[Frontiers In Bioscience, Landmark, 23, 2166-2176, June1, 2018]

Establishment of a porcine model of indomethacin-induced intestinal injury

Dan Yi1, Wenkai Liu1, Yongqing Hou1, Lei Wang1, Di Zhao1, Tao Wu1, Binying Ding1, Guoyao Wu1,2

1Hubei Collaborative Innovation Center for Animal Nutrition and Feed Safety, Hubei Key Laboratory of Animal Nutrition and Feed Science, Wuhan Polytechnic University, Wuhan 430023, China; 2Department of Animal Science, Texas A&M University, College Station, TX, USA 77843

TABLE OF CONTENT

1. Abstract
2. Introduction
3. IDMT induced intestinal injury of piglets
3.1. General study protocol
3.2. Changes in the body weight of piglets challenged with IDMT
3.3. Changes in the hematological indexes of piglets challenged with IDMT
3.4. Intestinal lesions and alterations of intestinal histology in piglets challenged with IDMT
3.5. Redox status in the plasma and intestine challenged with IDMT
3.6. Variation of gene expression profiles in the intestinal mucosa challenged with IDMT
4. Conclusion and perspectives
5. Acknowledgements
6. References

1. ABSTRACT

A useful animal model of intestinal injury is pivotal for studying its pathogenesis and developing nutritional interventions (e.g., amino acid supplementation). Here, we propose the use of indomethacin (IDMT) to induce intestinal inflammation in neonatal pigs. Fourteen-day-old piglets fed a milk replacer diet receive intraperitoneal administration of IDMT (5 mg/kg body weight) for 3 consecutive days. On day 4, blood and intestinal samples are obtained for physiological and biochemical analyses. IDMT increases blood DAO activity, I-FABP concentration, neutrophil and eosinophil numbers; intestinal MMP3 mRNA levels, MPO activity, and MDA concentration; but reduces the plasma concentration of citrulline (synthesized exclusively by enterocytes of the small intestine), intestinal GSH-Px activity, and mRNA levels for villin, I-FABP, TRPV6, AQP10, and KCNJ13. Moreover, extensive hemorrhagic spots, thinned intestinal wall, and ulcers in the distal jejunum and ileum are observed in IDMT-challenged piglets. Furthermore, IDMT decreases intestinal villus height and villus surface area in the piglet jejunum. Collectively, this work establishes a porcine model of intestinal injury for designing novel nutritional means to improve gut function in pigs and humans.

6. REFERENCES

1. Y Gao, F Han, X Huang, Y Rong, H Yi, Y Wang: Changes in gut microbial populations, intestinal morphology, expression of tight junction proteins, and cytokine production between two pig breeds after challenge with Escherichia coli K88: a comparative study. J Anim Sci 91, 5614-5625 (2013)
DOI: 10.2527/jas.2013-6528

2. AD Andersen, MS Cilieborg, C Lauridsen, AL Mørkbak, PT Sangild: Supplementation with Lactobacillus paracasei or Pediococcus pentosaceus does not prevent diarrhoea in neonatal pigs infected with Escherichia coli F18. Br J Nutr 118, 109-120 (2017)
DOI: 10.1017/S000711451700160X

3. T Wu, Y Lv, X Li, D Zhao, D Yi, L Wang, P Li, H Chen, Y Hou, J Gong, G Wu: Establishment of a recombinant Escherichia coli-induced piglet diarrhea model. Front Biosci (Landmark Ed) 23, 1517-1523 (2018)
DOI: 10.2741/658

4. YQ Hou, L Wang, W Zhang, ZG Yang, BY Ding, HL Zhu, YL Liu, YS Qiu, YL Yin, G Wu: Protective effects of N-acetylcysteine on intestinal functions of piglets challenged with lipopolysaccharide. Amino Acids 43, 1233-1242 (2012)
DOI: 10.1007/s00726-011-1191-9

5. D Yi, Y Hou, H Xiao, L Wang, Y Zhang, H Chen, T Wu, B Ding, CA Hu, G Wu: N-Acetylcysteine improves intestinal function in lipopolysaccharides-challenged piglets through multiple signaling pathways. Amino Acids 49, 1915-1929 (2017)
DOI: 10.1007/s00726-017-2389-2

6. CL Wells, RP Jechorek, SB Olmsted, SL Erlandsen: Effect of LPS on epithelial integrity and bacterial uptake in the polarized human enterocyte-like cell line Caco-2. Circ Shock 40, 276-288 (1993)
PMID: 8375030

7. A Anthony, AP Dhillon, G Nygard, M Hudson, C Piasecki, P Strong, MA Trevethick, NM Clayton, CC Jordan, RE Pounder, AJ Wakefield: Early histological features of small intestinal injury induced by indomethacin. Aliment Pharmacol Ther 7, 29-39 (1993)
DOI: 10.1111/j.1365-2036.1993.tb00066.x

8. CO Elson, RB Sartor, GS Tennyson, RH Riddell: Experimental models of inflammatory bowel disease. Gastroenterol 109, 1344-1367 (1995)
DOI: 10.1016/0016-5085(95)90599-5

9. K Higuchi, E Umegaki, T Watanabe, Y Yoda, E Morita, M Murano, S Tokioka, T Arakawa: Present status and strategy of NSAIDs-induced small bowel injury. J Gastroenterol 44, 879-888 (2009)
DOI: 10.1007/s00535-009-0102-2

10. E Roura, SJ Koopmans, JP Lallès, I Le Huerou-Luron, N de Jager, T Schuurman, D Val-Laillet: Critical review evaluating the pig as a model for human nutritional physiology. Nutr Res Rev 29, 60-90 (2016)
DOI: 10.1.017/S0954422416000020

11. L Wang, J Zhou, Y Hou, D Yi, B Ding, J Xie, Y Zhang, H Chen, T Wu, D Zhao, CA Hu, G Wu: N-Acetylcysteine supplementation alleviates intestinal injury in piglets infected by porcine epidemic diarrhea virus. Amino Acids 49, 1931-1943 (2017)
DOI: 10.1.007/s00726-017-2397-2

12. CY Xie, GJ Zhang, FR Zhang, SH Zhang, XF Zeng, PA Thacker, SY Qiao. Estimation of the optimal ratio of standardized ileal digestible tryptophan to lysine for finishing barrows fed low protein diets supplemented with crystalline amino acids. Czech J Anim Sci 59, 26-34 (2014)
DOI: 10.1.7221/7191-CJAS

13. Y Araki, A Andoh, J Takizawa, W Takizawa, Y Fujiyama: Clostridium butyricum, a probiotic derivative, suppresses dextran sulfate sodium-induced experimental colitis in rats. Int J Mol Med 13, 577-580 (2004)
DOI: 10.3.892/ijmm.13.4.5.7.7

14. AB Nygard, CB Jørgensen, S Cirera, M Fredholm: Selection of reference genes for gene expression studies in pig tissues using SYBR green qPCR. BMC Mol Biol 8, 67 (2007)
DOI: 10.1.186/1471-2199-8-67

15. KJ Livak, TD Schmittgen: Analysis of relative gene expression data using real-time quantitative PCR and the 2-ΔΔCT method. Methods 25, 402-408 (2001)
DOI: 10.3.892/ijo.2013.1.860

16. SJ Byun, TJ Lim, YJ Lim, JG Seo, MJ Chung: In vivo effects of s-pantoprazole, polaprenzinc, and probiotic blend on chronic small intestinal injury induced by indomethacin. Benef Microbes 7, 731-737 (2016)
DOI: 10.3.920/BM2016.0.029

17. LP Filaretova, TR Bagaeva, OY Morozova, D Zelena: A wider view on gastric erosion: detailed evaluation of complex somatic and behavioral changes in rats treated with indomethacin at gastric ulcerogenic dose. Endocr Regul 48, 163-172 (2014)
DOI: 10.4.149/endo_2014_04_163

18. M Kunes, J Kvetina, J Bures: Type and distribution of indomethacin-induced lesions in the gastrointestinal tract of rat. Neuro Endocrinol Lett, suppl 1, 96-100 (2009)
PMID: 20027152

19. CL Yan, HS Kim, JS Hong, JH Lee, YG Han, YH Jin, SW Son, SH Ha, YY Kim: Effect of Dietary sugar beet pulp supplementation on growth performance, nutrient digestibility, fecal microflora, blood profiles and diarrhea incidence in weaning pigs. J Anim Sci Technol 59, 18 (2017)
DOI: 10.1.186/s40781-017-0142-8

20. A Erman, B Chen-Gal, J Rosenfeld: The role of eicosanoids in cyclosporine nephrotoxicity in the rat. Biochem Pharmacol 38, 2153-2157 (1989)
DOI: 10.1.016/0006-2952(89)90070-1

21. S Takasu, M Mutoh, M Takahashi, H Nakagama: Lipoprotein lipase as a candidate target for cancer prevention/therapy. Biochem Res Int 2012, 398697 (2012)
DOI: 10.1.155/2012/398697

22. D Yi, YQ Hou, L Wang, BY Ding, ZG Yang, J Li, MH Long, YL Liu, G Wu: Dietary N-acetylcysteine supplementation alleviates liver injury in lipopolysaccharide-challenged piglets. Br J Nutr 111, 46-54 (2014)
DOI: 10.1.017/S0007114513002171

23. VE Stubbs, P Schratl, A Hartnell, TJ Williams, BA Peskar, A Heinemann, I Sabroe: Indomethacin causes prostaglandin D(2)-like and eotaxin-like selective responses in eosinophils and basophils. J Biol Chem 277, 26012-26020 (2002)
DOI: 10.1.074/jbc.M201803200

24. JY Li, Y Yu, S Hu, D Sun, YM Yao: Preventive effect of glutamine on intestinal barrier dysfunction induced by severe trauma. World J Gastroenterol 8, 168-171 (2002)
DOI: 10.3.748/wjg.v8.i1.1.68

25. G Wu, DA Knabe, NE Flynn: Synthesis of citrulline from glutamine in pig enterocytes. Biochem J 299, 115-121 (1994)
DOI: 10.1042/bj2990115

26. JM Rhoads, G Wu, J Galanko: Serum citrulline levels in infants with short bowel syndrome. J Pediatr 148:848-849 (2006)
DOI: 10.1016/j.jpeds.2005.06.015

27. P Crenn, B Messing, L Cynober: Citrulline as a biomarker of intestinal failure due to enterocyte mass reduction. Clin Nutr 27, 328-339 (2008)
DOI: 10.1.016/j.clnu.2008.0.2.0.05

28. L Ciobanu, M Taulescu, R Prundus, B Diaconu, V Andreica, C Catoi, O Pascu, M Tantau: Effects of rifaximin on indomethacin-induced intestinal damage in guinea-pigs. Eur Rev Med Pharmacol Sci 18, 344-351 (2014)
PMID:24563433

29. BJ Whittle, F László, SM Evans, S Moncada: Induction of nitric oxide synthase and microvascular injury in the rat jejunum provoked by indomethacin. Br J Pharmacol 116, 2286-2290 (1995) PMID: 8564261
DOI: 10.1111/j.1476-5381.1995.tb15066.x

30. CK Li, SL Pender, KM Pickard, V Chance, JA Holloway, A Huett, NS Gonçalves, JS Mudgett, G Dougan, G Frankel, TT MacDonald: Impaired immunity to intestinal bacterial infection in stromelysin-1 (matrix metalloproteinase-3)-deficient mice. J Immunol 173, 5171-5179 (2004)
DOI: 10.4.049/jimmunol.173.8.5.1.71

31. A Page-McCaw, AJ Ewald, Z Werb: Matrix metalloproteinases and the regulation of tissue remodelling. Nat Rev Mol Cell Biol 8, 221-233 (2007)
DOI: 10.1.038/nrm2125

32. C Carrasco-Pozo, RL Castillo, C Beltrán, A Miranda, J Fuentes, M Gotteland: Molecular mechanisms of gastrointestinal protection by quercetin against indomethacin-induced damage: role of NF-κB and Nrf2. J Nutr Biochem 27, 289-298 (2016)
DOI: 10.1.016/j.jnutbio.2015.0.9.0.16

33. RD Emkey, GR Emkey: Calcium metabolism and correcting calcium deficiencies. Endocrinol Metab Clin North Am 41, 527-556 (2012)
DOI: 10.1.016/j.ecl.2012.0.4.0.19

34. U Laforenza, E Miceli, G Gastaldi, MF Scaffino, U Ventura, JM Fontana, MN Orsenigo, GR Corazza: Solute transporters and aquaporins are impaired in celiac disease. Biol Cell 102, 457-467 (2010)
DOI: 10.1.042/BC20100023

35. G Wu: Amino acids: metabolism, functions, and nutrition. Amino Acids 37, 1-17 (2009)
DOI: 10.1.007/s00726-009-0269-0

36. YQ Hou, ZL Wu, ZL Dai, GH Wang, G Wu: Protein hydrolysates in animal nutrition: Industrial production, bioactive peptides, and functional significance. J Anim Sci Biotechnol 8, 24 (2017)
DOI: 10.1.186/s40104-017-0153-9

37. ZL Wu, YQ Hou, SD Hu, FW Bazer, CJ Meininger, CJ McNeal, G Wu: Catabolism and safety of supplemental L-arginine in animals. Amino Acids 48, 1541-1552 (2016)
DOI: 10.1.007/s00726-016-2245-9

38. XS Ma, ZL Dai, KJ Sun, YC Zhang, JQ Chen, Y Yang, P Tso, G Wu, ZL Wu: Intestinal epithelial cell endoplasmic reticulum stress and inflammatory bowel disease pathogenesis: An update review. Front Immunol 8, 1271 (2017)
DOI: 10.3.389/fimmu.2017.0.1271

39. L Yin, H Yang, J Li, Y Li, X Ding, G Wu, Y Yin: Pig models on intestinal development and therapeutics. Amino Acids 49, 2053-2063 (2017)
DOI: 10.1.007/s00726-017-2497-z

40. Q Jiang, S Chen, W Ren, G Liu, K Yao, G Wu, Y Yin: Escherichia coli aggravates endoplasmic reticulum stress and triggers CHOP-dependent apoptosis in weaned pigs. Amino Acids 49, 2073-2082 (2017)
DOI: 10.1.007/s00726-017-2492-4

41. D Yi, YQ Hou, HM Mei, L Wang, C-A Hu, G Wu: β-Conglycinin enhances autophagy in porcine enterocytes. Amino Acids 49, 203-207 (2017)
DOI: 10.1.007/s00726-016-2352-7

42. G Wu: Principles of Animal Nutrition. CRC Press, Boca Raton, Florida (2018)

Abbreviations: ADG, average daily gain; ALT, alanine transaminase; AST, aspartate transaminase; ALP, alkaline phosphatase; AQP10, aquaporin 10; BASO, basophils; CHOL, cholesterol; DAO, diamine oxidase; EOS, eosinophils; GSH-Px, glutathione peroxidase; H2O2, hydrogen peroxide; I-FABP, intestinal fatty acid-bonding protein; IL-8, interleukin 8; KCNJ13, potassium inwardly-rectifying channel, subfamily J, member 13; LYM, lymphocytes; MDA, malonaldehyde; MMP3, matrix metalloproteinase-3; MONO, monocytes; MPO, myeloperoxidase; NEUT, neutrophils; pBD-1, porcine β-defense 1; PLT, platelets; RBC, red blood cells; SOD, superoxide dismutase; TBIL, total bilirubin; TG, triglycerides; TP, total protein; TRPV6, transient receptor potential cation channel, subfamily V, member 6; WBC, white blood cells.

Key Words: Hematology, Indomethacin, Inflammation, Intestinal injury, Animal Model, Piglets, Review

Send correspondence to: Yongqing Hou, Hubei Collaborative Innovation Center for Animal Nutrition and Feed Safety, Hubei key Laboratory of Animal Nutrition and Feed Science, Wuhan Polytechnic University, Wuhan 430023, China, Tel: 86 2783956175, Fax: 86 2783956175, E-mail: houyq@aliyun.com