One large-scale zebrafish genetic mutation research center, Cardiovascular Research Center, Massachusetts General Hospital, which preserves thousands of zebrafish mutants with embryonic or organ defects, is located in Massachusetts. Clevers H. The intestinal crypt, a prototype stem cell compartment. The innate cell recruitment and barrier dysfunction in the MSP and Ron mutants require further investigation to understand how disturbance of this pathway leads to chronic inflammation. Cold Spring Harbor Conference on Zebrafish Development and Genetics, 2000. Fleming reported morphological changes and increased numbers of goblet cells under exposure to 75 µg/mL TNBS (48). PLoS Genet (2012) 8:e1002585. According to current evidence, zebrafish have orthologs of mammalian toll-like receptors (TLRs), which are the innate immune receptors that recognize specific microbial molecules (29), and have functionally conserved orthologs of human IBD susceptibility genes NOD1 and NOD2 (11). 15 Ernest S, Rauch GJ, Haffter P, et al. About 600,000 new cases of IBD are diagnosed in America every year (2). Cloning, characterization and expression analysis of interleukin-10 from the zebrafish (Danio rerion). Further studies confirmed the view that TLR signaling pathways recognize bacteria, resulting in the induced expression of immune molecules, including NF-κB and inflammatory cytokines (30). doi:10.1016/j.ijmm.2016.02.010, 82. Besides, the optical transparency of the embryos and their rapid development facilitate observation, manipulation, and drug screening (25). Dis Model Mech (2011) 4:711–2. Investigators demonstrated that the claudin family member CLDNC and the tetraspanin LOC565274 are both preferentially expressed in the zebrafish gastrointestinal tract. USA.gov. doi:10.1007/s40139-015-0079-x, 8. Science (1992) 256:668–70. Genome Res (2001) 11:1594–602. Recent insights into the genetics of inflammatory bowel disease. Recently, IL-22’s functions in intestinal inflammation in innate immunity were revealed (61). IL-23 participates in the development of Th17 cells and the innate immune response (53). Semova I, Carten JD, Stombaugh J, Mackey LC, Knight R, Farber SA, et al. In CD, the inflammation affects the whole digestive tract, whereas in UC, only the colon is involved. 2007 May;8(5):353-67. doi: 10.1038/nrg2091. Howe K, Clark MD, Torroja CF, Torrance J, Berthelot C, Muffato M, et al. Marjoram L, Bagnat M. Infection, inflammation and healing in zebrafish: intestinal inflammation. A number of active compounds were identified and most of them have similar functions in mammal models. A mutation in ubiquitin-like protein including PHD and RING finger domains 1 (UHRF1), a highly conserved gene in methylation, was identified as the affected locus. Collectively, the results suggest that a deeper insight into chemokines and immune homologs in zebrafish is required. In a zebrafish model for signaling pathway studies, investigators first focused on the MYD88 signaling pathway. Zoller M. Gastrointestinal tumors: metastasis and tetraspanins. Another compound leflunomide has also been approved in clinical trial to cure melanoma in combination with vemurafenib. The dysfunctional UHRF1 leads to hypomethylation of TNF-α promoter, which releases the transcription inhibition of the promoter, thereby leading to increased TNF-α in the intestinal epithelia. Defects in the ER stress response and autophagy result in intestinal inflammation (84). doi:10.1038/ng.175, 43. Since its emergence as an important model organism the molecular tools for studying zebrafish have been limited. established an enterocolitis score to evaluate inflammation. Jeu de Zebrafish un rôle important dans l'étude de l'hématopoïèse. Inflamm Bowel Dis (2006) 12(Suppl 1):S3–9. Unfortunately, traditional murine models are not efficient for the further study of IBD. The glafenine-induced phenotype was characterized by increased intestinal epithelial apoptosis and ER stress, but not by a reduction in the epithelial barrier function. The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. MYD88 is highly conserved in zebrafish (72, 73). doi:10.3109/02656730903213366, 65. Persistent physiological stresses can induce abnormalities in heart functions such as cardiac hypertrophy (CH), which can lead to morbidity and mortality. NLM HHS Controversy concerning the etiology of IBD exists because of its multifactorial pathogenesis. In addition, the adaptive immune system does not develop until 4 weeks after fertilization; however, this delay benefits the study of innate immunity. Although several studies have been performed based on the GWASs, their results may not be reliable. investigated gene expression changes in response to microbial colonization (75). Figure 2. Inflamm Bowel Dis (2007) 13:918–32. Therefore, this study identified a possible susceptibility gene for IBD. Mariner is defective in myosin VIIA : A zebrafish model for human hereditary deafness. Brugman et al. The pathogenesis of IBD is still unclear and many risk factors remain unidentified. Genome-wide association studies have proved that IL-23R is a susceptibility allele in IBD patients (26). CHM is a highly complex system, in which 4–20 herbs are often used in a formula in order to yield multiple pharmacological actions and to reduce potential adverse effects. Thus, zebrafish have the potential to act as a model in studies of the genetic and environmental aspects of IBD pathogenesis. Ogura Y, Bonen DK, Inohara N, Nicolae DL, Chen FF, Ramos R, et al. No Paneth cells, crypts, or submucosal glands have been detected in zebrafish (27, 28). The immune system is the basis of the interaction between the host and microbes. Microbial fingerprinting detects intestinal microbiota dysbiosis in Zebrafish models with chemically-induced enterocolitis. Hundorfean G, Neurath MF, Mudter J. Functional relevance of T helper 17 (Th17) cells and the IL-17 cytokine family in inflammatory bowel disease. Bates JM, Mittge E, Kuhlman J, Baden KN, Cheesman SE, Guillemin K. Distinct signals from the microbiota promote different aspects of zebrafish gut differentiation. So far, the most well-established model in IBD is the murine model (3). Zebrafish is an elegant vertebrate employed to model the pathological etiologies of human maladies such as cardiac diseases. doi:10.2174/1871530314666140922145333, 64. Inflamm Bowel Dis (2010) 16:1162–72. Pharmacol Rep (2015) 67:224–9. Another genetic screen identified a mutant, cdipthi559, which lacks phosphatidylinositol (PI) synthesis (38). Van Itallie CM, Anderson JM. Clark MD, Hennig S, Herwig R, Clifton SW, Marra MA, Lehrach H, et al. doi:10.1002/ibd.22929, 61. NF-κB is a nuclear transcription factor that regulates the genes that are believed to be necessary in promoting inflammation. Burkhart JG. doi:10.1002/ibd.21200, 49. Many Chinese herbs exhibit a large range of biological and pharmacological activities and their effects rely on the complex interactions … Am J Physiol Gastrointest Liver Physiol (2009) 296:G1140–9. These data suggested that the response to microbes is highly conserved. However, exposure to heat-killed microbes and LPS could restore the IAP activity, but not the glycan expression, suggesting that LPS induces IAP. The reviewer, KL, and handling Editor declared their shared affiliation, and the handling Editor states that the process nevertheless met the standards of a fair and objective review. Mennigen R, Nolte K, Rijcken E, Utech M, Loeffler B, Senninger N, et al. Zebrafish models can be used to determine whether the products of IBD susceptibility genes are pathogenic. Proteins and other functional molecules expressed in these regions have suggested the mechanisms of intestinal epithelial damage and defense, including epigenetic changes, the presence of endothelium stress, and the interaction between microbes and host immunity (33). To some extent, this is too slow for active IBD research (5). Current pharmaceutical research is mainly focused on the microbiota or the host inflammation response. These studies could reveal novel genetic risk factors in non-coding regions and define their distinct functions in IBD pathogenesis. Despite some limitations, zebrafish are superior to the existing models of intestinal inflammation. administered the hapten oxazolone intrarectally to adult wild-type and myeloperoxidase-reporter transgenic zebrafish (20). The application of our larval zebrafish model to epilepsy research is probably limited only by one's imagination. Genetic techniques are easier to perform in zebrafish compared with mice. Application of Humanized Zebrafish Model in the Suppression of SARS-CoV-2 Spike Protein Induced Pathology by Tri-Herbal Medicine Coronil via Cytokine Modulation Acharya Balkrishna, Siva Kumar Solleti, Sudeep Verma, Anurag Varshney Intestinal epithelium morphogenesis. doi:10.1016/j.resmic.2006.10.005, 35. Zebrafish models to study drug abuse-related phenotypes. doi:10.1111/febs.13976, 52. Holt A, Mitra S, van der Sar AM, Alnabulsi A, Secombes CJ, Bird S. Discovery of zebrafish (Danio rerio) interleukin-23 alpha (IL-23alpha) chain, a subunit important for the formation of IL-23, a cytokine involved in the development of Th17 cells and inflammation. Immunology (2006) 118:131–40. MCH is a conserved appetite-regulating neuropeptide that is implicated in the pathogenesis of IBD (71). Hence, the MYD88 mutant zebrafish will be useful in studies of IL-1R and TLR signaling in the host–microbe interaction and in intestinal inflammation. Groden J, Thliveris A, Samowitz W, Carlson M, Gelbert L, Albertsen H, et al. The composition of microbes in the host depends on the environment. The cdipthi559 zebrafish mutant has a deficiency in PI synthesis and shows characteristics of ER stress in the intestinal epithelium (39). 16 Bang PI, Sewell WF, Yelick P ,Malicki J. Behavioral screen for dominant mutations affecting zebrafish auditory system. doi:10.1038/nature12972, Keywords: zebrafish, inflammatory bowel disease, murine model, pathogenesis, drug screening, Citation: Hanyang L, Xuanzhe L, Xuyang C, Yujia Q, Jiarong F, Jun S and Zhihua R (2017) Application of Zebrafish Models in Inflammatory Bowel Disease. As a valuable animal model, it has contributed a lot to the understanding of IBD, in terms of the aspects including gut microbiota, immunoreaction, infection, and inheritance. Genesis (2011) 49:905–11. A protein complex containing claudin-7, the tetraspanin CO-029, and others in membrane microdomains has been identified (90). In nature, enteritis can develop spontaneously in some animals, and these are termed spontaneous IBD models. Gastroenterology (1985) 88:13–9. The gene profiles demonstrated that microbial colonization altered the expressions of 212 genes. Advantages of the zebrafish embryo as a model. Dis Model Mech (2011) 4:832–41. Apart from toxicity studies, another major application of zebrafish is to serve as an animal model for drug discovery , especially the in vivo evaluation of engineered nanomedicines. doi:10.1038/nrgastro.2014.201, 93. Goldsmith et al. Birth Defects Res C Embryo Today. Investigators have used IBD animal models for over 100 years, from drug-induced methods to genetic engineering models (20). doi:10.1007/s00439-014-1476-7, 36. The conservation of several core gut genes, such as NOD1 and NOD2, in zebrafish and mammals makes zebrafish an interesting model to study the pathogenesis of intestinal inflammation and injury (11, 34). doi:10.1089/zeb.2012.0824, 18. In addition to inflammation, loss of peristalsis and alteration of lipid metabolism have been documented (19, 48). Animal models of inflammatory bowel disease. Using the zebrafish IL-10 mutant model, further study of IL-10 functions might increase our understanding of the host–microbe interactions and intestinal inflammation in IBD (58). Cell (2013) 154:274–84. Spontaneous, heritable colitis in a new substrain of C3H/HeJ mice. Pharmacologic Therapies for the Management of Crohn’s Disease: Comparative Effectiveness. Huitema LF, Renn J, Logister I, Gray JK, Waltz SE, Flik G, et al. The accumulated effects included an increase of nuclear β-protein and excessive expression of downstream genes such as c-MYC and AXIN2 (13). doi:10.1016/j.molimm.2010.12.012, 55. PI alleviates pathological ER stress, allowing the ER to perform its anti-inflammatory effect. Paneth cells as a site of origin for intestinal inflammation. Zebrafish are also amenable to manipulation of brain activity: optog… Furthermore, using MO knockdown techniques, researchers can study the pathogenesis of IBD pathogenesis at the level of cytokines. IL-22 is increased in active Crohn’s disease and promotes proinflammatory gene expression and intestinal epithelial cell migration. The inflammatory bowel disease (IBD) susceptibility genes NOD1 and NOD2 have conserved anti-bacterial roles in zebrafish. Rawls JF, Samuel BS, Gordon JI. Imaging escape and avoidance behavior in zebrafish larvae. Applications. Kamada N, Seo SU, Chen GY, Nunez G. Role of the gut microbiota in immunity and inflammatory disease. Fishing for mutations. Although murine models have revealed the role of epithelial barrier function, the adaptive immune response and microbiota in the pathogenesis and susceptibility of IBD, and certain limitations, such as high cost, imaging limitations, and the difficulty of genetic manipulation techniques, have impeded their use in IBD research (24). Importantly, their findings demonstrated that homeostatic innate immune responses, but not inflammatory signals, contribute to the effects on epithelial proliferation. In addition to studies in genetics and developmental biology, zebrafish has also been widely used in human disease modeling and drug screening. The pathogenesis of IBD is still unclear and many risk factors remain unidentified. Cheesman SE, Guillemin K. We know you are in there: conversing with the indigenous gut microbiota. doi:10.1038/sj.embor.7400638, 14. The two most common types of IBD are ulcerative colitis (UC) and Crohn’s disease (CD). Dis Model Mech (2013) 6:146–59. In the oxalone-induced zebrafish model, the microbiota can influence the degree of enterocolitis. Intestinal crypt homeostasis revealed at single-stem-cell level by in vivo live imaging. doi:10.1089/zeb.2013.0917, 31. Gen Comp Endocrinol (2009) 161:133–7. Probiotic mixture VSL#3 protects the epithelial barrier by maintaining tight junction protein expression and preventing apoptosis in a murine model of colitis. IL-23 is expressed constitutively in the zebrafish intestine and is induced by LPSs administration or Mycobacterium marinum infection (54). Dev Comp Immunol (2012) 36:408–17. A comparative analysis of two models of colitis in rats. However, the exact function of IL-23 has not yet been determined. The score takes several factors into consideration, including the depletion of goblet cells, the infiltration of inflammatory cells and upregulation of pro-inflammatory cytokines (20). doi:10.1053/j.gastro.2009.07.069, 21. IAP-deficient zebrafish are more sensitive to LPS exposure. Besides, researches of the stem cells located at the base of the crypt of mammalian intestinal epithelium are heating up in recent years (94). Mizoguchi A. doi:10.1146/annurev.physiol.68.040104.131404, 90. Additionally, germ-free (GF) intestines failed to take up protein macromolecules in the distal intestine and presented a faster rate of peristalsis (79). Dev Comp Immunol (2013) 41:746–55. In this regard, recent studies show zebrafish being used as model to understand tumor progression, metastasis and dissemination. doi:10.1016/j.ygcen.2008.11.002, 69. Current scenario in inflammatory bowel disease: drug development prospects. Investigators compared conventionally reared (CV) zebrafish, GF zebrafish, and TNBS-induced enterocolitis zebrafish models. doi:10.1016/0016-5085(92)91710-L, 24. Therefore, the APC zebrafish model could be applied to genetic, drug screening, and toxicology studies for other intestinal diseases, including IBD. Zebrafish models could help investigators to study CXCL8, CCL13, and CCL14, which are difficult to study in murine models (62). Kaser A, Lee AH, Franke A, Glickman JN, Zeissig S, Tilg H, et al. In addition, GWASs have revealed that SNPs close to MST1 [encoding the macrophage-stimulating protein (MSP)] and MST1R [encoding the MSP receptor Ron (recepteur d’origine nantais)] were susceptibility factors of CD (41, 42). Gastroenterology (1994) 107:1726–35. Cell (2008) 134:743–56. Figure 1. Chemical genetic methods can also manipulate the host response to injury, which is convenient for use in IBD models (17). Anti-inflammatory actions of phosphatidylinositol. Abstract:Zebraﬁsh is an elegant vertebrate employed to model the pathological etiologies of human maladies such as cardiac diseases. FASEB J (2012) 26:4092–101. Dev Comp Immunol (2010) 34:352–9. To understand the effect of microbial colonization on the zebrafish host, Rawls et al. Application of Zebrafish Model in the Suppression of Drug-Induced Cardiac Hypertrophy by Traditional Indian Medicine Yogendra Ras. Thus, effective and convenient animal models are needed. A frameshift mutation in NOD2 associated with susceptibility to Crohn’s disease. Intronic cis-regulatory modules mediate tissue-specific and microbial control of angptl4/fiaf transcription. Thakur PC, Davison JM, Stuckenholz C, Lu L, Bahary N. Dysregulated phosphatidylinositol signaling promotes endoplasmic-reticulum-stress-mediated intestinal mucosal injury and inflammation in zebrafish. Zebrafish (2014) 11:255–64. Kokkotou E, Moss AC, Torres D, Karagiannides I, Cheifetz A, Liu S, et al. Another useful chemically induced zebrafish model was established by immersing the zebrafish in defined media mixed with TNBS. showed that the μ-opioid receptor agonist DALDA, a dermorphin analog (H-Tyr-d-Arg-Phe-Lys-NH2), alleviated ER stress to protect against intestinal injury in the glafenine-induced zebrafish model by inducing the unfolded protein response (UPR) (87). doi:10.5483/BMBRep.2005.38.5.571, 58. They established an enterocolitis model successfully using histological and molecular evidence. Gastroenterology (1992) 102:1524–34. MAPK refers to mitogen-activated protein kinase, which stimulates the inflammatory process of cells. APC mutations cause the spontaneous development of intestinal polyps (14–16). They used a forward genetic screen to identify mutants characterized by deficiencies in intestinal epithelial integrity (37). doi:10.1152/ajpgi.00513.2005, 60. Front. 3. In developmental biology, fluorescence-activated cell sorting is combined with microarray profiling to identify genes and proteins involved in the intestinal development (89). This not only demonstrated the fidelity of the chemically induced zebrafish enterocolitis models to IBD but also the feasibility of using zebrafish to identify novel drugs for treating IBD (19). doi:10.1073/pnas.1424089112, 38. Applications de Zebrafish dans la recherche. Adolph TE, Tomczak MF, Niederreiter L, Ko HJ, Bock J, Martinez-Naves E, et al. However, Bates et al. Antibiotics were administered to confirm the bacteria’s exacerbation of inflammation. Both these diseases are characterized by an abnormal response by the immune system, compromising diarrhea or rectal urgency, bleeding, abdominal pain, constipation, and loss of appetite (1). Zebrafish: from disease modeling to drug discovery. Additionally, ethanol-induced epithelial damage appears to be more severe in the MSP mutant. Unfortunately, murine models of CXCL8 deficiency are difficult to investigate. Investigators first established the zebrafish model by induction using non-steroidal anti-inflammatory drugs to simulate an impaired mucosal barrier function (88). Although there is no formal report of any subclinical human IBD medication tested to date, 5-ASA and prednisolone have been administrated and investigated for their pharmacodynamic responses. 1. Bringing a new drug to the market costs an average of US$2.6 billion and takes more than 10 years from discovery to regulatory approval. Our work introduces a methodology for automatically quantifying patterns that arise due to agent interactions. Interestingly, the expressions of the HSP70 and HSP110 family genes HSPa4 and HSP4b were increased in TNBS-induced enterocolitis zebrafish models (47). The predominant advantage for TNBS-induced zebrafish models is consistency with high-throughput technology and the capacity to build a poly-phenotype library (93). Get the latest public health information from CDC: https://www.coronavirus.gov, Get the latest research information from NIH: https://www.nih.gov/coronavirus, Find NCBI SARS-CoV-2 literature, sequence, and clinical content: https://www.ncbi.nlm.nih.gov/sars-cov-2/. Studies in experimental animals have indicated that the intestinal microbiota play a critical role in the pathogenesis of intestinal inflammation (80). Although chemically induced models construct an inflammatory environment, they do not match well with the criteria of IBD. Zebrafish assessment of cognitive improvement and anxiolysis: filling the gap between in vitro and rodent models for drug development. No use, distribution or reproduction is permitted which does not comply with these terms. The immune system of the zebrafish has some unique characteristics compared with mammals. Studies have revealed that the expressions of transcription factors (including NF-κB and AP-1) in the core of innate immunity and pro-inflammatory cytokines (including IL-1β, MMP9) depend on MYD88 signaling during bacterial infection. Claudins and epithelial paracellular transport. Elson CO, Sartor RB, Tennyson GS, Riddell RH. Sciences de la vie. doi:10.1038/nature11582, 27. 2. The use of zebrafish to study IBD takes advantage of the combination of the growing list of immune cell reporter fish and the optical transparency of the larvae early in life (<2 weeks). These models are characterized by the upregulated expression of cytokines, leukocytosis, and different degrees of morphological changes (19, 20, 48, 50). doi:10.1126/science.1651562, 16. These heterozygous mutations were confirmed to have a relationship with truncated forms of adenomatous polyposis coli (APC). Two ER stress factors, HSPα5 and XBP1, are increased in the intestinal epithelium. Further analyses of this dysbiosis indicated a significant relationship with enterocolitis. 2012 Jan;8(1):21-8. doi: 10.2217/fon.11.137. doi:10.1097/01.MIB.0000195385.19268.68, PubMed Abstract | CrossRef Full Text | Google Scholar. doi:10.1016/S0016-5085(85)80126-8, 22. While pattern formation has been studied extensively using experiments and mathematical models, methods for quantifying self-organization are limited to manual inspection or global measures in many applications. As discussed in the previous section, a simple application of this model would be to evaluate drugs useful in generalized epilepsy syndromes. Duplicated genes are one of the essential parts of the zebrafish genome, which indicates that homologs of mammal immune factors might not have conserved functions in zebrafish. doi:10.1096/fj.11-202663, 44. The vagus nerve: a tonic inhibitory influence associated with inflammatory bowel disease in a murine model. Curr Opin Drug Discov Devel. As a small whole-organism model, zebrafish can be used to comprehensively test and evaluate the activity and side effect of a compound at the same time, fulfilling high content screening. Zebrafish is emerging as an important model for studying obesity and related metabolic diseases. Nat Rev Gastroenterol Hepatol (2015) 12:318–20. 2003 Mar;6(2):218-23. Infect Immun (2006) 74:2436–41. Prog Biophys Mol Biol. This could be explained by the fact that epithelial turnover depends on microbes via MYD88, but not via the TNF receptor (78). Dis Model Mech (2013) 6:841–54. Proc Natl Acad Sci U S A (2008) 105:10613–8. Pathological changes analogous to human CD are observed in the SAMP1/Yit mouse model, especially in the distal ileum (23). One compound prostaglandin E2 has been subjected to clinical trial to test if it can promote the growth of umbilical cord blood units after transplantation. In vancomycin-treated zebrafish, the population of microbes was dominated by the Fusobacteria. Several zebrafish models have demonstrated intestinal immune disorders in recent years. Chemically induced intestinal damage models in zebrafish larvae. For genetic studies, the genetic manipulation of the murine models is difficult. Loss of HEG1 will affect the stabilization of vascular endothelial cell connection and eventually lead to dilated cardiomyopathy (DCM). In this short review and the accompanying poster, we highlight a few illustrative examples of the applications of the zebrafish model to the study of human health and disease. 5 ):353-67. doi: 10.1016/j.pbiomolbio.2009.01.011 host pro-inflammatory immune responses, but not by a mutation in the epithelial function. 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