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Denatonium as a bitter taste receptor agonist damages jejunal epithelial cells of yellow-feathered chickens via inducing apoptosis

Published online by Cambridge University Press:  16 December 2019

J. Jiang
College of Animal Science and Technology, Nanjing Agricultural University, No. 1 Weigang, Nanjing 210095, China
Z. Lv
College of Animal Science and Technology, Nanjing Agricultural University, No. 1 Weigang, Nanjing 210095, China
L. Qi
College of Animal Science and Technology, Nanjing Agricultural University, No. 1 Weigang, Nanjing 210095, China
H. Enayatullah
College of Animal Science and Technology, Nanjing Agricultural University, No. 1 Weigang, Nanjing 210095, China
Q. Wei
College of Animal Science and Technology, Nanjing Agricultural University, No. 1 Weigang, Nanjing 210095, China
D. Yu
College of Animal Science and Technology, Nanjing Agricultural University, No. 1 Weigang, Nanjing 210095, China
F. Shi*
College of Animal Science and Technology, Nanjing Agricultural University, No. 1 Weigang, Nanjing 210095, China
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The sense of bitter taste is critical for chickens to acquire and select feeds. It is important to understand the roles and mechanisms of bitter taste transduction in chickens. Denatonium is extensively used as a bitter taste receptor agonist to activate bitter taste receptors in recent studies. The objective of this study was to investigate the physiological effects and the potential molecular mechanisms of dietary exposure to a strong bitter taste receptor agonist on the jejunal epithelial cells of yellow-feathered chickens. A total of 240 yellow-feathered chickens were divided into four treatments receiving a normal diet (Control), a low-dose denatonium treatment (Control + 5 mg/kg denatonium), a middle-dose denatonium treatment (Control + 20 mg/kg denatonium) and a high-dose denatonium treatment (Control + 100 mg/kg denatonium) for 56 days, respectively. The results showed that dietary denatonium reduced (P < 0.05) the growth performance of chickens. High-dose denatonium damaged the morphology of the jejunal epithelium and decreased (P < 0.05) the activities of Ca2+-ATPase, sucrase and maltase after 56 days of exposure. Meanwhile, high-dose denatonium increased (P < 0.05) mRNA expressions of bitter taste receptors, which resulted in enhanced apoptosis in jejunal epithelial cells after 56 days of exposure. Furthermore, middle-dose and high-dose denatonium exhibited increased (P < 0.05) mRNA level of claudin 2 and decreased (P < 0.05) mRNA level of occludin after 28 days of exposure. Only high-dose denatonium decreased (P < 0.05) mRNA level of occludin after 56 days of exposure. In conclusion, denatonium manifested deleterious effects on the jejunum of chickens in a dose–effect manner via damaging the morphology of the jejunal epithelium, and inducing apoptosis associated with bitter taste receptors. Our data suggest that bitter-tasting feed additives may have side effects on the growth and development of intestines in chickens.

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© The Animal Consortium 2019

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Avau, B, Bauters, D, Steensels, S, Vancleef, L, Laermans, J, Lesuisse, J, Buyse, J, Lijnen, HR, Tack, J and Depoortere, I 2015. The gustatory signaling pathway and bitter taste receptors affect the development of obesity and adipocyte metabolism in mice. PLoS ONE 10, e0145538e0145538.CrossRefGoogle ScholarPubMed
Bai, K, Feng, C, Jiang, L, Zhang, L, Zhang, J, Zhang, L and Wang, T 2018. Dietary effects of Bacillus subtilis fmbj on growth performance, small intestinal morphology, and its antioxidant capacity of broilers. Poultry Science 97, 23122321.CrossRefGoogle ScholarPubMed
Cheled-Shoval, S, Behrens, M, Korb, A, Di Pizio, A, Meyerhof, W, Uni, Z and Niv, MY 2017. From cell to beak: in-vitro and in-vivo characterization of chicken bitter taste thresholds. Molecules 22, E821. /10.3390/molecules22050821CrossRefGoogle ScholarPubMed
Cheled-Shoval, SL, Behrens, M, Meyerhof, W, Niv, MY and Uni, Z 2014. Perinatal administration of a bitter tastant influences gene expression in chicken palate and duodenum. Journal of Agricultural & Food Chemistry 62, 1251212520.CrossRefGoogle ScholarPubMed
Cheled-Shoval, SL, Shelly, D and Zehava, U 2015. Bitter, sweet and umami taste receptors and downstream signaling effectors: expression in embryonic and growing chicken gastrointestinal tract. Poultry Science 227, 19281941.CrossRefGoogle Scholar
Chen, B, Wang, G, Li, W, Liu, W, Lin, R, Tao, J, Jiang, M, Chen, L and Wang, Y 2017a. Memantine attenuates cell apoptosis by suppressing the calpain-caspase-3 pathway in an experimental model of ischemic stroke. Experimental Cell Research 351, 163172.CrossRefGoogle Scholar
Chen, J, De Raeymaecker, J, Hovgaard, JB, Smaardijk, S, Vandecaetsbeek, I, Wuytack, F, Møller, JV, Eggermont, J, De Maeyer, M, Christensen, SB and Vangheluwe, P 2017b. Structure/activity relationship of thapsigargin inhibition on the purified Golgi/secretory pathway Ca(2+)/Mn(2+)-transport ATPase (SPCA1a). Journal of Biological Chemistry 292, 69386951.CrossRefGoogle Scholar
Chen, Z, Xie, J, Wang, B and Tang, J 2014. Effect of γ-aminobutyric acid on digestive enzymes, absorption function, and immune function of intestinal mucosa in heat-stressed chicken. Poultry Science 93, 24902500.CrossRefGoogle ScholarPubMed
Cosmetic Ingredient Review Expert Panel 2008. Final report of the safety assessment of Alcohol Denat., including SD Alcohol 3-A, SD Alcohol 30, SD Alcohol 39, SD Alcohol 39-B, SD Alcohol 39-C, SD Alcohol 40, SD Alcohol 40-B, and SD Alcohol 40-C, and the denaturants, Quassin, Brucine Sulfate/Brucine, and Denatonium Benzoate. International Journal of Toxicology 27, 143.CrossRefGoogle Scholar
Dang, D and Rao, R 2016. Calcium-ATPases: gene disorders and dysregulation in cancer. Biochimica et Biophysica Acta 1863, 13441350.CrossRefGoogle ScholarPubMed
Deloose, E, Janssen, P, Corsetti, M, Biesiekierski, J, Masuy, I, Rotondo, A, Van, OL, Depoortere, I and Tack, J 2017. Intragastric infusion of denatonium benzoate attenuates interdigestive gastric motility and hunger scores in healthy female volunteers. American Journal of Clinical Nutrition 105, 580588.CrossRefGoogle ScholarPubMed
Deshpande, DA, Wang, WCH, Mcilmoyle, EL, Robinett, KS, Schillinger, RM, An, SS, Sham, JSK and Liggett, SB 2010. Bitter taste receptors on airway smooth muscle bronchodilate by localized calcium signaling and reverse obstruction. Nature Medicine 16, 12991304.CrossRefGoogle ScholarPubMed
Freund, JR, Mansfield, CJ, Doghramji, LJ, Adappa, ND, Palmer, JN, Kennedy, DW, Reed, DR, Jiang, P and Lee, RJ 2018. Activation of airway epithelial bitter taste receptors by quinolones modulates calcium, cyclic-AMP, and nitric oxide signaling. The Journal of Biological Chemistry 293, 98249840.CrossRefGoogle ScholarPubMed
Goll, DE, Thompson, VF, Li, H, Wei, W and Cong, J 2003. The calpain system. Physiological Reviews 83, 731801.CrossRefGoogle ScholarPubMed
Günther, C, Neumann, H, Neurath, MF and Becker, C 2013. Apoptosis, necrosis and necroptosis: cell death regulation in the intestinal epithelium. Gut 62, 10621071.CrossRefGoogle ScholarPubMed
Iguchi, N, Ohkuri, T, Slack, JP, Zhong, P and Huang, L 2011. Sarco/Endoplasmic reticulum Ca2+-ATPases (SERCA) contribute to GPCR-mediated taste perception. PLoS ONE 6, e23165e23165.CrossRefGoogle ScholarPubMed
Jiang, J, Qi, L, Wei, Q and Shi, F 2017. Effects of daily exposure to saccharin sodium and rebaudioside A on the ovarian cycle and steroidogenesis in rats. Reproductive Toxicology 76, 3545.CrossRefGoogle ScholarPubMed
Kudo, KI, Nishimura, S and Tabata, S 2010. Distribution of taste buds in layer-type chickens: scanning electron microscopic observations. Animal Science Journal 79, 680685.CrossRefGoogle Scholar
, KT, Maurice, H and du Souich, P 1996. First-pass metabolism of lidocaine in the anesthetized rabbit. Contribution of the small intestine. Drug Metabolism and Disposition 24, 711716.Google ScholarPubMed
Lee, HL, Santé-Lhoutellier, V, Vigouroux, S, Briand, Y and Briand, M 2007. Calpain specificity and expression in Chicken tissues. Comparative Biochemistry and Physiology. Part B: Biochemistry and Molecular Biology 146, 8893.CrossRefGoogle ScholarPubMed
Li, Y, Cai, HY, Liu, GH, Dong, XL, Chang, WH, Zhang, S, Zheng, AJ and Chen, GL 2009. Effects of stress simulated by dexamethasone on jejunal glucose transport in broilers. Poultry Science 88, 330337.CrossRefGoogle ScholarPubMed
Lv, CF, Liu, G, Li, J, Li, RX, Mi, YL and Zhang, CQ 2017. Effect of melatonin on renewal of chicken small intestinal mucosa. Poultry Science 96, 29422949.Google Scholar
Niknafs, S and Roura, E 2018. Nutrient sensing, taste and feed intake in avian species. Nutrition Research Reviews 31, 256266.CrossRefGoogle ScholarPubMed
Nisha, S, Raja, C, Rajinder Pal, B and Prashen, C 2014. Differential expression of bitter taste receptors in non-cancerous breast epithelial and breast cancer cells. Biochemical & Biophysical Research Communications 446, 499503.Google Scholar
NRC (1994) Nutrient requirements of poultry. 9th rev. ed. National Academic Press, Washington, DC.Google Scholar
Roura, E, Baldwin, MW and Klasing, KC 2013. The avian taste system: potential implications in poultry nutrition. Animal Feed Science and Technology 180, 19.CrossRefGoogle Scholar
Samak, G, Chaudhry, KK, Gangwar, R, Narayanan, D, Jaggar, JH and Rao, R 2015. Calcium/Ask1/MKK7/JNK2/c-Src signalling cascade mediates disruption of intestinal epithelial tight junctions by dextran sulfate sodium. Biochemical Journal 465, 503515.CrossRefGoogle ScholarPubMed
Shah, AS, Yehuda, BS, Moninger, TO, Kline, JN and Welsh, MJ 2009. Motile cilia of human airway epithelia are chemosensory. Science 325, 11311134.CrossRefGoogle ScholarPubMed
Straub, SG, Mulvaney-Musa, J, Yajima, H, Weiland, GA and Sharp, GW 2003. Stimulation of insulin secretion by denatonium, one of the most bitter-tasting substances known. Diabetes 52, 356364.CrossRefGoogle ScholarPubMed
Turner, JR 2009. Intestinal mucosal barrier function in health and disease. Nature Reviews: Immunology 9, 799809.Google ScholarPubMed
Wang, H, Zhai, N, Chen, Y, Xu, H and Huang, K 2017. Cadmium induces Ca 2 + mediated, calpain-1/caspase-3-dependent apoptosis in primary cultured rat proximal tubular cells. Journal of Inorganic Biochemistry 172, 1622.CrossRefGoogle ScholarPubMed
Wen, X, Zhou, J, Zhang, D, Li, J, Wang, Q, Feng, N, Zhu, H, Song, Y, Li, H and Bai, C 2015. Denatonium inhibits growth and induces apoptosis of airway epithelial cells through mitochondrial signaling pathways. Respiratory research 16, 13. ScholarPubMed
Wu, SV, Rozengurt, N, Yang, M, Young, SH, Sinnett-Smith, J and Rozengurt, E 2002. Expression of bitter taste receptors of the T2R family in the gastrointestinal tract and enteroendocrine STC-1 cells. Proceedings of the National Academy of Sciences of the United States of America 99, 23922397.CrossRefGoogle ScholarPubMed
Yujing, S, Yuming, G and Zhong, W 2013. β-1,3/1,6-Glucan alleviated intestinal mucosal barrier impairment of broiler chickens challenged with Salmonella enterica serovar Typhimurium. Poultry Science 92, 17641773.Google Scholar
Zhang, Y, Ren, S, Liu, Y, Gao, K, Liu, Z and Zhang, Z 2017. Inhibition of starvation-triggered endoplasmic reticulum stress, autophagy, and apoptosis in ARPE-19 cells by Taurine through modulating the expression of Calpain-1 and Calpain-2. International Journal of Molecular Sciences 18, E2146. ScholarPubMed
Zheng, K, Lu, P, Delpapa, E, Bellve, K, Deng, R, Condon, JC, Fogarty, K, Lifshitz, LM, Simas, TAM, Shi, F and ZhuGe, R 2017. Bitter taste receptors as targets for tocolytics in preterm labor therapy. FASEB Journal 31, 40374052.CrossRefGoogle ScholarPubMed
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