology, Jinan University, Guangzhou, China; Department of Ophthalmology, The First Affiliated Hospital of Jinan University, Guangzhou, China
| | - Jiangman Liu
- International Ocular Surface Research Center, Key Laboratory for Regenerative Medicine, Institute of Ophthalmology, Jinan University, Guangzhou, China; Department of Pathology, School of Medicine, Jinan University, Guangzhou, China
| | - Jiayan Xiang
- International Ocular Surface Research Center, Key Laboratory for Regenerative Medicine, Institute of Ophthalmology, Jinan University, Guangzhou, China; Department of Ophthalmology, The First Affiliated Hospital of Jinan University, Guangzhou, China
| | - Ruyu Yan
- International Ocular Surface Research Center, Key Laboratory for Regenerative Medicine, Institute of Ophthalmology, Jinan University, Guangzhou, China; Department of Ophthalmology, The First Affiliated Hospital of Jinan University, Guangzhou, China
| | - Senmao Li
- International Ocular Surface Research Center, Key Laboratory for Regenerative Medicine, Institute of Ophthalmology, Jinan University, Guangzhou, China; Department of Ophthalmology, The First Affiliated Hospital of Jinan University, Guangzhou, China
| | - Qiwei Fan
- Department of Pathology, School of Medicine, Jinan University, Guangzhou, China
| | - Liyuan Lu
- International Ocular Surface Research Center, Key Laboratory for Regenerative Medicine, Institute of Ophthalmology, Jinan University, Guangzhou, China; Department of Ophthalmology, The First Affiliated Hospital of Jinan University, Guangzhou, China
| | - Jiaxin Wu
- International Ocular Surface Research Center, Key Laboratory for Regenerative Medicine, Institute of Ophthalmology, Jinan University, Guangzhou, China; Department of Ophthalmology, The First Affiliated Hospital of Jinan University, Guangzhou, China
| | - Yunxia Xue
- International Ocular Surface Research Center, Key Laboratory for Regenerative Medicine, Institute of Ophthalmology, Jinan University, Guangzhou, China; Department of Ophthalmology, The First Affiliated Hospital of Jinan University, Guangzhou, China
| | - Ting Fu
- International Ocular Surface Research Center, Key Laboratory for Regenerative Medicine, Institute of Ophthalmology, Jinan University, Guangzhou, China; Department of Ophthalmology, The First Affiliated Hospital of Jinan University, Guangzhou, China
| | - Jun Liu
- International Ocular Surface Research Center, Key Laboratory for Regenerative Medicine, Institute of Ophthalmology, Jinan University, Guangzhou, China; Department of Ophthalmology, The First Affiliated Hospital of Jinan University, Guangzhou, China
| | - Zhijie Li
- International Ocular Surface Research Center, Key Laboratory for Regenerative Medicine, Institute of Ophthalmology, Jinan University, Guangzhou, China; Department of Ophthalmology, The First Affiliated Hospital of Jinan University, Guangzhou, China.
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Ciurariu E, Tirziu AT, Varga NI, Hirtie B, Alexandru A, Ivan CS, Nicolescu L. Short-Chain Fatty Acids and the Gut-Retina Connection: A Systematic Review. Int J Mol Sci 2025; 26:2470. [PMID: 40141114 PMCID: PMC11941929 DOI: 10.3390/ijms26062470] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2025] [Revised: 03/01/2025] [Accepted: 03/05/2025] [Indexed: 03/28/2025] Open
Abstract
The interplay between gut microbiota and retinal health, known as the gut--retina axis, has gained increasing attention in recent years. Short-chain fatty acids (SCFAs), metabolites produced by gut microbiota, have been identified as key mediators of gut-retina communication. This systematic review explores the role of SCFAs in retinal health and their potential impact on the development and progression of retinal diseases, such as diabetic retinopathy (DR), age-related macular degeneration (AMD), and glaucoma. A literature search was conducted across multiple databases, including PubMed, Google Scholar, and Science Direct, to identify studies published between 2014 and December 2024. Studies were included if they investigated the effects of SCFAs on retinal structure, function, or disease pathogenesis in animal models or human subjects. The review included 10 original articles spanning both preclinical and clinical studies. Evidence suggests that SCFAs play a crucial role in maintaining retinal homeostasis through anti-inflammatory and neuroprotective mechanisms. Dysbiosis of the gut microbiota, leading to altered SCFA production, was associated with increased retinal inflammation, oxidative stress, and vascular dysfunction. Furthermore, reduced SCFA levels were linked to the progression of retinal diseases, such as diabetic retinopathy and age-related macular degeneration. Modulation of gut microbiota and SCFA levels through dietary interventions or probiotics may represent a novel therapeutic strategy for preventing or managing retinal diseases. Further research is needed to elucidate the precise molecular mechanisms underlying SCFA-mediated retinal protection and to evaluate the efficacy of targeted therapies in clinical settings.
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Affiliation(s)
- Elena Ciurariu
- Department of Functional Sciences, Physiology, Centre of Immuno-Physiology and Biotechnologies (CIFBIOTEH), “Victor Babeş” University of Medicine and Pharmacy, Eftimie Murgu Square, No. 2, 300041 Timisoara, Romania;
| | - Andreea-Talida Tirziu
- Doctoral School, Department of General Medicine, “Victor Babeş” University of Medicine and Pharmacy, Eftimie Murgu Square, No. 2, 300041 Timisoara, Romania; (N.-I.V.); (B.H.)
| | - Norberth-Istvan Varga
- Doctoral School, Department of General Medicine, “Victor Babeş” University of Medicine and Pharmacy, Eftimie Murgu Square, No. 2, 300041 Timisoara, Romania; (N.-I.V.); (B.H.)
| | - Bogdan Hirtie
- Doctoral School, Department of General Medicine, “Victor Babeş” University of Medicine and Pharmacy, Eftimie Murgu Square, No. 2, 300041 Timisoara, Romania; (N.-I.V.); (B.H.)
| | - Alexandru Alexandru
- Department of General Medicine, “Victor Babeş” University of Medicine and Pharmacy, Eftimie Murgu Square, No. 2, 300041 Timisoara, Romania; (A.A.); (C.-S.I.)
| | - Cristiana-Smaranda Ivan
- Department of General Medicine, “Victor Babeş” University of Medicine and Pharmacy, Eftimie Murgu Square, No. 2, 300041 Timisoara, Romania; (A.A.); (C.-S.I.)
| | - Laura Nicolescu
- Doctoral School, Faculty of Medicine, “Vasile Goldis” Western University, Bulevardul Revolutiei 94, 310025 Arad, Romania;
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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.
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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
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Huang Y, Wang S, Huang J, Shen Y, Zou L, Liu H. Investigating the Causal Relationship Between Gut Microbiota and Allergic Conjunctivitis: A Two-Sample Mendelian Randomization Study. Ocul Immunol Inflamm 2024; 32:2411-2420. [PMID: 39353056 DOI: 10.1080/09273948.2024.2388202] [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: 08/07/2023] [Revised: 07/28/2024] [Accepted: 07/30/2024] [Indexed: 10/04/2024]
Abstract
PURPOSE To investigate the causal association between gut microbiota and allergic conjunctivitis. METHODS A two-sample Mendelian randomization (MR) analysis was performed using the summary statistics of gut microbiota (18,340) from MiBio-Gen consortium and allergic conjunctivitis data (n = 218,792) obtained from the IEU Open GWAS project. F-statistics and sensitivity analyses were used to address potential biases and ensure the reliability of our findings. Reverse MR analysis was conducted to assess the possible of reverse causal relationships. RESULTS The inverse variance weighted estimates revealed the protective potential of the phylum Euryarchaeota against allergic conjunctivitis (OR = 0.87, p = 6.17 × 10-4). On the other hand, the genus Christensenellaceae R.7 group (OR = 0.75, p = 2.89 × 10-3), family Peptostreptococcaceae (OR = 0.83, p = 6.22 × 10-3), genus Lachnospiraceae FCS020 group (OR = 0.82, p = 0.02) all showed a suggestive protective association with allergic conjunctivitis. Additionally, sensitivity analysis confirmed the robustness of the above associations. In the reverse MR analysis, no significant causal association was found between gut microbiota and allergic conjunctivitis. CONCLUSION This study has revealed a potential causal correlation between the phylum Euryarchaeota and allergic conjunctivitis, offering new insights to improve prevention and treatment of this condition.
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Affiliation(s)
- Yuanyang Huang
- Department of Ophthalmology, Shanghai Children's Medical Center, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Shu Wang
- Department of Ophthalmology, Shanghai Children's Medical Center, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Jinfang Huang
- Department of Ophthalmology, Shanghai Children's Medical Center, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Yining Shen
- Department of Ophthalmology, Shanghai Children's Medical Center, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Leilei Zou
- Department of Ophthalmology, Shanghai Children's Medical Center, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Hong Liu
- Department of Ophthalmology, Shanghai Children's Medical Center, Shanghai Jiao Tong University School of Medicine, Shanghai, China
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Baldi S, Pagliai G, Di Gloria L, Pallecchi M, Barca F, Pieri B, Bartolucci G, Ramazzotti M, Amedei A, Palendri G, Sofi F. Beneficial Effects of Micronutrient Supplementation in Restoring the Altered Microbiota and Gut-Retina Axis in Patients with Neovascular Age-Related Macular Degeneration-A Randomized Clinical Trial. Nutrients 2024; 16:3971. [PMID: 39599758 PMCID: PMC11597754 DOI: 10.3390/nu16223971] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/17/2024] [Revised: 11/14/2024] [Accepted: 11/15/2024] [Indexed: 11/29/2024] Open
Abstract
Background/Objectives: Age-related macular degeneration (AMD) is a leading cause of visual impairment in the elderly and is characterized by a multifactorial etiology. Emerging evidence points to the potential involvement of the gut-retina axis in AMD pathogenesis, prompting exploration into novel therapeutic strategies. This study aims to investigate the effects of some micronutrients (such as lutein and zeaxanthin) and saffron (as a supplement)-known for their anti-inflammatory properties-on ophthalmological and microbial parameters in neovascular AMD (nAMD) patients. Methods: Thirty naive nAMD patients were randomized to receive daily micronutrient supplementation alongside anti-VEGF (vascular endothelial growth factor) therapy, or anti-VEGF treatment alone, over a 6-month period, with comparisons made to a healthy control (HC) group (N = 15). Ophthalmological assessments, biochemical measurements, and stool samples were obtained before and after treatment. Gut microbiota (GM) characterization was performed using 16S rRNA sequencing, while short-chain fatty acids (SCFAs), medium-chain fatty acids (MCFAs), and long-chain fatty acids (LCFAs) were analyzed with a gas chromatography-mass spectrometry protocol. Results: Compared to HC, nAMD patients exhibited reduced GM alpha diversity, altered taxonomic composition, and decreased total SCFA levels, in addition to elevated levels of proinflammatory octanoic and nonanoic acids. Micronutrient supplementation was associated with improved visual acuity relative to the group treated with anti-VEGF alone, along with a decrease in the total amount of MCFAs, which are metabolites known to have adverse ocular effects. Conclusions: In conclusion, despite certain limitations-such as the limited sample size and the low taxonomic resolution of 16S rRNA sequencing-this study highlights compositional and functional imbalances in the GM of nAMD patients and demonstrates that micronutrient supplementation may help restore the gut-retina axis. These findings suggest the therapeutic potential of micronutrients in enhancing ocular outcomes for nAMD patients, underscoring the complex interaction between GM and ocular health.
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Affiliation(s)
- Simone Baldi
- Department of Experimental and Clinical Medicine, University of Florence, 50134 Florence, Italy; (S.B.); (G.P.)
| | - Giuditta Pagliai
- Department of Experimental and Clinical Medicine, University of Florence, 50134 Florence, Italy; (S.B.); (G.P.)
| | - Leandro Di Gloria
- Department of Biomedical, Experimental and Clinical Sciences “Mario Serio”, University of Florence, 50134 Florence, Italy; (L.D.G.); (M.R.)
| | - Marco Pallecchi
- Department of Neuroscience, Psychology, Drug Research and Child Health NEUROFARBA, University of Florence, 50139 Florence, Italy; (M.P.); (G.B.)
| | - Francesco Barca
- Complex Operative Unit of Ophthalmology, Palagi Hospital, USL Toscana Centro, 50122 Florence, Italy; (F.B.); (B.P.); (G.P.)
| | - Benedetta Pieri
- Complex Operative Unit of Ophthalmology, Palagi Hospital, USL Toscana Centro, 50122 Florence, Italy; (F.B.); (B.P.); (G.P.)
| | - Gianluca Bartolucci
- Department of Neuroscience, Psychology, Drug Research and Child Health NEUROFARBA, University of Florence, 50139 Florence, Italy; (M.P.); (G.B.)
| | - Matteo Ramazzotti
- Department of Biomedical, Experimental and Clinical Sciences “Mario Serio”, University of Florence, 50134 Florence, Italy; (L.D.G.); (M.R.)
| | - Amedeo Amedei
- Department of Experimental and Clinical Medicine, University of Florence, 50134 Florence, Italy; (S.B.); (G.P.)
- Network of Immunity in Infection, Malignancy and Autoimmunity (NIIMA), Universal Scientific Education and Research Network (USERN), Florence, Italy
| | - Gianna Palendri
- Complex Operative Unit of Ophthalmology, Palagi Hospital, USL Toscana Centro, 50122 Florence, Italy; (F.B.); (B.P.); (G.P.)
| | - Francesco Sofi
- Department of Experimental and Clinical Medicine, University of Florence, 50134 Florence, Italy; (S.B.); (G.P.)
- Unit of Clinical Nutrition, Careggi University Hospital, 50134 Florence, Italy
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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.
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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.)
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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.
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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
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Tîrziu AT, Susan M, Susan R, Sonia T, Harich OO, Tudora A, Varga NI, Tiberiu-Liviu D, Avram CR, Boru C, Munteanu M, Horhat FG. From Gut to Eye: Exploring the Role of Microbiome Imbalance in Ocular Diseases. J Clin Med 2024; 13:5611. [PMID: 39337098 PMCID: PMC11432523 DOI: 10.3390/jcm13185611] [Citation(s) in RCA: 4] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/13/2024] [Revised: 09/16/2024] [Accepted: 09/18/2024] [Indexed: 09/30/2024] Open
Abstract
Background: The gut microbiome plays a crucial role in human health, and recent research has highlighted its potential impact on ocular health through the gut-eye axis. Dysbiosis, or an imbalance in the gut microbiota, has been implicated in various ocular diseases. Methods: A comprehensive literature search was conducted using relevant keywords in major electronic databases, prioritizing recent peer-reviewed articles published in English. Results: The gut microbiota influences ocular health through immune modulation, maintenance of the blood-retinal barrier, and production of beneficial metabolites. Dysbiosis can disrupt these mechanisms, contributing to ocular inflammation, tissue damage, and disease progression in conditions such as uveitis, age-related macular degeneration, diabetic retinopathy, dry eye disease, and glaucoma. Therapeutic modulation of the gut microbiome through probiotics, prebiotics, synbiotics, and fecal microbiota transplantation shows promise in preclinical and preliminary human studies. Conclusions: The gut-eye axis represents a dynamic and complex interplay between the gut microbiome and ocular health. Targeting the gut microbiome through innovative therapeutic strategies holds potential for improving the prevention and management of various ocular diseases.
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Affiliation(s)
- Andreea-Talida Tîrziu
- Department of General Medicine, Doctoral School, "Victor Babes" University of Medicine and Pharmacy, 300041 Timisoara, Romania
- Department of Ophthalmology, "Victor Babes" University of Medicine and Pharmacy, 300041 Timisoara, Romania
| | - Monica Susan
- Centre for Preventive Medicine, Department of Internal Medicine, "Victor Babes" University of Medicine and Pharmacy, Eftimie Murgu Square, No. 2, 300041 Timisoara, Romania
| | - Razvan Susan
- Centre for Preventive Medicine, Department of Family Medicine, "Victor Babes" University of Medicine and Pharmacy, Eftimie Murgu Square, No. 2, 300041 Timisoara, Romania
| | - Tanasescu Sonia
- Department of Pediatrics, "Victor Babes" University of Medicine and Pharmacy, Eftimie Murgu Sq. No. 2, 300041 Timisoara, Romania
| | - Octavia Oana Harich
- Department of Functional Sciences, "Victor Babes" University of Medicine and Pharmacy Timisoara, Eftimie Murgu Sq. No. 2, 300041 Timisoara, Romania
| | - Adelina Tudora
- Multidisciplinary Doctoral School, Vasile Goldis Western University of Arad, Strada Liviu Rebreanu 86, 310419 Arad, Romania
| | - Norberth-Istvan Varga
- Department of General Medicine, Doctoral School, "Victor Babes" University of Medicine and Pharmacy, 300041 Timisoara, Romania
| | - Dragomir Tiberiu-Liviu
- Medical Semiology II Discipline, Internal Medicine Department, "Victor Babes" University of Medicine and Pharmacy, Eftimie Murgu Square 2, 300041 Timisoara, Romania
| | - Cecilia Roberta Avram
- Department of Residential Training and Post-University Courses, "Vasile Goldis" Western University, 310414 Arad, Romania
| | - Casiana Boru
- Department of Medicine, "Vasile Goldis" University of Medicine and Pharmacy, 310414 Arad, Romania
| | - Mihnea Munteanu
- Department of Ophthalmology, "Victor Babes" University of Medicine and Pharmacy, 300041 Timisoara, Romania
| | - Florin George Horhat
- Multidisciplinary Research Center on Antimicrobial Resistance (MULTI-REZ), Microbiology Department, "Victor Babes" University of Medicine and Pharmacy, 300041 Timisoara, Romania
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11
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Nguyen Y, Rudd Zhong Manis J, Ronczkowski NM, Bui T, Oxenrider A, Jadeja RN, Thounaojam MC. Unveiling the gut-eye axis: how microbial metabolites influence ocular health and disease. Front Med (Lausanne) 2024; 11:1377186. [PMID: 38799150 PMCID: PMC11122920 DOI: 10.3389/fmed.2024.1377186] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/26/2024] [Accepted: 04/19/2024] [Indexed: 05/29/2024] Open
Abstract
The intricate interplay between the gut microbiota and ocular health has surpassed conventional medical beliefs, fundamentally reshaping our understanding of organ interconnectivity. This review investigates into the intricate relationship between gut microbiota-derived metabolites and their consequential impact on ocular health and disease pathogenesis. By examining the role of specific metabolites, such as short-chain fatty acids (SCFAs) like butyrate and bile acids (BAs), herein we elucidate their significant contributions to ocular pathologies, thought-provoking the traditional belief of organ sterility, particularly in the field of ophthalmology. Highlighting the dynamic nature of the gut microbiota and its profound influence on ocular health, this review underlines the necessity of comprehending the complex workings of the gut-eye axis, an emerging field of science ready for further exploration and scrutiny. While acknowledging the therapeutic promise in manipulating the gut microbiome and its metabolites, the available literature advocates for a targeted, precise approach. Instead of broad interventions, it emphasizes the potential of exploiting specific microbiome-related metabolites as a focused strategy. This targeted approach compared to a precision tool rather than a broad-spectrum solution, aims to explore the therapeutic applications of microbiome-related metabolites in the context of various retinal diseases. By proposing a nuanced strategy targeted at specific microbial metabolites, this review suggests that addressing specific deficiencies or imbalances through microbiome-related metabolites might yield expedited and pronounced outcomes in systemic health, extending to the eye. This focused strategy holds the potential in bypassing the irregularity associated with manipulating microbes themselves, paving a more efficient pathway toward desired outcomes in optimizing gut health and its implications for retinal diseases.
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Affiliation(s)
- Yvonne Nguyen
- Mercer University School of Medicine, Macon, GA, United States
| | | | | | - Tommy Bui
- Departments of Cellular Biology and Anatomy, Augusta University, Augusta, GA, United States
| | - Allston Oxenrider
- Departments of Cellular Biology and Anatomy, Augusta University, Augusta, GA, United States
| | - Ravirajsinh N. Jadeja
- Biochemistry and Molecular Biology, Medical College of Georgia at Augusta University, Augusta, GA, United States
| | - Menaka C. Thounaojam
- Departments of Cellular Biology and Anatomy, Augusta University, Augusta, GA, United States
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12
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Zhao S, Yan Q, Xu W, Zhang J. Gut microbiome in diabetic retinopathy: A systematic review and meta-analysis. Microb Pathog 2024; 189:106590. [PMID: 38402917 DOI: 10.1016/j.micpath.2024.106590] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/29/2023] [Accepted: 02/18/2024] [Indexed: 02/27/2024]
Abstract
CONTEXT Changes in the gut microbiome are linked with Type 2diabetes mellitus (T2DM) development, but alterations in patients with diabetic retinopathy (DR) are still being debated. OBJECTIVE To investigate the differences in biodiversity and relative abundance of gut microbiome between patients with DR and T2DM. METHODS A comprehensive search was performed in five electronic databases (PubMed, EMBASE, Cochrane Central Register of Controlled Trials, Web of Science, and CNKI) from the inception of each database through to August 2023. The standardized mean difference (SMD) and its 95% confidence interval (CI) were estimated using Stata 15.1. Furthermore, the alpha diversity index and relative abundance of the gut microbiome were calculated. The Egger test determined publication bias in the literature. RESULTS Seven case-control studies were included in the final dataset, comprising 195 patients with DR and 211 patients with T2DM. Compared to T2DM patients, patients in the DR group had a reduced but not significantly different α-diversity. The analysis of microbial composition at the phylum level revealed a marked increase in the relative abundance of Bacteroidetes(ES = 23.27, 95%CI[8.30, 38.23], P = 0.000) and a decline in Firmicutes(ES = 47.05, 95%CI[36.58, 57.52], P = 0.000), Proteobacteria (ES = 11.08, 95%CI[6.08, 16.07], P = 0.000) and Actinobacteria (ES = 10.43, 95%CI[1.64, 19.22], P = 0.001) in patients with DR when compared to those with T2DM. CONCLUSIONS An association exists between alterations in the gut microbiome of T2DM and the development and progression of DR. This suggests that re-establishing homeostasis of the gut microbiome could be a potential way to prevent or treat DR and requires further confirmation in future studies. REGISTRATION DATABASE Prospero. REGISTRATION NUMBER CRD42023455280.
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Affiliation(s)
- Shuang Zhao
- Shandong First Medical University, Jinan, China.
| | - Qi Yan
- Jiangsu Pei People's Hospital, China.
| | - Wanjing Xu
- Qingpu Branch of Zhongshan Hospital Affiliated to Fudan University, China.
| | - Juanmei Zhang
- The Department of Ophthalmology, Linyi People's Hospital, Linyi, China.
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13
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Wu J, Chen N, Grau E, Johnson L, Liu Y, Li C, Scott PA, Kim C, Sun D, Kaplan HJ, Shao H. Short chain fatty acids inhibit corneal inflammatory responses to TLR ligands via the ocular G-protein coupled receptor 43. Ocul Surf 2024; 32:48-57. [PMID: 38224777 PMCID: PMC11056309 DOI: 10.1016/j.jtos.2024.01.005] [Citation(s) in RCA: 8] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/09/2023] [Revised: 11/22/2023] [Accepted: 01/12/2024] [Indexed: 01/17/2024]
Abstract
PURPOSE Short chain fatty acids (SCFAs) produced by gut microbiota are known to play primary roles in gut homeostasis by immunomodulation partially through G-protein coupled receptors (GPR) 43. Using mouse models of TLR ligand induced keratitis, we investigated whether SCFAs and GPR43 play any regulatory roles in the pathogenesis of inflammatory responses in the eye. METHODS Both human and mouse eyes were labeled with a specific antibody for GPR43 and imaged by a laser scanning confocal microscope. Corneal cups from naïve C57BL/6J (B6) and GPR43 knockout (KO) mice were stimulated with TLR ligands in the presence or absence of sodium butyrate overnight and then processed for RT-PCR assay for expression of GPR43 and cytokines. Keratitis was induced by Poly I:C in wild type (WT) B6, GPR43KO and chimeric mice and the disease severity was evaluated by the corneal fluorescein staining test, and infiltrating cell staining and calculating in corneal whole mount. RESULTS GPR43 is expressed in both human and mouse eyes and the expression is bidirectionally regulated by TLR ligands and butyrate. Butyrate significantly inhibited inflammation caused by several TLR ligands such as Poly I:C, Flagellin, and CpG-ODN (TLR-3, 5 and 9 agonists, respectively) in WT, but not GPR43KO, mice. Butyrate inhibition of TLR-induced keratitis is mediated by the GPR43 expressed in tissue but not hematopoietic, cells. CONCLUSIONS This is the first report to demonstrate of the protective effect of SCFAs on microbial keratitis, and the dynamic expression and anti-inflammatory function of GPR43 in the eye. SCFAs can modulate inflammation and immunity in the eye through GPR43.
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Affiliation(s)
- Jun Wu
- Department of Ophthalmology and Visual Sciences, Kentucky Lions Eye Center, University of Louisville, School of Medicine, Louisville, KY, USA
| | - Nu Chen
- Department of Ophthalmology and Visual Sciences, Kentucky Lions Eye Center, University of Louisville, School of Medicine, Louisville, KY, USA
| | - Elizabeth Grau
- Department of Ophthalmology and Visual Sciences, Kentucky Lions Eye Center, University of Louisville, School of Medicine, Louisville, KY, USA
| | - Luke Johnson
- Department of Ophthalmology and Visual Sciences, Kentucky Lions Eye Center, University of Louisville, School of Medicine, Louisville, KY, USA
| | - Yongqing Liu
- Department of Medicine-oncology, University of Louisville, School of Medicine, Louisville, KY, USA
| | - Chi Li
- Department of Medicine-oncology, University of Louisville, School of Medicine, Louisville, KY, USA
| | - Patrick A Scott
- Department of Ophthalmology and Visual Sciences, Kentucky Lions Eye Center, University of Louisville, School of Medicine, Louisville, KY, USA
| | - Chang Kim
- Department of Pathology, Mary H. Weiser Food Allergy Center, 4025 Biomedical Science Research Building, 109 Zina Pitcher Place, Ann Arbor, MI, USA
| | - Deming Sun
- Doheny Eye Institute & Department Ophthalmology, David Geffen School of Medicine/UCLA, Los Angeles, CA, USA
| | - Henry J Kaplan
- Department of Ophthalmology and Biochemistry & Molecular Biology, St. Louis University School of Medicine, St. Louis, Missouri, USA
| | - Hui Shao
- Department of Ophthalmology and Visual Sciences, Kentucky Lions Eye Center, University of Louisville, School of Medicine, Louisville, KY, USA.
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14
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Yu Y, Liu Y, Meng Z. Role of traditional Chinese medicine in age-related macular degeneration: exploring the gut microbiota's influence. Front Pharmacol 2024; 15:1356324. [PMID: 38333011 PMCID: PMC10850396 DOI: 10.3389/fphar.2024.1356324] [Citation(s) in RCA: 4] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2023] [Accepted: 01/15/2024] [Indexed: 02/10/2024] Open
Abstract
The pathogenesis of age-related macular degeneration (AMD), a degenerative retinopathy, remains unclear. Administration of anti-vascular endothelial growth factor agents, antioxidants, fundus lasers, photodynamic therapy, and transpupillary warming has proven effective in alleviating symptoms; however, these interventions cannot prevent or reverse AMD. Increasing evidence suggests that AMD risk is linked to changes in the composition, abundance, and diversity of the gut microbiota (GM). Activation of multiple signaling pathways by GM metabolites, including lipopolysaccharides, oxysterols, short-chain fatty acids (SCFAs), and bile acids (BAs), influences retinal physiology. Traditional Chinese medicine (TCM), known for its multi-component and multi-target advantages, can help treat AMD by altering GM composition and regulating the levels of certain substances, such as lipopolysaccharides, reducing oxysterols, and increasing SCFA and BA contents. This review explores the correlation between GM and AMD and interventions for the two to provide new perspectives on treating AMD with TCM.
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Affiliation(s)
- Yujia Yu
- Shandong University of Traditional Chinese Medicine, Jinan, Shandong, China
| | - Yong Liu
- Affiliated Hospital of Shandong University of Traditional Chinese Medicine, Shandong Province Hospital of Traditional Chinese Medicine, Jinan, Shandong, China
| | - Zhaoru Meng
- The Hong Kong University of Science and Technology, Kowloon, Hong Kong SAR, China
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15
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Wang R, Wang QY, Bai Y, Bi YG, Cai SJ. Research progress of diabetic retinopathy and gut microecology. Front Microbiol 2023; 14:1256878. [PMID: 37744925 PMCID: PMC10513461 DOI: 10.3389/fmicb.2023.1256878] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2023] [Accepted: 08/23/2023] [Indexed: 09/26/2023] Open
Abstract
According to the prediction of the International Diabetes Federation, global diabetes mellitus (DM) patients will reach 783.2 million in 2045. The increasing incidence of DM has led to a global epidemic of diabetic retinopathy (DR). DR is a common microvascular complication of DM, which has a significant impact on the vision of working-age people and is one of the main causes of blindness worldwide. Substantial research has highlighted that microangiopathy and chronic low-grade inflammation are widespread in the retina of DR. Meanwhile, with the introduction of the gut-retina axis, it has also been found that DR is associated with gut microecological disorders. The disordered structure of the GM and the destruction of the gut barrier result in the release of abnormal GM flora metabolites into the blood circulation. In addition, this process induced alterations in the expression of various cytokines and proteins, which further modulate the inflammatory microenvironment, vascular damage, oxidative stress, and immune levels within the retina. Such alterations led to the development of DR. In this review, we discuss the corresponding alterations in the structure of the GM flora and its metabolites in DR, with a more detailed focus on the mechanism of gut microecology in DR. Finally, we summarize the potential therapeutic approaches of DM/DR, mainly regulating the disturbed gut microecology to restore the homeostatic level, to provide a new perspective on the prevention, monitoring, and treatment of DR.
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Affiliation(s)
- Rui Wang
- Department of Ophthalmology, Affiliated Hospital of Zunyi Medical University, Zunyi, China
- Special Key Laboratory of Ocular Diseases of Guizhou Province, Zunyi, China
| | - Qiu-Yuan Wang
- Department of Ophthalmology, Affiliated Hospital of Zunyi Medical University, Zunyi, China
- Special Key Laboratory of Ocular Diseases of Guizhou Province, Zunyi, China
| | - Yang Bai
- Special Key Laboratory of Ocular Diseases of Guizhou Province, Zunyi, China
| | - Ye-Ge Bi
- Special Key Laboratory of Ocular Diseases of Guizhou Province, Zunyi, China
| | - Shan-Jun Cai
- Department of Ophthalmology, Affiliated Hospital of Zunyi Medical University, Zunyi, China
- Special Key Laboratory of Ocular Diseases of Guizhou Province, Zunyi, China
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16
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Campagnoli LIM, Varesi A, Barbieri A, Marchesi N, Pascale A. Targeting the Gut-Eye Axis: An Emerging Strategy to Face Ocular Diseases. Int J Mol Sci 2023; 24:13338. [PMID: 37686143 PMCID: PMC10488056 DOI: 10.3390/ijms241713338] [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: 07/29/2023] [Revised: 08/20/2023] [Accepted: 08/26/2023] [Indexed: 09/10/2023] Open
Abstract
The human microbiota refers to a large variety of microorganisms (bacteria, viruses, and fungi) that live in different human body sites, including the gut, oral cavity, skin, and eyes. In particular, the presence of an ocular surface microbiota with a crucial role in maintaining ocular surface homeostasis by preventing colonization from pathogen species has been recently demonstrated. Moreover, recent studies underline a potential association between gut microbiota (GM) and ocular health. In this respect, some evidence supports the existence of a gut-eye axis involved in the pathogenesis of several ocular diseases, including age-related macular degeneration, uveitis, diabetic retinopathy, dry eye, and glaucoma. Therefore, understanding the link between the GM and these ocular disorders might be useful for the development of new therapeutic approaches, such as probiotics, prebiotics, symbiotics, or faecal microbiota transplantation through which the GM could be modulated, thus allowing better management of these diseases.
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Affiliation(s)
| | - Angelica Varesi
- Department of Biology and Biotechnology, University of Pavia, 27100 Pavia, Italy;
| | - Annalisa Barbieri
- Department of Drug Sciences, Unit of Pharmacology, University of Pavia, 27100 Pavia, Italy; (A.B.); (N.M.)
| | - Nicoletta Marchesi
- Department of Drug Sciences, Unit of Pharmacology, University of Pavia, 27100 Pavia, Italy; (A.B.); (N.M.)
| | - Alessia Pascale
- Department of Drug Sciences, Unit of Pharmacology, University of Pavia, 27100 Pavia, Italy; (A.B.); (N.M.)
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17
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Buonfiglio F, Pfeiffer N, Gericke A. Immunomodulatory and Antioxidant Drugs in Glaucoma Treatment. Pharmaceuticals (Basel) 2023; 16:1193. [PMID: 37765001 PMCID: PMC10535738 DOI: 10.3390/ph16091193] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/14/2023] [Revised: 08/02/2023] [Accepted: 08/18/2023] [Indexed: 09/29/2023] Open
Abstract
Glaucoma, a group of diseases characterized by progressive retinal ganglion cell loss, cupping of the optic disc, and a typical pattern of visual field defects, is a leading cause of severe visual impairment and blindness worldwide. Elevated intraocular pressure (IOP) is the leading risk factor for glaucoma development. However, glaucoma can also develop at normal pressure levels. An increased susceptibility of retinal ganglion cells to IOP, systemic vascular dysregulation, endothelial dysfunction, and autoimmune imbalances have been suggested as playing a role in the pathophysiology of normal-tension glaucoma. Since inflammation and oxidative stress play a role in all forms of glaucoma, the goal of this review article is to present an overview of the inflammatory and pro-oxidant mechanisms in the pathophysiology of glaucoma and to discuss immunomodulatory and antioxidant treatment approaches.
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Affiliation(s)
- Francesco Buonfiglio
- Department of Ophthalmology, University Medical Center, Johannes Gutenberg University Mainz, Langenbeckstrasse 1, 55131 Mainz, Germany;
| | | | - Adrian Gericke
- Department of Ophthalmology, University Medical Center, Johannes Gutenberg University Mainz, Langenbeckstrasse 1, 55131 Mainz, Germany;
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18
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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: 17] [Impact Index Per Article: 8.5] [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.
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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
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19
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Alfuzaie R. The Link Between Gastrointestinal Microbiome and Ocular Disorders. Clin Ophthalmol 2023; 17:2133-2140. [PMID: 37521153 PMCID: PMC10386868 DOI: 10.2147/opth.s415425] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/02/2023] [Accepted: 07/18/2023] [Indexed: 08/01/2023] Open
Abstract
The gut-eye axis has been hypothesized to be a factor in many eye pathologies. This review examines papers from PubMed about this topic. Bacterial commensals could either be protective by regulating the immune system or prove to be damaging to the gut mucosal wall and incite an inflammatory process. The balance between the two appears to be crucial in maintaining eye health. Imbalances have been implicated in ophthalmologic conditions. The use of probiotics, dietary modifications, antibiotics, and faecal microbiota transplant in mice with pathologies such as those encountered in our practice appears to reverse disease course or at least prevent its progression. Clinical trials are currently underway to investigate their clinical significance in diseased patients.
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20
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Zhang H, Mo Y. The gut-retina axis: a new perspective in the prevention and treatment of diabetic retinopathy. Front Endocrinol (Lausanne) 2023; 14:1205846. [PMID: 37469982 PMCID: PMC10352852 DOI: 10.3389/fendo.2023.1205846] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/14/2023] [Accepted: 06/19/2023] [Indexed: 07/21/2023] Open
Abstract
Diabetic retinopathy (DR) is a microvascular lesion that occurs as a complication of diabetes mellitus. Many studies reveal that retinal neurodegeneration occurs early in its pathogenesis, and abnormal retinal function can occur in patients without any signs of microvascular abnormalities. The gut microbiota is a large, diverse colony of microorganisms that colonize the human intestine. Studies indicated that the gut microbiota is involved in the pathophysiological processes of DR and plays an important role in its development. On the one hand, numerous studies demonstrated the involvement of gut microbiota in retinal neurodegeneration. On the other hand, alterations in gut bacteria in RD patients can cause or exacerbate DR. The present review aims to underline the critical relationship between gut microbiota and DR. After a brief overview of the composition, function, and essential role of the gut microbiota in ocular health, and the review explores the concept of the gut-retina axis and the conditions of the gut-retina axis crosstalk. Because gut dysbiosis has been associated with DR, the review intends to determine changes in the gut microbiome in DR, the hypothesized mechanisms linking to the gut-retina axis, and its predictive potential.
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Affiliation(s)
- Haiyan Zhang
- Chengdu University of Traditional Chinese Medicine, Sichuan, China
| | - Ya Mo
- Chengdu University of Traditional Chinese Medicine, Sichuan, China
- Affiliated Hospital of Chengdu University of Traditional Chinese Medicine, Sichuan, China
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21
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Golpour F, Abbasi-Alaei M, Babaei F, Mirzababaei M, Parvardeh S, Mohammadi G, Nassiri-Asl M. Short chain fatty acids, a possible treatment option for autoimmune diseases. Biomed Pharmacother 2023; 163:114763. [PMID: 37105078 DOI: 10.1016/j.biopha.2023.114763] [Citation(s) in RCA: 43] [Impact Index Per Article: 21.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/06/2023] [Revised: 04/09/2023] [Accepted: 04/20/2023] [Indexed: 04/29/2023] Open
Abstract
Gut microbiota can interact with the immune system through its metabolites. Short-chain fatty acids (SCFAs), as one of the most abundant metabolites of the resident gut microbiota play an important role in this crosstalk. SCFAs (acetate, propionate, and butyrate) regulate nearly every type of immune cell in the gut's immune cell repertoire regarding their development and function. SCFAs work through several pathways to impose protection towards colonic health and against local or systemic inflammation. Additionally, SCFAs play a role in the regulation of immune or non-immune pathways that can slow the development of autoimmunity either systematically or in situ. The present study aims to summarize the current knowledge on the immunomodulatory roles of SCFAs and the association between the SCFAs and autoimmune disorders such as celiac disease (CD), inflammatory bowel disease (IBD), rheumatoid arthritis (RA), multiple sclerosis (MS), systemic lupus erythematosus (SLE), type 1 diabetes (T1D) and other immune-mediated diseases, uncovering a brand-new therapeutic possibility to prevent or treat autoimmunity.
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Affiliation(s)
- Faezeh Golpour
- School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Mehrsa Abbasi-Alaei
- School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Fatemeh Babaei
- Department of Clinical Biochemistry, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Mohammadreza Mirzababaei
- Department of Clinical Biochemistry, School of Medicine, Kermanshah University of Medical Sciences, Kermanshah, Iran
| | - Siavash Parvardeh
- Department of Pharmacology, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Ghazaleh Mohammadi
- Cellular and Molecular Research Center, Research Institute for Prevention of Non-Communicable Diseases, Qazvin University of Medical Sciences, Qazvin, Iran; Department of Molecular Medicine, School of Medicine, Qazvin University of Medical Sciences, Qazvin, Iran.
| | - Marjan Nassiri-Asl
- Department of Pharmacology, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran; Neurobiology Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
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22
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Serban D, Dascalu AM, Arsene AL, Tribus LC, Vancea G, Pantea Stoian A, Costea DO, Tudosie MS, Stana D, Cristea BM, Nicolae VA, Tudor C, Costea AC, Comandasu M, Faur M, Tanasescu C. Gut Microbiota Dysbiosis in Diabetic Retinopathy-Current Knowledge and Future Therapeutic Targets. Life (Basel) 2023; 13:968. [PMID: 37109497 PMCID: PMC10144923 DOI: 10.3390/life13040968] [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: 03/16/2023] [Revised: 03/30/2023] [Accepted: 04/06/2023] [Indexed: 04/29/2023] Open
Abstract
Diabetic retinopathy is one of the major causes of blindness today, despite important achievements in diagnosis and therapy. The involvement of a gut-retina axis is thought to be a possible risk factor for several chronic eye disease, such as glaucoma, age-related macular degeneration, uveitis, and, recently, diabetic retinopathy. Dysbiosis may cause endothelial disfunction and alter retinal metabolism. This review analyzes the evidence regarding changes in gut microbiota in patients with DR compared with diabetics and healthy controls (HCs). A systematic review was performed on PubMed, Web of Science, and Google Scholar for the following terms: "gut microbiota" OR "gut microbiome" AND "diabetic retinopathy". Ultimately, 9 articles published between 2020 and 2022 presenting comparative data on a total of 228 T2DM patients with DR, 220 patients with T2DM, and 118 HCs were analyzed. All of the studies found a distinctive microbial beta diversity in DR vs. T2DM and HC, characterized by an altered Firmicutes/Bacteroidetes ratio, a decrease in butyrate producers, and an increase in LPS-expressing and pro-inflammatory species in the Bacteroidetes and Proteobacteria phyla. The probiotic species Bifidobacterium and Lactobacillus were decreased when compared with T2DM. Gut microbiota influence retinal health in multiple ways and may represent a future therapeutic target in DR.
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Affiliation(s)
- Dragos Serban
- Faculty of Medicine, “Carol Davila” University of Medicine and Pharmacy, 020021 Bucharest, Romania; (D.S.)
- Fourth Surgery Department, Emergency University Hospital Bucharest, 050098 Bucharest, Romania
| | - Ana Maria Dascalu
- Faculty of Medicine, “Carol Davila” University of Medicine and Pharmacy, 020021 Bucharest, Romania; (D.S.)
- Ophthalmology Department, Emergency University Hospital Bucharest, 050098 Bucharest, Romania
| | - Andreea Letitia Arsene
- Faculty of Pharmacy, “Carol Davila” University of Medicine and Pharmacy, 020021 Bucharest, Romania
| | - Laura Carina Tribus
- Faculty of Dental Medicine, “Carol Davila” University of Medicine and Pharmacy, 020021 Bucharest, Romania
- Department of Internal Medicine, Ilfov Emergency Clinic Hospital, 022113 Bucharest, Romania
| | - Geta Vancea
- Faculty of Medicine, “Carol Davila” University of Medicine and Pharmacy, 020021 Bucharest, Romania; (D.S.)
- “Victor Babes” Infectious and Tropical Disease Hospital, 030303 Bucharest, Romania
| | - Anca Pantea Stoian
- Faculty of Medicine, “Carol Davila” University of Medicine and Pharmacy, 020021 Bucharest, Romania; (D.S.)
| | - Daniel Ovidiu Costea
- Faculty of Medicine, Ovidius University Constanta, 900470 Constanta, Romania
- General Surgery Department, Emergency County Hospital Constanta, 900591 Constanta, Romania
| | - Mihail Silviu Tudosie
- Faculty of Medicine, “Carol Davila” University of Medicine and Pharmacy, 020021 Bucharest, Romania; (D.S.)
| | - Daniela Stana
- Ophthalmology Department, Emergency University Hospital Bucharest, 050098 Bucharest, Romania
| | - Bogdan Mihai Cristea
- Faculty of Medicine, “Carol Davila” University of Medicine and Pharmacy, 020021 Bucharest, Romania; (D.S.)
| | - Vanessa Andrada Nicolae
- Faculty of Medicine, “Carol Davila” University of Medicine and Pharmacy, 020021 Bucharest, Romania; (D.S.)
- Ophthalmology Department, Emergency University Hospital Bucharest, 050098 Bucharest, Romania
| | - Corneliu Tudor
- Faculty of Medicine, “Carol Davila” University of Medicine and Pharmacy, 020021 Bucharest, Romania; (D.S.)
- Fourth Surgery Department, Emergency University Hospital Bucharest, 050098 Bucharest, Romania
| | | | - Meda Comandasu
- Fourth Surgery Department, Emergency University Hospital Bucharest, 050098 Bucharest, Romania
| | - Mihai Faur
- Faculty of Medicine, University “Lucian Blaga”, 550169 Sibiu, Romania
- Department of Surgery, Emergency County Hospital Sibiu, 550245 Sibiu, Romania
| | - Ciprian Tanasescu
- Faculty of Medicine, University “Lucian Blaga”, 550169 Sibiu, Romania
- Department of Surgery, Emergency County Hospital Sibiu, 550245 Sibiu, Romania
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23
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Butyrate Ameliorates Intraocular Bacterial Infection by Promoting Autophagy and Attenuating the Inflammatory Response. Infect Immun 2023; 91:e0025222. [PMID: 36515524 PMCID: PMC9872663 DOI: 10.1128/iai.00252-22] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022] Open
Abstract
Despite an important link between the gut and ocular health, the role of the gut-eye axis remains elusive in ocular infections. In this study, we investigated the role of butyrate, a gut microbial metabolite, in the pathobiology of intraocular bacterial (Staphylococcus aureus) infection, endophthalmitis. We found that intravitreal administration of butyrate derivatives, sodium butyrate (NaB), or phenylbutyrate (PBA) reduced intraocular bacterial growth and retinal inflammatory response. The ocular tissue architecture and retinal function were preserved in butyrate-treated eyes. In cultured mouse bone marrow-derived macrophages (BMDMs) and human retinal Müller glia, NaB or PBA treatment reduced S. aureus-induced inflammatory response by inhibiting NOD-like receptor family pyrin domain containing 3 (NLRP3) inflammasome. However, in vivo data showed NLRP3-independent effects of butyrate. The butyrate-treated mouse retina and cells exhibited induced expression of antimicrobial molecules CRAMP (LL37) and S100A7/A8, resulting in increased bacterial phagocytosis and killing. Moreover, butyrate treatment enhanced AMP-activated protein kinase (AMPK)-dependent autophagy and promoted the co-localization of CRAMP in autophagosomes, indicating autophagy-mediated bacterial killing. Furthermore, pharmacological inhibition of autophagy in mice revealed its role in butyrate-mediated protection. Finally, butyrate exhibited synergy with antibiotic in promoting endophthalmitis resolution. Collectively, our study demonstrated the protective mechanisms of butyrate in ameliorating bacterial endophthalmitis. Therefore, butyrate derivatives could be explored as immunomodulatory and anti-bacterial therapeutics to improve visual outcomes in ocular bacterial infections.
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24
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Wang X, Yu C, Liu X, Yang J, Feng Y, Wu Y, Xu Y, Zhu Y, Li W. Fenofibrate Ameliorated Systemic and Retinal Inflammation and Modulated Gut Microbiota in High-Fat Diet-Induced Mice. Front Cell Infect Microbiol 2022; 12:839592. [PMID: 35719341 PMCID: PMC9201033 DOI: 10.3389/fcimb.2022.839592] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2021] [Accepted: 05/09/2022] [Indexed: 01/14/2023] Open
Abstract
Fenofibrate, as a lipid-lowering drug, has been reported to have a protective effect on the retina independent with plasma lipid levels. This study aimed to investigate that the ameliorative effects of fenofibrate on systemic and retinal inflammation, as well as gut microbiota dysbiosis in high-fat diet (HFD)-induced mice. C57BL/6J mice were randomly allocated into four groups: standard diet (SD) group; HFD group; SD plus fenofibrate (SD_ Fe) group; HFD plus fenofibrate (HFD_ Fe) group. After successfully establishing models (5 months), indicators associated with lipid, gut barrier, inflammation and gut microbiota were investigated. Our results showed that supplementing the HFD with fenofibrate decreased body weight gain, alleviated dyslipidemia and reversed the downregulation of short-chain fatty acid (SCFAs) in serum, retina and feces. Fenofibrate ameliorated intestinal barrier function damage in HFD-induced mice. Fenofibrate coadministration inhibited the levels of inflammatory factor and lipopolysaccharide (LPS) in the serum and attenuated inflammatory response in the retina of HFD-induced mice. Systemic LPS was positively correlated with a series of inflammatory factors in serum and retina, respectively. Fenofibrate supplementation down-regulated the abundances of LPS-associated bacteria in HFD mice, including Firmicutes and Proteobacteria at the phylum level, Desulfovibrionaceae at the family level, as well as unclassified_ Desulfovibrionaceae, Acetatifactor, Flavonifractor, Oscillibacter and Anaerotruncus at the genus level. However, fenofibrate treatment up-regulated the abundances of SCFA-associated bacteria in HFD mice, including Bacteroidetes at the phylum level, Porphyromonadaceae at the family level, as well as unclassified_Porphyromonadaceae, Barnesiella, Alloprevotella and Bifidobacterium at the genus level. In conclusion, our results confirmed fenofibrate could attenuate HFD-induced systemic and retinal inflammation, accompanying with restoration of intestinal barrier damage and modulation of gut microbiota/metabolites. This work provided an explanation for the ameliorative effects of fenofibrate on HFD-induced systemic and retinal inflammation might be partially related with the modulation of gut microbiota and its metabolites.
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Affiliation(s)
- Xue Wang
- Aier School of Ophthalmology, Central South University, Changsha, China
- University of Science and Technology of China, Suzhou Institute of Biomedical Engineering and Technology, Suzhou, China
| | - Chaofeng Yu
- Aier School of Ophthalmology, Central South University, Changsha, China
| | - Xiaomei Liu
- University of Science and Technology of China, Suzhou Institute of Biomedical Engineering and Technology, Suzhou, China
| | - Jiasong Yang
- Aier School of Ophthalmology, Central South University, Changsha, China
- Department of Ophthalmology, Shanghai Aier Eye Hospital, Shanghai, China
| | - Yuliang Feng
- Aier School of Ophthalmology, Central South University, Changsha, China
| | - Yajun Wu
- Aier School of Ophthalmology, Central South University, Changsha, China
| | - Yali Xu
- Aier School of Ophthalmology, Central South University, Changsha, China
| | - Yihua Zhu
- Department of Ophthalmology, First Affiliated Hospital of Fujian Medical University, Fuzhou, China
- *Correspondence: Wensheng Li, ; Yihua Zhu,
| | - Wensheng Li
- Aier School of Ophthalmology, Central South University, Changsha, China
- Department of Ophthalmology, Shanghai Aier Eye Hospital, Shanghai, China
- *Correspondence: Wensheng Li, ; Yihua Zhu,
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25
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Qin X, Zou H, Niu C. The STING pathway: An uncharacterized angle beneath the gut-retina axis. Exp Eye Res 2022; 217:108970. [PMID: 35114214 DOI: 10.1016/j.exer.2022.108970] [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: 11/27/2021] [Revised: 01/25/2022] [Accepted: 01/26/2022] [Indexed: 11/16/2022]
Abstract
The gut-retina axis is an emerging concept that describes a close interaction between the gut host-microbiota interface and the retina. Stimulator of interferon genes (STING) is a universally expressed adaptor protein localized in the endoplasmic reticulum. When activated by the cytosolic DNA sensor cyclic GMP-AMP synthase (cGAS), STING induces the activation of the transcription factor interferon regulatory factor 3 (IRF3) and nuclear factor-κB (NF-κB). Downstream effects include inflammation, autophagy, and programmed cell death. Dysregulation of the STING pathway has emerged as a crucial pathogenic mechanism underpinning a broad range of inflammatory diseases, autoimmune diseases, and cancer. Recently, a positive feedback loop between dysbiosis and aberrant activation of the intestinal STING pathway has been demonstrated, concurrently related to increased intestinal permeability. Alternations in the STING pathway have also been reported in the retina of patients with ocular diseases and retinal cells treated with pathological stimuli. Collectively, there is a chance that dysbiosis in patients with retinal diseases disrupts intestinal homeostasis and exacerbates barrier dysfunction through the erroneous accumulation of STING in the gut. Subsequent translocation of microbial products into the bloodstream allows access to the eye via the impaired blood-retina barrier, inducing the chronic activation of the STING pathway in the retina to participate in the disease progression. In this review, we explore how the alterations in the STING pathway could contribute to the gut disturbance and retinal pathologies and discuss its potential as a therapeutic target to treat the gut-retina axis-related diseases, which sheds some light on the better understanding of the crosstalk between the gut and retina.
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Affiliation(s)
- Xinran Qin
- Department of Ophthalmology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Haidong Zou
- Department of Ophthalmology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China; Shanghai Eye Diseases Prevention & Treatment Center, Shanghai Eye Hospital, Shanghai, China; Shanghai Engineering Center for Precise Diagnosis and Treatment of Eye Diseases, Shanghai, China; National Clinical Research Center for Eye Diseases, Shanghai, China; Shanghai Key Laboratory of Fundus Diseases, Shanghai, China.
| | - Chen Niu
- FosunLead Lingzhi Biomedical Technology Co. Ltd, Shanghai, China
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26
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Scuderi G, Troiani E, Minnella AM. Gut Microbiome in Retina Health: The Crucial Role of the Gut-Retina Axis. Front Microbiol 2022; 12:726792. [PMID: 35095780 PMCID: PMC8795667 DOI: 10.3389/fmicb.2021.726792] [Citation(s) in RCA: 34] [Impact Index Per Article: 11.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/17/2021] [Accepted: 12/20/2021] [Indexed: 12/12/2022] Open
Abstract
The term microbiome means not only a complex ecosystem of microbial species that colonize our body but also their genome and the surrounding environment in which they live. Recent studies support the existence of a gut-retina axis involved in the pathogenesis of several chronic progressive ocular diseases, including age-related macular disorders. This review aims to underline the importance of the gut microbiome in relation to ocular health. After briefly introducing the characteristics of the gut microbiome in terms of composition and functions, the role of gut microbiome dysbiosis, in the development or progression of retinal diseases, is highlighted, focusing on the relationship between gut microbiome composition and retinal health based on the recently investigated gut-retina axis.
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Affiliation(s)
- Gianluca Scuderi
- Ophthalmology Unit, NESMOS Department, St. Andrea Hospital, Sapienza University of Rome, Rome, Italy
- *Correspondence: Gianluca Scuderi,
| | - Emidio Troiani
- Cardiology Unit, State Hospital, Institute for Social Security, Cailungo, San Marino
| | - Angelo Maria Minnella
- Department of Ophthalmology, Fondazione Policlinico Universitario A. Gemelli-IRCCS, Catholic University of the Sacred Heart, Rome, Italy
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27
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Gut microbiota-mediated secondary bile acids regulate dendritic cells to attenuate autoimmune uveitis through TGR5 signaling. Cell Rep 2021; 36:109726. [PMID: 34551302 DOI: 10.1016/j.celrep.2021.109726] [Citation(s) in RCA: 114] [Impact Index Per Article: 28.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/06/2020] [Revised: 08/10/2021] [Accepted: 08/24/2021] [Indexed: 12/12/2022] Open
Abstract
Gut microbiota-mediated secondary bile acids (BAs) play an important role in energy balance and host metabolism via G protein-coupled receptors and/or nuclear receptors. Emerging evidence suggests that BAs are important for maintaining innate immune responses via these receptors. However, the effect of BAs on autoimmune uveitis is still unknown. Here, we demonstrate decreased microbiota-related secondary BA concentration in feces and serum of animals with experimental autoimmune uveitis (EAU). Restoration of the gut BAs pool attenuates severity of EAU in association with inhibition of nuclear factor κB (NF-κB)-related pro-inflammatory cytokines in dendritic cells (DCs). TGR5 deficiency partially reverses the inhibitory effect of deoxycholic acid (DCA) on DCs. TGR5 signaling also inhibits NF-κB activation via the cyclic AMP (cAMP)-protein kinase A (PKA) pathway in DCs. Additionally, both DCA and TGR5 agonists inhibit human monocyte-derived DC activation. Taken together, our results suggest that BA metabolism plays an important role in adaptive immune responses and might be a therapeutic target in autoimmune uveitis.
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28
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A Role for Folate in Microbiome-Linked Control of Autoimmunity. J Immunol Res 2021; 2021:9998200. [PMID: 34104654 PMCID: PMC8159645 DOI: 10.1155/2021/9998200] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/16/2021] [Accepted: 05/04/2021] [Indexed: 02/03/2023] Open
Abstract
The microbiome exerts considerable control over immune homeostasis and influences susceptibility to autoimmune and autoinflammatory disease (AD/AID) such as inflammatory bowel disease (IBD), multiple sclerosis (MS), type 1 diabetes (T1D), psoriasis, and uveitis. In part, this is due to direct effects of the microbiome on gastrointestinal (GI) physiology and nutrient transport, but also to indirect effects on immunoregulatory controls, including induction and stabilization of T regulatory cells (T reg). Secreted bacterial metabolites such as short-chain fatty acids (SCFA) are under intense investigation as mediators of these effects. In contrast, folate (vitamin B9), an essential micronutrient, has attracted less attention, possibly because it exerts global physiological effects which are difficult to differentiate from specific effects on the immune system. Here, we review the role of folate in AD/AID with some emphasis on sight-threatening autoimmune uveitis. Since folate is required for the generation and maintenance of T reg , we propose that one mechanism for microbiome-based control of AD/AID is via folate-dependent induction of GI tract T reg , particularly colonic T reg, via anergic T cells (T an). Hence, folate supplementation has potential prophylactic and/or therapeutic benefit in AID/AD.
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