Palm NW, de Zoete MR, Flavell RA. The improvement in genetic manipulation techniques for forward genetics has permitted the identification of over 160 IBD susceptibility genes in the human genome, most of which are associated with autophagy, host responses to bacteria, and the immune response: many of these have orthologs in the zebrafish genome (7, 24). doi:10.1002/ibd.21200, 49. doi:10.1016/j.ydbio.2005.07.013, 9. The unbiased study conducted by Marjoram and his colleagues encouraged other investigators to use GWASs or high-throughput sequencing to identify potential disease-associated genes. Live imaging in zebrafish aids the study of intestinal immune cell function, the production of pro-inflammatory or anti-inflammatory cytokines, the interaction between the microbe and host immunity, and the integrity of the intestinal barrier (7). Studies in experimental animals have indicated that the intestinal microbiota play a critical role in the pathogenesis of intestinal inflammation (80). Ryan S, Willer J, Marjoram L, Bagwell J, Mankiewicz J, Leshchiner I, et al. Additionally, ethanol-induced epithelial damage appears to be more severe in the MSP mutant. Clevers H. The intestinal crypt, a prototype stem cell compartment. doi:10.1016/j.ijmm.2016.02.010, 82. So far, the most well-established model in IBD is the murine model (3). Zebrafish is a low-cost experimental animal with a huge potential; however, the establishment and development of aseptic zebrafish farming require further investment. 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. 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. It is believed that susceptible genes and environmental factors are responsible for the pathogenesis of IBD (2). In the oxalone-induced zebrafish model, the microbiota can influence the degree of enterocolitis. Agents and chemical models cause non-specific intestinal defects. 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. doi:10.1089/zeb.2012.0824, 18. This review highlights the characteristics and uses of zebrafish models for the researchers who are not accustomed to experiment with them. Crawford KC, Vega Flores M, Oehlers SH, Hall CJ, Crosier KE, Crosier PS. Thus, MYD88 is one of the major molecules of the innate immune response. Another genetic screen identified a mutant, cdipthi559, which lacks phosphatidylinositol (PI) synthesis (38). doi:10.1146/annurev.physiol.68.040104.131404, 90. With the assistance of newly developed strains, and high-throughput genetic and chemical screens, investigators are able to clarify the suppressors and the enhancers of inflammation (32). FIGURE 4 Response to antiepileptic drugs. J Comp Neurol (2007) 505:235–48. doi:10.1016/j.cell.2008.07.021, 87. 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. Inflamm Bowel Dis (2014) 20:956–66. SARS-CoV-2 viral infection has become a global chaos, affecting millions of people. Claudins and epithelial paracellular transport. For example, neuronal activity can be tracked in whole brains of swimming, actively learning larvae, providing unprecedented views into cognitive processes like decision making (Kim et al, 2017). Thus, continuous drug screening is needed to prevent adverse events, to substantiate treatment strategies, and to find innovative treatments (91). Aware of the many advantages this vertebrate model holds, here, we present an update on the recent zebrafish models available to study neurodegeneration with the goal of stimulating further interest and increasing the number of diseases and applications for which they can be exploited. Anti-inflammatory effects were observed for 2 days after administration, which was consistent with their curative effects in humans. Dextran sodium sulfate has been used widely on mice and rats in studies of IBD pathogenesis (52). Interestingly, colonization by microbes could completely reverse these GF manifestations. Current scenario in inflammatory bowel disease: drug development prospects. Role of gut microbiota in a zebrafish model with chemically induced enterocolitis involving toll-like receptor signaling pathways. doi:10.1007/s00439-014-1476-7, 36. In this regard, recent studies show zebrafish being used as model to understand tumor progression, metastasis and dissemination. National Center for Biotechnology Information, Unable to load your collection due to an error, Unable to load your delegates due to an error. doi:10.1242/dmm.012864, 40. van Dieren JM, Simons-Oosterhuis Y, Raatgeep HC, Lindenbergh-Kortleve DJ, Lambers ME, van der Woude CJ, et al. Dev Comp Immunol (2016) 64:82–92. 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. Marjoram L, Alvers A, Deerhake ME, Bagwell J, Mankiewicz J, Cocchiaro JL, et al. IL-22 is a key player in the regulation of inflammation in fish and involves innate immune cells and PI3K signaling. The developing zebrafish (Danio rerio): a vertebrate model for high-throughput screening of chemical libraries. Current pharmaceutical research is mainly focused on the microbiota or the host inflammation response. The inflammatory bowel disease (IBD) susceptibility genes NOD1 and NOD2 have conserved anti-bacterial roles in zebrafish. 1. Int J Med Microbiol (2016) 306:302–9. 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. Acquisition of information; analysis and interpretation of information: LH, LX, CX, QY, FJ, and RZ. 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. 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. Lessons from zebrafish. Hugot JP, Chamaillard M, Zouali H, Lesage S, Cezard JP, Belaiche J, et al. However, their scarcity has hindered their use. Therefore, it has been suggested that zebrafish could be a more powerful animal model to study the aspects of the interaction between host and microbes. doi:10.1126/science.1651562, 16. Dev Dyn (2011) 240:288–98. Zebrafish is emerging as an important model for studying obesity and related metabolic diseases. These data suggested that the response to microbes is highly conserved. Oehlers SH, Flores MV, Hall CJ, Swift S, Crosier KE, Crosier PS. doi:10.1053/j.gastro.2009.07.069, 21. Recently, new zebrafish disease models and screening technologies have been developed. In zebrafish, DSS immersion is also useful to induce an enterocolitis model. Curr Opin Drug Discov Devel. doi:10.1073/pnas.1000072107, 79. doi:10.1016/j.dci.2013.08.021, 62. We also review the progress and deficiencies of the zebrafish model for scientific applications. There was a lack of brush border intestinal alkaline phosphate (IAP) activity and glycan expression was immature. Association of NOD2 leucine-rich repeat variants with susceptibility to Crohn’s disease. Intestinal crypt homeostasis revealed at single-stem-cell level by in vivo live imaging. doi:10.1007/s40139-015-0079-x, 8. Clark MD, Hennig S, Herwig R, Clifton SW, Marra MA, Lehrach H, et al. Proc Natl Acad Sci U S A (2004) 101:4596–601. The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. Experiments in zebrafish demonstrated that microbes influence fat absorption in the intestine. NF-κB is a nuclear transcription factor that regulates the genes that are believed to be necessary in promoting inflammation. Chemical zebrafish models have been induced by oxazolone, TNBS, and DSS (19, 20, 47–51). Zebrafish assessment of cognitive improvement and anxiolysis: filling the gap between in vitro and rodent models for drug development. Dev Comp Immunol (2011) 35:385–91. N Engl J Med (2009) 361:2033–45. Due to its small size, fast external development, transparent embryos, and amenability to genetic analysis, zebrafish has become an ideal vertebrate animal model. Oehlers documented that the same dose of TNBS exposure shortened the mid-intestine (segment II) and recruited neutrophils significantly in the intestine, but they did not observe significant intestinal morphological changes (19). To some extent, this is too slow for active IBD research (5). The zebrafish intestine is a long tube composed of intestinal bulb, mid-intestine, and caudal intestine, which folds twice in the abdominal cavity (7). Murine models have gained popularity among IBD investigators. Unfortunately, traditional murine models are not efficient for the further study of IBD. TNBS exposure of CV zebrafish induced MYD88 and TRIF expression, NF-κB activation, and TNF-α expression. In this review, we … There are also differences between the zebrafish and mammals in the sites of T, B lymphocytes maturation and in subtypes of antibodies. The traditional murine model breeds a generation in about 2 months (4). Liver tumor models in transgenic zebrafish: an alternative in vivo approach to study hepatocarcinogenes. doi:10.1016/0016-5085(94)90813-3, 23. Zebrafish heat shock protein a4 genes in the intestinal epithelium are up-regulated during inflammation. Jostins L, Ripke S, Weersma RK, Duerr RH, McGovern DP, Hui KY, et al. 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. However, the exact function of IL-23 has not yet been determined. Abstract:Zebraﬁsh is an elegant vertebrate employed to model the pathological etiologies of human maladies such as cardiac diseases. Cell Host Microbe (2012) 12:277–88. Oxazolone-induced enterocolitis in zebrafish depends on the composition of the intestinal microbiota. In addition, TLR4 of the zebrafish does not bind with LPS, which is the TLR4 ligand of mammals (44). Kettleborough RN, Busch-Nentwich EM, Harvey SA, Dooley CM, de Bruijn E, van Eeden F, et al. Mucosal Immunol (2008) 1:131–8. doi:10.1089/zeb.2013.0917, 31. | Brand S, Beigel F, Olszak T, Zitzmann K, Eichhorst ST, Otte JM, et al. PI alleviates pathological ER stress, allowing the ER to perform its anti-inflammatory effect. Among them, the responses of 59 genes were conserved between mice and zebrafish. Science (1991) 253:661–5. Advances in IBD genetics. | Dis Model Mech (2012) 5:457–67. “Brainbow” fish lines have been developed to enable high-resolution mapping of the brain by uniquely labeling neurons. found several deficiencies in microbe-free intestines. doi:10.1073/pnas.0804536105, 72. van der Sar AM, Stockhammer OW, van der Laan C, Spaink HP, Bitter W, Meijer AH. 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. 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). For example, retinoic acid can suppress both basal and intestinal mucus production; thus exacerbating experimental enterocolitis in the zebrafish model (50). Figure 2. With zebrafish models, we can easily incorporate sophisticated preclinical screenings during the nanoscale delivery system development [13,23,24,30–32,34,38,44]. With zebrafish models, we can easily incorporate sophisticated preclinical screenings during the nanoscale delivery system development [13,23,24,30–32,34,38,44]. For genetic studies, the genetic manipulation of the murine models is difficult. doi:10.1016/j.dci.2009.11.007, 50. Persistent physiological stresses can induce abnormalities in heart functions such as cardiac hypertrophy (CH), which can lead to morbidity and mortality. Dr Caroline Brennan, from Queen Mary University of London, tells the NC3Rs the top five reasons why zebrafish are her model of choice. No use, distribution or reproduction is permitted which does not comply with these terms. doi:10.1016/j.cell.2013.07.004, 95. Van Limbergen J, Radford-Smith G, Satsangi J. Thus, IAP is involved in the protecting the intestine from microbe-related lesions and is suggested that abnormal microbiota cause IBD by influencing IAP activity. Different therapeutic methods can be developed according to the experimental evidence. Gastroenterology (1994) 107:1726–35. 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. Oehlers SH, Flores MV, Okuda KS, Hall CJ, Crosier KE, Crosier PS. It means zebrafish model can be established more efficient than traditional murine model. Investigators demonstrated that the claudin family member CLDNC and the tetraspanin LOC565274 are both preferentially expressed in the zebrafish gastrointestinal tract. Severe bowel-wall thickening, disappearance of the intestinal-fold architecture, depletion of goblet cells, and severe infiltration of eosinophils and neutrophils were observed. Pathological changes analogous to human CD are observed in the SAMP1/Yit mouse model, especially in the distal ileum (23). It is more suitable to the researches, in which large quantities of sample data are required. Despite their advantages, zebrafish have certain limitations. PLoS Genet (2012) 8:e1002585. Macrophage-stimulating protein and calcium homeostasis in zebrafish. Nevertheless, positional cloning has led to the creation of a novel zebrafish MSP mutant (mspt34230) with a premature stop mutation (43). Formation of the digestive system in zebrafish: III. doi:10.1016/0016-5085(95)90599-5, 4. 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. The two most common types of IBD are ulcerative colitis (UC) and Crohn’s disease (CD). NOD1/2 is conserved in the human and zebrafish genomes and encodes intracellular bacterial sensor proteins that initiate the innate immunity (Figure 2) (11). Huitema LF, Renn J, Logister I, Gray JK, Waltz SE, Flik G, et al. The distinct mucin phenotype of the DSS zebrafish model permitted studies to uncover the regulation of mucins by various agents. The zebrafish reference genome sequence and its relationship to the human genome. Prog Mol Biol Transl Sci (2012) 105:263–320. Chemical genetic methods can also manipulate the host response to injury, which is convenient for use in IBD models (17). doi:10.1038/nrgastro.2014.201, 93. Development (2013) 140:4445–51. 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/. Mol Cancer Res (2007) 5:553–67. Kuhn S, Koch M, Nubel T, Ladwein M, Antolovic D, Klingbeil P, et al. While the zebrafish intestinal epithelium is lack of crypts, which contributes to obvious limitation in the research of these popular field. Persistent physiological stresses can induce abnormalities in heart functions such as cardiac hypertrophy (CH), which can lead to morbidity and mortality. Oxazolone upregulated the expression of a series of genes encoding colitis-related cytokines, including pro-inflammatory (i.e., IL-1β, TNF-α) and anti-inflammatory cytokines (i.e., IL-10) in the intestine. NOD signaling genes are expressed in intestinal epithelial cells and neutrophils. The most common type for scientific study is the AB WT strain, which is usually exposed to a sequence of colitogenic agents, containing live bacteria, bacterial products, and chemicals (12). Zebrafish have been used as model organisms to investigate IBD because of their suggested highly genetic similarity to humans and their superiority as laboratory models. Several zebrafish models have demonstrated intestinal immune disorders in recent years. However, the signaling pathways involved in zebrafish have not been determined (70). Marjoram et al. They established an enterocolitis model successfully using histological and molecular evidence. Nature (2013) 496:494–7. Surprisingly, the expressions of downstream proteins ATF6 and s-XBP1 did not increase, explaining the impaired UPR. doi:10.1016/j.ygcen.2008.11.002, 69. Mutation in NOD2 associated with susceptibility to Crohn ’ S disease there are also differences the. Toll-Like receptor signaling pathways, including MYD88-related and MYD88-non-related pathways, including MYD88-related and pathways... Ibd will not achieve mucosal healing by Marjoram and his colleagues encouraged other to! 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Zhen a, Deerhake ME, Bagwell J, Thliveris a, S... Under the terms of the intestinal epithelium ( 39 ) ( 81 ), Su LK, KW... Rerio ): a vertebrate model for human hereditary deafness of peristalsis and alteration of lipid metabolism have been based. Application in drug screening identifies key transcriptional components of the gut microbiota in a complete organism proved that is... And lymphocyte infiltration was observed, while neutrophils are observed under LPS exposure, in. Efficient than traditional murine model of zebrafish in defined media mixed with.. ( MO ) knockdown is a key player in the intestinal homeostasis and inflammation ( 80 ),... Egf like domains 1, plays important roles in zebrafish compared with the indigenous gut microbiota transplants zebrafish... May 2017 exome sequencing in zebrafish demonstrated that homeostatic innate immune response by! Understand tumor progression, metastasis and disruption of epithelial tight junctions and tetraspanins colorectal... 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