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Côco LZ, de Souza Belisário E, Vasquez EC, Pereira TMC, Aires R, Campagnaro BP. Probiotics: a promising future in the treatment of ulcerative colitis? Pharmacol Rep 2025; 77:645-657. [PMID: 40214948 DOI: 10.1007/s43440-025-00724-7] [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: 01/29/2025] [Revised: 03/25/2025] [Accepted: 04/03/2025] [Indexed: 05/13/2025]
Abstract
Ulcerative colitis is an idiopathic and chronic inflammatory bowel disease, characterized by inflammation of the mucosa of the colon and rectum. Clinical manifestations commonly include abdominal pain, diarrhea (with or without hematochezia), and weight loss. The pathogenesis of ulcerative colitis is multifactorial, involving a combination of genetic predispositions and lifestyle factors. High consumption of processed food, sedentary habits, alcohol intake, and stress are among the lifestyle factors implicated in disease onset and progression. Current treatment strategies focus on managing symptoms and inducing remission, however, the chronic nature of the disease, along with the adverse effects of conventional therapies, often compromises patient's quality of life. Therefore, exploring alternative therapies that can prolong remission and reduce symptom burden is important. Experimental evidence suggests that probiotics may extend remission duration in ulcerative colitis. Moreover, probiotics exhibit efficacy in amelioration clinical symptoms by reducing inflammation markers, preserving, and restoring intestinal epithelial. This review explores the advantages of the administration of probiotics in the treatment of ulcerative colitis, elucidating their mechanism of action.
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Affiliation(s)
- Larissa Zambom Côco
- Laboratory of Translational Physiology and Pharmacology, Pharmaceutical Sciences Graduate Program, Vila Velha University (UVV), R Mercurio s/n, 29102623, Vila Velha, 29102-920, ES, Brazil
| | - Eduarda de Souza Belisário
- Laboratory of Translational Physiology and Pharmacology, Pharmaceutical Sciences Graduate Program, Vila Velha University (UVV), R Mercurio s/n, 29102623, Vila Velha, 29102-920, ES, Brazil
| | - Elisardo Corral Vasquez
- Laboratory of Translational Physiology and Pharmacology, Pharmaceutical Sciences Graduate Program, Vila Velha University (UVV), R Mercurio s/n, 29102623, Vila Velha, 29102-920, ES, Brazil
| | - Thiago Melo Costa Pereira
- Laboratory of Translational Physiology and Pharmacology, Pharmaceutical Sciences Graduate Program, Vila Velha University (UVV), R Mercurio s/n, 29102623, Vila Velha, 29102-920, ES, Brazil
| | - Rafaela Aires
- Laboratory of Translational Physiology and Pharmacology, Pharmaceutical Sciences Graduate Program, Vila Velha University (UVV), R Mercurio s/n, 29102623, Vila Velha, 29102-920, ES, Brazil
| | - Bianca Prandi Campagnaro
- Laboratory of Translational Physiology and Pharmacology, Pharmaceutical Sciences Graduate Program, Vila Velha University (UVV), R Mercurio s/n, 29102623, Vila Velha, 29102-920, ES, Brazil.
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Fan F, Guo R, Pan K, Xu H, Chu X. Mucus and mucin: changes in the mucus barrier in disease states. Tissue Barriers 2025:2499752. [PMID: 40338015 DOI: 10.1080/21688370.2025.2499752] [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: 04/16/2025] [Accepted: 04/21/2025] [Indexed: 05/09/2025] Open
Abstract
In this review we discuss mucus, the viscoelastic secretion from goblet or mucous producing cells that covers and protects all non-keratinized wet epithelial surfaces. In addition to the surface of organs directly contacting with the external environment such as the eyes, this layer provides protection to the underlying gastrointestinal, respiratory and female reproductive tracts by trapping pathogens, irritants, environmental fine particles and potentially harmful foreign substances. Mucins, the primary structural components of mucus, form structurally different mucus layers at different sites in a process regulated by a variety of factors. Currently, more and more studies have shown that the mucus barrier is not only closely related to various intestinal mucus diseases, but also involved in the occurrence and development of various airway diseases and mucus-related diseases, thus it may become a new target for the treatment of various related diseases in the future. Since the dysfunction of the mucous layer is closely related to various pathological processes, in-depth understanding of its molecular mechanism and physiological role is of great theoretical and practical significance for disease prevention and treatment. Here, we discuss different aspects of the mucus layer by focusing on its chemical composition, synthetic pathways, and some of the characteristics of the mucus layer in physiological and pathological situations.
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Affiliation(s)
- Fangfang Fan
- School of Pharmacy, Anhui University of Chinese Medicine, Hefei, China
| | - Ruihan Guo
- School of Pharmacy, Anhui University of Chinese Medicine, Hefei, China
| | - Kun Pan
- School of Pharmacy, Anhui University of Chinese Medicine, Hefei, China
| | - Hongye Xu
- Quality Assurance department, Tongling Institutes for Food and Drug Control, Tongling, China
| | - Xiaoqin Chu
- School of Pharmacy, Anhui University of Chinese Medicine, Hefei, China
- Institute of Pharmaceutics, Anhui Academy of Chinese Medicine, Hefei, China
- Anhui Province Key Laboratory of Pharmaceutical Preparation Technology and Application, Hefei, China
- Engineering Technology Research Center of Modern Pharmaceutical Preparation, Hefei, Anhui Province, China
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3
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Torregrossa M, Davies L, Hans-Günther M, Simon JC, Franz S, Rinkevich Y. Effects of embryonic origin, tissue cues and pathological signals on fibroblast diversity in humans. Nat Cell Biol 2025; 27:720-735. [PMID: 40263573 DOI: 10.1038/s41556-025-01638-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/22/2024] [Accepted: 02/18/2025] [Indexed: 04/24/2025]
Abstract
Fibroblasts, once perceived as a uniform cell type, are now recognized as a mosaic of distinct populations with specialized roles in tissue homeostasis and pathology. Here we provide a global overview of the expanding compendium of fibroblast cell types and states, their diverse lineage origins and multifaceted functions across various human organs. By integrating insights from developmental biology, lineage tracing and single-cell technologies, we highlight the complex nature of fibroblasts. We delve into their origination from embryonic mesenchyme and tissue-resident populations, elucidating lineage-specific behaviours in response to physiological cues. Furthermore, we highlight the pivotal role of fibroblasts in orchestrating tissue repair, connective tissue remodelling and immune modulation across diverse pathologies. This knowledge is essential to develop novel fibroblast-targeted therapies to restore steady-state fibroblast function and advance regenerative medicine strategies across multiple diseases.
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Affiliation(s)
- Marta Torregrossa
- Department of Dermatology, Venereology and Allergology, Leipzig University Medical Faculty, Leipzig, Germany
| | - Lindsay Davies
- Department of Microbiology, Tumor and Cell Biology, Karolinska Institute, Stockholm, Sweden
| | - Machens Hans-Günther
- Department for Plastic Surgery and Hand Surgery, Klinikum Rechts der Isar, School of Medicine, Technical University of Munich, Munich, Germany
| | - Jan C Simon
- Department of Dermatology, Venereology and Allergology, Leipzig University Medical Faculty, Leipzig, Germany
| | - Sandra Franz
- Department of Dermatology, Venereology and Allergology, Leipzig University Medical Faculty, Leipzig, Germany.
| | - Yuval Rinkevich
- Chinese Institutes for Medical Research, Beijing, China.
- Capital Medical University, Beijing, China.
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4
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Luo D, Luo G, Xu H, Li K, Li Z, Zhang C. Inorganic dietary nanoparticles in intestinal barrier function of inflammatory bowel disease: allies or adversaries? Front Immunol 2025; 16:1563504. [PMID: 40270957 PMCID: PMC12014688 DOI: 10.3389/fimmu.2025.1563504] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/20/2025] [Accepted: 03/24/2025] [Indexed: 04/25/2025] Open
Abstract
Inorganic dietary nanoparticles (IDNPs) are frequently utilized as food additives and in packaging, resulting in their exposure becoming a substantial yet often overlooked concern for patients with inflammatory bowel disease (IBD). Considering that impaired intestinal barrier function plays a central role in the pathogenesis of IBD, this review concentrates on the roles and mechanisms of IDNPs in the intestinal barrier (physical, chemical, biological, and immune barriers) of IBD patients. Previous studies have shown that different types of nanoparticles have varying effects on animals in diverse states. In this context, factors such as the source, size, shape, dosage, and duration of action of the nanoparticles, as well as the species, gender, dietary habits, and age of the animals, significantly influence research outcomes. Future studies should undertake more comprehensive explorations into the effects and mechanisms of IDNPs with diverse sources and properties in IBD patients.
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Affiliation(s)
- Duo Luo
- Department of Geriatrics, Guangzhou First People’s Hospital, Guangzhou Medical University, Guangzhou, China
| | - Guifang Luo
- Department of Geriatrics, Guangzhou First People’s Hospital, Guangzhou Medical University, Guangzhou, China
| | - Haoming Xu
- Department of Gastroenterology and Hepatology, Guangzhou First People’s Hospital, Guangzhou Medical University, Guangzhou, China
| | - Kangbao Li
- Department of Geriatrics, Guangzhou First People’s Hospital, Guangzhou Medical University, Guangzhou, China
| | - Zhaotao Li
- Department of Gastroenterology, The First People’s Hospital of Foshan, Foshan, China
| | - Cong Zhang
- Department of Gastroenterology, The First People’s Hospital of Foshan, Foshan, China
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Murgiano M, Bartocci B, Puca P, di Vincenzo F, Del Gaudio A, Papa A, Cammarota G, Gasbarrini A, Scaldaferri F, Lopetuso LR. Gut Microbiota Modulation in IBD: From the Old Paradigm to Revolutionary Tools. Int J Mol Sci 2025; 26:3059. [PMID: 40243712 PMCID: PMC11988433 DOI: 10.3390/ijms26073059] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/12/2025] [Revised: 03/18/2025] [Accepted: 03/26/2025] [Indexed: 04/18/2025] Open
Abstract
Inflammatory bowel diseases (IBDs) are chronic inflammatory disorders primarily comprising two main conditions: ulcerative colitis and Crohn's disease. The gut microbiota's role in driving inflammation in IBD has garnered significant attention, yet the precise mechanisms through which the microbiota influences IBD pathogenesis remain largely unclear. Given the limited therapeutic options for IBD, alternative microbiota-targeted therapies-including prebiotics, probiotics, postbiotics, and symbiotics-have been proposed. While these approaches have shown promising results, microbiota modulation is still mainly considered an adjunct therapy to conventional treatments, with a demonstrated impact on patients' quality of life. Fecal microbiota transplantation (FMT), already approved for treating Clostridioides difficile infection, represents the first in a series of innovative microbiota-based therapies under investigation. Microbial biotherapeutics are emerging as personalized and cutting-edge tools for IBD management, encompassing next-generation probiotics, bacterial consortia, bacteriophages, engineered probiotics, direct metabolic pathway modulation, and nanotherapeutics. This review explores microbial modulation as a therapeutic strategy for IBDs, highlighting current approaches and examining promising tools under development to better understand their potential clinical applications in managing intestinal inflammatory disorders.
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Affiliation(s)
- Marco Murgiano
- Dipartimento di Medicina e Chirurgia Traslazionale, Università Cattolica del Sacro Cuore, 00168 Rome, Italy; (B.B.); (P.P.); (F.d.V.); (A.D.G.); (A.P.); (G.C.); (A.G.); (F.S.)
| | - Bianca Bartocci
- Dipartimento di Medicina e Chirurgia Traslazionale, Università Cattolica del Sacro Cuore, 00168 Rome, Italy; (B.B.); (P.P.); (F.d.V.); (A.D.G.); (A.P.); (G.C.); (A.G.); (F.S.)
| | - Pierluigi Puca
- Dipartimento di Medicina e Chirurgia Traslazionale, Università Cattolica del Sacro Cuore, 00168 Rome, Italy; (B.B.); (P.P.); (F.d.V.); (A.D.G.); (A.P.); (G.C.); (A.G.); (F.S.)
- Medicina Interna e Gastroenterologia, CEMAD Centro Malattie dell’Apparato Digerente, Dipartimento di Scienze Mediche e Chirurgiche, Fondazione Policlinico Universitario Gemelli IRCCS, 00168 Rome, Italy
| | - Federica di Vincenzo
- Dipartimento di Medicina e Chirurgia Traslazionale, Università Cattolica del Sacro Cuore, 00168 Rome, Italy; (B.B.); (P.P.); (F.d.V.); (A.D.G.); (A.P.); (G.C.); (A.G.); (F.S.)
| | - Angelo Del Gaudio
- Dipartimento di Medicina e Chirurgia Traslazionale, Università Cattolica del Sacro Cuore, 00168 Rome, Italy; (B.B.); (P.P.); (F.d.V.); (A.D.G.); (A.P.); (G.C.); (A.G.); (F.S.)
| | - Alfredo Papa
- Dipartimento di Medicina e Chirurgia Traslazionale, Università Cattolica del Sacro Cuore, 00168 Rome, Italy; (B.B.); (P.P.); (F.d.V.); (A.D.G.); (A.P.); (G.C.); (A.G.); (F.S.)
- Medicina Interna e Gastroenterologia, CEMAD Centro Malattie dell’Apparato Digerente, Dipartimento di Scienze Mediche e Chirurgiche, Fondazione Policlinico Universitario Gemelli IRCCS, 00168 Rome, Italy
| | - Giovanni Cammarota
- Dipartimento di Medicina e Chirurgia Traslazionale, Università Cattolica del Sacro Cuore, 00168 Rome, Italy; (B.B.); (P.P.); (F.d.V.); (A.D.G.); (A.P.); (G.C.); (A.G.); (F.S.)
- Medicina Interna e Gastroenterologia, CEMAD Centro Malattie dell’Apparato Digerente, Dipartimento di Scienze Mediche e Chirurgiche, Fondazione Policlinico Universitario Gemelli IRCCS, 00168 Rome, Italy
| | - Antonio Gasbarrini
- Dipartimento di Medicina e Chirurgia Traslazionale, Università Cattolica del Sacro Cuore, 00168 Rome, Italy; (B.B.); (P.P.); (F.d.V.); (A.D.G.); (A.P.); (G.C.); (A.G.); (F.S.)
- Medicina Interna e Gastroenterologia, CEMAD Centro Malattie dell’Apparato Digerente, Dipartimento di Scienze Mediche e Chirurgiche, Fondazione Policlinico Universitario Gemelli IRCCS, 00168 Rome, Italy
| | - Franco Scaldaferri
- Dipartimento di Medicina e Chirurgia Traslazionale, Università Cattolica del Sacro Cuore, 00168 Rome, Italy; (B.B.); (P.P.); (F.d.V.); (A.D.G.); (A.P.); (G.C.); (A.G.); (F.S.)
- Medicina Interna e Gastroenterologia, CEMAD Centro Malattie dell’Apparato Digerente, Dipartimento di Scienze Mediche e Chirurgiche, Fondazione Policlinico Universitario Gemelli IRCCS, 00168 Rome, Italy
| | - Loris Riccardo Lopetuso
- Dipartimento di Medicina e Chirurgia Traslazionale, Università Cattolica del Sacro Cuore, 00168 Rome, Italy; (B.B.); (P.P.); (F.d.V.); (A.D.G.); (A.P.); (G.C.); (A.G.); (F.S.)
- Dipartimento di Scienze della Vita, della Salute e delle Professioni Sanitarie, Università degli Studi Link, 00165 Rome, Italy
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Zeng X, Yin L, Zhang Y, Wang Q, Li J, Yin Y, Wang Q, Li J, Yang H. Dietary Iron Alleviates Dextran Sodium Sulfate-Induced Intestinal Injury by Regulating Regeneration of Intestinal Stem Cells in Weaned Mice. Biol Trace Elem Res 2025:10.1007/s12011-025-04546-9. [PMID: 39998602 DOI: 10.1007/s12011-025-04546-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/23/2024] [Accepted: 02/06/2025] [Indexed: 02/27/2025]
Abstract
Iron deficiency is the most common comorbidity of inflammatory bowel disease (IBD), but the effect of iron supplementation on the repair processes of intestinal injury in weaned mice is unknown. This study aimed to evaluate the potential mechanism of dietary iron on intestinal injury and intestinal regeneration in the dextran sodium sulfate (DSS)-induced colitis of the weaned mouse model. The mice were fed either a control diet containing (45.00 mg/kg Fe) or iron supplemental (448.30 mg/kg Fe) diet for 14 days, followed by a 7-day oral administration of 2.5% DSS to all mice. The result showed that at day 0 of the recovery period (0 DRP), the impact of iron on the gut index and intestinal morphology was found to be more significant in weaned mice compared to adult mice. At 3 DRP, the iron diet alleviated inflammation-induced weight loss, shortening of colon length, thickening of the muscle layer, and disruption of gut morphology. At 0, 3, and 7 DRP, we found that an iron diet increased intestinal stem cell (ISC) viability and protected epithelial integrity. Furthermore, FeSO4 significantly enhanced organoid viability and increased mRNA expression of differentiation, ISC, and retinol metabolism-related marker genes in the organoids compared with the control group. Overall, this study demonstrates that the iron diet accelerates intestinal regeneration after intestinal injury in weaned mice by activating the retinol metabolic pathway to regulate the proliferation and differentiation of ISCs.
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Affiliation(s)
- Xianglin Zeng
- Hunan International Joint Laboratory of Animal Intestinal Ecology and Health, Laboratory of Animal Nutrition and Human Health, College of Life Sciences, Hunan Normal University, Changsha, 410081, Hunan, China
| | - Lanmei Yin
- Hunan International Joint Laboratory of Animal Intestinal Ecology and Health, Laboratory of Animal Nutrition and Human Health, College of Life Sciences, Hunan Normal University, Changsha, 410081, Hunan, China.
- Hunan Provincial Key Laboratory of Animal Nutritional Physiology and Metabolic Process, Scientific Observing and Experimental Station of Animal Nutrition and Feed Science in South-Central, Ministry of Agriculture, Key Laboratory of Agro-Ecological Processes in Subtropical Region, Institute of Subtropical Agriculture, Hunan Provincial Engineering Research Center for Healthy Livestock and Poultry Production, Chinese Academy of Sciences, Changsha, 410125, Hunan, China.
| | - Yitong Zhang
- Hunan International Joint Laboratory of Animal Intestinal Ecology and Health, Laboratory of Animal Nutrition and Human Health, College of Life Sciences, Hunan Normal University, Changsha, 410081, Hunan, China
| | - Qianqian Wang
- Hunan International Joint Laboratory of Animal Intestinal Ecology and Health, Laboratory of Animal Nutrition and Human Health, College of Life Sciences, Hunan Normal University, Changsha, 410081, Hunan, China
| | - Jun Li
- Hunan International Joint Laboratory of Animal Intestinal Ecology and Health, Laboratory of Animal Nutrition and Human Health, College of Life Sciences, Hunan Normal University, Changsha, 410081, Hunan, China
| | - Yuebang Yin
- Hunan Provincial Key Laboratory of Animal Nutritional Physiology and Metabolic Process, Scientific Observing and Experimental Station of Animal Nutrition and Feed Science in South-Central, Ministry of Agriculture, Key Laboratory of Agro-Ecological Processes in Subtropical Region, Institute of Subtropical Agriculture, Hunan Provincial Engineering Research Center for Healthy Livestock and Poultry Production, Chinese Academy of Sciences, Changsha, 410125, Hunan, China
| | - Qiye Wang
- Hunan International Joint Laboratory of Animal Intestinal Ecology and Health, Laboratory of Animal Nutrition and Human Health, College of Life Sciences, Hunan Normal University, Changsha, 410081, Hunan, China
| | - Jianzhong Li
- Hunan International Joint Laboratory of Animal Intestinal Ecology and Health, Laboratory of Animal Nutrition and Human Health, College of Life Sciences, Hunan Normal University, Changsha, 410081, Hunan, China
| | - Huansheng Yang
- Hunan International Joint Laboratory of Animal Intestinal Ecology and Health, Laboratory of Animal Nutrition and Human Health, College of Life Sciences, Hunan Normal University, Changsha, 410081, Hunan, China.
- Hunan Provincial Key Laboratory of Animal Nutritional Physiology and Metabolic Process, Scientific Observing and Experimental Station of Animal Nutrition and Feed Science in South-Central, Ministry of Agriculture, Key Laboratory of Agro-Ecological Processes in Subtropical Region, Institute of Subtropical Agriculture, Hunan Provincial Engineering Research Center for Healthy Livestock and Poultry Production, Chinese Academy of Sciences, Changsha, 410125, Hunan, China.
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Dong XQ, Zhang YH, Luo J, Li MJ, Ma LQ, Qi YT, Miao YL. Keratin 1 modulates intestinal barrier and immune response via kallikrein kinin system in ulcerative colitis. World J Gastroenterol 2025; 31:102070. [PMID: 39958441 PMCID: PMC11752705 DOI: 10.3748/wjg.v31.i6.102070] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/08/2024] [Revised: 12/06/2024] [Accepted: 12/19/2024] [Indexed: 01/10/2025] Open
Abstract
BACKGROUND External factors in ulcerative colitis (UC) exacerbate colonic epithelial permeability and inflammatory responses. Keratin 1 (KRT1) is crucial in regulating these alterations, but its specific role in the progression of UC remains to be fully elucidated. AIM To explore the role and mechanisms of KRT1 in the regulation of colonic epithelial permeability and inflammation in UC. METHODS A KRT1 antibody concentration gradient test, along with a dextran sulfate sodium (DSS)-induced animal model, was implemented to investigate the role of KRT1 in modulating the activation of the kallikrein kinin system (KKS) and the cleavage of bradykinin (BK)/high molecular weight kininogen (HK) in UC. RESULTS Treatment with KRT1 antibody in Caco-2 cells suppressed cell proliferation, induced apoptosis, reduced HK expression, and increased BK expression. It further downregulated intestinal barrier proteins, including occludin, zonula occludens-1, and claudin, and negatively impacted the coagulation factor XII. These changes led to enhanced activation of BK and HK cleavage, thereby intensifying KKS-mediated inflammation in UC. In the DSS-induced mouse model, administration of KRT1 antibody mitigated colonic injury, increased colon length, alleviated weight loss, and suppressed inflammatory cytokines such as interleukin (IL)-1, IL-6, tumor necrosis factor-α. It also facilitated repair of the intestinal barrier, reducing DSS-induced injury. CONCLUSION KRT1 inhibits BK expression, suppresses inflammatory cytokines, and enhances markers of intestinal barrier function, thus ameliorating colonic damage and maintaining barrier integrity. KRT1 is a viable therapeutic target for UC.
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Affiliation(s)
- Xiang-Qian Dong
- Department of Gastroenterology, The First Affiliated Hospital of Kunming Medical University, Yunnan Province Clinical Research Center for Digestive Diseases, Kunming 650032, Yunnan Province, China
| | - Ying-Hui Zhang
- Department of Gastroenterology, Affiliated Hospital of Yunnan University, Kunming 650021, Yunnan Province, China
| | - Juan Luo
- Department of Gastroenterology, The First Affiliated Hospital of Kunming Medical University, Yunnan Province Clinical Research Center for Digestive Diseases, Kunming 650032, Yunnan Province, China
| | - Mao-Juan Li
- Department of Gastroenterology, The First Affiliated Hospital of Kunming Medical University, Yunnan Province Clinical Research Center for Digestive Diseases, Kunming 650032, Yunnan Province, China
| | - Lan-Qing Ma
- Department of Gastroenterology, The First Affiliated Hospital of Kunming Medical University, Yunnan Province Clinical Research Center for Digestive Diseases, Kunming 650032, Yunnan Province, China
| | - Ya-Ting Qi
- Department of Gastroenterology, The First Affiliated Hospital of Kunming Medical University, Yunnan Province Clinical Research Center for Digestive Diseases, Kunming 650032, Yunnan Province, China
| | - Ying-Lei Miao
- Department of Gastroenterology, The First Affiliated Hospital of Kunming Medical University, Yunnan Province Clinical Research Center for Digestive Diseases, Kunming 650032, Yunnan Province, China
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8
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van Wijngaarden EW, Arias SL, Rhee M, Silberstein MN, Brito IL. The role of human intestinal mucus in the prevention of microplastic uptake and cell damage. Biomater Sci 2025; 13:1010-1020. [PMID: 39810566 DOI: 10.1039/d4bm01574f] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/16/2025]
Abstract
An increase in plastic waste and its release into the environment has led to health concerns over microplastics (MPs) in the environment. The intestinal mucosal layer is a key defense mechanism against ingested MPs, preventing the migration of particles to other parts of the body. MP migration through intestinal mucus is challenging to study due to difficulties in obtaining intact mucus layers for testing and numerous formulations, shapes, and sizes of microplastics. Previous studies have primarily used mucus from animals, hydrogel models, and mucus samples from other parts of the body as substitutes. This study examines how different MP compositions, sizes (40-500 nm), and surface functionalizations alter MP migration through human intestinal mucus; how the mucus layer protects cells from MP uptake, toxicity, and inflammation; and how the intestinal mucus prevents the migration of other environmental toxins via MP particles. The presence of a mucus layer also provides critical protection against cytotoxicity, reactive oxygen species production, and uptake for all particles tested, although certain functionalizations, such as streptavidin, are particularly harmful to cells with high toxicity and inflammation. Understanding the properties that assist of impede the diffusion of MPs through mucus is relevant to the overall bioaccumulation and health effects of MPs as well as drug delivery purposes.
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Affiliation(s)
- Ellen W van Wijngaarden
- Sibley School of Mechanical and Aerospace Engineering, Cornell University, Ithaca, NY 14850, USA
- Engineered Living Materials Institute, Cornell University, Ithaca, NY 14850, USA.
| | - Sandra L Arias
- Meinig School of Biomedical Engineering, Cornell University, Ithaca, NY 14853, USA
| | - Matthew Rhee
- Meinig School of Biomedical Engineering, Cornell University, Ithaca, NY 14853, USA
| | - Meredith N Silberstein
- Sibley School of Mechanical and Aerospace Engineering, Cornell University, Ithaca, NY 14850, USA
- Engineered Living Materials Institute, Cornell University, Ithaca, NY 14850, USA.
| | - Ilana L Brito
- Engineered Living Materials Institute, Cornell University, Ithaca, NY 14850, USA.
- Meinig School of Biomedical Engineering, Cornell University, Ithaca, NY 14853, USA
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9
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Kiilerich KF, Andresen T, Darbani B, Gregersen LHK, Liljensøe A, Bennike TB, Holm R, Moeller JB, Andersen V. Advancing Inflammatory Bowel Disease Treatment by Targeting the Innate Immune System and Precision Drug Delivery. Int J Mol Sci 2025; 26:575. [PMID: 39859291 PMCID: PMC11765494 DOI: 10.3390/ijms26020575] [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: 11/13/2024] [Revised: 01/04/2025] [Accepted: 01/09/2025] [Indexed: 01/27/2025] Open
Abstract
Inflammatory bowel disease (IBD), encompassing Crohn's disease and ulcerative colitis, involves chronic inflammation of the gastrointestinal tract. Current immune-modulating therapies are insufficient for 30-50% of patients or cause significant side effects, emphasizing the need for new treatments. Targeting the innate immune system and enhancing drug delivery to inflamed gut regions are promising strategies. Neutrophils play a central role in IBD by releasing reactive oxygen species (ROS) and neutrophil extracellular traps (NETs) -DNA-based structures with cytotoxic proteins-that contribute to mucosal damage and inflammation. Recent studies linking ROS production, DNA repair, and NET formation have identified NETs as potential therapeutic targets, with preclinical models showing positive outcomes from NET inhibition. Innovative oral drug delivery systems designed to target gut inflammation directly-without systemic absorption-could improve treatment precision and reduce side effects. Advanced formulations utilize properties such as particle size, surface modifications, and ROS-triggered release to selectively target the distal ileum and colon. A dual strategy that combines a deeper understanding of IBD pathophysiology to identify inflammation-related therapeutic targets with advanced drug delivery systems may offer significant promise. For instance, pairing NET inhibition with ROS-responsive nanocarriers could enhance treatment efficacy, though further research is needed. This synergistic approach has the potential to greatly improve outcomes for IBD patients.
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Affiliation(s)
- Kat F. Kiilerich
- Department of Molecular Medicine, University of Southern Denmark, 5000 Odense, Denmark; (K.F.K.); (J.B.M.)
| | - Trine Andresen
- Department of Health Science and Technology, The Faculty of Medicine, Aalborg University, 9220 Aalborg Ø, Denmark; (T.A.); (T.B.B.)
| | - Behrooz Darbani
- Molecular Diagnostic and Clinical Research Unit, University Hospital of Southern Denmark, 6200 Aabenraa, Denmark; (B.D.); (L.H.K.G.); (A.L.)
| | - Laura H. K. Gregersen
- Molecular Diagnostic and Clinical Research Unit, University Hospital of Southern Denmark, 6200 Aabenraa, Denmark; (B.D.); (L.H.K.G.); (A.L.)
- Department of Regional Health Research, University of Southern Denmark, 5000 Odense, Denmark
| | - Anette Liljensøe
- Molecular Diagnostic and Clinical Research Unit, University Hospital of Southern Denmark, 6200 Aabenraa, Denmark; (B.D.); (L.H.K.G.); (A.L.)
| | - Tue B. Bennike
- Department of Health Science and Technology, The Faculty of Medicine, Aalborg University, 9220 Aalborg Ø, Denmark; (T.A.); (T.B.B.)
- Molecular Diagnostic and Clinical Research Unit, University Hospital of Southern Denmark, 6200 Aabenraa, Denmark; (B.D.); (L.H.K.G.); (A.L.)
| | - René Holm
- Department of Physics, Chemistry and Pharmacy, University of Southern Denmark, 5000 Odense, Denmark;
| | - Jesper B. Moeller
- Department of Molecular Medicine, University of Southern Denmark, 5000 Odense, Denmark; (K.F.K.); (J.B.M.)
- Danish Institute for Advanced Study, University of Southern Denmark, 5000 Odense, Denmark
| | - Vibeke Andersen
- Molecular Diagnostic and Clinical Research Unit, University Hospital of Southern Denmark, 6200 Aabenraa, Denmark; (B.D.); (L.H.K.G.); (A.L.)
- Department of Regional Health Research, University of Southern Denmark, 5000 Odense, Denmark
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10
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An S, Huh H, Ko JS, Moon JS, Cho KY. Establishment and Characterization of Patient-Derived Intestinal Organoids from Pediatric Crohn's Disease Patients. Pediatr Gastroenterol Hepatol Nutr 2024; 27:355-363. [PMID: 39563842 PMCID: PMC11570352 DOI: 10.5223/pghn.2024.27.6.355] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/22/2024] [Accepted: 10/07/2024] [Indexed: 11/21/2024] Open
Abstract
Purpose This study aimed to establish and characterize patient-derived intestinal organoids (PDOs) from children with Crohn's disease (CD). Methods To generate PDOs, endoscopic biopsy specimens were obtained from non-inflamed duodenal bulbs of normal controls and CD patients. To verify the presence of PDOs, histological staining and quantitative reverse transcription polymerase chain reaction (RT-qPCR) analyses were performed. Results PDOs were successfully established in normal controls (n=2) and CD patients (n=2). Hematoxylin and eosin staining of formalin-fixed, paraffin-embedded PDO sections revealed crypt and villus structures, whereas immunofluorescence staining with EpCAM and DAPI confirmed the epithelial-specific architecture of the PDOs. RT-qPCR results revealed a significant increase in Lgr5, Si, and Chga gene expression and a decrease in Olfm4 and Muc2 expression in CD patients compared to normal controls, suggesting altered stem cell activity and mucosal barrier function (p<0.05). Conclusion We successfully established and characterized PDOs in children with CD, providing a valuable tool for understanding the pathophysiology of the disease and evaluating potential therapeutic approaches. The differential gene expression of PDOs in CD patients might be caused by the complex interplay between epithelial adaptation and inflammation in the intestinal epithelium.
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Affiliation(s)
- Sunghyun An
- Department of Pediatrics, Hallym University Industry Academic Cooperation Foundation, Seoul, Korea
| | - Homin Huh
- Department of Pediatrics, Seoul National University College of Medicine, Seoul, Korea
| | - Jae Sung Ko
- Department of Pediatrics, Seoul National University College of Medicine, Seoul, Korea
| | - Jin Soo Moon
- Department of Pediatrics, Seoul National University College of Medicine, Seoul, Korea
| | - Ky Young Cho
- Department of Pediatrics, Hallym University Kangnam Sacred Heart Hospital, Seoul, Korea
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11
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Gentili M, Sabbatini S, Nunzi E, Lusenti E, Cari L, Mencacci A, Ballet N, Migliorati G, Riccardi C, Ronchetti S, Monari C. Glucocorticoid-Induced Leucine Zipper Protein and Yeast-Extracted Compound Alleviate Colitis and Reduce Fungal Dysbiosis. Biomolecules 2024; 14:1321. [PMID: 39456254 PMCID: PMC11506796 DOI: 10.3390/biom14101321] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/17/2024] [Revised: 10/14/2024] [Accepted: 10/15/2024] [Indexed: 10/28/2024] Open
Abstract
Inflammatory bowel diseases (IBD) have a complex, poorly understood pathogenesis and lack long-lasting effective treatments. Recent research suggests that intestinal fungal dysbiosis may play a role in IBD development. This study investigates the effects of the glucocorticoid-induced leucine zipper protein (GILZp)", known for its protective role in gut mucosa, and a yeast extract (Py) with prebiotic properties, either alone or combined, in DSS-induced colitis. Both treatments alleviated symptoms via overlapping or distinct mechanisms. In particular, they reduced the transcription levels of pro-inflammatory cytokines IL-1β and TNF-α, as well as the expression of the tight junction protein Claudin-2. Additionally, GILZp increased MUC2 transcription, while Py reduced IL-12p40 and IL-6 levels. Notably, both treatments were effective in restoring the intestinal burden of clinically important Candida and related species. Intestinal mycobiome analysis revealed that they were able to reduce colitis-associated fungal dysbiosis, and this effect was mainly the result of a decreased abundance of the Meyerozima genus, which was dominant in colitic mice. Overall, our results suggest that combined treatment regimens with GILZp and Py could represent a new strategy for the treatment of IBD by targeting multiple mechanisms, including the fungal dysbiosis.
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Affiliation(s)
- Marco Gentili
- Department of Medicine and Surgery, Pharmacology Division, University of Perugia, 06132 Perugia, Italy (E.L.); (L.C.); (G.M.); (C.R.)
| | - Samuele Sabbatini
- Department of Medicine and Surgery, Medical Microbiology Division, University of Perugia, 06132 Perugia, Italy; (S.S.); (A.M.)
| | - Emilia Nunzi
- Department of Medicine and Surgery, University of Perugia, 06132 Perugia, Italy;
| | - Eleonora Lusenti
- Department of Medicine and Surgery, Pharmacology Division, University of Perugia, 06132 Perugia, Italy (E.L.); (L.C.); (G.M.); (C.R.)
| | - Luigi Cari
- Department of Medicine and Surgery, Pharmacology Division, University of Perugia, 06132 Perugia, Italy (E.L.); (L.C.); (G.M.); (C.R.)
| | - Antonella Mencacci
- Department of Medicine and Surgery, Medical Microbiology Division, University of Perugia, 06132 Perugia, Italy; (S.S.); (A.M.)
| | - Nathalie Ballet
- Lesaffre Institute of Science & Technology, Lesaffre International, 59700 Marcq-en-Baroeul, France;
| | - Graziella Migliorati
- Department of Medicine and Surgery, Pharmacology Division, University of Perugia, 06132 Perugia, Italy (E.L.); (L.C.); (G.M.); (C.R.)
| | - Carlo Riccardi
- Department of Medicine and Surgery, Pharmacology Division, University of Perugia, 06132 Perugia, Italy (E.L.); (L.C.); (G.M.); (C.R.)
| | - Simona Ronchetti
- Department of Medicine and Surgery, Pharmacology Division, University of Perugia, 06132 Perugia, Italy (E.L.); (L.C.); (G.M.); (C.R.)
| | - Claudia Monari
- Department of Medicine and Surgery, Medical Microbiology Division, University of Perugia, 06132 Perugia, Italy; (S.S.); (A.M.)
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12
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Demirturk M, Cinar MS, Avci FY. The immune interactions of gut glycans and microbiota in health and disease. Mol Microbiol 2024; 122:313-330. [PMID: 38703041 DOI: 10.1111/mmi.15267] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/13/2023] [Revised: 04/11/2024] [Accepted: 04/12/2024] [Indexed: 05/06/2024]
Abstract
The human digestive system harbors a vast diversity of commensal bacteria and maintains a symbiotic relationship with them. However, imbalances in the gut microbiota accompany various diseases, such as inflammatory bowel diseases (IBDs) and colorectal cancers (CRCs), which significantly impact the well-being of populations globally. Glycosylation of the mucus layer is a crucial factor that plays a critical role in maintaining the homeostatic environment in the gut. This review delves into how the gut microbiota, immune cells, and gut mucus layer work together to establish a balanced gut environment. Specifically, the role of glycosylation in regulating immune cell responses and mucus metabolism in this process is examined.
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Affiliation(s)
- Mahmut Demirturk
- Department of Biochemistry, Emory Vaccine Center, Emory University School of Medicine, Atlanta, Georgia, USA
| | - Mukaddes Sena Cinar
- Department of Biochemistry, Emory Vaccine Center, Emory University School of Medicine, Atlanta, Georgia, USA
| | - Fikri Y Avci
- Department of Biochemistry, Emory Vaccine Center, Emory University School of Medicine, Atlanta, Georgia, USA
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13
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Li Q, Wang J. The Effect of Protein Nutritional Support on Inflammatory Bowel Disease and Its Potential Mechanisms. Nutrients 2024; 16:2302. [PMID: 39064745 PMCID: PMC11280054 DOI: 10.3390/nu16142302] [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: 06/13/2024] [Revised: 07/11/2024] [Accepted: 07/13/2024] [Indexed: 07/28/2024] Open
Abstract
Inflammatory bowel disease (IBD), a complex chronic inflammatory bowel disorder that includes Crohn's disease (CD) and Ulcerative Colitis (UC), has become a globally increasing health concern. Nutrition, as an important factor influencing the occurrence and development of IBD, has attracted more and more attention. As the most important nutrient, protein can not only provide energy and nutrition required by patients, but also help repair damaged intestinal tissue, enhance immunity, and thus alleviate inflammation. Numerous studies have shown that protein nutritional support plays a significant role in the treatment and remission of IBD. This article presents a comprehensive review of the pathogenesis of IBD and analyzes and summarizes the potential mechanisms of protein nutritional support in IBD. Additionally, it provides an overview of the clinical effects of protein nutritional support in IBD and its impact on clinical complications. Research findings reveal that protein nutritional support demonstrates significant benefits in improving clinical symptoms, reducing the risk of complications, and improving quality of life in IBD patients. Therefore, protein nutritional support is expected to provide a new approach for the treatment of IBD.
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Affiliation(s)
| | - Jing Wang
- Institute of Food and Nutrition Development, Ministry of Agriculture and Rural Affairs, Beijing 100081, China;
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14
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Yanar KE, Baysal S, Ulaş N, Aktaş MS, Timurkan MÖ, Aydın H. Prognostic potential of copper, zinc, copper/zinc ratio, cobalamin, and serum amyloid A in cats with panleukopenia. J Vet Intern Med 2024; 38:1535-1541. [PMID: 38613433 PMCID: PMC11099764 DOI: 10.1111/jvim.17077] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/10/2024] [Accepted: 04/03/2024] [Indexed: 04/15/2024] Open
Abstract
BACKGROUND Copper (Cu), zinc (Zn), and the copper/zinc ratio (Cu/Zn), which have been studied in gastrointestinal disorders of humans, may facilitate disease prognosis. OBJECTIVE Evaluate the predictive potential of Cu, Zn, cobalamin, and serum amyloid A (SAA) as prognostic indicators in cats with feline panleukopenia (FPV) on admission. ANIMALS Client-owned cats diagnosed with FPV and controls. METHODS Serum Cu and Zn concentrations were assessed using the spectrophotometric method and serum concentrations of SAA and cobalamin were measured by chemiluminescent immunoassay. RESULTS On admission, survivor cats with FPV had significantly higher serum Cu and SAA concentrations and Cu/Zn ratios and significantly lower serum Zn and cobalamin concentrations than controls. Furthermore, non-survivor cats with FPV had significantly higher serum Cu and SAA concentrations and Cu/Zn ratios and significantly lower cobalamin concentrations than survivors and controls. Prognostic thresholds were calculated, with positive predictive value (PPV) for survival of 90% for Cu (≥120.3 μg/dL), 90% for Cu/Zn (≥1.34), 90% for cobalamin (≤430.4 pg/mL), and 90% for SAA (≥0.85 mg/L). CONCLUSIONS AND CLINICAL IMPORTANCE Cu (0.93 area under curve [AUC]), Cu/Zn (0.95 AUC), cobalamin (0.98 AUC), and SAA (0.98 AUC) were excellent biomarkers for predicting prognosis in cats with FPV. Their effectiveness, as assessed by sensitivity (100%), specificity (80%), AUC (0.98), and PPV (90%) from receiver operating characteristic analysis, emphasizes the performance of cobalamin and SAA.
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Affiliation(s)
- Kerim Emre Yanar
- Department of Internal MedicineFaculty of Veterinary Medicine, Atatürk UniversityErzurum 25240Turkey
| | - Sümeyye Baysal
- Department of Internal MedicineFaculty of Veterinary Medicine, Atatürk UniversityErzurum 25240Turkey
| | - Nergis Ulaş
- Department of Internal MedicineFaculty of Veterinary Medicine, Atatürk UniversityErzurum 25240Turkey
| | - Mustafa Sinan Aktaş
- Department of Internal MedicineFaculty of Veterinary Medicine, Atatürk UniversityErzurum 25240Turkey
| | - Mehmet Özkan Timurkan
- Department of VirologyFaculty of Veterinary Medicine, Atatürk UniversityErzurum 25240Turkey
| | - Hakan Aydın
- Department of VirologyFaculty of Veterinary Medicine, Atatürk UniversityErzurum 25240Turkey
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15
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Hosokawa S, Yoshiaki N, Nishikawa T, Suzuki H, Kurokawa T, Shinagawa A, Yanoh K, Maeda Y, Kobayashi TK, Fulciniti F. Staining Pattern of Alcian Blue in Endometrial Cytology: Utility in Distinguishing Grade 1-Endometrial Endometrioid Carcinoma from Endometrial Glandular Stromal Breakdown. J Cytol 2024; 41:110-115. [PMID: 38779603 PMCID: PMC11108036 DOI: 10.4103/joc.joc_121_23] [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: 07/13/2023] [Revised: 10/20/2023] [Accepted: 03/18/2024] [Indexed: 05/25/2024] Open
Abstract
Background and Objective In endometrial cytology, differentiating endometrial glandular stromal breakdown (EGBD) from endometrial endometrioid carcinoma (G1-EEC) is often difficult. In this study, we provided a new focus on chondroitin sulfate (CS), a major substrate component of the endometrial stroma, and assessed the diagnostic utility of Alcian Blue (AB) staining in the differential diagnosis in liquid-based cytological (LBC) samples. Materials and Methods LBC specimens from 19 patients with a proliferative endometrium, 36 with EGBD, and 30 with G1-EEC who underwent endometrial cytology were stained with AB (pH 1.0), and their reactivity was observed. In addition, immunocytochemical staining of CS and CD31 was performed for five cases each to evaluate their interrelationship with blood vessels. Results Regarding the 30 G1-EEC cases, at least one of the three representative staining patterns was observed by AB staining: dot-like, microtubular, and finely branched linear patterns. Moreover, the inner portion of the tubular material observed by AB staining expressed CD31. Conversely, in the 36 EGBD cases, only five metaplastic clusters with irregular protrusions and condensed stromal clusters (CSCs) showed a dot-like positive pattern, and background CSCs did not show reactivity to AB staining in any of the cases. Furthermore, the vascular structure expressing CD31 in cell clusters was also unclear. Conclusions We demonstrated that AB staining shows different staining patterns in G1-EEC and EGBD, reflecting their different tissue structures. Our data provide new insights into endometrial cell diagnosis changes and demonstrate that AB staining is a potential new diagnostic aid tool for the differentiation of G1-EEC from EGBD.
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Affiliation(s)
- Sho Hosokawa
- Department of Medical Technology, Faculty of Health Sciences, Ehime Prefectural University of Health Sciences, Ehime, Japan
| | - Norimatsu Yoshiaki
- Department of Medical Technology, Faculty of Health Sciences, Ehime Prefectural University of Health Sciences, Ehime, Japan
| | - Takeshi Nishikawa
- Department of Pathology, Nara Medical University Hospital, Nara, Japan
| | - Hisae Suzuki
- Department of Pathology, Nara Medical University Hospital, Nara, Japan
| | - Tetsuji Kurokawa
- Department of Gynecology and Obstetrics, Faculty of Medical Sciences, University of Fukui, Fukui, Japan
| | - Akiko Shinagawa
- Department of Gynecology and Obstetrics, Faculty of Medical Sciences, University of Fukui, Fukui, Japan
| | - Kenji Yanoh
- Departments of Gynaecology, Suzuka General Hospital, Mie, Japan
| | - Yoshinobu Maeda
- Department of Diagnostic Pathology, Toyama Red Cross Hospital, Toyama, Japan
| | | | - Franco Fulciniti
- Clinical Cytopathology Service, Istituto Cantonale di Patologia, Locarno, Switzerland
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16
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Bravo Iniguez A, Du M, Zhu MJ. α-Ketoglutarate for Preventing and Managing Intestinal Epithelial Dysfunction. Adv Nutr 2024; 15:100200. [PMID: 38438107 PMCID: PMC11016550 DOI: 10.1016/j.advnut.2024.100200] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/22/2023] [Revised: 02/16/2024] [Accepted: 02/29/2024] [Indexed: 03/06/2024] Open
Abstract
The epithelium lining the intestinal tract serves a multifaceted role. It plays a crucial role in nutrient absorption and immune regulation and also acts as a protective barrier, separating underlying tissues from the gut lumen content. Disruptions in the delicate balance of the gut epithelium trigger inflammatory responses, aggravate conditions such as inflammatory bowel disease, and potentially lead to more severe complications such as colorectal cancer. Maintaining intestinal epithelial homeostasis is vital for overall health, and there is growing interest in identifying nutraceuticals that can strengthen the intestinal epithelium. α-Ketoglutarate, a metabolite of the tricarboxylic acid cycle, displays a variety of bioactive effects, including functioning as an antioxidant, a necessary cofactor for epigenetic modification, and exerting anti-inflammatory effects. This article presents a comprehensive overview of studies investigating the potential of α-ketoglutarate supplementation in preventing dysfunction of the intestinal epithelium.
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Affiliation(s)
| | - Min Du
- Department of Animal Sciences, Washington State University, Pullman, WA, United States
| | - Mei-Jun Zhu
- School of Food Science, Washington State University, Pullman, WA, United States.
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17
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Fancy N, Nitin, Kniffen D, Melvin M, Kazemian N, Sadeghi J, Letef CA, D'Aloisio L, Copp AG, Inaba R, Hans G, Jafaripour S, Haskey N, Raman M, Daneshgar P, Chadee K, Ghosh S, Gibson DL, Pakpour S, Zandberg W, Bergstrom KSB. Fecal-adherent mucus is a non-invasive source of primary human MUC2 for structural and functional characterization in health and disease. J Biol Chem 2024; 300:105675. [PMID: 38272223 PMCID: PMC10891339 DOI: 10.1016/j.jbc.2024.105675] [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: 06/02/2023] [Revised: 01/05/2024] [Accepted: 01/08/2024] [Indexed: 01/27/2024] Open
Abstract
The O-glycoprotein Mucin-2 (MUC2) forms the protective colon mucus layer. While animal models have demonstrated the importance of Muc2, few studies have explored human MUC2 in similar depth. Recent studies have revealed that secreted MUC2 is bound to human feces. We hypothesized human fecal MUC2 (HF-MUC2) was accessible for purification and downstream structural and functional characterization. We tested this via histologic and quantitative imaging on human fecal sections; extraction from feces for proteomic and O-glycomic characterization; and functional studies via growth and metabolic assays in vitro. Quantitative imaging of solid fecal sections showed a continuous mucus layer of varying thickness along human fecal sections with barrier functions intact. Lectin profiling showed HF-MUC2 bound several lectins but was weak to absent for Ulex europaeus 1 (α1,2 fucose-binding) and Sambucus nigra agglutinin (α2,6 sialic acid-binding), and did not have obvious b1/b2 barrier layers. HF-MUC2 separated by electrophoresis showed high molecular weight glycoprotein bands (∼1-2 MDa). Proteomics and Western analysis confirmed the enrichment of MUC2 and potential MUC2-associated proteins in HF-MUC2 extracts. MUC2 O-glycomics revealed diverse fucosylation, moderate sialylation, and little sulfation versus porcine colonic MUC2 and murine fecal Muc2. O-glycans were functional and supported the growth of Bacteroides thetaiotaomicron (B. theta) and short-chain fatty acid (SCFA) production in vitro. MUC2 could be similarly analyzed from inflammatory bowel disease stools, which displayed an altered glycomic profile and differential growth and SCFA production by B. theta versus healthy samples. These studies describe a new non-invasive platform for human MUC2 characterization in health and disease.
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Affiliation(s)
- Noah Fancy
- Biology, University of British Columbia-Okanagan, Kelowna, Canada
| | - Nitin
- Chemistry, University of British Columbia-Okanagan, Kelowna, Canada
| | - Darrek Kniffen
- Biology, University of British Columbia-Okanagan, Kelowna, Canada
| | - Mackenzie Melvin
- Biology, University of British Columbia-Okanagan, Kelowna, Canada
| | - Negin Kazemian
- School of Engineering, University of British Columbia-Okanagan, Kelowna, Canada
| | - Javad Sadeghi
- School of Engineering, University of British Columbia-Okanagan, Kelowna, Canada
| | - Clara A Letef
- Biology, University of British Columbia-Okanagan, Kelowna, Canada
| | - Leah D'Aloisio
- Biology, University of British Columbia-Okanagan, Kelowna, Canada
| | - Amanda G Copp
- Biology, University of British Columbia-Okanagan, Kelowna, Canada
| | - Rain Inaba
- Biology, University of British Columbia-Okanagan, Kelowna, Canada
| | - Geetkamal Hans
- Biology, University of British Columbia-Okanagan, Kelowna, Canada
| | - Simin Jafaripour
- Biology, University of British Columbia-Okanagan, Kelowna, Canada
| | - Natasha Haskey
- Biology, University of British Columbia-Okanagan, Kelowna, Canada
| | - Maitreyi Raman
- Cumming School of Medicine, University of Calgary, Calgary, Canada
| | | | - Kris Chadee
- Cumming School of Medicine, University of Calgary, Calgary, Canada
| | - Sanjoy Ghosh
- Biology, University of British Columbia-Okanagan, Kelowna, Canada
| | - Deanna L Gibson
- Biology, University of British Columbia-Okanagan, Kelowna, Canada
| | - Sepideh Pakpour
- School of Engineering, University of British Columbia-Okanagan, Kelowna, Canada
| | - Wesley Zandberg
- Chemistry, University of British Columbia-Okanagan, Kelowna, Canada
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18
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Wang CPJ, Ko GR, Lee YY, Park J, Park W, Park TE, Jin Y, Kim SN, Lee JS, Park CG. Polymeric DNase-I nanozymes targeting neutrophil extracellular traps for the treatment of bowel inflammation. NANO CONVERGENCE 2024; 11:6. [PMID: 38332364 PMCID: PMC10853102 DOI: 10.1186/s40580-024-00414-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/29/2023] [Accepted: 01/23/2024] [Indexed: 02/10/2024]
Abstract
Inflammatory bowel disease (IBD), including Crohn's disease and ulcerative colitis, is a family of chronic disorders along the gastrointestinal tract. Because of its idiopathic nature, IBD does not have a fundamental cure; current available therapies for IBD are limited to prolonged doses of immunomodulatory agents. While these treatments may reduce inflammation, limited therapeutic efficacy, inconsistency across patients, and adverse side effects from aggressive medications remain as major drawbacks. Recently, excessive production and accumulation of neutrophil extracellular traps (NETs) also known as NETosis have been identified to exacerbate inflammatory responses and induce further tissue damage in IBD. Such discovery invited many researchers to investigate NETs as a potential therapeutic target. DNase-I is a natural agent that can effectively destroy NETs and, therefore, potentially reduce NETs-induced inflammations even without the use of aggressive drugs. However, low stability and rapid clearance of DNase-I remain as major limitations for further therapeutic applications. In this research, polymeric nanozymes were fabricated to increase the delivery and therapeutic efficacy of DNase-I. DNase-I was immobilized on the surface of polymeric nanoparticles to maintain its enzymatic properties while extending its activity in the colon. Delivery of DNase-I using this platform allowed enhanced stability and prolonged activity of DNase-I with minimal toxicity. When administered to animal models of IBD, DNase-I nanozymes successfully alleviated various pathophysiological symptoms of IBD. More importantly, DNase-I nanozyme administration successfully attenuated neutrophil infiltration and NETosis in the colon compared to free DNase-I or mesalamine.
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Affiliation(s)
- Chi-Pin James Wang
- Department of Biomedical Engineering, SKKU Institute for Convergence, Sungkyunkwan University (SKKU), Suwon, Gyeonggi, 16419, Republic of Korea
- Department of Intelligent Precision Healthcare Convergence, SKKU Institute for Convergence, Sungkyunkwan University (SKKU), Suwon, Gyeonggi, 16419, Republic of Korea
| | - Ga Ryang Ko
- Department of Intelligent Precision Healthcare Convergence, SKKU Institute for Convergence, Sungkyunkwan University (SKKU), Suwon, Gyeonggi, 16419, Republic of Korea
| | - Yun Young Lee
- Department of Biomedical Engineering, College of Medicine, Seoul National University, Seoul, 03080, Republic of Korea
| | - Juwon Park
- Department of Tropical Medicine, Medical Microbiology, and Pharmacology, John A. Burns School of Medicine, University of Hawai'i at Manoa, Honolulu, HI, 96813, USA
| | - Wooram Park
- Department of Integrative Biotechnology, College of Biotechnology and Bioengineering, Sungkyunkwan University (SKKU), Suwon, Gyeonggi, 16419, Republic of Korea
| | - Tae-Eun Park
- Department of Biomedical Engineering, Ulsan National Institute of Science and Technology (UNIST), Ulsan, 44919, Republic of Korea
| | - Yoonhee Jin
- Department of Physiology, Yonsei University College of Medicine, Seoul, 03722, Republic of Korea
| | - Se-Na Kim
- Research and Development Center, MediArk Inc., Cheongju, Chungbuk, 28644, Republic of Korea.
- Department of Industrial Cosmetic Science, College of Bio-Health University System, Chungbuk National University, Cheongju, Chungbuk, 28644, Republic of Korea.
| | - Jung Seung Lee
- Department of Biomedical Engineering, SKKU Institute for Convergence, Sungkyunkwan University (SKKU), Suwon, Gyeonggi, 16419, Republic of Korea.
- Department of Intelligent Precision Healthcare Convergence, SKKU Institute for Convergence, Sungkyunkwan University (SKKU), Suwon, Gyeonggi, 16419, Republic of Korea.
| | - Chun Gwon Park
- Department of Biomedical Engineering, SKKU Institute for Convergence, Sungkyunkwan University (SKKU), Suwon, Gyeonggi, 16419, Republic of Korea.
- Department of Intelligent Precision Healthcare Convergence, SKKU Institute for Convergence, Sungkyunkwan University (SKKU), Suwon, Gyeonggi, 16419, Republic of Korea.
- Biomedical Institute for Convergence at SKKU (BICS), Sungkyunkwan University (SKKU), Suwon, Gyeonggi, 16419, Republic of Korea.
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19
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Ahmad S, Sands M, Greenberg E, Tangen L, Huang J, Irudayaraj JMK. Mucosal DNA methylome alteration in Crohn's disease: surgical and non-surgical groups. Front Genet 2023; 14:1244513. [PMID: 38046046 PMCID: PMC10691104 DOI: 10.3389/fgene.2023.1244513] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/22/2023] [Accepted: 11/09/2023] [Indexed: 12/05/2023] Open
Abstract
Crohn's disease (CD) is characterized as a chronic, relapsing, and progressive disorder with a complex etiology involving interactions between host, microbiome, and the external environment. Genome wide association studies (GWAS) suggest several genetic variations in the diseased individuals but that explains only a small proportion of susceptibility to disease conditions. This indicates the possible role of epigenome which links environmental factors to the genetic variation in the disease etiology. The current study is focused on the DNA methylome evolution with disease progression. We performed Reduced Representation Bisulfite Sequencing (RRBS) to analyze differential DNA methylation in the diseased and healthy mucosal tissues of 2 different groups of CD patients: non-surgical and surgical, categorized based on the severity of disease and standard of care needed. Patients in both groups have unique DNA methylation signature compared to the healthy tissue. After removing single nucleotide polymorphisms (SNPs), 1,671 differentially methylated loci were found in the non-surgical and 3,334 in the surgical group of which only 206 were found overlapping in both groups. Furthermore, differential DNA methylation was noted in some of the GWAS associated genes implicated in CD. Also, functional enrichment analysis showed high representation of several key pathways where differential methylations were observed, and these can be implicated in CD pathogenesis. We identified specific DNA methylation patterns in the mucosal DNA of surgical and non-surgical CD patients which indicates evolution of the methylome as the disease progresses from initial to the advance stage. These unique patterns can be used as DNA methylation signatures to identify different stages of the disease.
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Affiliation(s)
- Saeed Ahmad
- Biomedical Research Center, Mills Breast Cancer Institute, Carle Foundation Hospital, Urbana, IL, United States
- Department of Bioengineering, University of Illinois Urbana-Champaign, Champaign, IL, United States
| | - Mia Sands
- Biomedical Research Center, Mills Breast Cancer Institute, Carle Foundation Hospital, Urbana, IL, United States
- Department of Bioengineering, University of Illinois Urbana-Champaign, Champaign, IL, United States
| | - Eugene Greenberg
- Digestive Health Institute, Carle Foundation Hospital, Urbana, IL, United States
| | - Lyn Tangen
- Digestive Health Institute, Carle Foundation Hospital, Urbana, IL, United States
| | - Jiacheng Huang
- Biomedical Research Center, Mills Breast Cancer Institute, Carle Foundation Hospital, Urbana, IL, United States
- Department of Bioengineering, University of Illinois Urbana-Champaign, Champaign, IL, United States
| | - Joseph Maria Kumar Irudayaraj
- Biomedical Research Center, Mills Breast Cancer Institute, Carle Foundation Hospital, Urbana, IL, United States
- Department of Bioengineering, University of Illinois Urbana-Champaign, Champaign, IL, United States
- Carl Woese Institute for Genomic Biology, University of Illinois Urbana-Champaign, Champaign, IL, United States
- Cancer Center at Illinois, University of Illinois Urbana-Champaign, Champaign, IL, United States
- Carle Illinois College of Medicine, University of Illinois Urbana-Champaign, Champaign, IL, United States
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20
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Bellini G, Benvenuti L, Ippolito C, Frosini D, Segnani C, Rettura F, Pancetti A, Bertani L, D'Antongiovanni V, Palermo G, Del Prete E, Antonioli L, Nardini V, Morganti R, Pellegrini C, Bernardini N, Ceravolo R, Fornai M, Bellini M. Intestinal histomorphological and molecular alterations in patients with Parkinson's disease. Eur J Neurol 2023; 30:3440-3450. [PMID: 36263629 DOI: 10.1111/ene.15607] [Citation(s) in RCA: 15] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/24/2022] [Accepted: 09/22/2022] [Indexed: 11/28/2022]
Abstract
BACKGROUND AND PURPOSE Changes in gut microbiota composition, enteric inflammation, impairments of the intestinal epithelial barrier and neuroplastic changes in the enteric nervous system have been reported in Parkinson's disease (PD) patients and could contribute to the onset of both neurological and gastrointestinal symptoms. However, their mutual interplay has rarely been investigated. This study evaluated, in an integrated manner, changes in faecal microbiota composition, morphofunctional alterations of colonic mucosal barrier and changes of inflammatory markers in blood and stools of PD patients. METHODS Nineteen PD patients and nineteen asymptomatic subjects were enrolled. Blood lipopolysaccharide binding protein (LBP, marker of altered intestinal permeability) and interleukin-1β (IL-1β) levels, as well as stool IL-1β and tumour necrosis factor (TNF) levels, were evaluated. Gut microbiota analysis was performed. Epithelial mucins, collagen fibres, claudin-1 and S100-positive glial cells as markers of an impairment of the intestinal barrier, mucosal remodelling and enteric glial activation were evaluated on colonic mucosal specimens collected during colonoscopy. RESULTS Faecal microbiota analysis revealed a significant difference in the α-diversity in PD patients compared to controls, while no differences were found in the β-diversity. Compared to controls, PD patients showed significant chenags in plasma LBP levels, as well as faecal TNF and IL-1β levels. The histological analysis showed a decrease in epithelial neutral mucins and claudin-1 expression and an increased expression of acidic mucins, collagen fibres and S100-positive glial cells. CONCLUSIONS Parkinson's disease patients are characterized by enteric inflammation and increased intestinal epithelial barrier permeability, as well as colonic mucosal barrier remodelling, associated with changes in gut microbiota composition.
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Affiliation(s)
- Gabriele Bellini
- Neurology Unit, Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy
| | - Laura Benvenuti
- Unit of Pharmacology and Pharmacovigilance, Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy
| | - Chiara Ippolito
- Unit of Histology and Embryology, Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy
| | - Daniela Frosini
- Department of Medical Specialties, Neurology Unit, AOUP, Pisa, Italy
| | - Cristina Segnani
- Unit of Histology and Embryology, Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy
| | - Francesco Rettura
- Gastrointestinal Unit, Department of Translational Research and New Technologies in Medicine and Surgery, University of Pisa, Pisa, Italy
| | - Andrea Pancetti
- Gastrointestinal Unit, Department of Translational Research and New Technologies in Medicine and Surgery, University of Pisa, Pisa, Italy
| | - Lorenzo Bertani
- Gastrointestinal Unit, Department of Translational Research and New Technologies in Medicine and Surgery, University of Pisa, Pisa, Italy
- Department of Surgery and Gastroenterology, Tuscany North-West ASL, Pontedera Hospital, Pisa, Italy
| | - Vanessa D'Antongiovanni
- Unit of Pharmacology and Pharmacovigilance, Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy
| | - Giovanni Palermo
- Neurology Unit, Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy
| | | | - Luca Antonioli
- Unit of Pharmacology and Pharmacovigilance, Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy
| | - Vincenzo Nardini
- Anatomia Patologica 2, Azienda Ospedaliero-Universitaria Pisana, Pisa, Italy
| | | | - Carolina Pellegrini
- Unit of Histology and Embryology, Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy
| | - Nunzia Bernardini
- Unit of Histology and Embryology, Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy
| | - Roberto Ceravolo
- Neurology Unit, Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy
- Center for Neurodegenerative Diseases, Unit of Neurology, Parkinson's Disease and Movement Disorders, Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy
| | - Matteo Fornai
- Unit of Pharmacology and Pharmacovigilance, Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy
| | - Massimo Bellini
- Gastrointestinal Unit, Department of Translational Research and New Technologies in Medicine and Surgery, University of Pisa, Pisa, Italy
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21
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Wu S, Wu Z, Chen Y. Effect of Cordyceps militaris Powder Prophylactic Supplementation on Intestinal Mucosal Barrier Impairment and Microbiota-Metabolites Axis in DSS-Injured Mice. Nutrients 2023; 15:4378. [PMID: 37892453 PMCID: PMC10610503 DOI: 10.3390/nu15204378] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/05/2023] [Revised: 10/04/2023] [Accepted: 10/13/2023] [Indexed: 10/29/2023] Open
Abstract
Ulcerative colitis (UC) is a chronic and recurrent inflammatory disease with an unknown pathogenesis and increasing incidence. The objective of this study is to investigate the impact of prophylactic treatment with Cordyceps militaris on UC. The findings demonstrate that prophylactic supplementation of C. militaris powder effectively mitigates disease symptoms in DSS-injured mice, while also reducing the secretion of pro-inflammatory cytokines. Furthermore, C. militaris powder enhances the integrity of the intestinal mucosal barrier by up-regulating MUC2 protein expression and improving tight junction proteins (ZO-1, occludin, and claudin 1) in DSS-injured mice. Multiomics integration analyses revealed that C. militaris powder not only reshaped gut microbiota composition, with an increase in Lactobacillus, Odoribacter, and Mucispirillum, but also exerted regulatory effects on various metabolic pathways including amino acid, glyoxylates, dicarboxylates, glycerophospholipids, and arachidonic acid. Subsequent analysis further elucidated the intricate interplay of gut microbiota, the intestinal mucosal barrier, and metabolites, suggesting that the microbiota-metabolite axis may involve the effect of C. militaris on intestinal mucosal barrier repair in UC. Moreover, in vitro experiments demonstrated that peptides and polysaccharides, derived from C. militaris, exerted an ability to change the gut microbiota structure of UC patients' feces, particularly by promoting the growth of Lactobacillus. These findings suggest that regulatory properties of C. militaris on gut microbiota may underlie the potential mechanism responsible for the protective effect of C. militaris in UC. Consequently, our study will provide support for the utilization of C. militaris as a whole food-based ingredient against the occurrence and development of UC.
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Affiliation(s)
- Shujian Wu
- Shenzhen Clinical Research Center for Digestive Disease, Integrative Microecology Clinical Center, Shenzhen Key Laboratory of Gastrointestinal Microbiota and Disease, Shenzhen Technology Research Center of Gut Microbiota Transplantation, Shenzhen Hospital, Southern Medical University, Shenzhen 518100, China;
| | - Zaoxuan Wu
- State Key Laboratory of Organ Failure Research, Department of Gastroenterology, Nanfang Hospital, Southern Medical University, Guangzhou 510080, China;
| | - Ye Chen
- Shenzhen Clinical Research Center for Digestive Disease, Integrative Microecology Clinical Center, Shenzhen Key Laboratory of Gastrointestinal Microbiota and Disease, Shenzhen Technology Research Center of Gut Microbiota Transplantation, Shenzhen Hospital, Southern Medical University, Shenzhen 518100, China;
- State Key Laboratory of Organ Failure Research, Department of Gastroenterology, Nanfang Hospital, Southern Medical University, Guangzhou 510080, China;
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22
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Liu J, Fu L, Yin F, Yin L, Song X, Guo H, Liu J. Diosmetin Maintains Barrier Integrity by Reducing the Expression of ABCG2 in Colonic Epithelial Cells. JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY 2023. [PMID: 37269551 DOI: 10.1021/acs.jafc.3c00912] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/05/2023]
Abstract
Crohn's disease (CD) is a relapsing and chronic inflammatory bowel disease. Recent advances have highlighted that dysfunction of the barrier function formed by a polarized monolayer of columnar epithelial cells plays a crucial role in the pathophysiology of CD. At present, we reported that diosmetin increased cell viability by reducing the levels of TNFα and IL-6 in lipopolysaccharide (LPS)-treated colonic epithelial Caco-2 cells. Meanwhile, diosmetin conferred a direct effect on maintaining barrier integrity by reducing epithelial permeability and increasing the expression of proteins associated with tight junctions, including zonula occludens-l (ZO-1), occludin, and claudin-1, in LPS-treated Caco-2 cells and in 2,4,6-trinitrobenzene sulfonic acid-induced CD mice. Additionally, diosmetin decreased the protein content of adenosine triphosphate-binding cassette efflux transporter G2 (ABCG2) in vitro and in vivo. Over-expression of ABCG2 had an important impact on the epithelial permeability and barrier-related protein levels induced by LPS in Caco-2 cells. At the same time, Ko143, a specific ABCG2 inhibitor, dramatically enhanced the role of diosmetin in ZO-1 and occludin proteins in LPS-treated Caco-2 cells. Mechanically, diosmetin significantly attenuated the role of LPS in the phosphorylation of adenosine 5'-monophosphate (AMP)-activated protein kinase (AMPK), phosphatidylinositol-3-kinase (PI3K)/protein kinase B (PKB/AKT), and cAMP-response element binding protein (CREB) in Caco-2 cells. The AMPK inhibitor Compound C obviously prevented the effect of diosmetin on ZO-1 and occludin expression in LPS-treated Caco-2 cells. Taken together, the results of this study suggest that AMPK/AKT/CREB-mediated ABCG2 expression plays a crucial role in diosmetin, improving the barrier dysfunction in CD.
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Affiliation(s)
- Jinfan Liu
- Chongqing Key Laboratory of Medicinal Chemistry & Molecular Pharmacology, Chongqing University of Technology, Chongqing 400054, China
| | - Lu Fu
- Chongqing Key Laboratory of Medicinal Chemistry & Molecular Pharmacology, Chongqing University of Technology, Chongqing 400054, China
| | - Fei Yin
- Chongqing Key Laboratory of Medicinal Chemistry & Molecular Pharmacology, Chongqing University of Technology, Chongqing 400054, China
- College of Pharmacy and Bioengineering, Chongqing University of Technology, Chongqing 400054, People's Republic of China
| | - Li Yin
- Chongqing Key Laboratory of Medicinal Chemistry & Molecular Pharmacology, Chongqing University of Technology, Chongqing 400054, China
- College of Pharmacy and Bioengineering, Chongqing University of Technology, Chongqing 400054, People's Republic of China
| | - Xiaomei Song
- Department of Gastroenterology, Chongqing General Hospital, University of Chinese Academy of Sciences, Chongqing 401147, People's Republic of China
| | - Hong Guo
- Department of Gastroenterology, Chongqing General Hospital, University of Chinese Academy of Sciences, Chongqing 401147, People's Republic of China
| | - Jianhui Liu
- Chongqing Key Laboratory of Medicinal Chemistry & Molecular Pharmacology, Chongqing University of Technology, Chongqing 400054, China
- College of Pharmacy and Bioengineering, Chongqing University of Technology, Chongqing 400054, People's Republic of China
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23
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Wang Q, Xu K, Cai X, Wang C, Cao Y, Xiao J. Rosmarinic Acid Restores Colonic Mucus Secretion in Colitis Mice by Regulating Gut Microbiota-Derived Metabolites and the Activation of Inflammasomes. JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY 2023; 71:4571-4585. [PMID: 36883243 DOI: 10.1021/acs.jafc.2c08444] [Citation(s) in RCA: 33] [Impact Index Per Article: 16.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/18/2023]
Abstract
Maintaining a steady state of mucus barrier is an important potential target for polyphenol to exert its anticolitis activity. This study elucidates the pivotal role of polyphenol rosmaric acid (RA) in regulating the mucus barrier function and alleviating inflammation by identifying its gut microbiota-derived metabolites and evaluating its inhibitory effect on inflammasomes in colitis mice. Results demonstrated that RA treatment promoted the proliferation of goblet cells and restored the level of mucus secretion, especially Muc2. RA reshaped the microbiota of colitis mice, particularly the boost of core probiotics, such as p. Bacteroidaceae, f. Muribaculaceae, g. Muribaculaceae, g. Alistipes, and g. Clostridia_UCG-014. Nontargeted metabonomics and targeted metabonomics confirmed a significant increase in the bile acids and their metabolites (7-sulfocholic acid, stercobilin, chenodeoxycholic acid 3-sulfate, chenodeoxycholic acid sulfate, and ursodeoxycholic acid 3-sulfate), indole metabolites ((R)-2,3-dihydro-3,5-dihydroxy-2-oxo-3-indoleacetic acid, frovatriptan, 3-formyl-6-hydroxyindole, and brassicanal A), and short-chain fatty acids (SCFAs) (acetic acid, butyric acid, isobutyric acid, isovaleric acid, and valeric acid) that contributed to the strengthened mucus barrier function. In addition, being absorbed mainly in the lower digestive tract, RA inhibited the overexpression of inflammasomes (especially NLRP6) that occurred in colitis mice to promote the mucus secretion of goblet cells. These data confirmed that RA, as a promising candidate to enhance gut health, restored colonic mucus secretion in colitis mice by mediating the production of gut microbiota-derived metabolites and the overexpression of inflammasomes. The presented study provides scientific evidence explaining the apparent paradox of low bioavailability and high bioactivity in polyphenols.
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Affiliation(s)
- Qun Wang
- Guangdong Provincial Key Laboratory of Nutraceuticals and Functional Foods, College of Food Science, South China Agricultural University, Guangzhou 510642, China
| | - Kangjie Xu
- Guangdong Provincial Key Laboratory of Nutraceuticals and Functional Foods, College of Food Science, South China Agricultural University, Guangzhou 510642, China
| | - Xu Cai
- Medical Science Research Center, Zhongnan Hospital of Wuhan University, Wuhan 430071, China
| | - Chujing Wang
- Guangdong Provincial Key Laboratory of Nutraceuticals and Functional Foods, College of Food Science, South China Agricultural University, Guangzhou 510642, China
| | - Yong Cao
- Guangdong Provincial Key Laboratory of Nutraceuticals and Functional Foods, College of Food Science, South China Agricultural University, Guangzhou 510642, China
| | - Jie Xiao
- Guangdong Provincial Key Laboratory of Nutraceuticals and Functional Foods, College of Food Science, South China Agricultural University, Guangzhou 510642, China
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24
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Domene A, Orozco H, Rodríguez-Viso P, Monedero V, Zúñiga M, Vélez D, Devesa V. Intestinal homeostasis disruption in mice chronically exposed to arsenite-contaminated drinking water. Chem Biol Interact 2023; 373:110404. [PMID: 36791901 DOI: 10.1016/j.cbi.2023.110404] [Citation(s) in RCA: 12] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/22/2022] [Revised: 01/29/2023] [Accepted: 02/11/2023] [Indexed: 02/14/2023]
Abstract
Chronic exposure to inorganic arsenic [As(III) and As(V)] affects about 200 million people, and is linked to a greater incidence of certain types of cancer. Drinking water is the main route of exposure, so, in endemic areas, the intestinal mucosa is constantly exposed to the metalloid. However, studies on the intestinal toxicity of inorganic As are scarce. The objective of this study was to evaluate the toxicity of a chronic exposure to As(III) on the intestinal mucosa and its associated microbiota. For this purpose, BALB/c mice were exposed during 6 months through drinking water to As(III) (15 and 30 mg/L). Treatment with As(III) increased reactive oxygen species (43-64%) and lipid peroxidation (8-51%). A pro-inflammatory response was also observed, evidenced by an increase in fecal lactoferrin (23-29%) and mucosal neutrophil infiltration. As(III) also induced an increase in the colonic levels of pro-inflammatory cytokines (24-201%) and the activation of some pro-inflammatory signaling pathways. Reductions in the number of goblet cells and mucus production were also observed. Moreover, As(III) exposure resulted in changes in gut microbial alpha diversity but no differences in beta diversity. This suggested that the abundance of some taxa was significantly affected by As(III), although the composition of the population did not show significant alterations. Analysis of differential taxa agreed with this, 21 ASVs were affected in abundance or variability, especially ASVs from the family Muribaculaceae. Intestinal microbiota metabolism was also affected, as reductions in fecal concentration of short-chain fatty acids were observed. The effects observed on different components of the intestinal barrier may be responsible of the increased permeability in As(III) treated mice, evidenced by an increase in fecal albumin (48-66%). Moreover, serum levels of Lipopolysaccharide binding proteins and TNF-α were increased in animals treated with 30 mg/L of As(III), suggesting a low-level systemic inflammation.
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Affiliation(s)
- A Domene
- Instituto de Agroquímica y Tecnología de Alimentos, Calle Agustín Escardino 7, 46980, Paterna, Spain
| | - H Orozco
- Instituto de Agroquímica y Tecnología de Alimentos, Calle Agustín Escardino 7, 46980, Paterna, Spain
| | - P Rodríguez-Viso
- Instituto de Agroquímica y Tecnología de Alimentos, Calle Agustín Escardino 7, 46980, Paterna, Spain
| | - V Monedero
- Instituto de Agroquímica y Tecnología de Alimentos, Calle Agustín Escardino 7, 46980, Paterna, Spain
| | - M Zúñiga
- Instituto de Agroquímica y Tecnología de Alimentos, Calle Agustín Escardino 7, 46980, Paterna, Spain
| | - D Vélez
- Instituto de Agroquímica y Tecnología de Alimentos, Calle Agustín Escardino 7, 46980, Paterna, Spain
| | - V Devesa
- Instituto de Agroquímica y Tecnología de Alimentos, Calle Agustín Escardino 7, 46980, Paterna, Spain.
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25
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Hole MJ, Jørgensen KK, Holm K, Braadland PR, Meyer‐Myklestad MH, Medhus AW, Reikvam DH, Götz A, Grzyb K, Boberg KM, Karlsen TH, Kummen M, Hov JR. A shared mucosal gut microbiota signature in primary sclerosing cholangitis before and after liver transplantation. Hepatology 2023; 77:715-728. [PMID: 36056902 PMCID: PMC9936983 DOI: 10.1002/hep.32773] [Citation(s) in RCA: 20] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/14/2022] [Revised: 08/29/2022] [Accepted: 09/01/2022] [Indexed: 12/08/2022]
Abstract
BACKGROUND AND AIMS Several characteristic features of the fecal microbiota have been described in primary sclerosing cholangitis (PSC), whereas data on mucosal microbiota are less consistent. We aimed to use a large colonoscopy cohort to investigate key knowledge gaps, including the role of gut microbiota in PSC with inflammatory bowel disease (IBD), the effect of liver transplantation (LT), and whether recurrent PSC (rPSC) may be used to define consistent microbiota features in PSC irrespective of LT. APPROACH AND RESULTS We included 84 PSC and 51 liver transplanted PSC patients (PSC-LT) and 40 healthy controls (HCs) and performed sequencing of the 16S ribosomal RNA gene (V3-V4) from ileocolonic biopsies. Intraindividual microbial diversity was reduced in both PSC and PSC-LT versus HCs. An expansion of Proteobacteria was more pronounced in PSC-LT (up to 19% relative abundance) than in PSC (up to 11%) and HCs (up to 8%; Q FDR < 0.05). When investigating PSC before (PSC vs. HC) and after LT (rPSC vs. no-rPSC), increased variability (dispersion) in the PSC group was found. Five genera were associated with PSC before and after LT. A dysbiosis index calculated from the five genera, and the presence of the potential pathobiont, Klebsiella , were associated with reduced LT-free survival. Concomitant IBD was associated with reduced Akkermansia . CONCLUSIONS Consistent mucosal microbiota features associated with PSC, PSC-IBD, and disease severity, irrespective of LT status, highlight the usefulness of investigating PSC and rPSC in parallel, and suggest that the impact of gut microbiota on posttransplant liver health should be investigated further.
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Affiliation(s)
- Mikal Jacob Hole
- Norwegian PSC Research Centre, Department of Transplantation Medicine, Oslo University Hospital Rikshospitalet, Oslo, Norway
- Institute of Clinical Medicine, University of Oslo, Oslo, Norway
- Research Institute of Internal Medicine, Oslo University Hospital, Rikshospitalet, Oslo, Norway
| | - Kristin Kaasen Jørgensen
- Norwegian PSC Research Centre, Department of Transplantation Medicine, Oslo University Hospital Rikshospitalet, Oslo, Norway
- Department of Gastroenterology, Akershus University Hospital, Lørenskog, Norway
| | - Kristian Holm
- Norwegian PSC Research Centre, Department of Transplantation Medicine, Oslo University Hospital Rikshospitalet, Oslo, Norway
- Institute of Clinical Medicine, University of Oslo, Oslo, Norway
- Research Institute of Internal Medicine, Oslo University Hospital, Rikshospitalet, Oslo, Norway
| | - Peder R. Braadland
- Norwegian PSC Research Centre, Department of Transplantation Medicine, Oslo University Hospital Rikshospitalet, Oslo, Norway
- Institute of Clinical Medicine, University of Oslo, Oslo, Norway
- Research Institute of Internal Medicine, Oslo University Hospital, Rikshospitalet, Oslo, Norway
| | - Malin Holm Meyer‐Myklestad
- Institute of Clinical Medicine, University of Oslo, Oslo, Norway
- Department of Infectious Diseases, Oslo University Hospital, Ullevål, Oslo, Norway
- Department of Microbiology, Oslo University Hospital, Ullevål, Oslo, Norway
| | - Asle Wilhelm Medhus
- Department of Gastroenterology, Oslo University Hospital, Ullevål, Oslo, Norway
| | - Dag Henrik Reikvam
- Institute of Clinical Medicine, University of Oslo, Oslo, Norway
- Department of Infectious Diseases, Oslo University Hospital, Ullevål, Oslo, Norway
| | - Alexandra Götz
- Norwegian PSC Research Centre, Department of Transplantation Medicine, Oslo University Hospital Rikshospitalet, Oslo, Norway
- Institute of Clinical Medicine, University of Oslo, Oslo, Norway
- Research Institute of Internal Medicine, Oslo University Hospital, Rikshospitalet, Oslo, Norway
| | - Krzysztof Grzyb
- Division of Pathology, Oslo University Hospital, Rikshospitalet, Oslo, Norway
| | - Kirsten Muri Boberg
- Norwegian PSC Research Centre, Department of Transplantation Medicine, Oslo University Hospital Rikshospitalet, Oslo, Norway
- Institute of Clinical Medicine, University of Oslo, Oslo, Norway
- Section of Gastroenterology, Department of Transplantation Medicine, Oslo University Hospital, Rikshospitalet, Oslo, Norway
| | - Tom Hemming Karlsen
- Norwegian PSC Research Centre, Department of Transplantation Medicine, Oslo University Hospital Rikshospitalet, Oslo, Norway
- Institute of Clinical Medicine, University of Oslo, Oslo, Norway
- Research Institute of Internal Medicine, Oslo University Hospital, Rikshospitalet, Oslo, Norway
- Section of Gastroenterology, Department of Transplantation Medicine, Oslo University Hospital, Rikshospitalet, Oslo, Norway
| | - Martin Kummen
- Norwegian PSC Research Centre, Department of Transplantation Medicine, Oslo University Hospital Rikshospitalet, Oslo, Norway
- Institute of Clinical Medicine, University of Oslo, Oslo, Norway
- Department of Oncology, Oslo University Hospital, Oslo, Norway
| | - Johannes R. Hov
- Norwegian PSC Research Centre, Department of Transplantation Medicine, Oslo University Hospital Rikshospitalet, Oslo, Norway
- Institute of Clinical Medicine, University of Oslo, Oslo, Norway
- Research Institute of Internal Medicine, Oslo University Hospital, Rikshospitalet, Oslo, Norway
- Section of Gastroenterology, Department of Transplantation Medicine, Oslo University Hospital, Rikshospitalet, Oslo, Norway
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26
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Haneishi Y, Furuya Y, Hasegawa M, Picarelli A, Rossi M, Miyamoto J. Inflammatory Bowel Diseases and Gut Microbiota. Int J Mol Sci 2023; 24:ijms24043817. [PMID: 36835245 PMCID: PMC9958622 DOI: 10.3390/ijms24043817] [Citation(s) in RCA: 81] [Impact Index Per Article: 40.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/23/2023] [Revised: 02/13/2023] [Accepted: 02/13/2023] [Indexed: 02/17/2023] Open
Abstract
Inflammatory bowel disease (IBD) is an inflammatory disease of the gastrointestinal tract, the incidence of which has rapidly increased worldwide, especially in developing and Western countries. Recent research has suggested that genetic factors, the environment, microbiota, and immune responses are involved in the pathogenesis; however, the underlying causes of IBD are unclear. Recently, gut microbiota dysbiosis, especially a decrease in the abundance and diversity of specific genera, has been suggested as a trigger for IBD-initiating events. Improving the gut microbiota and identifying the specific bacterial species in IBD are essential for understanding the pathogenesis and treatment of IBD and autoimmune diseases. Here, we review the different aspects of the role played by gut microbiota in the pathogenesis of IBD and provide a theoretical basis for modulating gut microbiota through probiotics, fecal microbiota transplantation, and microbial metabolites.
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Affiliation(s)
- Yuri Haneishi
- Department of Applied Biological Science, Graduate School of Agriculture, Tokyo University of Agriculture and Technology, Fuchu-shi 183-8509, Tokyo, Japan
| | - Yuma Furuya
- Department of Applied Biological Science, Graduate School of Agriculture, Tokyo University of Agriculture and Technology, Fuchu-shi 183-8509, Tokyo, Japan
| | - Mayu Hasegawa
- Department of Applied Biological Science, Graduate School of Agriculture, Tokyo University of Agriculture and Technology, Fuchu-shi 183-8509, Tokyo, Japan
| | - Antonio Picarelli
- Department of Translational and Precision Medicine, Sapienza University of Rome, 00185 Rome, Italy
| | - Mauro Rossi
- Institute of Food Sciences, National Research Council (CNR), Via Roma 64, 83100 Avellino, Italy
| | - Junki Miyamoto
- Department of Applied Biological Science, Graduate School of Agriculture, Tokyo University of Agriculture and Technology, Fuchu-shi 183-8509, Tokyo, Japan
- Correspondence: ; Tel.: +81-42-367-5684
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27
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Kulhari U, Kundu S, Mugale MN, Sahu BD. Nuciferine alleviates intestinal inflammation by inhibiting MAPK/NF-κB and NLRP3/Caspase 1 pathways in vivo and in vitro. Int Immunopharmacol 2023; 115:109613. [PMID: 36577154 DOI: 10.1016/j.intimp.2022.109613] [Citation(s) in RCA: 18] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/19/2022] [Revised: 12/07/2022] [Accepted: 12/15/2022] [Indexed: 12/28/2022]
Abstract
Nuciferine (NCF) is an aporphine alkaloid and a principal bioactive constituent in the lotus plant. Herewith, we investigated the potential anti-inflammatory effect and underlying mechanisms of NCF employing dextran sulfate sodium (DSS)-induced ulcerative colitis in mice, a predominant intestinal inflammatory disease, and mouse RAW 264.7 cells in vitro. Lipopolysaccharide (LPS) was used to generate an inflammatory response in the RAW 264.7 cells. The disease activity index (DAI), colon morphology, colonoscopy, and colon histopathology were performed to assess experimental colitis. The biochemical assays, enzyme-linked immunosorbent assay (ELISA), and immunoblot analysis were performed to understand the underlying mechanisms. In RAW 264.7 cells, NCF pretreatment significantly decreased the expression of inducible nitric oxide synthase (iNOS), the expression and release of pro-inflammatory cytokines including interleukin (IL)-1β, IL-18, and tumor necrosis factor-α (TNF-α) and interfered with the activation of mitogen-activated protein kinase (MAPK), nuclear factor-κB (NF-κB), and NOD-like family pyrin domain containing 3 (NLRP3) signaling pathways. The oral treatment of NCF substantially alleviated the DSS-induced DAI, increased colon length, and restored colon morphology and histology. Compared to the DSS-induced mice, the proteins involved in the activation of MAPK/NF-κB/NLRP3 pathways and the cytokines were markedly decreased in the NCF-treated mice. Moreover, the tight junction architecture of the colon was well-maintained in NCF treatment groups by regulating the expression of claudin-1 and zonula occludens-1 (ZO-1) proteins. All these findings suggest that NCF can be a promising molecule to modulate ulcerative colitis.
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Affiliation(s)
- Uttam Kulhari
- Department of Pharmacology & Toxicology, National Institute of Pharmaceutical Education and Research (NIPER)-Guwahati, Changsari, 781101 Assam, India
| | - Sourav Kundu
- Department of Pharmacology & Toxicology, National Institute of Pharmaceutical Education and Research (NIPER)-Guwahati, Changsari, 781101 Assam, India
| | - Madhav Nilakanth Mugale
- Toxicology & Experimental Medicine, CSIR-Central Drug Research Institute (CDRI), Lucknow 226031, India
| | - Bidya Dhar Sahu
- Department of Pharmacology & Toxicology, National Institute of Pharmaceutical Education and Research (NIPER)-Guwahati, Changsari, 781101 Assam, India.
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Kim HR, Noh EM, Kim SY. Anti-inflammatory effect and signaling mechanism of 8-shogaol and 10-shogaol in a dextran sodium sulfate-induced colitis mouse model. Heliyon 2023; 9:e12778. [PMID: 36647352 PMCID: PMC9840358 DOI: 10.1016/j.heliyon.2022.e12778] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/10/2022] [Revised: 12/23/2022] [Accepted: 12/30/2022] [Indexed: 01/06/2023] Open
Abstract
Ethnopharmacological relevance Ginger (Zingiber officinale Roscoe) has been used for food and applied in Ayurvedic medicine in India for thousands of years. With a reputation for strong anti-inflammatory properties, it has been used for to treat colds, migraines, nausea, arthritis, and high blood pressure in China and Southeast Asia. The physiological activity of ginger is attributed to its functional components, including gingerol and shogaol, and their derivatives. Aim of the study We aimed to investigate the effects of 8- and 10-shogaol and their bioactive signaling mechanisms in a dextran sodium sulfate (DSS)-induced colitis mouse model. The anti-colitis efficacy of 6-, 8-, and 10-derivatives of gingerol and shogaol was comparatively analyzed. Materials and methods Colitis was induced by providing mice with drinking water containing 5% DSS (w/v) for 8 days. The 6-, 8-, and 10-derivatives of gingerol and shogaol were orally administered for two weeks at a dose of 30 mg/kg. Changes in body weight and disease activity index were measured. The levels of pro-inflammatory cytokines, iNOS and COX-2, as well as the phosphorylation of NF-κB were analyzed using ELISA, PCR, or western blotting. Mucin expression and mRNA levels were measured using alcian blue staining and PCR, respectively. The tight-junction-associated proteins occludin and ZO-1 were assessed using immunohistological staining. Results The 6-, 8-, and 10-derivatives of gingerol and shogaol exhibited anti-inflammatory effects by regulating NF-κB signaling. Among the compounds administered, 10-shogaol was the most effective against DSS-induced inflammation. Comparative analysis of the chemical structure showed that shogaol, a dehydrated analog of gingerol, was more effective. 6- and 10-shogaol showed similar effects on DSS-induced morphological changes in the colonic mucus layer, mucin expression, and tight junction proteins. Conclusions 6-, 8-, and 10-Gingerol and 6-, 8-, and 10-shogaol significantly improved the clinical symptoms and intestinal epithelial barrier damage in DSS-induced colitis in mice. The derivatives effectively inhibited DSS-induced inflammation through the regulation of NF-κB signaling. Moreover, 10-shogaol showed the most potent anti-inflammatory effect among the six compounds used in this study. The results indicate that 8- and 10-shogaol, both main ingredients in ginger, may serve as therapeutic candidates for the treatment of colitis.
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Affiliation(s)
| | - Eun-Mi Noh
- Corresponding author. Jeonju AgroBio-Materials Institute, 111-27 Wonjangdong-gil, Deokjin-gu, Jeonju, 54810, Republic of Korea.
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Serio R, Zizzo MG. The multiple roles of dopamine receptor activation in the modulation of gastrointestinal motility and mucosal function. Auton Neurosci 2023; 244:103041. [PMID: 36372052 DOI: 10.1016/j.autneu.2022.103041] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/11/2022] [Revised: 06/22/2022] [Accepted: 11/01/2022] [Indexed: 11/09/2022]
Abstract
Dopamine (DA) is a catecholamine regulatory molecule with potential role in physiology and physiopathology of the intestinal tract. Various cellular sources of DA have been indicated as enteric neurons, immune cells, intestinal flora and gastrointestinal epithelium. Moreover, DA is produced by nutritional tyrosine. All the five DA receptors, actually described, are present throughout the gut. Current knowledge of DA in this area is reviewed, focusing on gastrointestinal function in health and during inflammation. Research on animal models and humans are reported. A major obstacle to understanding the physiologic and/or pharmacological roles of enteric DA is represented by the multiplicity of receptors involved in the responses together with many signalling pathways related to each receptor subtype. It is mandatory to map precisely the distributions of DA receptors, to determine the relevance of a receptor in a specific location in order to explore novel therapies directed to dopaminergic targets that may be useful in the control of intestinal inflammation.
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Affiliation(s)
- Rosa Serio
- Department of Biological, Chemical and Pharmaceutical Sciences and Technologies (STEBICEF), University of Palermo, Viale delle Scienze, 90128 Palermo, Italy.
| | - Maria Grazia Zizzo
- Department of Biological, Chemical and Pharmaceutical Sciences and Technologies (STEBICEF), University of Palermo, Viale delle Scienze, 90128 Palermo, Italy; ATeN (Advanced Technologies Network) Center, University of Palermo, Viale delle Scienze, 90128 Palermo, Italy
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Therapeutic Efficacy of Novel HDAC Inhibitors SPA3052 and SPA3074 against Intestinal Inflammation in a Murine Model of Colitis. Pharmaceuticals (Basel) 2022; 15:ph15121515. [PMID: 36558966 PMCID: PMC9785328 DOI: 10.3390/ph15121515] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/26/2022] [Revised: 11/21/2022] [Accepted: 12/01/2022] [Indexed: 12/12/2022] Open
Abstract
Inflammatory bowel diseases (IBD) are digestive tract disorders that involve chronic inflammation with frequent recurrences. This study aimed to evaluate the efficacy of two novel histone deacetylase 8 (HDAC8) inhibitors, namely, SPA3052 and SPA3074, against dextran sulfate sodium (DSS)-induced experimental colitis. Male C57BL/6N mice were subjected to two cycles of 1.5% DSS followed by treatment with suberoylanilide hydroxamic acid (SAHA), SPA3052, or SPA3074 for 14 days. Our results showed that SPA3074 administration increased (>50%) the expression of occludin, a tight junction protein, which was significantly decreased (>100%) after DSS treatment. Moreover, SPA3074 upregulated suppressor of cytokine signaling 1 (SOCS1) protein expression, which is known to be a key suppressor of T-helper cell differentiation and pro-inflammatory cytokines expression. Furthermore, we observed a decrease in SOCS1-associated Akt phosphorylation and an increase in lower extracellular signal-regulated kinase 1 and 2 phosphorylation, which contributed to lower nuclear factor-kappa B activation. Th2 effector cytokines, especially interleukin-13, were also downregulated by SPA3074 treatment. This study suggests that HDAC8 might be a promising novel target for the development of IBD treatments and that the novel HDAC8 inhibitor SPA3074 is a new candidate for IBD therapeutics.
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Luo P, Li X, Gao Y, Chen Z, Zhang Q, Wang Z, Tian X. Central administration of human opiorphin alleviates dextran sodium sulfate-induced colitis in mice through activation of the endogenous opioid system. Front Pharmacol 2022; 13:904926. [PMID: 36176442 PMCID: PMC9513434 DOI: 10.3389/fphar.2022.904926] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/26/2022] [Accepted: 08/17/2022] [Indexed: 11/18/2022] Open
Abstract
The opioid system plays a crucial role in maintaining gastrointestinal homeostasis. Endogenous opioid peptide enkephalins have anti-inflammatory effect and participate in the treatment of inflammatory bowel diseases (IBDs). Here, we investigated the effect of natural enkephalinase inhibitor human opiorphin (HO) on dextran sodium sulfate (DSS)-induced colitis in mice. Our results showed that central administration of HO attenuated DSS-induced colitis, as indicated by the reduction of disease activity index (DAI) scores, macroscopic scores, histological scores, and the myeloperoxidase (MPO) activity. Moreover, HO alleviated DSS-induced inflammation by decreasing inflammatory cytokines TNF-α, IL-6, and IL-1β, and increasing anti-inflammatory cytokine IL-10 in both serum and colon tissues in DSS-treated mice. The potential anti-inflammatory effect of HO at a dose of 40 μg/kg was observed as evidenced by a decrease in nuclear factor κB (NF-κB) p65, toll-like receptor-4 (TLR-4), iNOS, and COX-2. HO also improved intestinal barrier function by enhancing the expression of tight junction proteins. Furthermore, HO treatment significantly inhibited activities of neutral endopeptidase (NEP) and aminopeptidase N (APN), elevated serum enkephalins concentrations, and increased expressions of mu and delta opioid receptors. In addition, pretreatment with opioid receptor antagonist naloxone hydrochloride (NH) compromised the protective effect of HO and aggravated colitis symptoms, as indicated by inhibited anti-inflammatory effects, disrupted intestinal barrier function, and decreased opioid receptor activity. In conclusion, these data indicate that HO protects against DSS-induced colitis by inhibiting TLR4/NF-κB pathway activation and improving intestinal barrier function through activation of the endogenous opioid system. Therefore, targeting the opioid system with peptidase inhibitors intervention would be a novel strategy in the therapy of IBD.
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Affiliation(s)
- Pan Luo
- College of Life Science and Technology, Gansu Agricultural University, Lanzhou, China
| | - Xuelin Li
- National Demonstration Center for Experimental Biology Education, School of Life Science, Lanzhou University, Lanzhou, China
| | - Yuan Gao
- College of Life Science and Technology, Gansu Agricultural University, Lanzhou, China
| | - Zhengjun Chen
- College of Life Science and Technology, Gansu Agricultural University, Lanzhou, China
| | - Quanwei Zhang
- College of Life Science and Technology, Gansu Agricultural University, Lanzhou, China
- *Correspondence: Quanwei Zhang, ; Zhimin Wang, ; Xiaozhu Tian,
| | - Zhimin Wang
- Gansu Provincial Hospital PET/CT Center, Lanzhou, China
- *Correspondence: Quanwei Zhang, ; Zhimin Wang, ; Xiaozhu Tian,
| | - Xiaozhu Tian
- National Demonstration Center for Experimental Biology Education, School of Life Science, Lanzhou University, Lanzhou, China
- *Correspondence: Quanwei Zhang, ; Zhimin Wang, ; Xiaozhu Tian,
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Wang JK, Wei W, Zhao DY, Wang HF, Zhang YL, Lei JP, Yao SK. Intestinal mucosal barrier in functional constipation: Dose it change? World J Clin Cases 2022; 10:6385-6398. [PMID: 35979313 PMCID: PMC9294902 DOI: 10.12998/wjcc.v10.i19.6385] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/01/2022] [Revised: 03/21/2022] [Accepted: 04/09/2022] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND The intestinal mucosal barrier is the first line of defense against numerous harmful substances, and it contributes to the maintenance of intestinal homeostasis. Recent studies reported that structural and functional changes in the intestinal mucosal barrier were involved in the pathogenesis of several intestinal diseases. However, no study thoroughly evaluated this barrier in patients with functional constipation (FC). AIM To investigate the intestinal mucosal barrier in FC, including the mucus barrier, intercellular junctions, mucosal immunity and gut permeability. METHODS Forty FC patients who fulfilled the Rome IV criteria and 24 healthy controls were recruited in the Department of Gastroenterology of China-Japan Friendship Hospital. The colonic mucus barrier, intercellular junctions in the colonic epithelium, mucosal immune state and gut permeability in FC patients were comprehensively examined. Goblet cells were stained with Alcian Blue/Periodic acid Schiff (AB/PAS) and counted. The ultrastructure of intercellular junctional complexes was observed under an electron microscope. Occludin and zonula occludens-1 (ZO-1) in the colonic mucosa were located and quantified using immunohistochemistry and quantitative real-time polymerase chain reaction. Colonic CD3+ intraepithelial lymphocytes (IELs) and CD3+ lymphocytes in the lamina propria were identified and counted using immunofluorescence. The serum levels of D-lactic acid and zonulin were detected using enzyme-linked immunosorbent assay. RESULTS Compared to healthy controls, the staining of mucus secreted by goblet cells was darker in FC patients, and the number of goblet cells per upper crypt in the colonic mucosa was significantly increased in FC patients (control, 18.67 ± 2.99; FC, 22.42 ± 4.09; P = 0.001). The intercellular junctional complexes in the colonic epithelium were integral in FC patients. The distribution of mucosal occludin and ZO-1 was not altered in FC patients. No significant differences were found in occludin (control, 5.76E-2 ± 1.62E-2; FC, 5.17E-2 ± 1.80E-2; P = 0.240) and ZO-1 (control, 2.29E-2 ± 0.93E-2; FC, 2.68E-2 ± 1.60E-2; P = 0.333) protein expression between the two groups. The mRNA levels in occludin and ZO-1 were not modified in FC patients compared to healthy controls (P = 0.145, P = 0.451, respectively). No significant differences were observed in the number of CD3+ IELs per 100 epithelial cells (control, 5.62 ± 2.06; FC, 4.50 ± 2.16; P = 0.070) and CD3+ lamina propria lymphocytes (control, 19.69 ± 6.04/mm2; FC, 22.70 ± 11.38/mm2; P = 0.273). There were no significant differences in serum D-lactic acid [control, 5.21 (4.46, 5.49) mmol/L; FC, 4.63 (4.31, 5.42) mmol/L; P = 0.112] or zonulin [control, 1.36 (0.53, 2.15) ng/mL; FC, 0.94 (0.47, 1.56) ng/mL; P = 0.185] levels between FC patients and healthy controls. CONCLUSION The intestinal mucosal barrier in FC patients exhibits a compensatory increase in goblet cells and integral intercellular junctions without activation of mucosal immunity or increased gut permeability.
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Affiliation(s)
- Jun-Ke Wang
- Graduate School, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing 100730, China
- Department of Gastroenterology, China-Japan Friendship Hospital, Beijing 100029, China
| | - Wei Wei
- Department of Clinical Nutrition and Department of Health Medicine, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, Beijing 100730, China
| | - Dong-Yan Zhao
- Graduate School, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing 100730, China
- Department of Gastroenterology, China-Japan Friendship Hospital, Beijing 100029, China
| | - Hui-Fen Wang
- Department of Gastroenterology, China-Japan Friendship Hospital, Beijing 100029, China
| | - Yan-Li Zhang
- Department of Gastroenterology, China-Japan Friendship Hospital, Beijing 100029, China
| | - Jie-Ping Lei
- Data and Project Management Unit, Institute of Clinical Medical Sciences, China-Japan Friendship Hospital, Beijing 100029, China
| | - Shu-Kun Yao
- Graduate School, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing 100730, China
- Department of Gastroenterology, China-Japan Friendship Hospital, Beijing 100029, China
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Wan Y, Zhang B. The Impact of Zinc and Zinc Homeostasis on the Intestinal Mucosal Barrier and Intestinal Diseases. Biomolecules 2022; 12:biom12070900. [PMID: 35883455 PMCID: PMC9313088 DOI: 10.3390/biom12070900] [Citation(s) in RCA: 46] [Impact Index Per Article: 15.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/13/2022] [Revised: 06/06/2022] [Accepted: 06/11/2022] [Indexed: 02/04/2023] Open
Abstract
Zinc is an essential trace element for living organisms, and zinc homeostasis is essential for the maintenance of the normal physiological functions of cells and organisms. The intestine is the main location for zinc absorption and excretion, while zinc and zinc homeostasis is also of great significance to the structure and function of the intestinal mucosal barrier. Zinc excess or deficiency and zinc homeostatic imbalance are all associated with many intestinal diseases, such as IBD (inflammatory bowel disease), IBS (irritable bowel syndrome), and CRC (colorectal cancer). In this review, we describe the role of zinc and zinc homeostasis in the intestinal mucosal barrier and the relevance of zinc homeostasis to gastrointestinal diseases.
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Kang Y, Park H, Choe BH, Kang B. The Role and Function of Mucins and Its Relationship to Inflammatory Bowel Disease. Front Med (Lausanne) 2022; 9:848344. [PMID: 35602503 PMCID: PMC9120656 DOI: 10.3389/fmed.2022.848344] [Citation(s) in RCA: 50] [Impact Index Per Article: 16.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/04/2022] [Accepted: 04/15/2022] [Indexed: 02/06/2023] Open
Abstract
Mucus is present throughout the gastrointestinal tract and is essential for regulating gut microbiota homeostasis and preventing disease by protecting the gastrointestinal barrier from microorganisms, pathogens and toxins or other irritants. Mucin (MUC)-2 is a secreted protein produced by epithelial goblet cells as the main component of mucus. Defects in the gastrointestinal tract, such as inflammation and ulcers, cause damage to the mucus barrier, which can worsen mucus quality and reduce mucus production. Therefore, we would like to review the characteristics of MUC2 and its role in intestinal disorders and highlight the importance of further studies. We also investigated whether the role of MUC2 differs between children and adults, ulcerative colitis (UC) and Crohn's disease (CD).
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Affiliation(s)
- Youra Kang
- Cell and Matrix Research Institute, School of Medicine, Kyungpook National University, Daegu, South Korea
| | - Hyeonjeong Park
- Cell and Matrix Research Institute, School of Medicine, Kyungpook National University, Daegu, South Korea
| | - Byung-Ho Choe
- Department of Pediatrics, School of Medicine, Kyungpook National University, Daegu, South Korea
| | - Ben Kang
- Department of Pediatrics, School of Medicine, Kyungpook National University, Daegu, South Korea
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Wong WY, Chan BD, Sham TT, Lee MML, Chan CO, Chau CT, Mok DKW, Kwan YW, Tai WCS. Lactobacillus casei Strain Shirota Ameliorates Dextran Sulfate Sodium-Induced Colitis in Mice by Increasing Taurine-Conjugated Bile Acids and Inhibiting NF-κB Signaling via Stabilization of Iκ Bα. Front Nutr 2022; 9:816836. [PMID: 35529468 PMCID: PMC9069136 DOI: 10.3389/fnut.2022.816836] [Citation(s) in RCA: 21] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/17/2021] [Accepted: 03/28/2022] [Indexed: 12/12/2022] Open
Abstract
Inflammatory bowel disease (IBD) is a chronic progressive intestinal inflammatory disease, characterized by an altered gut microbiota composition and accompanying alterations in circulatory bile acids. Increasing evidence supports the beneficial effect of probiotics intake on health. Introduction of probiotics to the intestines can modulate gut microbiota composition and in turn regulate the host immune system and modify the inflammatory response. Probiotics can also improve intestinal barrier function and exhibit a positive impact on host physiological and pathological conditions via gut microbiota-derived metabolites. Previous studies have demonstrated that Lactobacillus casei strain Shirota (LcS) treatment could inhibit clinical manifestation of colitis in dextran sulfate sodium (DSS)-induced mice, however, the underlying mechanisms remain unknown. In this study, we employed the DSS-induced acute colitis mouse model to investigate the anti-inflammatory effects of LcS and related mechanisms. Administration of LcS ameliorated the severity of DSS-induced colitis and enhanced intestinal integrity via induction of mucin-2 and occludin expression in colons. Fecal microbiota analysis showed that LcS increased the relative abundance of beneficial bacterial species in colitic mice, whereas the relative abundance of pathobionts was reduced. Additionally, LcS treatment modulated circulating bile acid profiles in colitic mice. In mice treated with LcS, we identified increased levels of primary taurine-conjugated bile acids, including taurocholic acid (TCA) and taurochenodeoxycholic acid (TCDCA). LcS treatment also increased the levels of secondary taurine-conjugated bile acids, including taurodeoxycholic acid (TDCA) and tauroursodeoxycholic acid (TUDCA). Moreover, LcS treatment exhibited a suppressive effect on the hydroxylated primary bile acids α-muricholic acid (α-MCA) and β-muricholic acid (β-MCA). We further demonstrated that LcS treatment suppressed the expression of pro-inflammatory mediators interferon-gamma (IFN-γ) and nitric oxide (NO), and increased the expression of the anti-inflammatory mediator interleukin-10 (IL-10) in colon tissues, potentially as a result of altered bile acid profiles. Mechanistically, we showed that LcS treatment suppressed the activation of nuclear factor-kappa B (NF-κB) signaling via stabilization of inhibitor of NF-κB alpha (IκBα). Altogether, we have demonstrated the therapeutic effects of LcS in DSS-induced colitis, providing new insights into its effect on bile acid metabolism and the related anti-inflammatory mechanisms. Our findings provide support for the application of LcS in the treatment of IBD.
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Affiliation(s)
- Wing-Yan Wong
- Department of Applied Biology and Chemical Technology, The Hong Kong Polytechnic University, Hung Hom, Hong Kong SAR, China
- The Laboratory for Probiotic and Prebiotic Research in Human Health, The Hong Kong Polytechnic University, Hung Hom, Hong Kong SAR, China
| | - Brandon Dow Chan
- Department of Applied Biology and Chemical Technology, The Hong Kong Polytechnic University, Hung Hom, Hong Kong SAR, China
- The Laboratory for Probiotic and Prebiotic Research in Human Health, The Hong Kong Polytechnic University, Hung Hom, Hong Kong SAR, China
| | - Tung-Ting Sham
- Department of Applied Biology and Chemical Technology, The Hong Kong Polytechnic University, Hung Hom, Hong Kong SAR, China
| | - Magnolia Muk-Lan Lee
- Department of Applied Biology and Chemical Technology, The Hong Kong Polytechnic University, Hung Hom, Hong Kong SAR, China
- The Laboratory for Probiotic and Prebiotic Research in Human Health, The Hong Kong Polytechnic University, Hung Hom, Hong Kong SAR, China
| | - Chi-On Chan
- Department of Applied Biology and Chemical Technology, The Hong Kong Polytechnic University, Hung Hom, Hong Kong SAR, China
- State Key Laboratory of Chinese Medicine and Molecular Pharmacology (Incubation), Shenzhen Research Institute, The Hong Kong Polytechnic University, Shenzhen, China
| | - Chung-Ting Chau
- School of Biomedical Sciences, The Chinese University of Hong Kong, Sha Tin, Hong Kong SAR, China
| | - Daniel Kam-Wah Mok
- Department of Applied Biology and Chemical Technology, The Hong Kong Polytechnic University, Hung Hom, Hong Kong SAR, China
- State Key Laboratory of Chinese Medicine and Molecular Pharmacology (Incubation), Shenzhen Research Institute, The Hong Kong Polytechnic University, Shenzhen, China
- Research Institute for Future Food, The Hong Kong Polytechnic University, Hung Hom, Hong Kong SAR, China
| | - Yiu-Wa Kwan
- School of Biomedical Sciences, The Chinese University of Hong Kong, Sha Tin, Hong Kong SAR, China
| | - William Chi-Shing Tai
- Department of Applied Biology and Chemical Technology, The Hong Kong Polytechnic University, Hung Hom, Hong Kong SAR, China
- The Laboratory for Probiotic and Prebiotic Research in Human Health, The Hong Kong Polytechnic University, Hung Hom, Hong Kong SAR, China
- State Key Laboratory of Chinese Medicine and Molecular Pharmacology (Incubation), Shenzhen Research Institute, The Hong Kong Polytechnic University, Shenzhen, China
- Research Institute for Future Food, The Hong Kong Polytechnic University, Hung Hom, Hong Kong SAR, China
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Serigado JM, Foulke-Abel J, Hines WC, Hanson JA, In J, Kovbasnjuk O. Ulcerative Colitis: Novel Epithelial Insights Provided by Single Cell RNA Sequencing. Front Med (Lausanne) 2022; 9:868508. [PMID: 35530046 PMCID: PMC9068527 DOI: 10.3389/fmed.2022.868508] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/02/2022] [Accepted: 03/14/2022] [Indexed: 12/22/2022] Open
Abstract
Ulcerative Colitis (UC) is a chronic inflammatory disease of the intestinal tract for which a definitive etiology is yet unknown. Both genetic and environmental factors have been implicated in the development of UC. Recently, single cell RNA sequencing (scRNA-seq) technology revealed cell subpopulations contributing to the pathogenesis of UC and brought new insight into the pathways that connect genome to pathology. This review describes key scRNA-seq findings in two major studies by Broad Institute and University of Oxford, investigating the transcriptomic landscape of epithelial cells in UC. We focus on five major findings: (1) the identification of BEST4 + cells, (2) colonic microfold (M) cells, (3) detailed comparison of the transcriptomes of goblet cells, and (4) colonocytes and (5) stem cells in health and disease. In analyzing the two studies, we identify the commonalities and differences in methodologies, results, and conclusions, offering possible explanations, and validated several cell cluster markers. In systematizing the results, we hope to offer a framework that the broad scientific GI community and GI clinicians can use to replicate or corroborate the extensive new findings that RNA-seq offers.
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Affiliation(s)
- Joao M. Serigado
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, University of New Mexico Health Sciences Center, Albuquerque, NM, United States
| | - Jennifer Foulke-Abel
- Division of Gastroenterology and Hepatology, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, United States
| | - William C. Hines
- Department of Biochemistry and Molecular Biology, University of New Mexico Health Sciences Center, Albuquerque, NM, United States
| | - Joshua A Hanson
- Department of Pathology, University of New Mexico Health Sciences Center, Albuquerque, NM, United States
| | - Julie In
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, University of New Mexico Health Sciences Center, Albuquerque, NM, United States
- Division of Gastroenterology and Hepatology, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, United States
| | - Olga Kovbasnjuk
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, University of New Mexico Health Sciences Center, Albuquerque, NM, United States
- Department of Microbiology and Immunology, University of Maryland School of Medicine, Baltimore, MD, United States
- *Correspondence: Olga Kovbasnjuk,
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Pergolizzi S, Alesci A, Centofanti A, Aragona M, Pallio S, Magaudda L, Cutroneo G, Lauriano ER. Role of Serotonin in the Maintenance of Inflammatory State in Crohn’s Disease. Biomedicines 2022; 10:biomedicines10040765. [PMID: 35453516 PMCID: PMC9030789 DOI: 10.3390/biomedicines10040765] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/25/2022] [Revised: 03/22/2022] [Accepted: 03/23/2022] [Indexed: 02/05/2023] Open
Abstract
Crohn’s disease (CD) is a chronic intestinal inflammation considered to be a major entity of inflammatory bowel diseases (IBDs), affecting different segments of the whole gastrointestinal tract. Peripheral serotonin (5-HT), a bioactive amine predominantly produced by gut enterochromaffin cells (ECs), is crucial in gastrointestinal functions, including motility, sensitivity, secretion, and the inflammatory response. These actions are mediated by a large family of serotonin receptors and specialized serotonin transporter (SERT) located on a variety of cell types in the gut. Several studies indicate that intestinal 5-HT signaling is altered in patients with inflammatory bowel disease. Paraformaldehyde-fixed intestinal tissues, obtained from fifteen patients with Crohn’s disease were analyzed by immunostaining for serotonin, Langerin/CD207, and alpha-Smooth Muscle Actin (α-SMA). As controls, unaffected (normal) intestinal specimens of seven individuals were investigated. This study aimed to show the expression of serotonin in dendritic cells (DCs) and myofibroblast which have been characterized with Langerin/CD207 and α-SMA, respectively; furthermore, for the first time, we have found the presence of serotonin in goblet cells. Our results show the correlation between different types of intestinal cells in the maintenance of the inflammatory state in CD linked to the recall of myofibroblasts.
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Affiliation(s)
- Simona Pergolizzi
- Department of Chemical, Biological, Pharmaceutical and Environmental Sciences, University of Messina, 98166 Messina, Italy;
- Correspondence: (S.P.); (A.A.); (A.C.)
| | - Alessio Alesci
- Department of Chemical, Biological, Pharmaceutical and Environmental Sciences, University of Messina, 98166 Messina, Italy;
- Correspondence: (S.P.); (A.A.); (A.C.)
| | - Antonio Centofanti
- Department of Biomedical and Dental Sciences and Morphofunctional Images, University of Messina, 98125 Messina, Italy; (L.M.); (G.C.)
- Correspondence: (S.P.); (A.A.); (A.C.)
| | - Marialuisa Aragona
- Department of Veterinary Sciences, University of Messina, Polo Universitario dell’Annunziata, 98168 Messina, Italy;
| | - Socrate Pallio
- Department of Clinical and Experimental Medicine, University of Messina, 98147 Messina, Italy;
| | - Ludovico Magaudda
- Department of Biomedical and Dental Sciences and Morphofunctional Images, University of Messina, 98125 Messina, Italy; (L.M.); (G.C.)
| | - Giuseppina Cutroneo
- Department of Biomedical and Dental Sciences and Morphofunctional Images, University of Messina, 98125 Messina, Italy; (L.M.); (G.C.)
| | - Eugenia Rita Lauriano
- Department of Chemical, Biological, Pharmaceutical and Environmental Sciences, University of Messina, 98166 Messina, Italy;
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Kopper JJ, Iennarella-Servantez C, Jergens AE, Sahoo DK, Guillot E, Bourgois-Mochel A, Martinez MN, Allenspach K, Mochel JP. Harnessing the Biology of Canine Intestinal Organoids to Heighten Understanding of Inflammatory Bowel Disease Pathogenesis and Accelerate Drug Discovery: A One Health Approach. FRONTIERS IN TOXICOLOGY 2022; 3:773953. [PMID: 35295115 PMCID: PMC8915821 DOI: 10.3389/ftox.2021.773953] [Citation(s) in RCA: 23] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/10/2021] [Accepted: 10/07/2021] [Indexed: 12/13/2022] Open
Abstract
In a recent issue of the Lancet, the prevalence of Inflammatory Bowel Disease (IBD) was estimated at 7 million worldwide. Overall, the burden of IBD is rising globally, with direct and indirect healthcare costs ranging between $14.6 and $31.6 billion in the U.S. alone in 2014. There is currently no cure for IBD, and up to 40% of patients do not respond to medical therapy. Although the exact determinants of the disease pathophysiology remain unknown, the prevailing hypothesis involves complex interplay among host genetics, the intestinal microenvironment (primarily bacteria and dietary constituents), and the mucosal immune system. Importantly, multiple chronic diseases leading to high morbidity and mortality in modern western societies, including type II diabetes, IBD and colorectal cancer, have epidemiologically been linked to the consumption of high-calorie, low-fiber, high monosaccharide, and high-fat diets (HFD). More specifically, data from our laboratory and others have shown that repeated consumption of HFD triggers dysbiotic changes of the gut microbiome concomitant with a state of chronic intestinal inflammation and increased intestinal permeability. However, progress in our understanding of the effect of dietary interventions on IBD pathogenesis has been hampered by a lack of relevant animal models. Additionally, current in vitro cell culture systems are unable to emulate the in vivo interplay between the gut microbiome and the intestinal epithelium in a realistic and translatable way. There remains, therefore, a critical need to develop translatable in vitro and in vivo models that faithfully recapitulate human gut-specific physiological functions to facilitate detailed mechanistic studies on the impact of dietary interventions on gut homeostasis. While the study of murine models has been pivotal in advancing genetic and cellular discoveries, these animal systems often lack key clinical signs and temporal pathological changes representative of IBD. Specifically, some limitations of the mouse model are associated with the use of genetic knockouts to induce immune deficiency and disease. This is vastly different from the natural course of IBD developing in immunologically competent hosts, as is the case in humans and dogs. Noteworthily, abundant literature suggests that canine and human IBD share common clinical and molecular features, such that preclinical studies in dogs with naturally occurring IBD present an opportunity to further our understanding on disease pathogenesis and streamline the development of new therapeutic strategies. Using a stepwise approach, in vitro mechanistic studies investigating the contribution of dietary interventions to chronic intestinal inflammation and "gut leakiness" could be performed in intestinal organoids and organoid derived monolayers. The biologic potential of organoids stems from the method's ability to harness hard-wired cellular programming such that the complexity of the disease background can be reflected more accurately. Likewise, the effect of therapeutic drug candidates could be evaluated in organoids prior to longitudinal studies in dog and human patients with IBD. In this review, we will discuss the value (and limitations) of intestinal organoids derived from a spontaneous animal disease model of IBD (i.e., the dog), and how it can heighten understanding of the interplay between dietary interventions, the gut microbiota and intestinal inflammation. We will also review how intestinal organoids could be used to streamline the preclinical development of therapeutic drug candidates for IBD patients and their best four-legged friends.
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Affiliation(s)
- Jamie J Kopper
- Veterinary Clinical Sciences, Iowa State University College of Veterinary Medicine, Ames, IA, United States.,SMART Translational Medicine, Biomedical Sciences, Iowa State University College of Veterinary Medicine, Ames, IA, United States
| | - Chelsea Iennarella-Servantez
- SMART Pharmacology, Biomedical Sciences, Iowa State University College of Veterinary Medicine, Ames, IA, United States.,SMART Translational Medicine, Biomedical Sciences, Iowa State University College of Veterinary Medicine, Ames, IA, United States
| | - Albert E Jergens
- Veterinary Clinical Sciences, Iowa State University College of Veterinary Medicine, Ames, IA, United States
| | - Dipak K Sahoo
- Veterinary Clinical Sciences, Iowa State University College of Veterinary Medicine, Ames, IA, United States.,SMART Translational Medicine, Biomedical Sciences, Iowa State University College of Veterinary Medicine, Ames, IA, United States
| | - Emilie Guillot
- 3D Health Solutions, Inc., ISU Research Park, Ames, IA, United States
| | - Agnes Bourgois-Mochel
- Veterinary Clinical Sciences, Iowa State University College of Veterinary Medicine, Ames, IA, United States
| | - Marilyn N Martinez
- Office of New Animal Drug Evaluation, Center for Veterinary Medicine, Food and Drug Administration, Rockville, MD, United States
| | - Karin Allenspach
- Veterinary Clinical Sciences, Iowa State University College of Veterinary Medicine, Ames, IA, United States.,SMART Translational Medicine, Biomedical Sciences, Iowa State University College of Veterinary Medicine, Ames, IA, United States.,3D Health Solutions, Inc., ISU Research Park, Ames, IA, United States
| | - Jonathan P Mochel
- SMART Pharmacology, Biomedical Sciences, Iowa State University College of Veterinary Medicine, Ames, IA, United States.,SMART Translational Medicine, Biomedical Sciences, Iowa State University College of Veterinary Medicine, Ames, IA, United States.,3D Health Solutions, Inc., ISU Research Park, Ames, IA, United States
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Lu Q, Yang MF, Liang YJ, Xu J, Xu HM, Nie YQ, Wang LS, Yao J, Li DF. Immunology of Inflammatory Bowel Disease: Molecular Mechanisms and Therapeutics. J Inflamm Res 2022; 15:1825-1844. [PMID: 35310454 PMCID: PMC8928114 DOI: 10.2147/jir.s353038] [Citation(s) in RCA: 94] [Impact Index Per Article: 31.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2021] [Accepted: 02/26/2022] [Indexed: 12/12/2022] Open
Abstract
As a main digestive organ and an important immune organ, the intestine plays a vital role in resisting the invasion of potential pathogens into the body. Intestinal immune dysfunction remains important pathogenesis of inflammatory bowel disease (IBD). In this review, we explained the interactions among symbiotic flora, intestinal epithelial cells, and the immune system, clarified the operating mechanism of the intestinal immune system, and highlighted the immunological pathogenesis of IBD, with a focus on the development of immunotherapy for IBD. In addition, intestinal fibrosis is a significant complication in patients with long-term IBD, and we reviewed the immunological pathogenesis involved in the development of intestinal fibrogenesis and provided novel antifibrotic immunotherapies for IBD.
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Affiliation(s)
- Quan Lu
- Department of Gastroenterology, Shenzhen People’s Hospital (The Second Clinical Medical College, Jinan University), Shenzhen, Guangdong, People’s Republic of China
- Department of Gastroenterology, Shenzhen People’s Hospital (The First Affiliated Hospital, Southern University of Science and Technology), Shenzhen, Guangdong, People’s Republic of China
| | - Mei-feng Yang
- Department of Hematology, Yantian District People’s Hospital, Shenzhen, Guangdong, People’s Republic of China
| | - Yu-jie Liang
- Department of Child and Adolescent Psychiatry, Shenzhen Kangning Hospital, Shenzhen, Guangdong, People’s Republic of China
| | - Jing Xu
- Department of Gastroenterology and Hepatology, Guangzhou First People’s Hospital (School of Medicine of South China University of Technology), Guangzhou, Guangdong, People’s Republic of China
| | - Hao-ming Xu
- Department of Gastroenterology and Hepatology, Guangzhou First People’s Hospital (School of Medicine of South China University of Technology), Guangzhou, Guangdong, People’s Republic of China
| | - Yu-qiang Nie
- Department of Gastroenterology and Hepatology, Guangzhou First People’s Hospital (School of Medicine of South China University of Technology), Guangzhou, Guangdong, People’s Republic of China
| | - Li-sheng Wang
- Department of Gastroenterology, Shenzhen People’s Hospital (The Second Clinical Medical College, Jinan University), Shenzhen, Guangdong, People’s Republic of China
- Department of Gastroenterology, Shenzhen People’s Hospital (The First Affiliated Hospital, Southern University of Science and Technology), Shenzhen, Guangdong, People’s Republic of China
| | - Jun Yao
- Department of Gastroenterology, Shenzhen People’s Hospital (The Second Clinical Medical College, Jinan University), Shenzhen, Guangdong, People’s Republic of China
- Department of Gastroenterology, Shenzhen People’s Hospital (The First Affiliated Hospital, Southern University of Science and Technology), Shenzhen, Guangdong, People’s Republic of China
| | - De-feng Li
- Department of Gastroenterology, Shenzhen People’s Hospital (The Second Clinical Medical College, Jinan University), Shenzhen, Guangdong, People’s Republic of China
- Department of Gastroenterology, Shenzhen People’s Hospital (The First Affiliated Hospital, Southern University of Science and Technology), Shenzhen, Guangdong, People’s Republic of China
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40
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Baccharis dracunculifolia DC Hydroalcoholic Extract Improves Intestinal and Hippocampal Inflammation and Decreases Behavioral Changes of Colitis Mice. EVIDENCE-BASED COMPLEMENTARY AND ALTERNATIVE MEDICINE 2022; 2022:5833840. [PMID: 35295931 PMCID: PMC8920628 DOI: 10.1155/2022/5833840] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 12/28/2021] [Accepted: 02/07/2022] [Indexed: 11/26/2022]
Abstract
The hydroalcoholic extract of B. dracunculifolia (HEBD) and its major compound p-coumaric acid were evaluated against the severity of intestinal inflammation and behavioral changes like depressive and anxious behavior in colitis mice. Colitis was induced in Swiss mice by oral dextran sulfate sodium (DSS) administration for five days. The mice received vehicle (10 ml/kg), HEBD (3, 30, or 300 mg/kg), or p-coumaric acid (15 mg/kg) orally, once a day for twelve days. Behavioral tests were performed on the 11th and 12th days after the beginning of the treatments. Moreover, the colon, cortex, and hippocampus were collected to analyze oxidative and inflammatory parameters. The treatment with HEBD (300 mg/Kg), but not p-coumaric acid, showed decreased disease activity index (DAI) values compared to the vehicle group and partially preserved the villi architecture and mucin levels. Furthermore, the HEBD increased the antioxidant defenses in the colon and hippocampus and reduced the myeloperoxidase activity and IL-6 levels in the colon from colitis mice. Colitis mice treated with HEBD did not show depressive-like behavior in the tail suspension test. HEBD reduced colon inflammation, while it maintains antioxidant defenses and mucin levels in this tissue. It may reduce neuropsychiatric comorbidities associated with colitis through its antioxidant effects.
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41
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Markandey M, Bajaj A, Ilott NE, Kedia S, Travis S, Powrie F, Ahuja V. Gut microbiota: sculptors of the intestinal stem cell niche in health and inflammatory bowel disease. Gut Microbes 2022; 13:1990827. [PMID: 34747326 PMCID: PMC8583176 DOI: 10.1080/19490976.2021.1990827] [Citation(s) in RCA: 41] [Impact Index Per Article: 13.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/04/2023] Open
Abstract
Intestinal epithelium represents a dynamic and diverse cellular system that continuously interacts with gut commensals and external cues. Intestinal stem cells, which lie at the heart of epithelial renewal and turnover, proliferate to maintain a steady stem cell population and differentiate to form functional epithelial cell types. This rather sophisticated assembly-line is maintained by an elaborate micro-environment, sculpted by a myriad of host and gut microbiota-derived signals, forming an intestinal stem cell niche. This complex, yet crucial signaling niche undergoes dynamic changes during homeostasis and chronic intestinal inflammation. Inflammatory bowel disease refers to a chronic inflammatory response toward pathogenic or commensal microbiota, in a genetically susceptible host. Compositional and functional alterations in gut microbiota are pathognomonic of IBD.The present review highlights the modulatory role of gut microbiota on the intestinal stem cell niche during homeostasis and inflammatory bowel disease. We discuss the mechanisms of direct action of gut commensals (through microbiota-derived or microbiota-influenced metabolites) on ISCs, followed by their effects via other epithelial and immune cell types.
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Affiliation(s)
- Manasvini Markandey
- Department of Gastroenterology and Human Nutrition, All India Institute of Medical Sciences, New Delhi, India
| | - Aditya Bajaj
- Department of Gastroenterology and Human Nutrition, All India Institute of Medical Sciences, New Delhi, India
| | | | - Saurabh Kedia
- Department of Gastroenterology and Human Nutrition, All India Institute of Medical Sciences, New Delhi, India
| | - Simon Travis
- Translational Gastroenterology Unit, NIHR Oxford Biomedical Research Centre, Oxford University Hospitals NHS Foundation Trust, Oxford, UK
| | - Fiona Powrie
- Kennedy Institute of Rheumatology, University of Oxford, Oxford, UK
| | - Vineet Ahuja
- Department of Gastroenterology and Human Nutrition, All India Institute of Medical Sciences, New Delhi, India,CONTACT Vineet Ahuja Department of Gastroenterology and Human Nutrition, All India Institute of Medical Sciences, New Delhi, India, 110029
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Sun Z, Gu P, Xu H, Zhao W, Zhou Y, Zhou L, Zhang Z, Wang W, Han R, Chai X, An S. Human Umbilical Cord Mesenchymal Stem Cells Improve Locomotor Function in Parkinson's Disease Mouse Model Through Regulating Intestinal Microorganisms. Front Cell Dev Biol 2022; 9:808905. [PMID: 35127723 PMCID: PMC8810651 DOI: 10.3389/fcell.2021.808905] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/04/2021] [Accepted: 12/10/2021] [Indexed: 12/18/2022] Open
Abstract
Parkinson's disease (PD) is a progressive neurological disorder characterized by loss of neurons that synthesize dopamine, and subsequent impaired movement. Umbilical cord mesenchymal stem cells (UC-MSCs) exerted neuroprotection effects in a rodent model of PD. However, the mechanism underlying UC-MSC-generated neuroprotection was not fully elucidated. In the present study, we found that intranasal administration of UC-MSCs significantly alleviated locomotor deficits and rescued dopaminergic neurons by inhibiting neuroinflammation in a PD mouse model induced by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP, a toxic agent which selectively destroys nigrostriatal neurons but does not affect dopaminergic neurons elsewhere). Furthermore, UC-MSC treatment altered gut microbiota composition characterized by decreased phylum Proteobacteria, class Gammaproteobacteria, family Enterobacteriaceae, and genus Escherichia-Shigella. In addition, the neurotransmitter dopamine in the striatum and 5-hydroxytryptamine in the colon were also modulated by UC-MSCs. Meanwhile, UC-MSCs significantly maintained intestinal goblet cells, which secrete mucus as a mechanical barrier against pathogens. Furthermore, UC-MSCs alleviate the level of TNF-α and IL-6 as well as the conversion of NF-κB expression in the colon, indicating that inflammatory responses were blocked by UC-MSCs. PICRUSt showed that some pathways including bacterial invasion of epithelial cells, fluorobenzoate degradation, and pathogenic Escherichia coli infection were significantly reversed by UC-MSCs. These data suggest that the beneficial effects were detected following UC-MSC intranasal transplantation in MPTP-treated mice. There is a possible neuroprotective role of UC-MSCs in MPTP-induced PD mice by cross talk between the brain and gut.
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Affiliation(s)
- Zhengqin Sun
- Department of Neurology, The First Hospital of Hebei Medical University, Shijiazhuang, China
- Hebei Provincial Engineering Laboratory of Plant Bioreactor Preparation Technology, Shijiazhuang, China
| | - Ping Gu
- Department of Neurology, The First Hospital of Hebei Medical University, Shijiazhuang, China
| | - Hongjun Xu
- Hebei Provincial Engineering Laboratory of Plant Bioreactor Preparation Technology, Shijiazhuang, China
- Research Center, Hebei University of Chinese Medicine, Shijiazhuang, China
- College of Integrated Chinese and Western Medicine, Hebei University of Chinese Medicine, Shijiazhuang, China
| | - Wei Zhao
- Hebei Provincial Engineering Laboratory of Plant Bioreactor Preparation Technology, Shijiazhuang, China
- Research Center, Hebei University of Chinese Medicine, Shijiazhuang, China
- College of Integrated Chinese and Western Medicine, Hebei University of Chinese Medicine, Shijiazhuang, China
- Affiliated Hospital of Hebei University of Engineering, Handan, China
| | - Yongjie Zhou
- Hebei Provincial Engineering Laboratory of Plant Bioreactor Preparation Technology, Shijiazhuang, China
- Research Center, Hebei University of Chinese Medicine, Shijiazhuang, China
- College of Integrated Chinese and Western Medicine, Hebei University of Chinese Medicine, Shijiazhuang, China
| | - Luyang Zhou
- Hebei Provincial Engineering Laboratory of Plant Bioreactor Preparation Technology, Shijiazhuang, China
- Research Center, Hebei University of Chinese Medicine, Shijiazhuang, China
- College of Integrated Chinese and Western Medicine, Hebei University of Chinese Medicine, Shijiazhuang, China
| | - Zhongxia Zhang
- Department of Neurology, The First Hospital of Hebei Medical University, Shijiazhuang, China
- Hebei Provincial Engineering Laboratory of Plant Bioreactor Preparation Technology, Shijiazhuang, China
| | - Wenting Wang
- Department of Neurology, The First Hospital of Hebei Medical University, Shijiazhuang, China
| | - Rui Han
- Department of Neurology, The First Hospital of Hebei Medical University, Shijiazhuang, China
| | - Xiqing Chai
- Department of Neurology, The First Hospital of Hebei Medical University, Shijiazhuang, China
| | - Shengjun An
- Hebei Provincial Engineering Laboratory of Plant Bioreactor Preparation Technology, Shijiazhuang, China
- Research Center, Hebei University of Chinese Medicine, Shijiazhuang, China
- College of Integrated Chinese and Western Medicine, Hebei University of Chinese Medicine, Shijiazhuang, China
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Craig CF, Filippone RT, Stavely R, Bornstein JC, Apostolopoulos V, Nurgali K. Neuroinflammation as an etiological trigger for depression comorbid with inflammatory bowel disease. J Neuroinflammation 2022; 19:4. [PMID: 34983592 PMCID: PMC8729103 DOI: 10.1186/s12974-021-02354-1] [Citation(s) in RCA: 51] [Impact Index Per Article: 17.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/05/2021] [Accepted: 12/14/2021] [Indexed: 02/06/2023] Open
Abstract
Patients with inflammatory bowel disease (IBD) suffer from depression at higher rates than the general population. An etiological trigger of depressive symptoms is theorised to be inflammation within the central nervous system. It is believed that heightened intestinal inflammation and dysfunction of the enteric nervous system (ENS) contribute to impaired intestinal permeability, which facilitates the translocation of intestinal enterotoxins into the blood circulation. Consequently, these may compromise the immunological and physiological functioning of distant non-intestinal tissues such as the brain. In vivo models of colitis provide evidence of increased blood–brain barrier permeability and enhanced central nervous system (CNS) immune activity triggered by intestinal enterotoxins and blood-borne inflammatory mediators. Understanding the immunological, physiological, and structural changes associated with IBD and neuroinflammation may aid in the development of more tailored and suitable pharmaceutical treatment for IBD-associated depression.
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Affiliation(s)
- Colin F Craig
- Institute for Heath and Sport, Victoria University, Western Centre for Health, Research and Education, Sunshine Hospital, Melbourne, VIC, Australia
| | - Rhiannon T Filippone
- Institute for Heath and Sport, Victoria University, Western Centre for Health, Research and Education, Sunshine Hospital, Melbourne, VIC, Australia
| | - Rhian Stavely
- Institute for Heath and Sport, Victoria University, Western Centre for Health, Research and Education, Sunshine Hospital, Melbourne, VIC, Australia.,Department of Pediatric Surgery, Pediatric Surgery Research Laboratories, Massachusetts General Hospital, Harvard Medical School, Boston, MA, 02114, USA
| | - Joel C Bornstein
- Department of Anatomy and Physiology, The University of Melbourne, Melbourne, Australia
| | - Vasso Apostolopoulos
- Institute for Heath and Sport, Victoria University, Western Centre for Health, Research and Education, Sunshine Hospital, Melbourne, VIC, Australia.,Immunology Program, Australian Institute of Musculoskeletal Science (AIMSS), Melbourne, VIC, Australia
| | - Kulmira Nurgali
- Institute for Heath and Sport, Victoria University, Western Centre for Health, Research and Education, Sunshine Hospital, Melbourne, VIC, Australia. .,Department of Medicine Western Health, Faculty of Medicine, Dentistry and Health Sciences, The University of Melbourne, Melbourne, VIC, Australia. .,Regenerative Medicine and Stem Cells Program, Australian Institute of Musculoskeletal Science (AIMSS), Melbourne, VIC, Australia. .,Institute for Health and Sport, Victoria University, Level 4 Research Labs, Western Centre for Health Research and Education, Sunshine Hospital, 176 Furlong Road, St Albans, VIC, 3021, Australia.
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Rehman NU, Ansari MN, Palla AH, Karim A, Imam F, Raish M, Hamad AM, Noman M. Myrica salicifolia Hochst. ex A. Rich. suppress acetic acid-induced ulcerative colitis in rats by reducing TNF-alpha and interleukin-6, oxidative stress parameters and improving mucosal protection. Hum Exp Toxicol 2022; 41:9603271221102518. [PMID: 35561078 DOI: 10.1177/09603271221102518] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/17/2022]
Abstract
Ulcerative colitis (UC) is an inflammatory bowel disease (IBD) with rising prevalence in developing countries, and limited success of current therapies, natural products have immense potential for therapy due to their "disease modifying and side-effect neutralizing" potential. Myrica salicifolia is traditionally used for gastrointestinal diseases and have reported antiinflammatory activities, but its use in IBD has not yet been studied. Therefore, in the present study, the effects of the root extract of M. salicifolia (Ms.Cr) were investigated using the acetic acid-induced UC model in rats. For 6 days, the rats were given either vehicle (10 mL/kg), lower (200 mg/kg), and higher (400 mg/kg) doses of Ms.Cr, or the positive control drug (prednisolone; 2 mg/kg) orally. A single dosage of 5% acetic acid (1.0 mL) was administered intrarectally to rats on day 6 to induce UC. Disease activity index (DAI), histological observations, the biochemical parameters related to oxidative stress, and specific cytokines such as interleukin-6 (IL-6) and the tumor necrosis factor-α (TNF-α) were determined to assess the effect of Ms.Cr. In comparison to the AA-induced colitis rats, Ms.Cr's pretreatment significantly decreased DAI, colonic ulceration, and inflammatory score. Total glutathione levels and catalase activity were considerably recovered in the colitis group treated with Ms.Cr, whereas enhanced lipid peroxidation in colon tissues was significantly decreased. Moreover, Ms.Cr pretreatment also caused inhibition of the activation of IL-6 and TNF-α in the colonic tissues of respective groups. Based on these findings, Ms.Cr might be developed to treat UC in the future.
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Affiliation(s)
- N U Rehman
- Department of Pharmacology and Toxicology, College of Pharmacy, 248406Prince Sattam Bin Abdulaziz University, Al-Kharj, Kingdom of Saudi Arabia
| | - M N Ansari
- Department of Pharmacology and Toxicology, College of Pharmacy, 248406Prince Sattam Bin Abdulaziz University, Al-Kharj, Kingdom of Saudi Arabia
| | - A H Palla
- Department of Biological and Biomedical Sciences (Pharmacology), Medical College, 9615Aga Khan University, Karachi, Pakistan
| | - A Karim
- Department of Biological Sciences, 445232National University of Medical Sciences, Rawalpindi, Pakistan.,Department of Pharmacognosy, School of Pharmacy, College of Health Sciences, Mekelle University, Mekelle, Ethiopia
| | - F Imam
- Department of Pharmacology and Toxicology, College of Pharmacy, 37850King Saud University, Riyadh, Kingdom of Saudi Arabia
| | - M Raish
- Department of Pharmaceutics, College of Pharmacy, 37850King Saud University, Riyadh, Saudi Arabia
| | - A M Hamad
- Department of Basic Sciences, Preparatory Year Deanship, 204568Prince Sattam Bin Abdulaziz University, Al-Kharj, Kingdom of Saudi Arabia.,Department of Histopathology and Cytopathology, Faculty of Medical Laboratory Sciences, University of Gezira, Wad Madani, Sudan
| | - M Noman
- Riphah Institute of Pharmaceutical Sciences, 66783Riphah International University, Islamabad, Pakistan
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45
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Guo W, Zeng M, Zhu S, Li S, Qian Y, Wu H. Phycocyanin Ameliorates Mouse Colitis via Phycocyanobilin-Dependent Antioxidant and Anti-Inflammatory Protection of Intestinal Epithelial Barrier. Food Funct 2022; 13:3294-3307. [DOI: 10.1039/d1fo02970c] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022]
Abstract
Phycocyanin is a typical microalgal active compound with antioxidant and anti-inflammatory efficacy, and the pigment moiety phycocyanobilin has been recently proposed as its active structural component. Here, to explore the...
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46
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Popov J, Caputi V, Nandeesha N, Rodriguez DA, Pai N. Microbiota-Immune Interactions in Ulcerative Colitis and Colitis Associated Cancer and Emerging Microbiota-Based Therapies. Int J Mol Sci 2021; 22:11365. [PMID: 34768795 PMCID: PMC8584103 DOI: 10.3390/ijms222111365] [Citation(s) in RCA: 50] [Impact Index Per Article: 12.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/07/2021] [Revised: 10/02/2021] [Accepted: 10/05/2021] [Indexed: 02/07/2023] Open
Abstract
Ulcerative colitis (UC) is a chronic autoimmune disorder affecting the colonic mucosa. UC is a subtype of inflammatory bowel disease along with Crohn's disease and presents with varying extraintestinal manifestations. No single etiology for UC has been found, but a combination of genetic and environmental factors is suspected. Research has focused on the role of intestinal dysbiosis in the pathogenesis of UC, including the effects of dysbiosis on the integrity of the colonic mucosal barrier, priming and regulation of the host immune system, chronic inflammation, and progression to tumorigenesis. Characterization of key microbial taxa and their implications in the pathogenesis of UC and colitis-associated cancer (CAC) may present opportunities for modulating intestinal inflammation through microbial-targeted therapies. In this review, we discuss the microbiota-immune crosstalk in UC and CAC, as well as the evolution of microbiota-based therapies.
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Affiliation(s)
- Jelena Popov
- Division of Pediatric Gastroenterology and Nutrition, Department of Pediatrics, McMaster University, Hamilton, ON L8S 4L8, Canada;
- College of Medicine and Health, University College Cork, T12 XF62 Cork, Ireland
| | - Valentina Caputi
- Department of Poultry Science, University of Arkansas, Fayetteville, AR 72701, USA;
| | - Nandini Nandeesha
- School of Medicine, Royal College of Surgeons in Ireland, D02 YN77 Dublin, Ireland;
| | | | - Nikhil Pai
- Division of Pediatric Gastroenterology and Nutrition, Department of Pediatrics, McMaster University, Hamilton, ON L8S 4L8, Canada;
- Farncombe Family Digestive Health Research Institute, McMaster University, Hamilton, ON L8S 4L8, Canada
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47
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Achasova KM, Kozhevnikova EN, Borisova MA, Litvinova EA. Fucose Ameliorates Tritrichomonas sp.-Associated Illness in Antibiotic-Treated Muc2-/- Mice. Int J Mol Sci 2021; 22:ijms221910699. [PMID: 34639039 PMCID: PMC8509520 DOI: 10.3390/ijms221910699] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/15/2021] [Accepted: 09/30/2021] [Indexed: 02/06/2023] Open
Abstract
The mucus layer in the intestine plays a critical role in regulation of host–microbe interactions and maintaining homeostasis. Disruptions of the mucus layer due to genetic, environmental, or immune factors may lead to inflammatory bowel diseases (IBD). IBD frequently are accompanied with infections, and therefore are treated with antibiotics. Hence, it is important to evaluate risks of antibiotic treatment in individuals with vulnerable gut barrier and chronic inflammation. Mice with a knockout of the Muc2 gene, encoding the main glycoprotein component of the mucus, demonstrate a close contact of the microbes with the gut epithelium which leads to chronic inflammation resembling IBD. Here we demonstrate that the Muc2−/− mice harboring a gut protozoan infection Tritrichomonas sp. are susceptible to an antibiotic-induced depletion of the bacterial microbiota. Suppression of the protozoan infection with efficient metronidazole dosage or L-fucose administration resulted in amelioration of an illness observed in antibiotic-treated Muc2−/− mice. Fucose is a monosaccharide presented abundantly in gut glycoproteins, including Mucin2, and is known to be involved in host–microbe interactions, in particular in microbe adhesion. We suppose that further investigation of the role of fucose in protozoan adhesion to host cells may be of great value.
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Affiliation(s)
- Kseniya M. Achasova
- Siberian Federal Scientific Centre of Agro-BioTechnologies of the Russian Academy of Sciences, 630501 Krasnoobsk, Russia; (K.M.A.); (E.N.K.)
- Scientific Research Institute of Neurosciences and Medicine, 630117 Novosibirsk, Russia
- Institute of Molecular and Cellular Biology, The Siberian Branch of the Russian Academy of Sciences, 630090 Novosibirsk, Russia
| | - Elena N. Kozhevnikova
- Siberian Federal Scientific Centre of Agro-BioTechnologies of the Russian Academy of Sciences, 630501 Krasnoobsk, Russia; (K.M.A.); (E.N.K.)
- Scientific Research Institute of Neurosciences and Medicine, 630117 Novosibirsk, Russia
- Institute of Molecular and Cellular Biology, The Siberian Branch of the Russian Academy of Sciences, 630090 Novosibirsk, Russia
- The Laboratory of Biotechnology, Novosibirsk State Agrarian University, 630039 Novosibirsk, Russia
| | - Mariya A. Borisova
- Federal Research Center Institute of Cytology and Genetics of the Siberian Branch of the Russian Academy of Sciences, 630090 Novosibirsk, Russia;
| | - Ekaterina A. Litvinova
- Siberian Federal Scientific Centre of Agro-BioTechnologies of the Russian Academy of Sciences, 630501 Krasnoobsk, Russia; (K.M.A.); (E.N.K.)
- Scientific Research Institute of Neurosciences and Medicine, 630117 Novosibirsk, Russia
- Correspondence: ; Tel.: +7-923-147-94-64
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48
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Lucarini E, Nocentini A, Bonardi A, Chiaramonte N, Parisio C, Micheli L, Toti A, Ferrara V, Carrino D, Pacini A, Romanelli MN, Supuran CT, Ghelardini C, Di Cesare Mannelli L. Carbonic Anhydrase IV Selective Inhibitors Counteract the Development of Colitis-Associated Visceral Pain in Rats. Cells 2021; 10:2540. [PMID: 34685520 PMCID: PMC8533707 DOI: 10.3390/cells10102540] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/22/2021] [Revised: 09/19/2021] [Accepted: 09/20/2021] [Indexed: 01/16/2023] Open
Abstract
Persistent pain affecting patients with inflammatory bowel diseases (IBDs) is still very difficult to treat. Carbonic anhydrase (CA) represents an intriguing pharmacological target considering the anti-hyperalgesic efficacy displayed by CA inhibitors in both inflammatory and neuropathic pain models. The aim of this work was to evaluate the effect of inhibiting CA IV, particularly when expressed in the gut, on visceral pain associated with colitis induced by 2,4-di-nitrobenzene sulfonic acid (DNBS) in rats. Visceral sensitivity was assessed by measuring animals' abdominal responses to colorectal distension. Repeated treatment with the selective CA IV inhibitors AB-118 and NIK-67 effectively counteracted the development of visceral pain induced by DNBS. In addition to pain relief, AB-118 showed a protective effect against colon damage. By contrast, the anti-hyperalgesic activity of NIK-67 was independent of colon healing, suggesting a direct protective effect of NIK-67 on visceral sensitivity. The enzymatic activity and the expression of CA IV resulted significantly increased after DNBS injection. NIK-67 normalised CA IV activity in DNBS animals, while AB-118 was partially effective. None of these compounds influenced CA IV expression through the colon. Although further investigations are needed to study the underlying mechanisms, CA IV inhibitors are promising candidates in the search for therapies to relieve visceral pain in IBDs.
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Affiliation(s)
- Elena Lucarini
- Department of Neuroscience, Psychology, Drug Research and Child Health (NEUROFARBA), Pharmacology and Toxicology Section, University of Florence, Viale Gaetano Pieraccini 6, 50139 Florence, Italy; (E.L.); (C.P.); (L.M.); (A.T.); (V.F.); (C.G.)
| | - Alessio Nocentini
- Department of Neuroscience, Psychology, Drug Research and Child Health (NEUROFARBA), Pharmaceutical and Nutraceutical Sciences Section, University of Florence, Via Ugo Schiff 6, 50019 Florence, Italy; (A.N.); (A.B.); (N.C.); (M.N.R.); (C.T.S.)
| | - Alessandro Bonardi
- Department of Neuroscience, Psychology, Drug Research and Child Health (NEUROFARBA), Pharmaceutical and Nutraceutical Sciences Section, University of Florence, Via Ugo Schiff 6, 50019 Florence, Italy; (A.N.); (A.B.); (N.C.); (M.N.R.); (C.T.S.)
| | - Niccolò Chiaramonte
- Department of Neuroscience, Psychology, Drug Research and Child Health (NEUROFARBA), Pharmaceutical and Nutraceutical Sciences Section, University of Florence, Via Ugo Schiff 6, 50019 Florence, Italy; (A.N.); (A.B.); (N.C.); (M.N.R.); (C.T.S.)
| | - Carmen Parisio
- Department of Neuroscience, Psychology, Drug Research and Child Health (NEUROFARBA), Pharmacology and Toxicology Section, University of Florence, Viale Gaetano Pieraccini 6, 50139 Florence, Italy; (E.L.); (C.P.); (L.M.); (A.T.); (V.F.); (C.G.)
| | - Laura Micheli
- Department of Neuroscience, Psychology, Drug Research and Child Health (NEUROFARBA), Pharmacology and Toxicology Section, University of Florence, Viale Gaetano Pieraccini 6, 50139 Florence, Italy; (E.L.); (C.P.); (L.M.); (A.T.); (V.F.); (C.G.)
| | - Alessandra Toti
- Department of Neuroscience, Psychology, Drug Research and Child Health (NEUROFARBA), Pharmacology and Toxicology Section, University of Florence, Viale Gaetano Pieraccini 6, 50139 Florence, Italy; (E.L.); (C.P.); (L.M.); (A.T.); (V.F.); (C.G.)
| | - Valentina Ferrara
- Department of Neuroscience, Psychology, Drug Research and Child Health (NEUROFARBA), Pharmacology and Toxicology Section, University of Florence, Viale Gaetano Pieraccini 6, 50139 Florence, Italy; (E.L.); (C.P.); (L.M.); (A.T.); (V.F.); (C.G.)
| | - Donatello Carrino
- Department of Experimental and Clinical Medicine, Anatomy and Histology Section, University of Florence, Largo Brambilla 3, 50134 Florence, Italy; (D.C.); (A.P.)
| | - Alessandra Pacini
- Department of Experimental and Clinical Medicine, Anatomy and Histology Section, University of Florence, Largo Brambilla 3, 50134 Florence, Italy; (D.C.); (A.P.)
| | - Maria Novella Romanelli
- Department of Neuroscience, Psychology, Drug Research and Child Health (NEUROFARBA), Pharmaceutical and Nutraceutical Sciences Section, University of Florence, Via Ugo Schiff 6, 50019 Florence, Italy; (A.N.); (A.B.); (N.C.); (M.N.R.); (C.T.S.)
| | - Claudiu T. Supuran
- Department of Neuroscience, Psychology, Drug Research and Child Health (NEUROFARBA), Pharmaceutical and Nutraceutical Sciences Section, University of Florence, Via Ugo Schiff 6, 50019 Florence, Italy; (A.N.); (A.B.); (N.C.); (M.N.R.); (C.T.S.)
| | - Carla Ghelardini
- Department of Neuroscience, Psychology, Drug Research and Child Health (NEUROFARBA), Pharmacology and Toxicology Section, University of Florence, Viale Gaetano Pieraccini 6, 50139 Florence, Italy; (E.L.); (C.P.); (L.M.); (A.T.); (V.F.); (C.G.)
| | - Lorenzo Di Cesare Mannelli
- Department of Neuroscience, Psychology, Drug Research and Child Health (NEUROFARBA), Pharmacology and Toxicology Section, University of Florence, Viale Gaetano Pieraccini 6, 50139 Florence, Italy; (E.L.); (C.P.); (L.M.); (A.T.); (V.F.); (C.G.)
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49
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Arukha AP, Freguia CF, Mishra M, Jha JK, Kariyawasam S, Fanger NA, Zimmermann EM, Fanger GR, Sahay B. Lactococcus lactis Delivery of Surface Layer Protein A Protects Mice from Colitis by Re-Setting Host Immune Repertoire. Biomedicines 2021; 9:1098. [PMID: 34572293 PMCID: PMC8470720 DOI: 10.3390/biomedicines9091098] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/25/2021] [Revised: 08/23/2021] [Accepted: 08/25/2021] [Indexed: 12/13/2022] Open
Abstract
Inflammatory bowel disease (IBD) is characterized by gastrointestinal inflammation comprised of Crohn's disease and ulcerative colitis. Centers for Disease Control and Prevention report that 1.3% of the population of the United States (approximately 3 million people) were affected by the disease in 2015, and the number keeps increasing over time. IBD has a multifactorial etiology, from genetic to environmental factors. Most of the IBD treatments revolve around disease management, by reducing the inflammatory signals. We previously identified the surface layer protein A (SlpA) of Lactobacillus acidophilus that possesses anti-inflammatory properties to mitigate murine colitis. Herein, we expressed SlpA in a clinically relevant, food-grade Lactococcus lactis to further investigate and characterize the protective mechanisms of the actions of SlpA. Oral administration of SlpA-expressing L. lactis (R110) mitigated the symptoms of murine colitis. Oral delivery of R110 resulted in a higher expression of IL-27 by myeloid cells, with a synchronous increase in IL-10 and cMAF in T cells. Consistent with murine studies, human dendritic cells exposed to R110 showed exquisite differential gene regulation, including IL-27 transcription, suggesting a shared mechanism between the two species, hence positioning R110 as potentially effective at treating colitis in humans.
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Affiliation(s)
- Ananta Prasad Arukha
- Department of Infectious Diseases and Immunology, University of Florida, Gainesville, FL 32608, USA; (A.P.A.); (M.M.)
- Comparative, Diagnostic and Population Medicine, University of Florida, Gainesville, FL 32608, USA;
| | | | - Meerambika Mishra
- Department of Infectious Diseases and Immunology, University of Florida, Gainesville, FL 32608, USA; (A.P.A.); (M.M.)
| | - Jyoti K. Jha
- Rise Therapeutics, Rockville, MD 20850, USA; (C.F.F.); (J.K.J.); (G.R.F.)
| | - Subhashinie Kariyawasam
- Comparative, Diagnostic and Population Medicine, University of Florida, Gainesville, FL 32608, USA;
| | | | - Ellen M. Zimmermann
- Division of Gastroenterology, University of Florida College of Medicine, Gainesville, FL 32608, USA;
| | - Gary R. Fanger
- Rise Therapeutics, Rockville, MD 20850, USA; (C.F.F.); (J.K.J.); (G.R.F.)
| | - Bikash Sahay
- Department of Infectious Diseases and Immunology, University of Florida, Gainesville, FL 32608, USA; (A.P.A.); (M.M.)
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50
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Chou CL, Chen TJ, Tian YF, Chan TC, Yeh CF, Li WS, Tsai HH, Li CF, Lai HY. Upregulated MUC2 Is an Unfavorable Prognostic Indicator for Rectal Cancer Patients Undergoing Preoperative CCRT. J Clin Med 2021; 10:3030. [PMID: 34300195 PMCID: PMC8304358 DOI: 10.3390/jcm10143030] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/22/2021] [Revised: 07/04/2021] [Accepted: 07/05/2021] [Indexed: 12/12/2022] Open
Abstract
For locally advanced rectal cancer patients, introducing neoadjuvant concurrent chemoradiotherapy (CCRT) before radical resection allows tumor downstaging and increases the rate of anus retention. Since accurate staging before surgery and sensitivity prediction to CCRT remain challenging, a more precise genetic biomarker is urgently needed to enhance the management of such situations. The epithelial mucous barrier can protect the gut lumen, but aberrant mucin synthesis may defend against drug penetration. In this study, we focused on genes related to maintenance of gastrointestinal epithelium (GO: 0030277) and identified mucin 2 (MUC2) as the most significantly upregulated gene correlated with CCRT resistance through a public rectal cancer transcriptome dataset (GSE35452). We retrieved 172 records of rectal cancer patients undergoing CCRT accompanied by radical resection from our biobank. We also assessed the expression level of MUC2 using immunohistochemistry. The results showed that upregulated MUC2 immunoexpression was considerably correlated with the pre-CCRT and post-CCRT positive nodal status (p = 0.001 and p < 0.001), advanced pre-CCRT and post-CCRT tumor status (p = 0.022 and p < 0.001), vascular invasion (p = 0.015), and no or little response to CCRT (p = 0.006). Upregulated MUC2 immunoexpression was adversely prognostic for all three endpoints, disease-specific survival (DSS), local recurrence-free survival (LRFS), and metastasis-free survival (MeFS) (all p < 0.0001), at the univariate level. Moreover, upregulated MUC2 immunoexpression was an independent prognostic factor for worse DSS (p < 0.001), LRFS (p = 0.008), and MeFS (p = 0.003) at the multivariate level. Collectively, these results imply that upregulated MUC2 expression is characterized by a more advanced clinical course and treatment resistance in rectal cancer patients undergoing CCRT, revealing the potential prognostic utility of MUC2 expression.
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Affiliation(s)
- Chia-Lin Chou
- Division of Colon and Rectal Surgery, Department of Surgery, Chi Mei Medical Center, Tainan 710, Taiwan; (C.-L.C.); (Y.-F.T.)
| | - Tzu-Ju Chen
- Department of Clinical Pathology, Chi Mei Medical Center, Tainan 710, Taiwan; (T.-J.C.); (H.-H.T.)
- Department of Medical Technology, Chung Hwa University of Medical Technology, Tainan 717, Taiwan;
- Institute of Biomedical Sciences, National Sun Yat-Sen University, Kaohsiung 804, Taiwan
| | - Yu-Feng Tian
- Division of Colon and Rectal Surgery, Department of Surgery, Chi Mei Medical Center, Tainan 710, Taiwan; (C.-L.C.); (Y.-F.T.)
| | - Ti-Chun Chan
- Department of Medical Research, Chi Mei Medical Center, Tainan 710, Taiwan;
- National Institute of Cancer Research, National Health Research Institutes, Tainan 704, Taiwan
| | - Cheng-Fa Yeh
- Department of Internal Medicine, Chi Mei Medical Center, Tainan 710, Taiwan;
| | - Wan-Shan Li
- Department of Medical Technology, Chung Hwa University of Medical Technology, Tainan 717, Taiwan;
- Institute of Precision Medicine, National Sun Yat-Sen University, Kaohsiung 804, Taiwan
| | - Hsin-Hwa Tsai
- Department of Clinical Pathology, Chi Mei Medical Center, Tainan 710, Taiwan; (T.-J.C.); (H.-H.T.)
- Department of Medical Research, Chi Mei Medical Center, Tainan 710, Taiwan;
| | - Chien-Feng Li
- Department of Clinical Pathology, Chi Mei Medical Center, Tainan 710, Taiwan; (T.-J.C.); (H.-H.T.)
- Department of Medical Research, Chi Mei Medical Center, Tainan 710, Taiwan;
- National Institute of Cancer Research, National Health Research Institutes, Tainan 704, Taiwan
- Institute of Precision Medicine, National Sun Yat-Sen University, Kaohsiung 804, Taiwan
- Department of Pathology, School of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung 807, Taiwan
| | - Hong-Yue Lai
- Department of Clinical Pathology, Chi Mei Medical Center, Tainan 710, Taiwan; (T.-J.C.); (H.-H.T.)
- Department of Medical Research, Chi Mei Medical Center, Tainan 710, Taiwan;
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