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Flanagan K, Gassner K, Lang M, Ozelyte J, Hausmann B, Crepaz D, Pjevac P, Gasche C, Berry D, Vesely C, Pereira FC. Human-derived microRNA 21 regulates indole and L-tryptophan biosynthesis transcripts in the gut commensal Bacteroides thetaiotaomicron. mBio 2025; 16:e0392824. [PMID: 39878512 PMCID: PMC11898669 DOI: 10.1128/mbio.03928-24] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/17/2024] [Accepted: 01/08/2025] [Indexed: 01/31/2025] Open
Abstract
In the gut, microRNAs (miRNAs) produced by intestinal epithelial cells are secreted into the lumen and can shape the composition and function of the gut microbiome. Crosstalk between gut microbes and the host plays a key role in irritable bowel syndrome (IBS) and inflammatory bowel diseases, yet little is known about how the miRNA-gut microbiome axis contributes to the pathogenesis of these conditions. Here, we investigate the ability of miR-21, a miRNA that we found decreased in fecal samples from IBS patients, to associate with and regulate gut microbiome function. When incubated with the human fecal microbiota, miR-21 revealed a rapid internalization or binding to microbial cells, which varied in extent across different donor samples. Fluorescence-activated cell sorting and sequencing of microbial cells incubated with fluorescently labeled miR-21 identified organisms belonging to the genera Bacteroides, Limosilactobacillus, Ruminococcus, or Coprococcus, which predominantly interacted with miR-21. Surprisingly, these and other genera also interacted with a miRNA scramble control, suggesting that physical interaction and/or uptake of these miRNAs by gut microbiota is not sequence-dependent. Nevertheless, transcriptomic analysis of the gut commensal Bacteroides thetaiotaomicron revealed a miRNA sequence-specific effect on bacterial transcript levels. Supplementation of miR-21, but not of small RNA controls, resulted in significantly altered levels of many cellular transcripts and increased transcription of a biosynthetic operon for indole and L-tryptophan, metabolites known to regulate host inflammation and colonic motility. Our study identifies a novel putative miR-21-dependent pathway of regulation of intestinal function through the gut microbiome with implications for gastrointestinal conditions. IMPORTANCE The mammalian gut represents one of the largest and most dynamic host-microbe interfaces. Host-derived microRNAs (miRNAs), released from the gut epithelium into the lumen, have emerged as important contributors to host-microbe crosstalk. Levels of several miRNAs are altered in the stool of patients with irritable bowel syndrome or inflammatory bowel disease. Understanding how miRNAs interact with and shape gut microbiota function is crucial as it may enable the development of new targeted treatments for intestinal diseases. This study provides evidence that the miRNA miR-21 can rapidly associate with diverse microbial cells form the gut and increase levels of transcripts involved in tryptophan synthesis in a ubiquitous gut microbe. Tryptophan catabolites regulate key functions, such as gut immune response or permeability. Therefore, this mechanism represents an unexpected host-microbe interaction and suggests that host-derived miR-21 may help regulate gut function via the gut microbiota.
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Affiliation(s)
- Kayla Flanagan
- Centre for Microbiology and Environmental Systems Science, Department of Microbiology and Ecosystem Science, Division of Microbial Ecology, University of Vienna, Vienna, Austria
| | - Kirsten Gassner
- Centre for Microbiology and Environmental Systems Science, Department of Microbiology and Ecosystem Science, Division of Microbial Ecology, University of Vienna, Vienna, Austria
| | - Michaela Lang
- Centre for Microbiology and Environmental Systems Science, Department of Microbiology and Ecosystem Science, Division of Microbial Ecology, University of Vienna, Vienna, Austria
| | - Jurgita Ozelyte
- Centre for Microbiology and Environmental Systems Science, Department of Microbiology and Ecosystem Science, Division of Microbial Ecology, University of Vienna, Vienna, Austria
| | - Bela Hausmann
- Joint Microbiome Facility, Medical University of Vienna and University of Vienna, Vienna, Austria
- Department of Laboratory Medicine, Division of Clinical Microbiology, Medical University of Vienna, Vienna, Austria
| | - Daniel Crepaz
- Centre for Microbiology and Environmental Systems Science, Department of Microbiology and Ecosystem Science, Division of Microbial Ecology, University of Vienna, Vienna, Austria
| | - Petra Pjevac
- Centre for Microbiology and Environmental Systems Science, Department of Microbiology and Ecosystem Science, Division of Microbial Ecology, University of Vienna, Vienna, Austria
- Joint Microbiome Facility, Medical University of Vienna and University of Vienna, Vienna, Austria
| | - Christoph Gasche
- Department of Internal Medicine III, Division of Gastroenterology and Hepatology, Medical University of Vienna, Vienna, Austria
| | - David Berry
- Centre for Microbiology and Environmental Systems Science, Department of Microbiology and Ecosystem Science, Division of Microbial Ecology, University of Vienna, Vienna, Austria
- Joint Microbiome Facility, Medical University of Vienna and University of Vienna, Vienna, Austria
| | - Cornelia Vesely
- Center of Anatomy and Cell Biology, Division of Cell and Developmental Biology, Medical University of Vienna, Vienna, Austria
| | - Fatima C. Pereira
- Centre for Microbiology and Environmental Systems Science, Department of Microbiology and Ecosystem Science, Division of Microbial Ecology, University of Vienna, Vienna, Austria
- School of Biological Sciences, University of Southampton, Southampton, United Kingdom
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Berthet L, Viennois E. Challenges and hopes of gastrointestinal miRNA regulation: The example of stachyose. Cell Metab 2025; 37:307-309. [PMID: 39908984 DOI: 10.1016/j.cmet.2025.01.010] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/14/2025] [Accepted: 01/14/2025] [Indexed: 02/07/2025]
Abstract
There is growing evidence that micro-RNAs (miRNAs) are key players in the regulation of gut health. In this issue of Cell Metabolism, Li et al.1 uncovered that the dietary fiber stachyose can modulate the luminal miRNA load of the intestinal tracts by binding to HSP90β, thereby altering the gut's microbial composition.
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Affiliation(s)
- Louis Berthet
- Université Paris Cité, Center for Research on Inflammation, UMR 1149, INSERM, 75018 Paris, France
| | - Emilie Viennois
- Université Paris Cité, Center for Research on Inflammation, UMR 1149, INSERM, 75018 Paris, France.
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Mukherjee S, Chopra A, Karmakar S, Bhat SG. Periodontitis increases the risk of gastrointestinal dysfunction: an update on the plausible pathogenic molecular mechanisms. Crit Rev Microbiol 2025; 51:187-217. [PMID: 38602474 DOI: 10.1080/1040841x.2024.2339260] [Citation(s) in RCA: 12] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/04/2023] [Revised: 02/28/2024] [Accepted: 04/01/2024] [Indexed: 04/12/2024]
Abstract
Periodontitis is an immuno-inflammatory disease of the soft tissues surrounding the teeth. Periodontitis is linked to many communicable and non-communicable diseases such as diabetes, cardiovascular disease, rheumatoid arthritis, and cancers. The oral-systemic link between periodontal disease and systemic diseases is attributed to the spread of inflammation, microbial products and microbes to distant organ systems. Oral bacteria reach the gut via swallowed saliva, whereby they induce gut dysbiosis and gastrointestinal dysfunctions. Some periodontal pathogens like Porphyromonas. gingivalis, Klebsiella, Helicobacter. Pylori, Streptococcus, Veillonella, Parvimonas micra, Fusobacterium nucleatum, Peptostreptococcus, Haemophilus, Aggregatibacter actinomycetomcommitans and Streptococcus mutans can withstand the unfavorable acidic, survive in the gut and result in gut dysbiosis. Gut dysbiosis increases gut inflammation, and induce dysplastic changes that lead to gut dysfunction. Various studies have linked oral bacteria, and oral-gut axis to various GIT disorders like inflammatory bowel disease, liver diseases, hepatocellular and pancreatic ductal carcinoma, ulcerative colitis, and Crohn's disease. Although the correlation between periodontitis and GIT disorders is well established, the intricate molecular mechanisms by which oral microflora induce these changes have not been discussed extensively. This review comprehensively discusses the intricate and unique molecular and immunological mechanisms by which periodontal pathogens can induce gut dysbiosis and dysfunction.
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Affiliation(s)
- Sayantan Mukherjee
- Department of Periodontology, Manipal College of Dental Sciences, Manipal, Manipal Academy of Higher Education, Manipal, Karnataka, India
| | - Aditi Chopra
- Department of Periodontology, Manipal College of Dental Sciences, Manipal, Manipal Academy of Higher Education, Manipal, Karnataka, India
| | - Shaswata Karmakar
- Department of Periodontology, Manipal College of Dental Sciences, Manipal, Manipal Academy of Higher Education, Manipal, Karnataka, India
| | - Subraya Giliyar Bhat
- Department of Preventive Dental Sciences, Division of Periodontology, College of Dental Surgery, Iman Abdulrahman Bin Faizal University, Dammam, Saudi Arabia
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Kumar P, Kedia S, Ahuja V. Target potential of miRNAs in ulcerative colitis: what do we know? Expert Opin Ther Targets 2024; 28:829-841. [PMID: 39307951 DOI: 10.1080/14728222.2024.2408423] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/09/2024] [Revised: 09/17/2024] [Accepted: 09/20/2024] [Indexed: 09/27/2024]
Abstract
INTRODUCTION The global rise in ulcerative colitis (UC) incidence highlights the urgent need for enhanced diagnostic and therapeutic strategies. Recent advances in genome-wide association studies (GWAS) have identified genetic loci associated with UC, providing insights into the disease's molecular mechanisms, including immune modulation, mucosal defense, and epithelial barrier function. Despite these findings, many GWAS signals are located in non-coding regions and are linked to low risk, suggesting that protein-coding genes alone do not fully explain UC's pathophysiology. Emerging research emphasizes the potential of microRNAs (miRNAs) as biomarkers and therapeutic targets due to their crucial role in UC. This review explores the current understanding of miRNAs in UC, including their mechanisms of action and their potential as both biomarkers and therapeutic targets. The present review provides the latest update on their potential as a biomarker and therapeutic target. AREAS COVERED This review synthesizes an extensive literature search on miRNAs in UC, focusing on their roles in the mucosal barrier, innate and adaptive immunity, and their potential applications as biomarkers and therapeutic modalities. EXPERT OPINION While miRNAs present promising opportunities as biomarkers and novel therapeutic agents in UC, challenges in validation, specificity, delivery, and clinical application need to be addressed through rigorous, large-scale studies.
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Affiliation(s)
- Peeyush Kumar
- 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
| | - Vineet Ahuja
- Department of Gastroenterology and Human Nutrition, All India Institute of Medical sciences, New Delhi, India
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Ramadan YN, Kamel AM, Medhat MA, Hetta HF. MicroRNA signatures in the pathogenesis and therapy of inflammatory bowel disease. Clin Exp Med 2024; 24:217. [PMID: 39259390 PMCID: PMC11390904 DOI: 10.1007/s10238-024-01476-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/04/2024] [Accepted: 08/20/2024] [Indexed: 09/13/2024]
Abstract
Inflammatory bowel disease (IBD) is a persistent inflammatory illness of the gastrointestinal tract (GIT) triggered by an inappropriate immune response to environmental stimuli in genetically predisposed persons. Unfortunately, IBD patients' quality of life is negatively impacted by the symptoms associated with the disease. The exact etiology of IBD pathogenesis is not fully understood, but the emerging research indicated that the microRNA (miRNA) plays an important role. miRNAs have been documented to possess a significant role in regulating pro- and anti-inflammatory pathways, in addition to their roles in several physiological processes, including cell growth, proliferation, and apoptosis. Variations in the miRNA profiles might be a helpful prognostic indicator and a valuable tool in the differential diagnosis of IBD. Most interestingly, these miRNAs have a promising therapeutic target in several pre-clinical animal studies and phase 2 clinical studies to alleviate inflammation and improve patient's quality of life. This comprehensive review discusses the current knowledge about the significant physiological role of different miRNAs in the health of the intestinal immune system and addresses the role of the most relevant differentially expressed miRNAs in IBD, identify their potential targets, and emphasize their diagnostic and therapeutic potential for future research.
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Affiliation(s)
- Yasmin N Ramadan
- Department of Microbiology and Immunology, Faculty of Pharmacy, Assiut University, Assiut, 71515, Egypt.
| | - Ayat M Kamel
- Department of Microbiology and Immunology, Faculty of Pharmacy, Assiut University, Assiut, 71515, Egypt
| | - Mohammed A Medhat
- Tropical Medicine and Gastroenterology Department, Faculty of Medicine, Assiut University, Assiut, 71515, Egypt
| | - Helal F Hetta
- Division of Microbiology, Immunology and Biotechnology, Department of Natural Products and Alternative Medicine, Faculty of Pharmacy, University of Tabuk, 71491, Tabuk, Saudi Arabia
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Wu X, Shen J, Zhong Y, Zhao X, Zhou W, Gao P, Wang X, An W. Large-Scale Isolation of Milk Exosomes for Skincare. Pharmaceutics 2024; 16:930. [PMID: 39065627 PMCID: PMC11279399 DOI: 10.3390/pharmaceutics16070930] [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: 04/23/2024] [Revised: 05/31/2024] [Accepted: 06/14/2024] [Indexed: 07/28/2024] Open
Abstract
Exosomes are small membrane vesicles in a cell culture. They are secreted by most cells and originate from the endosomal pathway. A variety of proteins, lipids, and genetic materials have been shown to be carried by exosomes. Once taken up by neighboring or distant cells, the bioactive compounds in exosomes can regulate the condition of recipient cells. Typically, producing exosomes in large quantities requires cell culture, resulting in high production costs. However, exosomes are abundant in milk and can be isolated on a large scale at a low cost. In our study, we found that milk exosomes can promote the synthesis and reconstruction of stratum corneum lipids, enhance skin barrier function, and provide greater protection for the skin. Furthermore, milk exosomes have anti-inflammatory properties that can reduce skin irritation, redness, and other symptoms, giving immediate relief. They also exhibit antioxidant activity, which helps neutralize free radicals and slows down the skin aging process. Additionally, milk exosomes inhibit melanin production, aiding in skin whitening. Ongoing research has uncovered the benefits of milk exosomes for skin improvement and their application in cosmetics, skin healthcare, and other fields, and these applications are continuing to expand.
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Affiliation(s)
| | | | | | | | | | | | - Xudong Wang
- China National Biotech Group (CNBG), Sinopharm Group, National Vaccine & Serum Institute (NVSI), No. 38 Jing Hai Second Road, Beijing 101111, China; (X.W.); (J.S.); (Y.Z.); (X.Z.); (W.Z.); (P.G.)
| | - Wenlin An
- China National Biotech Group (CNBG), Sinopharm Group, National Vaccine & Serum Institute (NVSI), No. 38 Jing Hai Second Road, Beijing 101111, China; (X.W.); (J.S.); (Y.Z.); (X.Z.); (W.Z.); (P.G.)
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Onisor D, Brusnic O, Banescu C, Carstea C, Sasaran M, Stoian M, Avram C, Boicean A, Boeriu A, Dobru D. miR-155 and miR-21 as Diagnostic and Therapeutic Biomarkers for Ulcerative Colitis: There Is Still a Long Way to Go. Biomedicines 2024; 12:1315. [PMID: 38927522 PMCID: PMC11201222 DOI: 10.3390/biomedicines12061315] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/12/2024] [Revised: 06/03/2024] [Accepted: 06/08/2024] [Indexed: 06/28/2024] Open
Abstract
(1) Elucidating the role of miRNAs (miRs) in ulcerative colitis may provide new insights into disease pathogenesis, diagnosis, treatment, and monitoring We aimed to investigate whether plasma levels of miR-21-5p and miR-155-5p may be used to differentiate between patients with organic disease such as ulcerative colitis (UC) and Clostridioides difficile infection (CDI), and patients with functional disease such as irritable bowel syndrome with diarrhea (IBS-D). (2) Serological samples were collected to quantify miR-155 and -21 expression, which was carried out through quantitative real-time polymerase chain reaction (qRT-PCR), from 84 patients: 34 with acute UC (group 1), 17 with CDI (group 2), and 33 with IBS-D (control group). (3) In this study, we found that the expression levels of miR-155-5p were almost the same for the two conditions and the control group (UC: 4.22 ± 1.61, CDI: 3.94 ± 1.62, IBS-D: 4.26 ± 1.26), with no significant differences either for ΔCt- or for ΔΔCt-derived parameters (p = 0.74 and p = 0.73, respectively). For miR-21, ΔCt levels presented significantly higher values among the ulcerative colitis group (p < 0.01), but the most important expression fold change was noticed in patients with CDI (UC:4.11 ± 8,46, CDI: 4.94 ± 9.68, IBS-D: 2.83 ± 5.41). (4) Circulating miR-155 and miR-21 were upregulated in UC, CDI, and IBS-D, but differentiation was not possible among them. But their involvement in the pathogenesis of the three diseases makes them suitable for improving the accuracy of diagnosis and facilitating the development of personalized treatment strategies.
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Affiliation(s)
- Danusia Onisor
- Department of Internal Medicine VII, George Emil Palade University of Medicine, Pharmacy, Science and Technology of Targu Mures, Gheorghe Marinescu Street No. 38, 540136 Targu Mures, Romania; (D.O.); (A.B.); (D.D.)
- Gastroenterology Department, Mureș County Clinical Hospital, 540072 Targu Mures, Romania
| | - Olga Brusnic
- Department of Internal Medicine VII, George Emil Palade University of Medicine, Pharmacy, Science and Technology of Targu Mures, Gheorghe Marinescu Street No. 38, 540136 Targu Mures, Romania; (D.O.); (A.B.); (D.D.)
- Gastroenterology Department, Mureș County Clinical Hospital, 540072 Targu Mures, Romania
| | - Claudia Banescu
- Genetics Department, Center for Advanced Medical and Pharmaceutical Research, George Emil Palade University of Medicine, Pharmacy, Science and Technology of Targu Mures, Gheorghe Marinescu Street No. 38, 540136 Targu Mures, Romania; (C.B.); (C.C.)
| | - Claudia Carstea
- Genetics Department, Center for Advanced Medical and Pharmaceutical Research, George Emil Palade University of Medicine, Pharmacy, Science and Technology of Targu Mures, Gheorghe Marinescu Street No. 38, 540136 Targu Mures, Romania; (C.B.); (C.C.)
| | - Maria Sasaran
- Department of Pediatrics III, George Emil Palade University of Medicine, Pharmacy, Science and Technology of Targu Mures, Gheorghe Marinescu Street No. 38, 540136 Targu Mures, Romania;
| | - Mircea Stoian
- Department of Anesthesiology and Intensive Care, George Emil Palade University of Medicine, Pharmacy, Sciences and Technology of Targu Mures, 540139 Targu Mures, Romania;
| | - Calin Avram
- Department of Medical Informatics and Biostatistics, George Emil Palade University of Medicine, Pharmacy, Science and Technology of Targu Mures, Gheorghe Marinescu Street No. 38, 540136 Targu Mures, Romania
| | - Adrian Boicean
- Faculty of Medicine, Lucian Blaga University of Sibiu, 550169 Sibiu, Romania;
| | - Alina Boeriu
- Department of Internal Medicine VII, George Emil Palade University of Medicine, Pharmacy, Science and Technology of Targu Mures, Gheorghe Marinescu Street No. 38, 540136 Targu Mures, Romania; (D.O.); (A.B.); (D.D.)
- Gastroenterology Department, Mureș County Clinical Hospital, 540072 Targu Mures, Romania
| | - Daniela Dobru
- Department of Internal Medicine VII, George Emil Palade University of Medicine, Pharmacy, Science and Technology of Targu Mures, Gheorghe Marinescu Street No. 38, 540136 Targu Mures, Romania; (D.O.); (A.B.); (D.D.)
- Gastroenterology Department, Mureș County Clinical Hospital, 540072 Targu Mures, Romania
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Li L, Jiang H, Qiu Z, Wang Z, Hu Z. EFFECT OF MIR-21-3P ON INTESTINAL INJURY IN RATS WITH TRAUMATIC HEMORRHAGIC SHOCK RESUSCITATED WITH THE SODIUM BICARBONATE RINGER'S SOLUTION. Shock 2024; 61:776-782. [PMID: 38517274 DOI: 10.1097/shk.0000000000002297] [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: 03/23/2024]
Abstract
ABSTRACT Background : This study aims to determine the impact and mechanism of miR-21-3p on intestinal injury and intestinal glycocalyx during fluid resuscitation in traumatic hemorrhagic shock (THS), and the different impacts of sodium lactate Ringer's solution (LRS) and sodium bicarbonate Ringer's solution (BRS) for resuscitation on intestinal damage. Methods : A rat model of THS was induced by hemorrhage from the left femur fracture. The pathological changes of intestinal tissues and glycocalyx structure were observed by hematoxylin-eosin staining and transmission electron microscope. MiR-21-3p expression in intestinal tissues was detected by real-time quantitative polymerase chain reaction. The expression of glycocalyx-, cell junction-, and PI3K/Akt/NF-κB signaling pathway-related proteins was analyzed by western blot. Results : MiR-21-3p expression was increased in THS rats, which was suppressed by resuscitation with BRS. BRS or LRS aggravated the intestinal injury and damaged intestinal glycocalyx in THS rats. The expression of SDC-1, HPA, β-catenin, MMP2, and MMP9 was upregulated, the expression of E-cad was downregulated, and the PI3K/Akt/NF-κB signaling pathway was activated in THS rats, which were further aggravated by BRS or LRS. The adverse effect of LRS was more serious than BRS. MiR-21-3p overexpression deteriorated the injury of intestinal tissues and intestinal glycocalyx; increased the expression of SDC-1, HPA, β-catenin, MMP2, and MMP9 while decreasing E-cad expression; and activated the PI3K/Akt/NF-κB signaling pathway in BRS-resuscitated THS rats. Conclusion : MiR-21-3p aggravated intestinal tissue injury and intestinal glycocalyx damage through activating PI3K/Akt/NF-κB signaling pathway in rats with THS resuscitated with BRS.
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Affiliation(s)
| | | | | | - Zhenjie Wang
- Department of Emergency Surgery, The First Affiliated Hospital of Bengbu Medical College, Bengbu, Anhui, China
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Oliveira ECSD, Quaglio AEV, Grillo TG, Di Stasi LC, Sassaki LY. MicroRNAs in inflammatory bowel disease: What do we know and what can we expect? World J Gastroenterol 2024; 30:2184-2190. [PMID: 38690020 PMCID: PMC11056918 DOI: 10.3748/wjg.v30.i16.2184] [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: 01/20/2024] [Revised: 02/09/2024] [Accepted: 03/19/2024] [Indexed: 04/26/2024] Open
Abstract
MicroRNAs (miRNAs), small non-coding RNAs composed of 18-24 nucleotides, are potent regulators of gene expression, contributing to the regulation of more than 30% of protein-coding genes. Considering that miRNAs are regulators of inflammatory pathways and the differentiation of intestinal epithelial cells, there is an interest in exploring their importance in inflammatory bowel disease (IBD). IBD is a chronic and multifactorial disease of the gastrointestinal tract; the main forms are Crohn's disease and ulcerative colitis. Several studies have investigated the dysregulated expression of miRNAs in IBD, demonstrating their important roles as regulators and potential biomarkers of this disease. This editorial presents what is known and what is expected regarding miRNAs in IBD. Although the important regulatory roles of miRNAs in IBD are clearly established, biomarkers for IBD that can be applied in clinical practice are lacking, emphasizing the importance of further studies. Discoveries regarding the influence of miRNAs on the inflammatory process and the exploration of their role in gene regulation are expected to provide a basis for the use of miRNAs not only as potent biomarkers in IBD but also as therapeutic targets for the control of inflammatory processes in personalized medicine.
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Affiliation(s)
| | | | - Thais Gagno Grillo
- Department of Internal Medicine, Medical School, São Paulo State University (Unesp), Botucatu 18618-686, São Paulo, Brazil
| | - Luiz Claudio Di Stasi
- Department of Biophysics and Pharmacology, Institute of Biosciences, São Paulo State University (Unesp), Botucatu 18618-689, São Paulo, Brazil
| | - Ligia Yukie Sassaki
- Department of Internal Medicine, Medical School, São Paulo State University (Unesp), Botucatu 18618-686, São Paulo, Brazil
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Yang Y, Zhang H, Wang Y, Xu J, Shu S, Wang P, Ding S, Huang Y, Zheng L, Yang Y, Xiong C. Promising dawn in the management of pulmonary hypertension: The mystery veil of gut microbiota. IMETA 2024; 3:e159. [PMID: 38882495 PMCID: PMC11170974 DOI: 10.1002/imt2.159] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 09/19/2023] [Revised: 11/15/2023] [Accepted: 11/25/2023] [Indexed: 06/18/2024]
Abstract
The gut microbiota is a complex community of microorganisms inhabiting the intestinal tract, which plays a vital role in human health. It is intricately involved in the metabolism, and it also affects diverse physiological processes. The gut-lung axis is a bidirectional pathway between the gastrointestinal tract and the lungs. Recent research has shown that the gut microbiome plays a crucial role in immune response regulation in the lungs and the development of lung diseases. In this review, we present the interrelated factors concerning gut microbiota and the associated metabolites in pulmonary hypertension (PH), a lethal disease characterized by elevated pulmonary vascular pressure and resistance. Our research team explored the role of gut-microbiota-derived metabolites in cardiovascular diseases and established the correlation between metabolites such as putrescine, succinate, trimethylamine N-oxide (TMAO), and N, N, N-trimethyl-5-aminovaleric acid with the diseases. Furthermore, we found that specific metabolites, such as TMAO and betaine, have significant clinical value in PH, suggesting their potential as biomarkers in disease management. In detailing the interplay between the gut microbiota, their metabolites, and PH, we underscored the potential therapeutic approaches modulating this microbiota. Ultimately, we endeavor to alleviate the substantial socioeconomic burden associated with this disease. This review presents a unique exploratory analysis of the link between gut microbiota and PH, intending to propel further investigations in the gut-lung axis.
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Affiliation(s)
- Yicheng Yang
- State Key Laboratory of Cardiovascular Disease, Department of Cardiology Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College Beijing China
| | - Hanwen Zhang
- State Key Laboratory of Cardiovascular Disease, Department of Cardiology Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College Beijing China
| | - Yaoyao Wang
- State Key Laboratory of Cardiovascular Disease, Department of Nephrology Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College Beijing China
| | - Jing Xu
- State Key Laboratory of Cardiovascular Disease, Department of Cardiology Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College Beijing China
- Department of Genetics University Medical Center Groningen, University of Groningen Groningen The Netherlands
| | - Songren Shu
- State Key Laboratory of Cardiovascular Disease, Department of Cardiac Surgery Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College Beijing China
| | - Peizhi Wang
- State Key Laboratory of Cardiovascular Disease, Department of Cardiology Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College Beijing China
- Center for Molecular Cardiology University of Zurich Zurich Switzerland
| | - Shusi Ding
- China National Clinical Research Center for Neurological Diseases, Tiantan Hospital, Advanced Innovation Center for Human Brain Protection The Capital Medical University Beijing China
| | - Yuan Huang
- State Key Laboratory of Cardiovascular Disease, Department of Cardiac Surgery Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College Beijing China
| | - Lemin Zheng
- China National Clinical Research Center for Neurological Diseases, Tiantan Hospital, Advanced Innovation Center for Human Brain Protection The Capital Medical University Beijing China
- Key Laboratory of Molecular Cardiovascular Sciences of Ministry of Education, NHC Key Laboratory of Cardiovascular Molecular Biology and Regulatory Peptides, School of Basic Medical Sciences, Health Science Center The Institute of Cardiovascular Sciences and Institute of Systems Biomedicine, Peking University Beijing China
| | - Yuejin Yang
- State Key Laboratory of Cardiovascular Disease, Department of Cardiology Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College Beijing China
| | - Changming Xiong
- State Key Laboratory of Cardiovascular Disease, Department of Cardiology Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College Beijing China
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Luo L, Zhang W, You S, Cui X, Tu H, Yi Q, Wu J, Liu O. The role of epithelial cells in fibrosis: Mechanisms and treatment. Pharmacol Res 2024; 202:107144. [PMID: 38484858 DOI: 10.1016/j.phrs.2024.107144] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/02/2023] [Revised: 02/19/2024] [Accepted: 03/12/2024] [Indexed: 03/19/2024]
Abstract
Fibrosis is a pathological process that affects multiple organs and is considered one of the major causes of morbidity and mortality in multiple diseases, resulting in an enormous disease burden. Current studies have focused on fibroblasts and myofibroblasts, which directly lead to imbalance in generation and degradation of extracellular matrix (ECM). In recent years, an increasing number of studies have focused on the role of epithelial cells in fibrosis. In some cases, epithelial cells are first exposed to external physicochemical stimuli that may directly drive collagen accumulation in the mesenchyme. In other cases, the source of stimulation is mainly immune cells and some cytokines, and epithelial cells are similarly altered in the process. In this review, we will focus on the multiple dynamic alterations involved in epithelial cells after injury and during fibrogenesis, discuss the association among them, and summarize some therapies targeting changed epithelial cells. Especially, epithelial mesenchymal transition (EMT) is the key central step, which is closely linked to other biological behaviors. Meanwhile, we think studies on disruption of epithelial barrier, epithelial cell death and altered basal stem cell populations and stemness in fibrosis are not appreciated. We believe that therapies targeted epithelial cells can prevent the progress of fibrosis, but not reverse it. The epithelial cell targeting therapies will provide a wonderful preventive and delaying action.
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Affiliation(s)
- Liuyi Luo
- Xiangya Stomatological Hospital & Xiangya School of Stomatology, Central South University, Changsha, Hunan, China; Academician Workstation for Oral-maxilofacial and Regenerative Medicine, Central South University, Changsha, Hunan, China
| | - Wei Zhang
- Department of Oral Medicine, Xiangya Hospital, Central South University, Changsha, Hunan, China
| | - Siyao You
- Xiangya Stomatological Hospital & Xiangya School of Stomatology, Central South University, Changsha, Hunan, China; Academician Workstation for Oral-maxilofacial and Regenerative Medicine, Central South University, Changsha, Hunan, China
| | - Xinyan Cui
- Xiangya Stomatological Hospital & Xiangya School of Stomatology, Central South University, Changsha, Hunan, China; Academician Workstation for Oral-maxilofacial and Regenerative Medicine, Central South University, Changsha, Hunan, China
| | - Hua Tu
- Xiangya Stomatological Hospital & Xiangya School of Stomatology, Central South University, Changsha, Hunan, China; Academician Workstation for Oral-maxilofacial and Regenerative Medicine, Central South University, Changsha, Hunan, China
| | - Qiao Yi
- Xiangya Stomatological Hospital & Xiangya School of Stomatology, Central South University, Changsha, Hunan, China; Academician Workstation for Oral-maxilofacial and Regenerative Medicine, Central South University, Changsha, Hunan, China
| | - Jianjun Wu
- Xiangya Stomatological Hospital & Xiangya School of Stomatology, Central South University, Changsha, Hunan, China; Academician Workstation for Oral-maxilofacial and Regenerative Medicine, Central South University, Changsha, Hunan, China.
| | - Ousheng Liu
- Xiangya Stomatological Hospital & Xiangya School of Stomatology, Central South University, Changsha, Hunan, China; Academician Workstation for Oral-maxilofacial and Regenerative Medicine, Central South University, Changsha, Hunan, China.
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12
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Casado-Bedmar M, Roy M, Berthet L, Hugot JP, Yang C, Manceau H, Peoc'h K, Chassaing B, Merlin D, Viennois E. Fecal let-7b and miR-21 directly modulate the intestinal microbiota, driving chronic inflammation. Gut Microbes 2024; 16:2394249. [PMID: 39224018 PMCID: PMC11376420 DOI: 10.1080/19490976.2024.2394249] [Citation(s) in RCA: 7] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/07/2023] [Revised: 08/08/2024] [Accepted: 08/14/2024] [Indexed: 09/04/2024] Open
Abstract
Inflammatory bowel diseases (IBD) etiology is multifactorial. Luminal microRNAs (miRNAs) have been suspected to play a role in the promotion of chronic inflammation, but the extent to which fecal miRNAs are interacting with the intestinal ecosystem in a way that contribute to diseases, including IBD, remains unknown. Here, fecal let-7b and miR-21 were found elevated, associated with inflammation, and correlating with multiple bacteria in IBD patients and IL-10-/- mice, model of spontaneous colitis. Using an in vitro microbiota modeling system, we revealed that these two miRNAs can directly modify the composition and function of complex human microbiota, increasing their proinflammatory potential. In vivo investigations revealed that luminal increase of let-7b drastically alters the intestinal microbiota and enhances macrophages' associated proinflammatory cytokines (TNF, IL-6, and IL-1β). Such proinflammatory effects are resilient and dependent on the bacterial presence. Moreover, we identified that besides impairing the intestinal barrier function, miR-21 increases myeloperoxidase and antimicrobial peptides secretion, causing intestinal dysbiosis. More importantly, in vivo inhibition of let-7b and miR-21 with anti-miRNAs significantly improved the intestinal mucosal barrier function and promoted a healthier host-microbiota interaction in the intestinal lining, which altogether conferred protection against colitis. In summary, we provide evidence of the functional significance of fecal miRNAs in host-microbiota communication, highlighting their therapeutic potential in intestinal inflammation and dysbiosis-related conditions, such as IBD.
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Affiliation(s)
| | - Maryline Roy
- Center for Research on Inflammation, Université Paris Cité, Paris, France
| | - Louis Berthet
- Center for Research on Inflammation, Université Paris Cité, Paris, France
| | - Jean-Pierre Hugot
- Center for Research on Inflammation, Université Paris Cité, Paris, France
- Department of Pediatric Gastroenterology, Hôpital Robert Debré, Assistance Publique Hôpitaux de Paris (AP-HP), Paris, France
| | - Chunhua Yang
- Institute for Biomedical Sciences, Center for Inflammation, Immunity and Infection, Digestive Disease Research Group, Georgia State University, Atlanta, GA, USA
| | - Hana Manceau
- Center for Research on Inflammation, Université Paris Cité, Paris, France
- Laboratory of Clinical Biochemistry, Beaujon Hospital, APHP, Clichy, France
| | - Katell Peoc'h
- Center for Research on Inflammation, Université Paris Cité, Paris, France
- Laboratory of Clinical Biochemistry, Beaujon Hospital, APHP, Clichy, France
| | - Benoit Chassaing
- Microbiome-Host Interactions, Institut Pasteur, Université Paris Cité, INSERM U1306, Paris, France
- Mucosal Microbiota in Chronic Inflammatory Diseases, INSERM U1016, CNRS UMR8104, Université Paris Cité, Paris, France
- CHRU Nancy, IHU Infiny, Nancy, France
| | - Didier Merlin
- Institute for Biomedical Sciences, Center for Inflammation, Immunity and Infection, Digestive Disease Research Group, Georgia State University, Atlanta, GA, USA
- Veterans Affairs Medical Center, Decatur, GA, USA
| | - Emilie Viennois
- Center for Research on Inflammation, Université Paris Cité, Paris, France
- CHRU Nancy, IHU Infiny, Nancy, France
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13
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Seoudi SS, Allam EA, El-Kamel AH, Elkafrawy H, El-Moslemany RM. Targeted delivery of budesonide in acetic acid induced colitis: impact on miR-21 and E-cadherin expression. Drug Deliv Transl Res 2023; 13:2930-2947. [PMID: 37184747 PMCID: PMC10545600 DOI: 10.1007/s13346-023-01363-2] [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] [Accepted: 05/03/2023] [Indexed: 05/16/2023]
Abstract
Inflammatory bowel disease (IBD) is characterized by chronic inflammation along the gastrointestinal tract. For IBD effective treatment, developing an orally administered stable drug delivery system capable of targeting inflammation sites is a key challenge. Herein, we report pH responsive hyaluronic (HA) coated Eudragit S100 (ES) nanoparticles (NPs) for the targeted delivery of budesonide (BUD) (HA-BUD-ES-NPs). HA-BUD-ES-NPs showed good colloidal properties (274.8 ± 2.9 nm and - 24.6 ± 2.8 mV) with high entrapment efficiency (98.3 ± 3.41%) and pH-dependent release profile. The negative potential following incubation in simulated gastrointestinal fluids reflected the stability of HA coat. In vitro studies on Caco-2 cells showed HA-BUD-ES-NPs biocompatibility and enhanced cellular uptake and anti-inflammatory effects as shown by the significant reduction in IL-8 and TNF-α. The oral administration of HA-BUD-ES-NPs in an acetic acid induced colitis rat model significantly mitigated the symptoms of IBD, and improved BUD therapeutic efficacy compared to drug suspension. This was proved via the improvement in disease activity index and ulcer score in addition to refined histopathological findings. Also, the assessment of inflammatory markers, epithelial cadherin, and mi-R21 all reflected the higher efficiency of HA-BUD-ES-NPs compared to free drug and uncoated formulation. We thus suggest that HA-BUD-ES-NPs provide a promising drug delivery platform for the management and site specific treatment of IBD.
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Affiliation(s)
- Shaymaa S Seoudi
- Department of Pharmaceutics, Faculty of Pharmacy, Alexandria University, Alexandria, Egypt
| | - Eman A Allam
- Department of Medical Physiology, Faculty of Medicine, Alexandria University, Alexandria, Egypt
| | - Amal H El-Kamel
- Department of Pharmaceutics, Faculty of Pharmacy, Alexandria University, Alexandria, Egypt
| | - Hagar Elkafrawy
- Department of Medical Biochemistry, Faculty of Medicine, Alexandria University, Alexandria, Egypt
- Center of Excellence for Research in Regenerative Medicine and Applications (CERRMA), Faculty of Medicine, Alexandria University, Alexandria, Egypt
| | - Riham M El-Moslemany
- Department of Pharmaceutics, Faculty of Pharmacy, Alexandria University, Alexandria, Egypt.
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14
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Zhang J, Wu J, Wang G, He L, Zheng Z, Wu M, Zhang Y. Extracellular Vesicles: Techniques and Biomedical Applications Related to Single Vesicle Analysis. ACS NANO 2023; 17:17668-17698. [PMID: 37695614 DOI: 10.1021/acsnano.3c03172] [Citation(s) in RCA: 11] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 09/12/2023]
Abstract
Extracellular vesicles (EVs) are extensively dispersed lipid bilayer membrane vesicles involved in the delivery and transportation of molecular payloads to certain cell types to facilitate intercellular interactions. Their significant roles in physiological and pathological processes make EVs outstanding biomarkers for disease diagnosis and treatment monitoring as well as ideal candidates for drug delivery. Nevertheless, differences in the biogenesis processes among EV subpopulations have led to a diversity of biophysical characteristics and molecular cargos. Additionally, the prevalent heterogeneity of EVs has been found to substantially hamper the sensitivity and accuracy of disease diagnosis and therapeutic monitoring, thus impeding the advancement of clinical applications. In recent years, the evolution of single EV (SEV) analysis has enabled an in-depth comprehension of the physical properties, molecular composition, and biological roles of EVs at the individual vesicle level. This review examines the sample acquisition tactics prior to SEV analysis, i.e., EV isolation techniques, and outlines the current state-of-the-art label-free and label-based technologies for SEV identification. Furthermore, the challenges and prospects of biomedical applications based on SEV analysis are systematically discussed.
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Affiliation(s)
- Jie Zhang
- Guangdong Key Laboratory of Chiral Molecule and Drug Discovery, School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006, P. R. China
| | - Jiacheng Wu
- Guangdong Key Laboratory of Chiral Molecule and Drug Discovery, School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006, P. R. China
| | - Guanzhao Wang
- Guangdong Key Laboratory of Chiral Molecule and Drug Discovery, School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006, P. R. China
| | - Luxuan He
- Guangdong Key Laboratory of Chiral Molecule and Drug Discovery, School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006, P. R. China
| | - Ziwei Zheng
- Guangdong Key Laboratory of Chiral Molecule and Drug Discovery, School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006, P. R. China
| | - Minhao Wu
- Department of Immunology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou 510080, P. R. China
| | - Yuanqing Zhang
- Guangdong Key Laboratory of Chiral Molecule and Drug Discovery, School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006, P. R. China
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15
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Macias-Ceja DC, Mendoza-Ballesteros MT, Ortega-Albiach M, Barrachina MD, Ortiz-Masià D. Role of the epithelial barrier in intestinal fibrosis associated with inflammatory bowel disease: relevance of the epithelial-to mesenchymal transition. Front Cell Dev Biol 2023; 11:1258843. [PMID: 37822869 PMCID: PMC10562728 DOI: 10.3389/fcell.2023.1258843] [Citation(s) in RCA: 12] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/14/2023] [Accepted: 09/14/2023] [Indexed: 10/13/2023] Open
Abstract
In inflammatory bowel disease (IBD), chronic inflammation in the gastrointestinal tract can lead to tissue damage and remodelling, which can ultimately result in fibrosis. Prolonged injury and inflammation can trigger the activation of fibroblasts and extracellular matrix (ECM) components. As fibrosis progresses, the tissue becomes increasingly stiff and less functional, which can lead to complications such as intestinal strictures, obstructive symptoms, and eventually, organ dysfunction. Epithelial cells play a key role in fibrosis, as they secrete cytokines and growth factors that promote fibroblast activation and ECM deposition. Additionally, epithelial cells can undergo a process called epithelial-mesenchymal transition, in which they acquire a more mesenchymal-like phenotype and contribute directly to fibroblast activation and ECM deposition. Overall, the interactions between epithelial cells, immune cells, and fibroblasts play a critical role in the development and progression of fibrosis in IBD. Understanding these complex interactions may provide new targets for therapeutic interventions to prevent or treat fibrosis in IBD. In this review, we have collected and discussed the recent literature highlighting the contribution of epithelial cells to the pathogenesis of the fibrotic complications of IBD, including evidence of EMT, the epigenetic control of the EMT, the potential influence of the intestinal microbiome in EMT, and the possible therapeutic strategies to target EMT. Finally we discuss the pro-fibrotic interactions epithelial-immune cells and epithelial-fibroblasts cells.
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Affiliation(s)
- Dulce C. Macias-Ceja
- Departamento de Farmacología and CIBEREHD, Facultad de Medicina, Universidad de Valencia, Valencia, Spain
| | | | | | - M. Dolores Barrachina
- Departamento de Farmacología and CIBEREHD, Facultad de Medicina, Universidad de Valencia, Valencia, Spain
| | - Dolores Ortiz-Masià
- Departamento de Farmacología and CIBEREHD, Facultad de Medicina, Universidad de Valencia, Valencia, Spain
- Departamento de Medicina, Facultad de Medicina, Universidad de Valencia, Valencia, Spain
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16
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Lee Y, Kim Y, Park S, Heo G, Chung HY, Im E. Cannabinoid receptor type 1 in the aging gut regulates the mucosal permeability via miR-191-5p. Front Endocrinol (Lausanne) 2023; 14:1241097. [PMID: 37693348 PMCID: PMC10485608 DOI: 10.3389/fendo.2023.1241097] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/16/2023] [Accepted: 08/11/2023] [Indexed: 09/12/2023] Open
Abstract
Background Aging is associated with a broad loss of function throughout the body, and gastrointestinal (GI) dysfunction can occur with aging. The endocannabinoid (eCB) system plays a pivotal role in various GI diseases, and alterations in the eCB system have been observed during brain and skin aging. Therefore, we investigated the putative role of the eCB system in aging-related changes in the intestine. Methods The expression of cannabinoid receptor type 1 (CB1) was investigated in rat intestinal tissues using quantitative real-time PCR. Cellular senescence was induced by hydrogen peroxide (H2O2) and hydroxyurea (HU) in rat and human intestinal epithelial cells. Cellular permeability was evaluated by transepithelial electrical resistance (TEER) measurement. Results and Discussion The expression of CB1 was decreased in the small intestine of aged rats compared to that of young rats. Senescent cells showed reduced TEER values and decreased expression of ZO-1, indicating increased intestinal permeability, which is tightly regulated by the CB1 signaling. In silico miRNA analysis suggested that ZO-1 was a direct target gene of miR-191-5p. Increased expression of miR-191-5p by HU was restored by CB1 agonist ACEA co-treatment. Moreover, NF-κB p65 activation was associated with CB1-related miR-191-5p signaling. In conclusion, aging-induced CB1 reduction leads to increased intestinal permeability and decreased ZO-1 expression via upregulation of miR-191-5p and NF-κB p65 activation. Taken together, these results suggest that CB1 signaling may be a useful strategy to reduce intestinal permeability in aging-related and other inflammatory conditions in the gut.
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Affiliation(s)
- Yunna Lee
- College of Pharmacy, Pusan National University, Busan, Republic of Korea
- Research Institute for Drug Development, Pusan National University, Busan, Republic of Korea
| | - Yuju Kim
- College of Pharmacy, Pusan National University, Busan, Republic of Korea
| | - Soyeong Park
- College of Pharmacy, Pusan National University, Busan, Republic of Korea
- Research Institute for Drug Development, Pusan National University, Busan, Republic of Korea
| | - Gwangbeom Heo
- College of Pharmacy, Pusan National University, Busan, Republic of Korea
- Research Institute for Drug Development, Pusan National University, Busan, Republic of Korea
| | - Hae Young Chung
- College of Pharmacy, Pusan National University, Busan, Republic of Korea
- Research Institute for Drug Development, Pusan National University, Busan, Republic of Korea
| | - Eunok Im
- College of Pharmacy, Pusan National University, Busan, Republic of Korea
- Research Institute for Drug Development, Pusan National University, Busan, Republic of Korea
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17
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Datta N, Johnson C, Kao D, Gurnani P, Alexander C, Polytarchou C, Monaghan TM. MicroRNA-based therapeutics for inflammatory disorders of the microbiota-gut-brain axis. Pharmacol Res 2023; 194:106870. [PMID: 37499702 DOI: 10.1016/j.phrs.2023.106870] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/11/2023] [Revised: 07/22/2023] [Accepted: 07/24/2023] [Indexed: 07/29/2023]
Abstract
An emerging but less explored shared pathophysiology across microbiota-gut-brain axis disorders is aberrant miRNA expression, which may represent novel therapeutic targets. miRNAs are small, endogenous non-coding RNAs that are important transcriptional repressors of gene expression. Most importantly, they regulate the integrity of the intestinal epithelial and blood-brain barriers and serve as an important communication channel between the gut microbiome and the host. A well-defined understanding of the mode of action, therapeutic strategies and delivery mechanisms of miRNAs is pivotal in translating the clinical applications of miRNA-based therapeutics. Accumulating evidence links disorders of the microbiota-gut-brain axis with a compromised gut-blood-brain-barrier, causing gut contents such as immune cells and microbiota to enter the bloodstream leading to low-grade systemic inflammation. This has the potential to affect all organs, including the brain, causing central inflammation and the development of neurodegenerative and neuropsychiatric diseases. In this review, we have examined in detail miRNA biogenesis, strategies for therapeutic application, delivery mechanisms, as well as their pathophysiology and clinical applications in inflammatory gut-brain disorders. The research data in this review was drawn from the following databases: PubMed, Google Scholar, and Clinicaltrials.gov. With increasing evidence of the pathophysiological importance for miRNAs in microbiota-gut-brain axis disorders, therapeutic targeting of cross-regulated miRNAs in these disorders displays potentially transformative and translational potential. Further preclinical research and human clinical trials are required to further advance this area of research.
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Affiliation(s)
- Neha Datta
- School of Medicine, University of Nottingham, Nottingham, UK
| | - Charlotte Johnson
- NIHR Nottingham Biomedical Research Centre, University of Nottingham, Nottingham, UK; Nottingham Digestive Diseases Centre, School of Medicine, University of Nottingham, Nottingham, UK
| | - Dina Kao
- Division of Gastroenterology, Department of Medicine, University of Alberta, Edmonton, Alberta, Canada
| | - Pratik Gurnani
- Division of Molecular Therapeutics & Formulation, School of Pharmacy, University of Nottingham, Nottingham, UK
| | - Cameron Alexander
- Division of Molecular Therapeutics & Formulation, School of Pharmacy, University of Nottingham, Nottingham, UK
| | - Christos Polytarchou
- Department of Biosciences, John van Geest Cancer Research Centre, School of Science & Technology, Nottingham Trent University, Nottingham, UK.
| | - Tanya M Monaghan
- NIHR Nottingham Biomedical Research Centre, University of Nottingham, Nottingham, UK; Nottingham Digestive Diseases Centre, School of Medicine, University of Nottingham, Nottingham, UK.
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18
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Alfaifi J, Germain A, Heba AC, Arnone D, Gailly L, Ndiaye NC, Viennois E, Caron B, Peyrin-Biroulet L, Dreumont N. Deep Dive Into MicroRNAs in Inflammatory Bowel Disease. Inflamm Bowel Dis 2023; 29:986-999. [PMID: 36545755 DOI: 10.1093/ibd/izac250] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/29/2022] [Indexed: 06/02/2023]
Abstract
Inflammatory bowel disease (IBD), which includes ulcerative colitis and Crohn's disease, is thought to develop in genetically predisposed individuals as a consequence of complex interactions between dysregulated inflammatory stimuli, immunological responses, and environmental factors. The pathogenesis of IBD has yet to be fully understood. The global increase in the incidence of IBD suggests a gap in the current understanding of the disease. The development of a new diagnostic tool for inflammatory bowel disease that is both less invasive and more cost-effective would allow for better management of this condition. MicroRNAs (miRNAs) are a class of noncoding RNAs with important roles as posttranscriptional regulators of gene expression, which has led to new insights into understanding IBD. Using techniques such as microarrays and real-time polymerase chain reactions, researchers have investigated the patterns in which patients with Crohn's disease and ulcerative colitis show alterations in the expression of miRNA in tissue, blood, and feces. These miRNAs are found to be differentially expressed in IBD and implicated in its pathogenesis through alterations in autophagy, intestinal barrier, and immune homeostasis. In this review, we discuss the miRNA expression profiles associated with IBD in tissue, peripheral blood, and feces and provide an overview of the miRNA mechanisms involved in IBD.
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Affiliation(s)
- Jaber Alfaifi
- Department of Hepatobiliary, Colorectal, and Digestive Surgery, Nancy University Hospital, University of Lorraine, Nancy, France
- NGERE (Nutrition-Genetics and Exposure to Environmental Risks), INSERM, University of Lorraine, Nancy, France
| | - Adeline Germain
- Department of Hepatobiliary, Colorectal, and Digestive Surgery, Nancy University Hospital, University of Lorraine, Nancy, France
- NGERE (Nutrition-Genetics and Exposure to Environmental Risks), INSERM, University of Lorraine, Nancy, France
| | - Anne-Charlotte Heba
- NGERE (Nutrition-Genetics and Exposure to Environmental Risks), INSERM, University of Lorraine, Nancy, France
| | - Djésia Arnone
- NGERE (Nutrition-Genetics and Exposure to Environmental Risks), INSERM, University of Lorraine, Nancy, France
| | - Laura Gailly
- NGERE (Nutrition-Genetics and Exposure to Environmental Risks), INSERM, University of Lorraine, Nancy, France
| | - Ndeye Coumba Ndiaye
- NGERE (Nutrition-Genetics and Exposure to Environmental Risks), INSERM, University of Lorraine, Nancy, France
| | - Emilie Viennois
- INSERM U1149, Center of Research on Inflammation, Université de Paris, Paris, France
| | - Bénédicte Caron
- NGERE (Nutrition-Genetics and Exposure to Environmental Risks), INSERM, University of Lorraine, Nancy, France
- Department of Gastroenterology, Nancy University Hospital, University of Lorraine, Nancy, France
| | - Laurent Peyrin-Biroulet
- NGERE (Nutrition-Genetics and Exposure to Environmental Risks), INSERM, University of Lorraine, Nancy, France
- Department of Gastroenterology, Nancy University Hospital, University of Lorraine, Nancy, France
| | - Natacha Dreumont
- NGERE (Nutrition-Genetics and Exposure to Environmental Risks), INSERM, University of Lorraine, Nancy, France
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19
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Li X, Zhang M, Zhou G, Xie Z, Wang Y, Han J, Li L, Wu Q, Zhang S. Role of Rho GTPases in inflammatory bowel disease. Cell Death Dis 2023; 9:24. [PMID: 36690621 PMCID: PMC9871048 DOI: 10.1038/s41420-023-01329-w] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/07/2022] [Revised: 01/08/2023] [Accepted: 01/11/2023] [Indexed: 01/24/2023]
Abstract
Rat sarcoma virus homolog (Rho) guanosine triphosphatases (GTPases) function as "molecular switch" in cellular signaling regulation processes and are associated with the pathogenesis of inflammatory bowel disease (IBD). This chronic intestinal tract inflammation primarily encompasses two diseases: Crohn's disease and ulcerative colitis. The pathogenesis of IBD is complex and considered to include four main factors and their interactions: genetics, intestinal microbiota, immune system, and environment. Recently, several novel pathogenic components have been identified. In addition, potential therapies for IBD targeting Rho GTPases have emerged and proven to be clinically effective. This review mainly focuses on Rho GTPases and their possible mechanisms in IBD pathogenesis. The therapeutic possibility of Rho GTPases is also discussed.
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Affiliation(s)
- Xiaoling Li
- grid.12981.330000 0001 2360 039XDivision of Gastroenterology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, PR China
| | - Mudan Zhang
- grid.12981.330000 0001 2360 039XDivision of Gastroenterology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, PR China
| | - Gaoshi Zhou
- grid.12981.330000 0001 2360 039XDivision of Gastroenterology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, PR China
| | - Zhuo Xie
- grid.12981.330000 0001 2360 039XDivision of Gastroenterology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, PR China
| | - Ying Wang
- grid.12981.330000 0001 2360 039XDivision of Gastroenterology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, PR China
| | - Jing Han
- grid.12981.330000 0001 2360 039XDivision of Gastroenterology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, PR China
| | - Li Li
- grid.12981.330000 0001 2360 039XDivision of Gastroenterology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, PR China
| | - Qirui Wu
- grid.12981.330000 0001 2360 039XDivision of Gastroenterology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, PR China
| | - Shenghong Zhang
- grid.12981.330000 0001 2360 039XDivision of Gastroenterology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, PR China
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20
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Nikolaieva N, Sevcikova A, Omelka R, Martiniakova M, Mego M, Ciernikova S. Gut Microbiota-MicroRNA Interactions in Intestinal Homeostasis and Cancer Development. Microorganisms 2022; 11:microorganisms11010107. [PMID: 36677399 PMCID: PMC9867529 DOI: 10.3390/microorganisms11010107] [Citation(s) in RCA: 26] [Impact Index Per Article: 8.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/17/2022] [Revised: 12/21/2022] [Accepted: 12/28/2022] [Indexed: 01/03/2023] Open
Abstract
Pre-clinical models and clinical studies highlight the significant impact of the host-microbiota relationship on cancer development and treatment, supporting the emerging trend for a microbiota-based approach in clinical oncology. Importantly, the presence of polymorphic microbes is considered one of the hallmarks of cancer. The epigenetic regulation of gene expression by microRNAs affects crucial biological processes, including proliferation, differentiation, metabolism, and cell death. Recent evidence has documented the existence of bidirectional gut microbiota-microRNA interactions that play a critical role in intestinal homeostasis. Importantly, alterations in microRNA-modulated gene expression are known to be associated with inflammatory responses and dysbiosis in gastrointestinal disorders. In this review, we summarize the current findings about miRNA expression in the intestine and focus on specific gut microbiota-miRNA interactions linked to intestinal homeostasis, the immune system, and cancer development. We discuss the potential clinical utility of fecal miRNA profiling as a diagnostic and prognostic tool in colorectal cancer, and demonstrate how the emerging trend of gut microbiota modulation, together with the use of personalized microRNA therapeutics, might bring improvements in outcomes for patients with gastrointestinal cancer in the era of precision medicine.
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Affiliation(s)
- Nataliia Nikolaieva
- Department of Genetics, Cancer Research Institute, Biomedical Research Center of Slovak Academy of Sciences, 845 05 Bratislava, Slovakia
| | - Aneta Sevcikova
- Department of Genetics, Cancer Research Institute, Biomedical Research Center of Slovak Academy of Sciences, 845 05 Bratislava, Slovakia
| | - Radoslav Omelka
- Department of Botany and Genetics, Faculty of Natural Sciences and Informatics, Constantine the Philosopher University in Nitra, 949 74 Nitra, Slovakia
| | - Monika Martiniakova
- Department of Zoology and Anthropology, Faculty of Natural Sciences and Informatics, Constantine the Philosopher University in Nitra, 949 74 Nitra, Slovakia
| | - Michal Mego
- National Cancer Institute and Faculty of Medicine, Comenius University, 813 72 Bratislava, Slovakia
| | - Sona Ciernikova
- Department of Genetics, Cancer Research Institute, Biomedical Research Center of Slovak Academy of Sciences, 845 05 Bratislava, Slovakia
- Correspondence: ; Tel.: +421-02-3229519
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Dai YC, Qiao D, Fang CY, Chen QQ, Que RY, Xiao TG, Zheng L, Wang LJ, Zhang YL. Single-cell RNA-sequencing combined with bulk RNA-sequencing analysis of peripheral blood reveals the characteristics and key immune cell genes of ulcerative colitis. World J Clin Cases 2022; 10:12116-12135. [PMID: 36483809 PMCID: PMC9724533 DOI: 10.12998/wjcc.v10.i33.12116] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/26/2022] [Revised: 09/27/2022] [Accepted: 10/27/2022] [Indexed: 11/22/2022] Open
Abstract
BACKGROUND Ulcerative colitis (UC) is a complicated disease caused by the interaction between genetic and environmental factors that affects mucosal homeostasis and triggers an inappropriate immune response. Single-cell RNA sequencing (scRNA-seq) can be used to rapidly obtain the precise gene expression patterns of thousands of cells in the intestine, analyze the characteristics of cells with the same phenotype, and provide new insights into the growth and development of intestinal organs, the clonal evolution of cells, and immune cell changes. These findings can provide new ideas for the diagnosis and treatment of intestinal diseases. AIM To identify clinical phenotypes and biomarkers that can predict the response of UC patients to specific therapeutic drugs and thus aid the diagnosis and treatment of UC. METHODS Using the Gene Expression Omnibus (GEO) database, we analyzed peripheral blood cell subtypes of patients with UC by scRNA-seq combined with bulk RNA sequencing (RNA-seq) to reveal the core genes of UC. We then combined weighted gene correlation network analysis (WGCNA) and least absolute shrinkage and selection operator (LASSO) analysis to reveal diagnostic markers of UC. RESULTS After processing the scRNA-seq data, we obtained data from approximately 24340 cells and identified 17 cell types. Through intercellular communication analysis, we selected monocyte marker genes as the candidate gene set for the prediction model. Construction of a WGCNA coexpression network identified RhoB, cathepsin D (CTSD) and zyxin (ZYX) as core genes. Immune infiltration analysis showed that these three core genes were strongly correlated with immune cells. Functional enrichment analysis showed that the differentially expressed genes were closely related to immune and inflammatory responses, which are associated with many challenges in the diagnosis and treatment of UC. CONCLUSION Through scRNA-seq analysis, LASSO diagnostic model building and WGCNA, we identified RhoB, CTSD and ZYX as core genes of UC that are closely related to monocyte infiltration that may serve as diagnostic markers and molecular targets for UC therapeutic intervention.
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Affiliation(s)
- Yan-Cheng Dai
- Department of Gastroenterology, Shanghai Traditional Chinese Medicine-Integrated Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 200082, China
| | - Dan Qiao
- Department of Gastroenterology, Shanghai Traditional Chinese Medicine-Integrated Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 200082, China
| | - Chen-Ye Fang
- Department of Gastroenterology, Traditional Chinese Medicine Hospital of Ningbo, Ningbo 315000, Zhejiang Province, China
| | - Qiu-Qin Chen
- Department of Pathology, Shanghai Traditional Chinese Medicine-Integrated Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 200082, China
| | - Ren-Ye Que
- Department of Gastroenterology, Shanghai Traditional Chinese Medicine-Integrated Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 200082, China
| | - Tie-Gang Xiao
- Department of Gastroenterology, Shanghai Traditional Chinese Medicine-Integrated Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 200082, China
| | - Lie Zheng
- Department of Gastroenterology, Traditional Chinese Medicine Hospital of Xi’an 730000, Shaanxi Province, China
| | - Li-Juan Wang
- Experimental Education Center, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China
| | - Ya-Li Zhang
- Institute of Digestive Diseases, LongHua Hospital Shanghai University of Traditional Chinese Medicine, Shanghai 200032, China
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22
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Fan Y, Qin M, Zhu J, Chen X, Luo J, Chen T, Sun J, Zhang Y, Xi Q. MicroRNA sensing and regulating microbiota-host crosstalk via diet motivation. Crit Rev Food Sci Nutr 2022; 64:4116-4133. [PMID: 36287029 DOI: 10.1080/10408398.2022.2139220] [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] [Indexed: 11/03/2022]
Abstract
Accumulating evidence has demonstrated that diet-derived gut microbiota participates in the regulation of host metabolism and becomes the foundation for precision-based nutritional interventions and the biomarker for potential individual dietary recommendations. However, the specific mechanism of the gut microbiota-host crosstalk remains unclear. Recent studies have identified that noncoding RNAs, as important elements in the regulation of the initiation and termination of gene expression, mediate microbiota-host communication. Besides, the cross-kingdom regulation of non-host derived microRNAs also influence microbiota-host crosstalk via diet motivation. Hence, understanding the relationship between gut microbiota, miRNAs, and host metabolism is indispensable to revealing individual differences in dietary motivation and providing targeted recommendations and strategies. In this review, we first present an overview of the interaction between diet, host genetics, and gut microbiota and collected some latest research associated with microRNAs modulated gut microbiota and intestinal homeostasis. Then, specifically described the possible molecular mechanisms of microRNAs in sensing and regulating gut microbiota-host crosstalk. Lastly, summarized the prospect of microRNAs as biomarkers in disease diagnosis, and the disadvantages of microRNAs in regulating gut microbiota-host crosstalk. We speculated that microRNAs could become potential novel circulating biomarkers for personalized dietary strategies to achieve precise nutrition in future clinical research implications.
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Affiliation(s)
- Yaotian Fan
- Guangdong Provincial Key Laboratory of Animal Nutrition Control, National Engineering Research Center for Breeding Swine Industry, College of Animal Science, South China Agricultural University, Guangzhou, China
| | - Mengran Qin
- Guangdong Provincial Key Laboratory of Animal Nutrition Control, National Engineering Research Center for Breeding Swine Industry, College of Animal Science, South China Agricultural University, Guangzhou, China
| | - Jiahao Zhu
- Guangdong Provincial Key Laboratory of Animal Nutrition Control, National Engineering Research Center for Breeding Swine Industry, College of Animal Science, South China Agricultural University, Guangzhou, China
| | - Xingping Chen
- Guangdong Provincial Key Laboratory of Animal Nutrition Control, National Engineering Research Center for Breeding Swine Industry, College of Animal Science, South China Agricultural University, Guangzhou, China
- Key Laboratory of Animal Nutrition in Jiangxi Province, Jiangxi Agricultural University, Nanchang, China
| | - Junyi Luo
- Guangdong Provincial Key Laboratory of Animal Nutrition Control, National Engineering Research Center for Breeding Swine Industry, College of Animal Science, South China Agricultural University, Guangzhou, China
| | - Ting Chen
- Guangdong Provincial Key Laboratory of Animal Nutrition Control, National Engineering Research Center for Breeding Swine Industry, College of Animal Science, South China Agricultural University, Guangzhou, China
| | - Jiajie Sun
- Guangdong Provincial Key Laboratory of Animal Nutrition Control, National Engineering Research Center for Breeding Swine Industry, College of Animal Science, South China Agricultural University, Guangzhou, China
| | - Yongliang Zhang
- Guangdong Provincial Key Laboratory of Animal Nutrition Control, National Engineering Research Center for Breeding Swine Industry, College of Animal Science, South China Agricultural University, Guangzhou, China
| | - Qianyun Xi
- Guangdong Provincial Key Laboratory of Animal Nutrition Control, National Engineering Research Center for Breeding Swine Industry, College of Animal Science, South China Agricultural University, Guangzhou, China
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Zhao X, Cui DJ, Yang LC, Yuan WQ, Yan F. Long Noncoding RNA FBXL19-AS1-Mediated Ulcerative Colitis-Associated Intestinal Epithelial Barrier Defect. Tissue Eng Regen Med 2022; 19:1077-1088. [PMID: 36048401 PMCID: PMC9478015 DOI: 10.1007/s13770-022-00479-9] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/23/2022] [Revised: 06/18/2022] [Accepted: 07/04/2022] [Indexed: 10/14/2022] Open
Abstract
BACKGROUND This study commenced to uncover the role of long non-coding RNA FBXL19 antisense RNA 1 (FBXL19-AS1) in the development of ulcerative colitis (UC) and its possible mechanism. METHODS FBXL19-AS1 expression in the colonic sigmoid mucosa of UC patients was detected. A colitis model was induced in mice using 5% dextran sodium sulfate. Hematoxylin-eosin staining was performed for histopathological examination. Apoptosis was detected by Tunel staining and tissue fibrosis was detected by immunohistochemistry. Also, intestinal permeability was examined. The concentrations of inflammatory factors IL-1β and IL-18 were detected by enzyme-linked immunosorbent assay. The relationship between FBXL19-AS1, miR-339-3p and RHOB was verified by RNA immunoprecipitation assay and dual luciferase reporter assay. RESULTS The expression of FBXL19-AS1 was increased in dextran sodium sulfate (DSS)-induced colitis mouse model. FBXL19-AS1 interference or miR-339-3p overexpression inhibited DSS-induced colonic epithelial cell apoptosis and inflammatory response, and improved intestinal epithelial barrier defects, thereby ameliorating DSS-induced colitis injury in mice. FBXL19-AS1 sponged miR-339-3p while miR-339-3p targeted RHOB. Overexpression of RHOB reversed the protective effect of inhibition of FBXL19-AS1 on DSS-induced colitis in mice. CONCLUSION FBXL19-AS1 reduces miR-339-3p-mediated targeting of RHOB and aggravates intestinal epithelial barrier defect in DSS-induced colitis in mice.
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Affiliation(s)
- Xun Zhao
- Department of Gastroenterology, Guizhou Provincial People's Hospital, Medical College of Guizhou University, No. 83, East Zhongshan Road, Guiyang City, 550002, Guizhou Province, China.
| | - De-Jun Cui
- Department of Gastroenterology, Guizhou Provincial People's Hospital, Medical College of Guizhou University, No. 83, East Zhongshan Road, Guiyang City, 550002, Guizhou Province, China
| | - Liu-Chan Yang
- Department of Gastroenterology, Guizhou Provincial People's Hospital, Medical College of Guizhou University, No. 83, East Zhongshan Road, Guiyang City, 550002, Guizhou Province, China
| | - Wen-Qiang Yuan
- Department of Gastroenterology, Guizhou Provincial People's Hospital, Medical College of Guizhou University, No. 83, East Zhongshan Road, Guiyang City, 550002, Guizhou Province, China
| | - Fang Yan
- Department of Gastroenterology, Guizhou Provincial People's Hospital, Medical College of Guizhou University, No. 83, East Zhongshan Road, Guiyang City, 550002, Guizhou Province, China
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24
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Yang J, Pei G, Sun X, Xiao Y, Miao C, Zhou L, Wang B, Yang L, Yu M, Zhang ZS, Keller ET, Yao Z, Wang Q. RhoB affects colitis through modulating cell signaling and intestinal microbiome. MICROBIOME 2022; 10:149. [PMID: 36114582 PMCID: PMC9482252 DOI: 10.1186/s40168-022-01347-3] [Citation(s) in RCA: 19] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/07/2022] [Accepted: 08/09/2022] [Indexed: 05/28/2023]
Abstract
BACKGROUND The pathogenesis of inflammatory bowel diseases (IBD) is multifactorial, and diagnostic and treatment strategies for IBD remain to be developed. RhoB regulates multiple cell functions; however, its role in colitis is unexplored. RESULTS Here, we found RhoB was dramatically increased in colon tissues of ulcerative colitis (UC) patients and mice with DSS-induced colitis. Compared with wild type mice, RhoB+/- and RhoB-/- mice developed milder DSS-induced colitis and increased goblet cell numbers and IEC proliferation. Decreased RhoB promoted goblet cell differentiation and epithelial regeneration through inhibiting Wnt signaling pathway and activating p38 MAPK signaling pathway. Moreover, increased SCFA-producing bacteria and SCFA concentrations were detected in intestinal microbiome of both RhoB+/- and RhoB-/- mice and upregulated SCFA receptor expression was also observed. CONCLUSIONS Taken together, a higher level of RhoB is associated with UC, which also contributes to UC development through modulating cell signaling and altering intestinal bacterial composition and metabolites. These observations suggest that RhoB has potential as a biomarker and a treatment target for UC. Video Abstract.
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Affiliation(s)
- Jianming Yang
- Key Laboratory of Immune Microenvironment and Disease (Ministry of Education), Tianjin Institute of Immunology, Tianjin Institute of Urology, Department of Immunology, School of Basic Medical Sciences, Tianjin Medical University, 22 Qixiangtai Road, Heping District 300070, Tianjin, 300070, China
| | - Geng Pei
- Key Laboratory of Immune Microenvironment and Disease (Ministry of Education), Tianjin Institute of Immunology, Tianjin Institute of Urology, Department of Immunology, School of Basic Medical Sciences, Tianjin Medical University, 22 Qixiangtai Road, Heping District 300070, Tianjin, 300070, China
| | - Xuan Sun
- Key Laboratory of Immune Microenvironment and Disease (Ministry of Education), Tianjin Institute of Immunology, Tianjin Institute of Urology, Department of Immunology, School of Basic Medical Sciences, Tianjin Medical University, 22 Qixiangtai Road, Heping District 300070, Tianjin, 300070, China
| | - Yawen Xiao
- Key Laboratory of Immune Microenvironment and Disease (Ministry of Education), Tianjin Institute of Immunology, Tianjin Institute of Urology, Department of Immunology, School of Basic Medical Sciences, Tianjin Medical University, 22 Qixiangtai Road, Heping District 300070, Tianjin, 300070, China
| | - Chunhui Miao
- Key Laboratory of Immune Microenvironment and Disease (Ministry of Education), Tianjin Institute of Immunology, Tianjin Institute of Urology, Department of Immunology, School of Basic Medical Sciences, Tianjin Medical University, 22 Qixiangtai Road, Heping District 300070, Tianjin, 300070, China
| | - Lu Zhou
- Department of Gastroenterology and Hepatology, Tianjin Medical University general hospital, Tianjin Medical University, Tianjin, 300070, China
| | - Bangmao Wang
- Department of Gastroenterology and Hepatology, Tianjin Medical University general hospital, Tianjin Medical University, Tianjin, 300070, China
| | - Liu Yang
- Key Laboratory of Immune Microenvironment and Disease (Ministry of Education), Tianjin Institute of Immunology, Tianjin Institute of Urology, Department of Immunology, School of Basic Medical Sciences, Tianjin Medical University, 22 Qixiangtai Road, Heping District 300070, Tianjin, 300070, China
| | - Mingyu Yu
- Key Laboratory of Immune Microenvironment and Disease (Ministry of Education), Tianjin Institute of Immunology, Tianjin Institute of Urology, Department of Immunology, School of Basic Medical Sciences, Tianjin Medical University, 22 Qixiangtai Road, Heping District 300070, Tianjin, 300070, China
| | - Zhi-Song Zhang
- State Key Laboratory of Medicinal Chemical Biology and College of Pharmacy, Collaborative Innovation Center for Biotherapy, Tianjin Key Laboratory of Molecular Drug Research, Nankai University, Tianjin, 300350, China
| | - Evan T Keller
- Department of Urology, Biointerfaces Institute, University of Michigan, Ann Arbor, MI, USA
| | - Zhi Yao
- Key Laboratory of Immune Microenvironment and Disease (Ministry of Education), Tianjin Institute of Immunology, Tianjin Institute of Urology, Department of Immunology, School of Basic Medical Sciences, Tianjin Medical University, 22 Qixiangtai Road, Heping District 300070, Tianjin, 300070, China
- The Province and Ministry Co-sponsored Collaborative Innovation Center for Medical Epigenetics, Tianjin Medical University, Tianjin, 300070, China
| | - Quan Wang
- Key Laboratory of Immune Microenvironment and Disease (Ministry of Education), Tianjin Institute of Immunology, Tianjin Institute of Urology, Department of Immunology, School of Basic Medical Sciences, Tianjin Medical University, 22 Qixiangtai Road, Heping District 300070, Tianjin, 300070, China.
- The Province and Ministry Co-sponsored Collaborative Innovation Center for Medical Epigenetics, Tianjin Medical University, Tianjin, 300070, China.
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Dong Y, Xu T, Xiao G, Hu Z, Chen J. Opportunities and challenges for synthetic biology in the therapy of inflammatory bowel disease. Front Bioeng Biotechnol 2022; 10:909591. [PMID: 36032720 PMCID: PMC9399643 DOI: 10.3389/fbioe.2022.909591] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2022] [Accepted: 07/15/2022] [Indexed: 11/13/2022] Open
Abstract
Inflammatory bowel disease (IBD) is a complex, chronic intestinal inflammatory disorder that primarily includes Crohn’s disease (CD) and ulcerative colitis (UC). Although traditional antibiotics and immunosuppressants are known as the most effective and commonly used treatments, some limitations may be expected, such as limited efficacy in a small number of patients and gut flora disruption. A great many research studies have been done with respect to the etiology of IBD, while the composition of the gut microbiota is suggested as one of the most influential factors. Along with the development of synthetic biology and the continuing clarification of IBD etiology, broader prospects for novel approaches to IBD therapy could be obtained. This study presents an overview of the currently existing treatment options and possible therapeutic targets at the preclinical stage with respect to microbial synthesis technology in biological therapy. This study is highly correlated to the following topics: microbiota-derived metabolites, microRNAs, cell therapy, calreticulin, live biotherapeutic products (LBP), fecal microbiota transplantation (FMT), bacteriophages, engineered bacteria, and their functional secreted synthetic products for IBD medical implementation. Considering microorganisms as the main therapeutic component, as a result, the related clinical trial stability, effectiveness, and safety analysis may be the major challenges for upcoming research. This article strives to provide pharmaceutical researchers and developers with the most up-to-date information for adjuvant medicinal therapies based on synthetic biology.
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Affiliation(s)
- Yumeng Dong
- College of Food Science and Nutritional Engineering, China Agricultural University, Beijing, China
- Suzhou U-Synbio Co., Ltd., Suzhou, China
| | - Tiangang Xu
- College of Food Science and Nutritional Engineering, China Agricultural University, Beijing, China
| | - Guozheng Xiao
- College of Food Science and Nutritional Engineering, China Agricultural University, Beijing, China
| | - Ziyan Hu
- College of Food Science and Nutritional Engineering, China Agricultural University, Beijing, China
| | - Jingyu Chen
- College of Food Science and Nutritional Engineering, China Agricultural University, Beijing, China
- *Correspondence: Jingyu Chen,
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26
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Yarani R, Shojaeian A, Palasca O, Doncheva NT, Jensen LJ, Gorodkin J, Pociot F. Differentially Expressed miRNAs in Ulcerative Colitis and Crohn’s Disease. Front Immunol 2022; 13:865777. [PMID: 35734163 PMCID: PMC9208551 DOI: 10.3389/fimmu.2022.865777] [Citation(s) in RCA: 31] [Impact Index Per Article: 10.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2022] [Accepted: 04/13/2022] [Indexed: 12/14/2022] Open
Abstract
Differential microRNA (miRNA or miR) regulation is linked to the development and progress of many diseases, including inflammatory bowel disease (IBD). It is well-established that miRNAs are involved in the differentiation, maturation, and functional control of immune cells. miRNAs modulate inflammatory cascades and affect the extracellular matrix, tight junctions, cellular hemostasis, and microbiota. This review summarizes current knowledge of differentially expressed miRNAs in mucosal tissues and peripheral blood of patients with ulcerative colitis and Crohn’s disease. We combined comprehensive literature curation with computational meta-analysis of publicly available high-throughput datasets to obtain a consensus set of miRNAs consistently differentially expressed in mucosal tissues. We further describe the role of the most relevant differentially expressed miRNAs in IBD, extract their potential targets involved in IBD, and highlight their diagnostic and therapeutic potential for future investigations.
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Affiliation(s)
- Reza Yarani
- Translational Type 1 Diabetes Research, Department of Clinical Research, Steno Diabetes Center Copenhagen, Gentofte, Denmark
- Interventional Regenerative Medicine and Imaging Laboratory, Department of Radiology, Stanford University School of Medicine, Palo Alto, CA, United States
- *Correspondence: Reza Yarani, ; Flemming Pociot,
| | - Ali Shojaeian
- Research Center for Molecular Medicine, Hamadan University of Medical Sciences, Hamadan, Iran
| | - Oana Palasca
- Novo Nordisk Foundation Center for Protein Research, University of Copenhagen, Copenhagen, Denmark
- Center for Non-Coding RNA in Technology and Health, University of Copenhagen, Copenhagen, Denmark
- Department of Veterinary and Animal Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Nadezhda T. Doncheva
- Novo Nordisk Foundation Center for Protein Research, University of Copenhagen, Copenhagen, Denmark
- Center for Non-Coding RNA in Technology and Health, University of Copenhagen, Copenhagen, Denmark
- Department of Veterinary and Animal Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Lars Juhl Jensen
- Novo Nordisk Foundation Center for Protein Research, University of Copenhagen, Copenhagen, Denmark
- Center for Non-Coding RNA in Technology and Health, University of Copenhagen, Copenhagen, Denmark
| | - Jan Gorodkin
- Center for Non-Coding RNA in Technology and Health, University of Copenhagen, Copenhagen, Denmark
- Department of Veterinary and Animal Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Flemming Pociot
- Translational Type 1 Diabetes Research, Department of Clinical Research, Steno Diabetes Center Copenhagen, Gentofte, Denmark
- Center for Non-Coding RNA in Technology and Health, University of Copenhagen, Copenhagen, Denmark
- Copenhagen Diabetes Research Center, Department of Pediatrics, Herlev University Hospital, Herlev, Denmark
- Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
- *Correspondence: Reza Yarani, ; Flemming Pociot,
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27
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Wu G, Zhang D, Yang L, Wu Q, Yuan L. MicroRNA-200c-5p targets NIMA Related Kinase 7 (NEK7) to inhibit NOD-like receptor 3 (NLRP3) inflammasome activation, MODE-K cell pyroptosis, and inflammatory bowel disease in mice. Mol Immunol 2022; 146:57-68. [DOI: 10.1016/j.molimm.2022.03.121] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/19/2021] [Revised: 03/21/2022] [Accepted: 03/27/2022] [Indexed: 12/30/2022]
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EpisomiR, a New Family of miRNAs, and Its Possible Roles in Human Diseases. Biomedicines 2022; 10:biomedicines10061280. [PMID: 35740302 PMCID: PMC9220071 DOI: 10.3390/biomedicines10061280] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/27/2022] [Revised: 05/24/2022] [Accepted: 05/26/2022] [Indexed: 11/26/2022] Open
Abstract
MicroRNAs (miRNAs) are synthesized through a canonical pathway and play a role in human diseases, such as cancers and cardiovascular, neurodegenerative, psychiatric, and chronic inflammatory diseases. The development of sequencing technologies has enabled the identification of variations in noncoding miRNAs. These miRNA variants, called isomiRs, are generated through a non-canonical pathway, by several enzymes that alter the length and sequence of miRNAs. The isomiR family is, now, expanding further to include episomiRs, which are miRNAs with different modifications. Since recent findings have shown that isomiRs reflect the cell-specific biological function of miRNAs, knowledge about episomiRs and isomiRs can, possibly, contribute to the optimization of diagnosis and therapeutic technology for precision medicine.
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29
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Moonwiriyakit A, Pathomthongtaweechai N, Steinhagen PR, Chantawichitwong P, Satianrapapong W, Pongkorpsakol P. Tight junctions: from molecules to gastrointestinal diseases. Tissue Barriers 2022; 11:2077620. [PMID: 35621376 PMCID: PMC10161963 DOI: 10.1080/21688370.2022.2077620] [Citation(s) in RCA: 42] [Impact Index Per Article: 14.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/18/2022] Open
Abstract
Intestinal epithelium functions as a tissue barrier to prevent interaction between the internal compartment and the external milieu. Intestinal barrier function also determines epithelial polarity for the absorption of nutrients and the secretion of waste products. These vital functions require strong integrity of tight junction proteins. In fact, intestinal tight junctions that seal the paracellular space can restrict mucosal-to-serosal transport of hostile luminal contents. Tight junctions can form both an absolute barrier and a paracellular ion channel. Although defective tight junctions potentially lead to compromised intestinal barrier and the development and progression of gastrointestinal (GI) diseases, no FDA-approved therapies that recover the epithelial tight junction barrier are currently available in clinical practice. Here, we discuss the impacts and regulatory mechanisms of tight junction disruption in the gut and related diseases. We also provide an overview of potential therapeutic targets to restore the epithelial tight junction barrier in the GI tract.
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Affiliation(s)
- Aekkacha Moonwiriyakit
- Chakri Naruebodindra Medical Institute, Faculty of Medicine Ramathibodi Hospital, Mahidol University, Samut Prakan, Thailand
| | - Nutthapoom Pathomthongtaweechai
- Chakri Naruebodindra Medical Institute, Faculty of Medicine Ramathibodi Hospital, Mahidol University, Samut Prakan, Thailand
| | - Peter R Steinhagen
- Department of Hepatology and Gastroenterology, Charité Medical School, Berlin, Germany
| | | | | | - Pawin Pongkorpsakol
- Princess Srisavangavadhana College of Medicine, Chulabhorn Royal Academy, Bangkok, Thailand
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30
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Xiao X, Mao X, Chen D, Yu B, He J, Yan H, Wang J. miRNAs Can Affect Intestinal Epithelial Barrier in Inflammatory Bowel Disease. Front Immunol 2022; 13:868229. [PMID: 35493445 PMCID: PMC9043318 DOI: 10.3389/fimmu.2022.868229] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/02/2022] [Accepted: 03/18/2022] [Indexed: 11/17/2022] Open
Abstract
The most obvious pathological characterization of inflammatory bowel disease (IBD) is intestinal epithelium erosion and severe inflammation invasion. Micro-ribonucleic acids (miRNA or microRNA), single-stranded noncoding RNAs of ~22 nucleotides, have been considered as the potential therapeutic targets in the pathogenesis of IBD. Many previous studies have focused on the mechanisms that miRNAs use to regulate inflammation, immunity, and microorganisms in IBD. The review highlights in detail the findings of miRNAs in the intestinal epithelial barrier of IBD, and focuses on their gene targets, signaling pathways associated with IBD, and some potential therapies. It will be beneficial for the elucidation of the interaction between miRNAs and the intestinal epithelial barrier in IBD and provide a theoretical reference for preventing and treating IBD in the future.
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Affiliation(s)
- Xiangjun Xiao
- Institute of Animal Nutrition, Sichuan Agricultural University, Key Laboratory for Animal Disease-Resistance Nutrition of China Ministry of Education, Key Laboratory of Animal Disease-Resistant Nutrition and Feed of China Ministry of Agriculture and Rural Affairs, Key Laboratory of Animal Disease-Resistant Nutrition of Sichuan Province, Chengdu, China
| | - Xiangbing Mao
- Institute of Animal Nutrition, Sichuan Agricultural University, Key Laboratory for Animal Disease-Resistance Nutrition of China Ministry of Education, Key Laboratory of Animal Disease-Resistant Nutrition and Feed of China Ministry of Agriculture and Rural Affairs, Key Laboratory of Animal Disease-Resistant Nutrition of Sichuan Province, Chengdu, China
| | - Daiwen Chen
- Institute of Animal Nutrition, Sichuan Agricultural University, Key Laboratory for Animal Disease-Resistance Nutrition of China Ministry of Education, Key Laboratory of Animal Disease-Resistant Nutrition and Feed of China Ministry of Agriculture and Rural Affairs, Key Laboratory of Animal Disease-Resistant Nutrition of Sichuan Province, Chengdu, China
| | - Bing Yu
- Institute of Animal Nutrition, Sichuan Agricultural University, Key Laboratory for Animal Disease-Resistance Nutrition of China Ministry of Education, Key Laboratory of Animal Disease-Resistant Nutrition and Feed of China Ministry of Agriculture and Rural Affairs, Key Laboratory of Animal Disease-Resistant Nutrition of Sichuan Province, Chengdu, China
| | - Jun He
- Institute of Animal Nutrition, Sichuan Agricultural University, Key Laboratory for Animal Disease-Resistance Nutrition of China Ministry of Education, Key Laboratory of Animal Disease-Resistant Nutrition and Feed of China Ministry of Agriculture and Rural Affairs, Key Laboratory of Animal Disease-Resistant Nutrition of Sichuan Province, Chengdu, China
| | - Hui Yan
- Institute of Animal Nutrition, Sichuan Agricultural University, Key Laboratory for Animal Disease-Resistance Nutrition of China Ministry of Education, Key Laboratory of Animal Disease-Resistant Nutrition and Feed of China Ministry of Agriculture and Rural Affairs, Key Laboratory of Animal Disease-Resistant Nutrition of Sichuan Province, Chengdu, China
| | - Jianping Wang
- Institute of Animal Nutrition, Sichuan Agricultural University, Key Laboratory for Animal Disease-Resistance Nutrition of China Ministry of Education, Key Laboratory of Animal Disease-Resistant Nutrition and Feed of China Ministry of Agriculture and Rural Affairs, Key Laboratory of Animal Disease-Resistant Nutrition of Sichuan Province, Chengdu, China
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Mohammad Rahimi H, Yadegar A, Asadzadeh Aghdaei H, Mirjalali H, Zali MR. Modulation of microRNAs and claudin-7 in Caco-2 cell line treated with Blastocystis sp., subtype 3 soluble total antigen. BMC Microbiol 2022; 22:111. [PMID: 35459091 PMCID: PMC9027909 DOI: 10.1186/s12866-022-02528-8] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/09/2022] [Accepted: 04/13/2022] [Indexed: 12/15/2022] Open
Abstract
Background Blastocystis sp., is a eukaryote of the large intestine, which is reported from almost all countries. The pathogenesis of this protist is not clear. The current study aimed to analyze the effects of Blastocystis sp., ST3 soluble total antigen (B3STA) on the microRNAs (miRNAs) involved in the gut permeability and also pro-inflammatory cytokines, occludin, and claudin-7. Methods Blastocystis sp., ST3 isolated from stool sample was purified, and its soluble total antigen was extracted using freeze and thawing. The Caco-2 cell line was treated with B3STA for 24 h and the expression levels of mir-16, mir-21, mir-29a, mir-223, and mir-874 were analyzed. In addition, the expression levels of il-8, il-15, occludin, and claudin-7 genes were assessed. Results B3STA significantly upregulated the expression of mir-223, and mir-874, and downregulated mir-29a. The expression of mir-16 and mir-21 was not significant. In addition, the expression of il-8 and il-15 was not significant. B3STA significantly decreased the expression level of claudin-7 (P-value < 0.0001), but the expression of occludin was not significant. Our results showed significant correlation between all studied miRNAs, except mir-29a, with downregulation of claudin-7. Conclusions This is the first study investigating the effects of Blastocystis sp., ST3 isolated from symptomatic subjects on the expression levels of miRNAs involved in the gut permeability. Our results demonstrated that B3STA may change miRNA expression, which are involved in the gut barrier integrity, and downregulates claudin-7, which is known as sealing factor.
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Affiliation(s)
- Hanieh Mohammad Rahimi
- Foodborne and Waterborne Diseases Research Center, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Abbas Yadegar
- Foodborne and Waterborne Diseases Research Center, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Hamid Asadzadeh Aghdaei
- Basic and Molecular Epidemiology of Gastrointestinal Disorders Research Center, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Hamed Mirjalali
- Foodborne and Waterborne Diseases Research Center, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
| | - Mohammad Reza Zali
- Gastroenterology and Liver Diseases Research Center, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran, Iran
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Casado-Bedmar M, Viennois E. MicroRNA and Gut Microbiota: Tiny but Mighty-Novel Insights into Their Cross-talk in Inflammatory Bowel Disease Pathogenesis and Therapeutics. J Crohns Colitis 2021; 16:992-1005. [PMID: 34918052 PMCID: PMC9282881 DOI: 10.1093/ecco-jcc/jjab223] [Citation(s) in RCA: 42] [Impact Index Per Article: 10.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/12/2021] [Revised: 12/06/2021] [Accepted: 12/14/2021] [Indexed: 12/24/2022]
Abstract
MicroRNAs [miRNAs], small non-coding RNAs, have recently been described as crucial contributors to intestinal homeostasis. They can interact with the gut microbiota in a reciprocal manner and deeply affect host health status, leading to several disorders when unbalanced. Inflammatory bowel disease [IBD] is a chronic inflammation of the gastrointestinal tract that co-occurs with alterations of the gut microbiota, and whose aetiology remains largely unclear. On one hand, host miRNA could be playing a relevant role in IBD pathophysiology by shaping the gut microbiota. The gut microbiome, on the other hand, may regulate the expression of host miRNAs, resulting in intestinal epithelial dysfunction, altered autophagy, and immune hyperactivation. Interestingly, it has been hypothesised that their reciprocal impact may be used for therapeutic goals. This review describes the latest research and suggests mechanisms through which miRNA and intestinal microbiota, as joint actors, may participate specifically in IBD pathophysiology. Furthermore, we discuss the diagnostic power and therapeutic potential resulting from their bidirectional communication after faecal transplantation, probiotics intake, or anti-miRNAs or miRNA mimics administration. The current literature is summarised in the present work in a comprehensive manner, hoping to provide a better understanding of the miRNA-microbiota cross-talk and to facilitate their application in IBD.
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Affiliation(s)
- Maite Casado-Bedmar
- INSERM, U1149, Center for Research on Inflammation, Université de Paris, Paris, France
| | - Emilie Viennois
- Corresponding author: Emilie Viennois, INSERM, U1149, Center for Research on Inflammation, Université de Paris, 75018 Paris, France.
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Role of microRNAs in the Pathophysiology of Ulcerative Colitis. IMMUNO 2021. [DOI: 10.3390/immuno1040039] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/17/2022] Open
Abstract
Ulcerative colitis (UC) is an intractable disorder characterized by a chronic inflammation of the colon. Studies have identified UC as a multifactorial disorder affected by both genetic and environmental factors; however, the precise mechanism remains unclear. Recent advances in the field of microRNA (miRNA) research have identified an association between this small non-coding RNA in the pathophysiology of UC and altered miRNA expression profiles in patients with UC. Nevertheless, the roles of individual miRNAs are uncertain due to heterogeneity in both research samples and clinical backgrounds. In this review, we focus on miRNA expression in colonic mucosa where inflammation occurs in UC and discuss the potential roles of individual miRNAs in disease development, outlining the pathophysiology of UC.
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The Impact of MicroRNAs during Inflammatory Bowel Disease: Effects on the Mucus Layer and Intercellular Junctions for Gut Permeability. Cells 2021; 10:cells10123358. [PMID: 34943865 PMCID: PMC8699384 DOI: 10.3390/cells10123358] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2021] [Revised: 11/23/2021] [Accepted: 11/25/2021] [Indexed: 12/15/2022] Open
Abstract
Research on inflammatory bowel disease (IBD) has produced mounting evidence for the modulation of microRNAs (miRNAs) during pathogenesis. MiRNAs are small, non-coding RNAs that interfere with the translation of mRNAs. Their high stability in free circulation at various regions of the body allows researchers to utilise miRNAs as biomarkers and as a focus for potential treatments of IBD. Yet, their distinct regulatory roles at the gut epithelial barrier remain elusive due to the fact that there are several external and cellular factors contributing to gut permeability. This review focuses on how miRNAs may compromise two components of the gut epithelium that together form the initial physical barrier: the mucus layer and the intercellular epithelial junctions. Here, we summarise the impact of miRNAs on goblet cell secretion and mucin structure, along with the proper function of various junctional proteins involved in paracellular transport, cell adhesion and communication. Knowledge of how this elaborate network of cells at the gut epithelial barrier becomes compromised as a result of dysregulated miRNA expression, thereby contributing to the development of IBD, will support the generation of miRNA-associated biomarker panels and therapeutic strategies that detect and ameliorate gut permeability.
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Yao D, Zhou Z, Wang P, Zheng L, Huang Y, Duan Y, Liu B, Li Y. MiR-125-5p/IL-6R axis regulates macrophage inflammatory response and intestinal epithelial cell apoptosis in ulcerative colitis through JAK1/STAT3 and NF-κB pathway. Cell Cycle 2021; 20:2547-2564. [PMID: 34747340 DOI: 10.1080/15384101.2021.1995128] [Citation(s) in RCA: 21] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2023] Open
Abstract
This study explored the effects of miR-125-5p and interleukin-6 receptor (IL-6 R) on ulcerative colitis (UC) cell models and mouse models. The sera derived from UC patients and healthy subjects were collected for expression analysis. UC in vitro models and in vivo model were constructed and used. Expressions of miR-125-5p, IL-6 R, AK1/STAT3 and NF-κB pathways, and inflammatory factors, histopathology and apoptosis were determined by conducting a series of molecular experiments. The relationship between miR-125-5p and IL-6 R was analyzed by TargetScan7.2 and verified by dual-luciferase assay. The disease activity index (DAI) score, weight change, and colon length of the mice were recorded and analyzed. Decreased expression of miR-125-5p in the sera of UC patients was related to the increased expression of its target gene IL-6 R. In vitro, up-regulation of miR-125-5p decreased IL-6 R expression, contents of inflammatory factors in THP-1 cells and cell apoptosis of NCM460, and inhibited the activation of JAK1/STAT3 and NF-κB pathway. However, down-regulation of miR-125-5p produced the opposite effects to its up-regulation. IL-6 R overexpression partially reversed the effects of miR-125-5p up-regulation on UC cell models. In vivo, miR-125-5p overexpression significantly improved the severity of colitis, including DAI score, colon length, tissue damage, apoptosis, and inflammatory response, in the mice in the UC group. In addition, miR-125-5p up-regulation significantly reduced the expression of IL-6 R in the UC mice, and reduced the expression levels of JAK1, STAT3 and p65 phosphorylation. MiR-125-5p targeting IL-6 R regulates macrophage inflammatory response and intestinal epithelial cell apoptosis in ulcerative colitis through JAK1/STAT3 and NF-κB pathway.
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Affiliation(s)
- Danhua Yao
- Department of General Surgery, Shanghai Ninth People's Hospital, Shanghai JiaoTong University School of Medicine, Shanghai, China
| | - Zhiyuan Zhou
- Department of General Surgery, Shanghai Ninth People's Hospital, Shanghai JiaoTong University School of Medicine, Shanghai, China
| | - Pengfei Wang
- Department of General Surgery, Shanghai Ninth People's Hospital, Shanghai JiaoTong University School of Medicine, Shanghai, China
| | - Lei Zheng
- Department of General Surgery, Shanghai Ninth People's Hospital, Shanghai JiaoTong University School of Medicine, Shanghai, China
| | - Yuhua Huang
- Department of General Surgery, Shanghai Ninth People's Hospital, Shanghai JiaoTong University School of Medicine, Shanghai, China
| | - Yantao Duan
- Department of General Surgery, Shanghai Ninth People's Hospital, Shanghai JiaoTong University School of Medicine, Shanghai, China
| | - Bin Liu
- Department of General Surgery, Shanghai Ninth People's Hospital, Shanghai JiaoTong University School of Medicine, Shanghai, China
| | - Yousheng Li
- Department of General Surgery, Shanghai Ninth People's Hospital, Shanghai JiaoTong University School of Medicine, Shanghai, China
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Lai CY, Yeh KY, Liu BF, Chang TM, Chang CH, Liao YF, Liu YW, Her GM. MicroRNA-21 Plays Multiple Oncometabolic Roles in Colitis-Associated Carcinoma and Colorectal Cancer via the PI3K/AKT, STAT3, and PDCD4/TNF-α Signaling Pathways in Zebrafish. Cancers (Basel) 2021; 13:5565. [PMID: 34771727 PMCID: PMC8583575 DOI: 10.3390/cancers13215565] [Citation(s) in RCA: 21] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/17/2021] [Revised: 11/02/2021] [Accepted: 11/02/2021] [Indexed: 01/05/2023] Open
Abstract
Colorectal cancer (CRC) is a leading cause of cancer-related mortality worldwide. Patients with inflammatory bowel disease (IBD) have a high risk of developing CRC. Inflammatory cytokines are regulated by complex gene networks and regulatory RNAs, especially microRNAs. MicroRNA-21 (miR-21) is amongst the most frequently upregulated microRNAs in inflammatory responses and cancer development. miR-21 has become a target for genetic and pharmacological regulation in various diseases. However, the association between inflammation and tumorigenesis in the gut is largely unknown. Hence, in this study, we generated a zebrafish model (ImiR-21) with inducible overexpression of miR-21 in the intestine. The results demonstrate that miR-21 can induce CRC or colitis-associated cancer (CAC) in ImiR-21 through the PI3K/AKT, PDCD4/TNF-α, and IL-6/STAT3 signaling network. miR-21 activated the PI3K/AKT and NF-κB signaling pathways, leading to initial inflammation; thereafter, miR-21 and TNF-α repressed PDCD4 and its tumor suppression activity. Eventually, active STAT3 stimulated a strong inflammatory response and activated the invasion/metastasis process of tumor cells. Hence, our findings indicate that miR-21 is critical for the development of CRC/CAC via the PI3K/AKT, STAT3, and PDCD4/TNF-α signaling networks.
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Affiliation(s)
- Chi-Yu Lai
- Institute of Biopharmaceutical Sciences, National Yang Ming Chiao Tung University, Taipei 112, Taiwan; (C.-Y.L.); (B.-F.L.); (Y.-W.L.)
| | - Kun-Yun Yeh
- Division of Hemato-Oncology, Department of Internal Medicine, Chang-Chung Memorial Hospital, Keelung 204, Taiwan;
| | - Bi-Feng Liu
- Institute of Biopharmaceutical Sciences, National Yang Ming Chiao Tung University, Taipei 112, Taiwan; (C.-Y.L.); (B.-F.L.); (Y.-W.L.)
| | - Tzu-Ming Chang
- Division of Surgical Oncology, Department of Surgery, Cheng Hsin General Hospital, Taipei 112, Taiwan; (T.-M.C.); (C.-H.C.)
| | - Chuan-Hsun Chang
- Division of Surgical Oncology, Department of Surgery, Cheng Hsin General Hospital, Taipei 112, Taiwan; (T.-M.C.); (C.-H.C.)
- Division of General Surgery, Cheng Hsin General Hospital, Taipei 112, Taiwan
| | - Yung-Feng Liao
- Laboratory of Molecular Neurobiology, Institute of Cellular and Organismic Biology, Academia Sinica, ICOB 238, 128 Sec. 2 Academia Rd., Taipei 11529, Taiwan;
| | - Yi-Wen Liu
- Institute of Biopharmaceutical Sciences, National Yang Ming Chiao Tung University, Taipei 112, Taiwan; (C.-Y.L.); (B.-F.L.); (Y.-W.L.)
| | - Guor Mour Her
- Institute of Biopharmaceutical Sciences, National Yang Ming Chiao Tung University, Taipei 112, Taiwan; (C.-Y.L.); (B.-F.L.); (Y.-W.L.)
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Fortea M, Albert-Bayo M, Abril-Gil M, Ganda Mall JP, Serra-Ruiz X, Henao-Paez A, Expósito E, González-Castro AM, Guagnozzi D, Lobo B, Alonso-Cotoner C, Santos J. Present and Future Therapeutic Approaches to Barrier Dysfunction. Front Nutr 2021; 8:718093. [PMID: 34778332 PMCID: PMC8582318 DOI: 10.3389/fnut.2021.718093] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2021] [Accepted: 09/29/2021] [Indexed: 12/12/2022] Open
Abstract
There is converging and increasing evidence, but also uncertainty, for the role of abnormal intestinal epithelial barrier function in the origin and development of a growing number of human gastrointestinal and extraintestinal inflammatory disorders, and their related complaints. Despite a vast literature addressing factors and mechanisms underlying changes in intestinal permeability in humans, and its connection to the appearance and severity of clinical symptoms, the ultimate link remains to be established in many cases. Accordingly, there are no directives or clinical guidelines related to the therapeutic management of intestinal permeability disorders that allow health professionals involved in the management of these patients to carry out a consensus treatment based on clinical evidence. Instead, there are multiple pseudoscientific approaches and commercial propaganda scattered on the internet that confuse those affected and health professionals and that often lack scientific rigor. Therefore, in this review we aim to shed light on the different therapeutic options, which include, among others, dietary management, nutraceuticals and medical devices, microbiota and drugs, and epigenetic and exosomes-manipulation, through an objective evaluation of the scientific publications in this field. Advances in the knowledge and management of intestinal permeability will sure enable better options of dealing with this group of common disorders to enhance quality of life of those affected.
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Affiliation(s)
- Marina Fortea
- Laboratory for Enteric NeuroScience, Translational Research Center for GastroIntestinal Disorders, University of Leuven, Leuven, Belgium
| | - Mercé Albert-Bayo
- Laboratory of Neuro-Immuno-Gastroenterology, Digestive System Research Unit, Vall d'Hebron Institut de Recerca (VHIR), Vall d'Hebron Hospital Universitari, Barcelona, Spain
| | - Mar Abril-Gil
- Laboratory of Neuro-Immuno-Gastroenterology, Digestive System Research Unit, Vall d'Hebron Institut de Recerca (VHIR), Vall d'Hebron Hospital Universitari, Barcelona, Spain
| | - John-Peter Ganda Mall
- Laboratory of Neuro-Immuno-Gastroenterology, Digestive System Research Unit, Vall d'Hebron Institut de Recerca (VHIR), Vall d'Hebron Hospital Universitari, Barcelona, Spain
- Department of Biomedical and Clinical Sciences, Linköping University, Linköping, Sweden
| | - Xavier Serra-Ruiz
- Department of Gastroenterology, Vall d'Hebron Hospital Universitari, Barcelona, Spain
| | - Alejandro Henao-Paez
- Department of Gastroenterology, Vall d'Hebron Hospital Universitari, Barcelona, Spain
| | - Elba Expósito
- Laboratory of Neuro-Immuno-Gastroenterology, Digestive System Research Unit, Vall d'Hebron Institut de Recerca (VHIR), Vall d'Hebron Hospital Universitari, Barcelona, Spain
| | - Ana María González-Castro
- Laboratory of Neuro-Immuno-Gastroenterology, Digestive System Research Unit, Vall d'Hebron Institut de Recerca (VHIR), Vall d'Hebron Hospital Universitari, Barcelona, Spain
| | - Danila Guagnozzi
- Laboratory of Neuro-Immuno-Gastroenterology, Digestive System Research Unit, Vall d'Hebron Institut de Recerca (VHIR), Vall d'Hebron Hospital Universitari, Barcelona, Spain
- Department of Gastroenterology, Vall d'Hebron Hospital Universitari, Barcelona, Spain
- Facultad de Medicina, Universitat Autònoma de Barcelona, Bellaterra, Spain
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERHED), Instituto de Salud Carlos III, Madrid, Spain
| | - Beatriz Lobo
- Laboratory of Neuro-Immuno-Gastroenterology, Digestive System Research Unit, Vall d'Hebron Institut de Recerca (VHIR), Vall d'Hebron Hospital Universitari, Barcelona, Spain
- Department of Gastroenterology, Vall d'Hebron Hospital Universitari, Barcelona, Spain
- Facultad de Medicina, Universitat Autònoma de Barcelona, Bellaterra, Spain
| | - Carmen Alonso-Cotoner
- Laboratory of Neuro-Immuno-Gastroenterology, Digestive System Research Unit, Vall d'Hebron Institut de Recerca (VHIR), Vall d'Hebron Hospital Universitari, Barcelona, Spain
- Department of Gastroenterology, Vall d'Hebron Hospital Universitari, Barcelona, Spain
- Facultad de Medicina, Universitat Autònoma de Barcelona, Bellaterra, Spain
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERHED), Instituto de Salud Carlos III, Madrid, Spain
| | - Javier Santos
- Laboratory of Neuro-Immuno-Gastroenterology, Digestive System Research Unit, Vall d'Hebron Institut de Recerca (VHIR), Vall d'Hebron Hospital Universitari, Barcelona, Spain
- Department of Gastroenterology, Vall d'Hebron Hospital Universitari, Barcelona, Spain
- Facultad de Medicina, Universitat Autònoma de Barcelona, Bellaterra, Spain
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERHED), Instituto de Salud Carlos III, Madrid, Spain
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Role of MicroRNA in Inflammatory Bowel Disease: Clinical Evidence and the Development of Preclinical Animal Models. Cells 2021; 10:cells10092204. [PMID: 34571853 PMCID: PMC8468560 DOI: 10.3390/cells10092204] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/04/2021] [Revised: 08/24/2021] [Accepted: 08/24/2021] [Indexed: 12/11/2022] Open
Abstract
The dysregulation of microRNA (miRNA) is implicated in cancer, inflammation, cardiovascular disorders, drug resistance, and aging. While most researchers study miRNA's role as a biomarker, for example, to distinguish between various sub-forms or stages of a given disease of interest, research is also ongoing to utilize these small nucleic acids as therapeutics. An example of a common pleiotropic disease that could benefit from miRNA-based therapeutics is inflammatory bowel disease (IBD), which is characterized by chronic inflammation of the small and large intestines. Due to complex interactions between multiple factors in the etiology of IBD, development of therapies that effectively maintain remission for this disease is a significant challenge. In this review, we discuss the role of dysregulated miRNA expression in the context of clinical ulcerative colitis (UC) and Crohn's disease (CD)-the two main forms of IBD-and the various preclinical mouse models of IBD utilized to validate the therapeutic potential of targeting these miRNA. Additionally, we highlight advances in the development of genetically engineered animal models that recapitulate clinical miRNA expression and provide powerful preclinical models to assess the diagnostic and therapeutic promise of miRNA in IBD.
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Guo H, Gao J, Qian Y, Wang H, Liu J, Peng Q, Zhou Y, Wang K. miR-125b-5p inhibits cell proliferation by targeting ASCT2 and regulating the PI3K/AKT/mTOR pathway in an LPS-induced intestinal mucosa cell injury model. Exp Ther Med 2021; 22:838. [PMID: 34149884 PMCID: PMC8210225 DOI: 10.3892/etm.2021.10270] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/26/2020] [Accepted: 05/17/2021] [Indexed: 12/11/2022] Open
Abstract
Intestinal barrier injury is an important cause of death in patients with acquired immune deficiency syndrome (AIDS). Therefore, it is of great significance to identify a therapeutic target for intestinal barrier injury to delay the progression of AIDS. microRNA (miRNA/miR)-125b-5p has an extensive role in cancer and controlling intestinal epithelial barrier function, but its role in human immunodeficiency virus-related intestinal mucosal damage remains unknown. The present study was designed to explore the effects of miR-125b-5p on lipopolysaccharide (LPS)-induced intestinal mucosal injury and the underlying mechanism. The expression of miR-125b-5p and ASCT2 mRNA was detected in colon biopsy samples of 10 patients with AIDS and 10 control healthy subjects. Human intestinal embryonic mucosa cells (CCC-HIE-2) were used to establish an LPS-induced intestinal mucosa cell injury model in vitro. Cell proliferation and apoptosis were determined by MTT assays and flow cytometry, respectively. miR-125b-5p levels and ASCT2 mRNA and protein expression levels in the LPS-induced intestinal mucosa cell injury model were detected by reverse transcription-quantitative PCR (RT-qPCR) and western blotting. The interaction between miR-125b-5p and ASCT2 was analyzed using a dual luciferase reporter assay. The results demonstrated that miR-125b-5p levels were increased and ASCT2 mRNA expression levels were decreased in colon samples from patients with AIDS and in LPS-induced intestinal mucosa cells. In the LPS-induced intestinal mucosa cell injury model, transfection with miR-125b-5p mimic inhibited cell proliferation and promoted cell apoptosis, while transfection with a miR-125b-5p inhibitor increased cell proliferation and attenuated cell apoptosis. Furthermore, miR-125b-5p mimic transfection resulted in a decrease of ASCT2 mRNA and protein expression, whereas the inhibitor increased ASCT2 mRNA and protein expression. Dual luciferase reporter assays suggested that ASCT2 was a direct target of miR-125b-5p, and its restoration weakened the effect of miR-125b-5p on LPS-induced intestinal mucosa cell injury. Transfection with the miR-125b-5p mimic also exhibited a suppressive effect on the PI3K/AKT/mTOR pathway in the LPS-induced intestinal mucosal cell injury model. Overall, the present study indicated that miR-125b-5p accelerated LPS-induced intestinal mucosa cell injury by targeting ASCT2 and upregulating the PI3K/AKT/mTOR pathway. The current findings may provide novel targets for the treatment of intestinal barrier injury in patients with AIDS.
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Affiliation(s)
- Huiming Guo
- Department of Gynaecology, The First Affiliated Hospital of Kunming Medical University, Kunming, Yunnan 650032, P.R. China.,NHC Key Laboratory of Drug Addiction Medicine, Kunming Medical University, Kunming, Yunnan 650500, P.R. China
| | - Jianyuan Gao
- NHC Key Laboratory of Drug Addiction Medicine, Kunming Medical University, Kunming, Yunnan 650500, P.R. China
| | - Yuan Qian
- NHC Key Laboratory of Drug Addiction Medicine, Kunming Medical University, Kunming, Yunnan 650500, P.R. China
| | - Huawei Wang
- NHC Key Laboratory of Drug Addiction Medicine, Kunming Medical University, Kunming, Yunnan 650500, P.R. China
| | - Jiang Liu
- NHC Key Laboratory of Drug Addiction Medicine, Kunming Medical University, Kunming, Yunnan 650500, P.R. China
| | - Qingyan Peng
- NHC Key Laboratory of Drug Addiction Medicine, Kunming Medical University, Kunming, Yunnan 650500, P.R. China.,The Scientific Research Laboratory Center, The First Affiliated Hospital of Kunming Medical University, Kunming, Yunnan 650032, P.R. China
| | - Yong Zhou
- NHC Key Laboratory of Drug Addiction Medicine, Kunming Medical University, Kunming, Yunnan 650500, P.R. China.,The Scientific Research Laboratory Center, The First Affiliated Hospital of Kunming Medical University, Kunming, Yunnan 650032, P.R. China
| | - Kunhua Wang
- NHC Key Laboratory of Drug Addiction Medicine, Kunming Medical University, Kunming, Yunnan 650500, P.R. China
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Loss of Setd2 associates with aberrant microRNA expression and contributes to inflammatory bowel disease progression in mice. Genomics 2021; 113:2441-2454. [PMID: 34052319 DOI: 10.1016/j.ygeno.2021.05.034] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/12/2020] [Revised: 05/25/2021] [Accepted: 05/26/2021] [Indexed: 12/12/2022]
Abstract
Both SETD2-mediated H3K36me3 and miRNAs play critical epigenetic roles in inflammatory bowel disease (IBD) and involve in the dysfunctional intestinal barrier. However, little is known about cross-talk between these two types of regulators in IBD progression. We performed small RNA sequencing of Setd2 epithelium-specific knockout mice (Setd2Vil-KO) and wild-type controls, both with DSS-induced colitis, and designed a framework for integrative analysis. Firstly, we integrated the downloaded ChIP-seq data with miRNA expression profiles and identified a significant intersection of pre-miRNA expression and H3K36me3 modification. A significant inverse correlation was detected between changes of H3K36me3 modification and expression of the 171 peak-covered miRNAs. We further integrated RNA-seq data with predicted miRNA targets to screen negatively regulated miRNA-mRNA pairs and found the H3K36me3-associated differentially expressed microRNAs significantly enriched in cell-cell junction and signaling pathways. Using network analysis, we identified ten hub miRNAs, among which six are H3K36me3-associated, suggesting therapeutic targets for IBD patients with SETD2-deficiency.
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Leroux C, Chervet ML, German JB. Perspective: Milk microRNAs as Important Players in Infant Physiology and Development. Adv Nutr 2021; 12:1625-1635. [PMID: 34022770 PMCID: PMC8483967 DOI: 10.1093/advances/nmab059] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/27/2020] [Revised: 01/08/2021] [Accepted: 04/14/2021] [Indexed: 12/16/2022] Open
Abstract
Evolutionary selective pressure on lactation has resulted in milk that provides far more than simply essential nutrients, delivering a complex repertoire of agents from hormones to intact cells. Human infants are born with low barrier integrity of their gut, which means that many of the complex biopolymer components of milk enter and circulate in lymph and blood, reaching organs throughout the body. Due to this state of gut maturation, all components of milk are potentially part of the crosstalk between mother and infants. This article highlights the functions of milk's complex biopolymers, more specifically the potential role of microRNAs (miRNAs) contained in extracellular vesicles in human milk. miRNAs are key effectors in the regulation of many biological processes during early-age development, and consequently milk-sourced miRNAs must be considered to provide unique biological assets to the infant during breastfeeding. This article interprets the evidence of the potential action of human milk miRNAs on infant development, taking into account their abundance in milk based on the literature and current knowledge. Human milk miRNAs appear to influence lipid and glucose metabolism, gut maturation, neurogenesis, and immunity. We also show growing evidence that human milk miRNAs are epigenetic modulators that play a pivotal role in the regulation of tissue-specific gene expression throughout life. Furthermore, this article addresses the ongoing debate regarding the potential influence of human milk miRNAs on viral infection as a new research area. This article highlights that these bioactive molecules are now being incorporated into our overall understanding of nutrient needs for healthy infant development, preparing each individual infant to succeed as a healthy and protected adult throughout its life. In essence, miRNAs are a new language in the Rosetta stone of health that is mammalian lactation.
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Affiliation(s)
| | - Mathilde Lea Chervet
- Foods for Health Institute, Department of Food Science and Technology, University of California, Davis, Davis, CA, USA
| | - J Bruce German
- Foods for Health Institute, Department of Food Science and Technology, University of California, Davis, Davis, CA, USA
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Jung H, Kim JS, Lee KH, Tizaoui K, Terrazzino S, Cargnin S, Smith L, Koyanagi A, Jacob L, Li H, Hong SH, Yon DK, Lee SW, Kim MS, Wasuwanich P, Karnsakul W, Shin JI, Kronbichler A. Roles of microRNAs in inflammatory bowel disease. Int J Biol Sci 2021; 17:2112-2123. [PMID: 34131410 PMCID: PMC8193269 DOI: 10.7150/ijbs.59904] [Citation(s) in RCA: 32] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2021] [Accepted: 05/08/2021] [Indexed: 12/12/2022] Open
Abstract
Inflammatory bowel disease (IBD) is a chronic inflammatory disease of the gastrointestinal tract that mainly affects young people. IBD is associated with various gastrointestinal symptoms, and thus, affects the quality of life of patients. Currently, the pathogenesis of IBD is poorly understood. Although intestinal bacteria and host immune response are thought to be major factors in its pathogenesis, a sufficient explanation of their role in its pathophysiologic mechanism has not been presented. MicroRNAs (miRNAs), which are small RNA molecules that regulate gene expression, have gained attention as they are known to participate in the molecular interactions of IBD. Recent studies have confirmed the important role of miRNAs in targeting certain molecules in signaling pathways that regulate the homeostasis of the intestinal barrier, inflammatory reactions, and autophagy of the intestinal epithelium. Several studies have identified the specific miRNAs associated with IBD from colon tissues or serum samples of IBD patients and have attempted to use them as useful diagnostic biomarkers. Furthermore, some studies have attempted to treat IBD through intracolonic administration of specific miRNAs in the form of nanoparticle. This review summarizes the latest findings on the role of miRNAs in the pathogenesis, diagnosis, and treatment of IBD.
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Affiliation(s)
- HyunTaek Jung
- Yonsei University College of Medicine, Seoul, Republic of Korea
| | - Jae Seok Kim
- Department of Nephrology, Yonsei University Wonju College of Medicine, Wonju, Republic of Korea
| | - Keum Hwa Lee
- Department of Pediatrics, Yonsei University College of Medicine, Seoul, Republic of Korea
| | - Kalthoum Tizaoui
- Laboratory Microorganisms and Active Biomolecules, Sciences Faculty of Tunis, University Tunis El Manar, Tunis, Tunisia
| | - Salvatore Terrazzino
- Department of Pharmaceutical Sciences and Interdepartmental Research Center of Pharmacogenetics and Pharmacogenomics (CRIFF), University of Piemonte Orientale, Novara, Italy
| | - Sarah Cargnin
- Department of Pharmaceutical Sciences and Interdepartmental Research Center of Pharmacogenetics and Pharmacogenomics (CRIFF), University of Piemonte Orientale, Novara, Italy
| | - Lee Smith
- The Cambridge Centre for Sport and Exercise Science, Anglia Ruskin University, Cambridge, CB1 1PT, UK
| | - Ai Koyanagi
- Research and Development Unit, Parc Sanitari Sant Joan de Déu, CIBERSAM, 08830 Barcelona, Spain.,ICREA, Pg. Lluis Companys 23, 08010 Barcelona, Spain
| | - Louis Jacob
- Research and Development Unit, Parc Sanitari Sant Joan de Déu, CIBERSAM, 08830 Barcelona, Spain.,Faculty of Medicine, University of Versailles Saint-Quentin-en-Yvelines, 78000 Versailles, France
| | - Han Li
- University of Florida College of Medicine, Gainesville, FL 32610, USA
| | - Sung Hwi Hong
- Yonsei University College of Medicine, Seoul, Republic of Korea
| | - Dong Keon Yon
- Department of Pediatrics, Seoul National University Children's Hospital, Seoul National University College of Medicine, Seoul, Republic of Korea
| | - Seung Won Lee
- Department of Data Science, Sejong University College of Software Convergence, Seoul, Republic of Korea
| | - Min Seo Kim
- Korea University, College of Medicine, Seoul, Republic of Korea
| | - Paul Wasuwanich
- University of Florida College of Medicine, Gainesville, FL 32610, USA
| | - Wikrom Karnsakul
- Division of Pediatric Gastroenterology, Hepatology, and Nutrition, Department of Pediatrics, Johns Hopkins University School of Medicine, Baltimore, USA
| | - Jae Il Shin
- Department of Pediatrics, Yonsei University College of Medicine, Seoul, Republic of Korea
| | - Andreas Kronbichler
- Department of Internal Medicine IV (Nephrology and Hypertension), Medical University Innsbruck, Innsbruck, Austria
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Valter M, Verstockt S, Finalet Ferreiro JA, Cleynen I. Extracellular Vesicles in Inflammatory Bowel Disease: Small Particles, Big Players. J Crohns Colitis 2021; 15:499-510. [PMID: 32905585 DOI: 10.1093/ecco-jcc/jjaa179] [Citation(s) in RCA: 34] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
Extracellular vesicles are nanovesicles released by many cell types into the extracellular space. They are important mediators of intercellular communication, enabling the functional transfer of molecules from one cell to another. Moreover, their molecular composition reflects the physiological status of the producing cell and tissue. Consequently, these vesicles have been involved in many [patho]physiological processes such as immunomodulation and intestinal epithelial repair, both key processes involved in inflammatory bowel disease. Given that these vesicles are present in many body fluids, they also provide opportunities for diagnostic, prognostic, and therapeutic applications. In this review, we summarise functional roles of extracellular vesicles in health and disease, with a focus on immune regulation and intestinal barrier integrity, and review recent studies on extracellular vesicles and inflammatory bowel disease. We also elaborate on their clinical potential in inflammatory bowel disease.
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Affiliation(s)
- M Valter
- Laboratory for Complex Genetics, Department of Human Genetics, KU Leuven, Leuven, Belgium
| | - Sare Verstockt
- Translational Research center for Gastrointestinal Disorders [TARGID], Department of Chronic Diseases, Metabolism and Ageing [CHROMETA], KU Leuven, Leuven, Belgium
| | - J A Finalet Ferreiro
- Laboratory for Complex Genetics, Department of Human Genetics, KU Leuven, Leuven, Belgium
| | - I Cleynen
- Laboratory for Complex Genetics, Department of Human Genetics, KU Leuven, Leuven, Belgium
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Morris NL, Choudhry MA. Maintenance of gut barrier integrity after injury: Trust your gut microRNAs. J Leukoc Biol 2021; 110:979-986. [PMID: 33577717 DOI: 10.1002/jlb.3ru0120-090rr] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2020] [Revised: 01/20/2021] [Accepted: 01/21/2021] [Indexed: 12/11/2022] Open
Abstract
The gastrointestinal (GI) tract is a highly dynamic structure essential for digestion, nutrient absorption, and providing an interface to prevent gut bacterial translocation. In order to maintain the barrier function, the gut utilizes many defense mechanisms including proliferation, apoptosis, and apical junctional complexes. Disruption of any of these parameters due to injury or disease could negatively impact the intestinal barrier function and homeostasis resulting in increased intestine inflammation, permeability, bacterial dysbiosis, and tissue damage. MicroRNAs are small noncoding RNA sequences that are master regulators of normal cellular homeostasis. These regulatory molecules affect cellular signaling pathways and potentially serve as candidates for providing a mechanism of impaired gut barrier integrity following GI-related pathologic conditions, ethanol exposure, or trauma such as burn injury. MicroRNAs influence cellular apoptosis, proliferation, apical junction complex expression, inflammation, and the microbiome. Due to their widespread functional affiliations, altered expression of microRNAs are associated with many pathologic conditions. This review explores the role of microRNAs in regulation of intestinal barrier integrity. The studies reviewed demonstrate that microRNAs largely impact intestine barrier function and provide insight behind the observed adverse effects following ethanol and burn injury. Furthermore, these studies suggest that microRNAs are excellent candidates for therapeutic intervention or for biomarkers to manage gut barrier integrity following trauma such as burn injury and other GI-related pathologic conditions.
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Affiliation(s)
- Niya L Morris
- Alcohol Research Program, Loyola University Chicago Health Sciences Division, Maywood, Illinois, USA.,Burn & Shock Trauma Research Institute, Loyola University Chicago Health Sciences Division, Maywood, Illinois, USA.,Integrative Cell Biology Program, Loyola University Chicago Health Sciences Division, Maywood, Illinois, USA.,Current address: Department of Medicine: Pulmonary, Allergy, Critical Care and Sleep, Emory University/Atlanta VA Medical Center, Decatur, Geogia, USA
| | - Mashkoor A Choudhry
- Alcohol Research Program, Loyola University Chicago Health Sciences Division, Maywood, Illinois, USA.,Burn & Shock Trauma Research Institute, Loyola University Chicago Health Sciences Division, Maywood, Illinois, USA.,Integrative Cell Biology Program, Loyola University Chicago Health Sciences Division, Maywood, Illinois, USA.,Department of Surgery, Loyola University Chicago Health Sciences Division, Maywood, Illinois, USA
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Zhao Y, Zeng Y, Zeng D, Wang H, Zhou M, Sun N, Xin J, Khalique A, Rajput DS, Pan K, Shu G, Jing B, Ni X. Probiotics and MicroRNA: Their Roles in the Host-Microbe Interactions. Front Microbiol 2021; 11:604462. [PMID: 33603718 PMCID: PMC7885260 DOI: 10.3389/fmicb.2020.604462] [Citation(s) in RCA: 33] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/09/2020] [Accepted: 12/07/2020] [Indexed: 12/13/2022] Open
Abstract
Probiotics are widely accepted to be beneficial for the maintenance of the gut homeostasis - the dynamic and healthy interactions between host and gut microorganisms. In addition, emerging as a key molecule of inter-domain communication, microRNAs (miRNAs) can also mediate the host-microbe interactions. However, a comprehensive description and summary of the association between miRNAs and probiotics have not been reported yet. In this review, we have discussed the roles of probiotics and miRNAs in host-microbe interactions and proposed the association of probiotics with altered miRNAs in various intestinal diseases and potential molecular mechanisms underlying the action of probiotics. Furthermore, we provided a perspective of probiotics-miRNA-host/gut microbiota axis applied in search of disease management highly associated with the gut microbiome, which will potentially prove to be beneficial for future studies.
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Affiliation(s)
- Ying Zhao
- Animal Microecology Institute, College of Veterinary, Sichuan Agricultural University, Chengdu, China
| | - Yan Zeng
- Animal Microecology Institute, College of Veterinary, Sichuan Agricultural University, Chengdu, China
| | - Dong Zeng
- Animal Microecology Institute, College of Veterinary, Sichuan Agricultural University, Chengdu, China
| | - Hesong Wang
- Guangdong Provincial Key Laboratory of Gastroenterology, Department of Gastroenterology, Institute of Gastroenterology of Guangdong Province, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Mengjia Zhou
- Sichuan Academy of Animal Sciences, Animal Breeding and Genetics Key Laboratory of Sichuan Province, Chengdu, China
| | - Ning Sun
- Animal Microecology Institute, College of Veterinary, Sichuan Agricultural University, Chengdu, China
| | - Jinge Xin
- Animal Microecology Institute, College of Veterinary, Sichuan Agricultural University, Chengdu, China
| | - Abdul Khalique
- Animal Microecology Institute, College of Veterinary, Sichuan Agricultural University, Chengdu, China
| | - Danish Sharafat Rajput
- Animal Microecology Institute, College of Veterinary, Sichuan Agricultural University, Chengdu, China
| | - Kangcheng Pan
- Animal Microecology Institute, College of Veterinary, Sichuan Agricultural University, Chengdu, China
| | - Gang Shu
- Animal Microecology Institute, College of Veterinary, Sichuan Agricultural University, Chengdu, China
| | - Bo Jing
- Animal Microecology Institute, College of Veterinary, Sichuan Agricultural University, Chengdu, China
| | - Xueqin Ni
- Animal Microecology Institute, College of Veterinary, Sichuan Agricultural University, Chengdu, China
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Pradhan R, Ngo PA, Martínez-Sánchez LDC, Neurath MF, López-Posadas R. Rho GTPases as Key Molecular Players within Intestinal Mucosa and GI Diseases. Cells 2021; 10:cells10010066. [PMID: 33406731 PMCID: PMC7823293 DOI: 10.3390/cells10010066] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/23/2020] [Revised: 12/22/2020] [Accepted: 12/28/2020] [Indexed: 02/07/2023] Open
Abstract
Rho proteins operate as key regulators of the cytoskeleton, cell morphology and trafficking. Acting as molecular switches, the function of Rho GTPases is determined by guanosine triphosphate (GTP)/guanosine diphosphate (GDP) exchange and their lipidation via prenylation, allowing their binding to cellular membranes and the interaction with downstream effector proteins in close proximity to the membrane. A plethora of in vitro studies demonstrate the indispensable function of Rho proteins for cytoskeleton dynamics within different cell types. However, only in the last decades we have got access to genetically modified mouse models to decipher the intricate regulation between members of the Rho family within specific cell types in the complex in vivo situation. Translationally, alterations of the expression and/or function of Rho GTPases have been associated with several pathological conditions, such as inflammation and cancer. In the context of the GI tract, the continuous crosstalk between the host and the intestinal microbiota requires a tight regulation of the complex interaction between cellular components within the intestinal tissue. Recent studies demonstrate that Rho GTPases play important roles for the maintenance of tissue homeostasis in the gut. We will summarize the current knowledge on Rho protein function within individual cell types in the intestinal mucosa in vivo, with special focus on intestinal epithelial cells and T cells.
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Villota SD, Toledo-Rodriguez M, Leach L. Compromised barrier integrity of human feto-placental vessels from gestational diabetic pregnancies is related to downregulation of occludin expression. Diabetologia 2021; 64:195-210. [PMID: 33001231 PMCID: PMC7716932 DOI: 10.1007/s00125-020-05290-6] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/01/2020] [Accepted: 08/18/2020] [Indexed: 12/16/2022]
Abstract
AIMS/HYPOTHESIS Reduced occupancy of junctional occludin is a feature of human placental vessels in the diabetic milieu. However, the functional consequence of this and whether this loss is due to differential expression of occludin splice variants is not known. Our study aimed to investigate the effects of gestational diabetes mellitus (GDM), and its treatment, on endothelial junctional integrity, gene and protein expression of occludin splice variants, and potential regulation of expression by microRNAs (miRNAs). METHODS Term placentas were obtained from normal pregnancies (n = 21), and pregnancies complicated by GDM where glucose levels were controlled by diet (n = 11) or metformin (n = 6). Gene and microRNA (miRNA) expression were determined by quantitative real-time PCR; protein expression by immunoblotting; endothelial junctional occupancy by fluorescence microscopy and systematic sampling; and paracellular leakage by perfusion of placental microvascular beds with 76 Mr dextran. Transfection studies of miRNAs that target OCLN were performed in HUVECs, and the trans-endothelial electrical resistance and tracer permeability of the HUVECs were measured. RESULTS All three predicted OCLN gene splice variants and two occludin protein isoforms were found in human placental samples. In placental samples from diet-controlled GDM (d-GDM) pregnancies we found a lower percentage of conduit vessels showing occludin immunoreactivity (12%, p < 0.01), decreased levels of the fully functional occludin isoform-A protein (29%), and differential gene expression of OCLN variant 2 (33% decrease), variant 3 (3.3-fold increase). These changes were not seen in samples from the group with metformin-controlled GDM. In d-GDM placentas, increased numbers of conduit microvessels demonstrated extravasation of 76 Mr dextran (2.0-fold). In d-GDM expression of one of the five potential miRNAs targeting OCLN, miR-181a-5p, expression was 2.1-fold that in normal pregnancies. Experimental overexpression of miR-181a-5p in HUVECs from normal pregnancies resulted in a highly significant downregulation of OCLN variant 1 (69%) and variant 2 (46%) gene expression, with decreased trans-endothelial resistance (78%) and increase in tracer permeability (1.3-fold). CONCLUSIONS/INTERPRETATION Downregulation of expression of OCLN variant 2 and the fully functional occludin isoform-A protein are a feature of placentas in d-GDM pregnancies. These may be behind the loss of junctional occludin and the increased extravasation of exogenous dextran observed. miR-181a-5p was in part responsible for the downregulation of occludin in placentas from d-GDM pregnancies. Induced overexpression of miR-181a-5p compromised the integrity of the endothelial barrier. Our data suggest that, despite good glucose control, the adoption of lifestyle changes alone during a GDM pregnancy may not be enough to prevent an alteration in the expression of occludin and the subsequent functional consequences in placentas and impaired vascular barrier function in offspring. Graphical abstract.
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Affiliation(s)
| | | | - Lopa Leach
- School of Life Sciences, University of Nottingham, Nottingham, UK.
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Battistini C, Ballan R, Herkenhoff ME, Saad SMI, Sun J. Vitamin D Modulates Intestinal Microbiota in Inflammatory Bowel Diseases. Int J Mol Sci 2020; 22:E362. [PMID: 33396382 PMCID: PMC7795229 DOI: 10.3390/ijms22010362] [Citation(s) in RCA: 81] [Impact Index Per Article: 16.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/07/2020] [Revised: 12/26/2020] [Accepted: 12/28/2020] [Indexed: 02/06/2023] Open
Abstract
Inflammatory bowel disease (IBD) is a chronic inflammation of the gastrointestinal tract (GIT), including Crohn's disease (CD) and ulcerative colitis (UC), which differ in the location and lesion extensions. Both diseases are associated with microbiota dysbiosis, with a reduced population of butyrate-producing species, abnormal inflammatory response, and micronutrient deficiency (e.g., vitamin D hypovitaminosis). Vitamin D (VitD) is involved in immune cell differentiation, gut microbiota modulation, gene transcription, and barrier integrity. Vitamin D receptor (VDR) regulates the biological actions of the active VitD (1α,25-dihydroxyvitamin D3), and is involved in the genetic, environmental, immune, and microbial aspects of IBD. VitD deficiency is correlated with disease activity and its administration targeting a concentration of 30 ng/mL may have the potential to reduce disease activity. Moreover, VDR regulates functions of T cells and Paneth cells and modulates release of antimicrobial peptides in gut microbiota-host interactions. Meanwhile, beneficial microbial metabolites, e.g., butyrate, upregulate the VDR signaling. In this review, we summarize the clinical progress and mechanism studies on VitD/VDR related to gut microbiota modulation in IBD. We also discuss epigenetics in IBD and the probiotic regulation of VDR. Furthermore, we discuss the existing challenges and future directions. There is a lack of well-designed clinical trials exploring the appropriate dose and the influence of gender, age, ethnicity, genetics, microbiome, and metabolic disorders in IBD subtypes. To move forward, we need well-designed therapeutic studies to examine whether enhanced vitamin D will restore functions of VDR and microbiome in inhibiting chronic inflammation.
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Affiliation(s)
- Carolina Battistini
- Department of Pharmaceutical and Biochemical Technology, School of Pharmaceutical Sciences, University of São Paulo, Av. Lineu Prestes, 580, São Paulo, SP 05508-000, Brazil; (C.B.); (R.B.); (M.E.H.)
- Food Research Center, University of São Paulo, Rua do Lago, 250, São Paulo, SP 05508-080, Brazil
| | - Rafael Ballan
- Department of Pharmaceutical and Biochemical Technology, School of Pharmaceutical Sciences, University of São Paulo, Av. Lineu Prestes, 580, São Paulo, SP 05508-000, Brazil; (C.B.); (R.B.); (M.E.H.)
- Food Research Center, University of São Paulo, Rua do Lago, 250, São Paulo, SP 05508-080, Brazil
| | - Marcos Edgar Herkenhoff
- Department of Pharmaceutical and Biochemical Technology, School of Pharmaceutical Sciences, University of São Paulo, Av. Lineu Prestes, 580, São Paulo, SP 05508-000, Brazil; (C.B.); (R.B.); (M.E.H.)
- Food Research Center, University of São Paulo, Rua do Lago, 250, São Paulo, SP 05508-080, Brazil
| | - Susana Marta Isay Saad
- Department of Pharmaceutical and Biochemical Technology, School of Pharmaceutical Sciences, University of São Paulo, Av. Lineu Prestes, 580, São Paulo, SP 05508-000, Brazil; (C.B.); (R.B.); (M.E.H.)
- Food Research Center, University of São Paulo, Rua do Lago, 250, São Paulo, SP 05508-080, Brazil
| | - Jun Sun
- Division of Gastroenterology and Hepatology, Department of Medicine, University of Illinois at Chicago, Chicago, IL 60612, USA
- Department of Microbiology and Immunology, UIC Cancer Center, University of Illinois at Chicago, Chicago, IL 60612, USA
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MicroRNA Biomarkers in IBD-Differential Diagnosis and Prediction of Colitis-Associated Cancer. Int J Mol Sci 2020; 21:ijms21217893. [PMID: 33114313 PMCID: PMC7660644 DOI: 10.3390/ijms21217893] [Citation(s) in RCA: 70] [Impact Index Per Article: 14.0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/24/2020] [Revised: 10/20/2020] [Accepted: 10/21/2020] [Indexed: 12/14/2022] Open
Abstract
Inflammatory bowel disease (IBD) includes Crohn's disease (CD) and ulcerative colitis (UC). These are chronic autoimmune diseases of unknown etiology affecting the gastrointestinal tract. The IBD population includes a heterogeneous group of patients with varying disease courses requiring personalized treatment protocols. The complexity of the disease often delays the diagnosis and the initiation of appropriate treatments. In a subset of patients, IBD leads to colitis-associated cancer (CAC). MicroRNAs are single-stranded regulatory noncoding RNAs of 18 to 22 nucleotides with putative roles in the pathogenesis of IBD and colorectal cancer. They have been explored as biomarkers and therapeutic targets. Both tissue-derived and circulating microRNAs have emerged as promising biomarkers in the differential diagnosis and in the prognosis of disease severity of IBD as well as predictive biomarkers in drug resistance. In addition, knowledge of the cellular localization of differentially expressed microRNAs is a prerequisite for deciphering the biological role of these important epigenetic regulators and the cellular localization may even contribute to an alternative repertoire of biomarkers. In this review, we discuss findings based on RT-qPCR, microarray profiling, next generation sequencing and in situ hybridization of microRNA biomarkers identified in the circulation and in tissue biopsies.
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50
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Ghafouri-Fard S, Eghtedarian R, Taheri M. The crucial role of non-coding RNAs in the pathophysiology of inflammatory bowel disease. Biomed Pharmacother 2020; 129:110507. [DOI: 10.1016/j.biopha.2020.110507] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/15/2020] [Revised: 06/25/2020] [Accepted: 07/02/2020] [Indexed: 02/07/2023] Open
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