Deoxynivalenol (DON), also known as vomitoxin, is a mycotoxin that can cause antifeeding and vomiting in animals. However, the mechanism of DON inducing anorexia is complicated. Studies have shown that intestinal hormones play a significant part in the anorexia caused by DON. We adopted the "modeling of acute antifeeding in mice" as the basic experimental model, and used two methods of gavage and intraperitoneal injection to explore the effect of intestinal hormones on the antifeedant response induced by DON in mice. We found that 1 and 2.5 mg/kg·bw of DON can acutely induce anorexia and increase the plasma intestinal hormones CCK, PYY, GIP, and GLP-1 in mice within 3 h. Direct injection of exogenous intestinal hormones CCK, PYY, GIP, and GLP-1 can trigger anorexia behavior in mice. Furthermore, the PYY receptor antagonist JNJ-31020028, GLP-1 receptor antagonist Exendin(9-39), CCK receptor antagonist Proglumide, GIP receptor antagonist GIP(3-30)NH2 attenuated both intestinal hormone and DON-induced anorectic responses. These results indicate that intestinal hormones play a critical role in the anorexia response induced by DON.

Biomedical Research Center University Hospital Hradec Kralove 500 05 Hradec Kralove Czech Republic

Department of Chemistry Faculty of Science University of Hradec Králové Rokitanského 62 500 03 Hradec Kralove Czech Republic

MOE Joint International Research Laboratory of Animal Health and Food Safety Engineering Center of Innovative Veterinary Drugs College of Veterinary Medicine Nanjing Agricultural University Nanjing 210095 China

Shandong Vocational Animal Science and Veterinary College 88 Shengli East Street Weifang 261061 China

See more in PubMed

Tran S.T., Smith T.K., Girgis G.N. A survey of free and conjugated deoxynivalenol in the 2008 corn crop in Ontario, Canada. J. Sci. Food Agric. 2012;92:37–41. doi: 10.1002/jsfa.4674. PubMed DOI

García G.R., Payros D., Pinton P., Dogi C.A., Laffitte J., Neves M., González Pereyra M.L., Cavaglieri L.R., Oswald I.P. Intestinal toxicity of deoxynivalenol is limited by Lactobacillus rhamnosus RC007 in pig jejunum explants. Arch. Toxicol. 2018;92:983–993. doi: 10.1007/s00204-017-2083-x. PubMed DOI

Pinton P., Oswald I.P. Effect of deoxynivalenol and other Type B trichothecenes on the intestine: A review. Toxins. 2014;6:1615–1643. doi: 10.3390/toxins6051615. PubMed DOI PMC

van der Fels-Klerx H.J. Evaluation of performance of predictive models for deoxynivalenol in wheat. Risk Anal. 2014;34:380–390. doi: 10.1111/risa.12103. PubMed DOI

Waśkiewicz A., Beszterda M., Kostecki M., Zielonka Ł., Goliński P., Gajęcki M. Deoxynivalenol in the gastrointestinal tract of immature gilts under per os toxin application. Toxins. 2014;6:973–987. doi: 10.3390/toxins6030973. PubMed DOI PMC

Schwartz M.W. Central nervous system regulation of food intake. Obesity. 2006;14:1s–8s. doi: 10.1038/oby.2006.275. PubMed DOI

Sjölund K., Sandén G., Håkanson R., Sundler F. Endocrine cells in human intestine: An immunocytochemical study. Gastroenterology. 1983;85:1120–1130. doi: 10.1016/S0016-5085(83)80080-8. PubMed DOI

Santos-Hernández M., Miralles B., Amigo L., Recio I. Intestinal Signaling of Proteins and Digestion-Derived Products Relevant to Satiety. J. Agric. Food Chem. 2018;66:10123–10131. doi: 10.1021/acs.jafc.8b02355. PubMed DOI

Atalayer D., Astbury N.M. Anorexia of aging and gut hormones. Aging Dis. 2013;4:264–275. doi: 10.14336/AD.2013.0400264. PubMed DOI PMC

Schalla M.A., Stengel A. The Role of Ghrelin in Anorexia Nervosa. Int. J. Mol. Sci. 2018;19:2117. doi: 10.3390/ijms19072117. PubMed DOI PMC

Terciolo C., Maresca M., Pinton P., Oswald I.P. Review article: Role of satiety hormones in anorexia induction by Trichothecene mycotoxins. Food Chem. Toxicol. 2018;121:701–714. doi: 10.1016/j.fct.2018.09.034. PubMed DOI

Zhang J., Liu S., Zhang H., Li Y., Wu W., Zhang H. Gut satiety hormones cholecystokinin and glucagon-like Peptide-1(7-36) amide mediate anorexia induction by trichothecenes T-2 toxin, HT-2 toxin, diacetoxyscirpenol and neosolaniol. Toxicol. Appl. Pharmacol. 2017;335:49–55. doi: 10.1016/j.taap.2017.09.020. PubMed DOI

Rowlands J., Heng J., Newsholme P., Carlessi R. Pleiotropic Effects of GLP-1 and Analogs on Cell Signaling, Metabolism, and Function. Front. Endocrinol. 2018;9:672. doi: 10.3389/fendo.2018.00672. PubMed DOI PMC

Harding R.K., McDonald T.J. Identification and characterization of the emetic effects of peptide YY. Peptides. 1989;10:21–24. doi: 10.1016/0196-9781(89)90069-7. PubMed DOI

Challis B.G., Pinnock S.B., Coll A.P., Carter R.N., Dickson S.L., O’Rahilly S. Acute effects of PYY3-36 on food intake and hypothalamic neuropeptide expression in the mouse. Biochem. Biophys. Res. Commun. 2003;311:915–919. doi: 10.1016/j.bbrc.2003.10.089. PubMed DOI

Batterham R.L., Cowley M.A., Small C.J., Herzog H., Cohen M.A., Dakin C.L., Wren A.M., Brynes A.E., Low M.J., Ghatei M.A., et al. Gut hormone PYY(3-36) physiologically inhibits food intake. Nature. 2002;418:650–654. doi: 10.1038/nature00887. PubMed DOI

Kanoski S.E., Fortin S.M., Arnold M., Grill H.J., Hayes M.R. Peripheral and central GLP-1 receptor populations mediate the anorectic effects of peripherally administered GLP-1 receptor agonists, liraglutide and exendin-4. Endocrinology. 2011;152:3103–3112. doi: 10.1210/en.2011-0174. PubMed DOI PMC

van Bloemendaal L., Ten Kulve J.S., la Fleur S.E., Ijzerman R.G., Diamant M. Effects of glucagon-like peptide 1 on appetite and body weight: Focus on the CNS. J. Endocrinol. 2014;221:T1–T16. doi: 10.1530/JOE-13-0414. PubMed DOI

Seino Y., Yabe D. Glucose-dependent insulinotropic polypeptide and glucagon-like peptide-1: Incretin actions beyond the pancreas. J. Diabetes Investig. 2013;4:108–130. doi: 10.1111/jdi.12065. PubMed DOI PMC

Wu W., Zhou H.R., Bursian S.J., Pan X., Link J.E., Berthiller F., Adam G., Krantis A., Durst T., Pestka J.J. Comparison of anorectic and emetic potencies of deoxynivalenol (vomitoxin) to the plant metabolite deoxynivalenol-3-glucoside and synthetic deoxynivalenol derivatives EN139528 and EN139544. Toxicol. 2014;142:167–181. doi: 10.1093/toxsci/kfu166. PubMed DOI PMC

Jia H., Wu W.D., Lu X., Zhang J., He C.H., Zhang H.B. Role of Glucagon-Like Peptide-1 and Gastric Inhibitory Peptide in Anorexia Induction Following Oral Exposure to the Trichothecene Mycotoxin Deoxynivalenol (Vomitoxin) Toxicol. Sci. 2017;159:16–24. doi: 10.1093/toxsci/kfx112. PubMed DOI

Flannery B.M., Clark E.S., Pestka J.J. Anorexia induction by the trichothecene deoxynivalenol (vomitoxin) is mediated by the release of the gut satiety hormone peptide YY. Toxicol. Sci. 2012;130:289–297. doi: 10.1093/toxsci/kfs255. PubMed DOI PMC

Wu W., Zhou H.R., He K., Pan X., Sugita-Konishi Y., Watanabe M., Zhang H., Pestka J.J. Role of cholecystokinin in anorexia induction following oral exposure to the 8-ketotrichothecenes deoxynivalenol, 15-acetyldeoxynivalenol, 3-acetyldeoxynivalenol, fusarenon X, and nivalenol. Toxicol. Sci. 2014;138:278–289. doi: 10.1093/toxsci/kft335. PubMed DOI PMC

Flannery B.M., Wu W., Pestka J.J. Characterization of deoxynivalenol-induced anorexia using mouse bioassay. Food Chem. Toxicol. 2011;49:1863–1869. doi: 10.1016/j.fct.2011.05.004. PubMed DOI PMC

Pestka J.J. Deoxynivalenol-induced proinflammatory gene expression: Mechanisms and pathological sequelae. Toxins. 2010;2:1300–1317. doi: 10.3390/toxins2061300. PubMed DOI PMC

Zhou H.R., Pestka J.J. Deoxynivalenol (Vomitoxin)-Induced Cholecystokinin and Glucagon-Like Peptide-1 Release in the STC-1 Enteroendocrine Cell Model Is Mediated by Calcium-Sensing Receptor and Transient Receptor Potential Ankyrin-1 Channel. Toxicol. Sci. 2015;145:407–417. doi: 10.1093/toxsci/kfv061. PubMed DOI PMC

Brothers S.P., Saldanha S.A., Spicer T.P., Cameron M., Mercer B.A., Chase P., McDonald P., Wahlestedt C., Hodder P.S. Selective and brain penetrant neuropeptide y y2 receptor antagonists discovered by whole-cell high-throughput screening. Mol. Pharmacol. 2010;77:46–57. doi: 10.1124/mol.109.058677. PubMed DOI PMC

Sloth B., Holst J.J., Flint A., Gregersen N.T., Astrup A. Effects of PYY1-36 and PYY3-36 on appetite, energy intake, energy expenditure, glucose and fat metabolism in obese and lean subjects. Am. J. Physiol. Endocrinol. Metab. 2007;292:E1062–E1068. doi: 10.1152/ajpendo.00450.2006. PubMed DOI

Hao S., Sternini C., Raybould H.E. Role of CCK1 and Y2 receptors in activation of hindbrain neurons induced by intragastric administration of bitter taste receptor ligands. Am. J. Physiol. Regul. Integr. Comp. Physiol. 2008;294:R33–R38. doi: 10.1152/ajpregu.00675.2007. PubMed DOI

Crawley J.N., Corwin R.L. Biological actions of cholecystokinin. Peptides. 1994;15:731–755. doi: 10.1016/0196-9781(94)90104-X. PubMed DOI

Shillabeer G., Davison J.S. Proglumide, a cholecystokinin antagonist, increases gastric emptying in rats. Am. J. Physiol. 1987;252:R353–R360. doi: 10.1152/ajpregu.1987.252.2.R353. PubMed DOI

Baggio L.L., Drucker D.J. Biology of incretins: GLP-1 and GIP. Gastroenterology. 2007;132:2131–2157. doi: 10.1053/j.gastro.2007.03.054. PubMed DOI

Hansen L.S., Sparre-Ulrich A.H., Christensen M., Knop F.K., Hartmann B., Holst J.J., Rosenkilde M.M. N-terminally and C-terminally truncated forms of glucose-dependent insulinotropic polypeptide are high-affinity competitive antagonists of the human GIP receptor. Br. J. Pharmacol. 2016;173:826–838. doi: 10.1111/bph.13384. PubMed DOI PMC

Wu W., Bates M.A., Bursian S.J., Flannery B., Zhou H.-R., Link J.E., Zhang H., Pestka J.J. Peptide YY3–36 and 5-Hydroxytryptamine Mediate Emesis Induction by Trichothecene Deoxynivalenol (Vomitoxin) Toxicol. Sci. 2013;133:186–195. doi: 10.1093/toxsci/kft033. PubMed DOI PMC

Sparre-Ulrich A.H., Gabe M.N., Gasbjerg L.S., Christiansen C.B., Svendsen B., Hartmann B., Holst J.J., Rosenkilde M.M. GIP(3-30)NH(2) is a potent competitive antagonist of the GIP receptor and effectively inhibits GIP-mediated insulin, glucagon, and somatostatin release. Biochem. Pharmacol. 2017;131:78–88. doi: 10.1016/j.bcp.2017.02.012. PubMed DOI

Emetic Response to T-2 Toxin Correspond to Secretion of Glucagon-like Peptide-17-36 Amide and Glucose-Dependent Insulinotropic Polypeptide

Glucose-Dependent Insulinotropic Polypeptide and Substance P Mediate Emetic Response Induction by Masked Trichothecene Deoxynivalenol-3-Glucoside through Ca2+ Signaling