Protective effects of pre-treatment with exogenous porcine glucagon-like peptide-2 and its microspheres of piglets with lipopolysaccharide-induced intestinal inflammation
Jie Wu A , Keke Qi A and Ziwei Xu A *A Institute of Animal Science, Zhejiang Academy of Agricultural Sciences, Hangzhou, Zhejiang 310021, China.
Animal Production Science 63(1) 51-58 https://doi.org/10.1071/AN22218
Submitted: 6 June 2022 Accepted: 25 August 2022 Published: 23 September 2022
© 2023 The Author(s) (or their employer(s)). Published by CSIRO Publishing
Abstract
Context: Glucagon-like peptide-2 (GLP-2) is an intestinotrophic growth hormone that can accelerate intestinal development and recovery from injury. However, the half-life of GLP-2 is short, thus it must be administered frequently. Moreover, its effects during weaning are unclear.
Aims: We tested the effects of porcine GLP-2 (pGLP-2) and pGLP-2 microspheres on lipopolysaccharide (LPS)-induced intestinal inflammation in weaning piglets.
Methods: Eighteen female weaning piglets aged 21 days (5.38 ± 0.72 kg initial bodyweight) were randomly assigned to three treatment groups: (1) control, (2) GLP-2, and (3) GLP-2 microsphere (MS) group. Control piglets were injected intraperitoneally with 3 mL of saline solution from Days 1 to 7, GLP-2 piglets were injected intraperitoneally with 100 μg pGLP-2/kg bodyweight from Days 1 to 7, and MS piglets were injected intraperitoneally with 200 mg GLP-2 microspheres on Day 1 and with 3 mL saline solution from Days 2 to 7. On Day 8, all piglets were injected with 100 μg LPS/kg bodyweight.
Key results: Piglets in the GLP-2 and MS groups showed markedly increased average daily weight gain on Day 7, decreased serum myeloperoxidase, LPS and keratinocyte growth factor levels, and increased serum interleukin-10 levels compared with the control group. In addition, the GLP-2 group showed decreased myeloperoxidase content in the duodenum and ileum, and reduced caspase-3 activity in the duodenum and jejunum, whereas MS piglets showed decreased myeloperoxidase levels and suppressed caspase-3 activity in the duodenum and jejunum. Moreover, administration of pGLP-2 or pGLP-2 microspheres resulted in decreased interleukin-8 and interferon-γ mRNA expression levels in the jejunum, as compared with the control group.
Conclusions: Our results indicated that pGLP-2 promotes growth, and ameliorates LPS-induced serum and intestinal inflammatory responses in piglets. Furthermore, pGLP-2 microspheres can achieve similar therapeutic effects as pGLP-2 under the premise of fewer injections.
Implications: pGLP-2 microspheres have considerable potential for the treatment of weaning-induced intestinal inflammation in piglets.
Keywords: body weight, intestinal inflammation, lipopolysaccharide, microspheres, mRNA expression, piglets, porcine glucagon-like peptide-2, serum.
References
Alters SE, McLaughlin B, Spink B, Lachinyan T, Wang C-W, Podust V, Schellenberger V, Stemmer WPC (2012) GLP2-2G-XTEN: a pharmaceutical protein with improved serum half-life and efficacy in a rat Crohn’s disease model. PLoS ONE 7, e50630| GLP2-2G-XTEN: a pharmaceutical protein with improved serum half-life and efficacy in a rat Crohn’s disease model.Crossref | GoogleScholarGoogle Scholar |
Anderson JM, Shive MS (2012) Biodegradation and biocompatibility of PLA and PLGA microspheres. Advanced Drug Delivery Reviews 64, 72–82.
| Biodegradation and biocompatibility of PLA and PLGA microspheres.Crossref | GoogleScholarGoogle Scholar |
Boushey RP, Yusta B, Drucker DJ (1999) Glucagon-like peptide 2 decreases mortality and reduces the severity of indomethacin-induced murine enteritis. American Journal of Physiology-Endocrinology and Metabolism 277, E937–E947.
| Glucagon-like peptide 2 decreases mortality and reduces the severity of indomethacin-induced murine enteritis.Crossref | GoogleScholarGoogle Scholar |
Burrin DG, Stoll B, Guan X, Cui L, Chang X, Holst JJ (2005) Glucagon-like peptide 2 dose-dependently activates intestinal cell survival and proliferation in neonatal piglets. Endocrinology 146, 22–32.
| Glucagon-like peptide 2 dose-dependently activates intestinal cell survival and proliferation in neonatal piglets.Crossref | GoogleScholarGoogle Scholar |
Chance WT, Sheriff S, McCarter F, Ogle C (2001) Glucagon-like peptide-2 stimulates gut mucosal growth and immune response in burned rats. Journal of Burn Care & Rehabilitation 22, 136–143.
| Glucagon-like peptide-2 stimulates gut mucosal growth and immune response in burned rats.Crossref | GoogleScholarGoogle Scholar |
Deng QH, Jia G, Zhao H, Chen ZL, Chen XL, Liu GM, Wang KN (2016) The prolonged effect of glucagon-like peptide 2 pretreatment on growth performance and intestinal development of weaned piglets. Journal of Animal Science and Biotechnology 7, 28
| The prolonged effect of glucagon-like peptide 2 pretreatment on growth performance and intestinal development of weaned piglets.Crossref | GoogleScholarGoogle Scholar |
Guan L-L, Gong D-Z, Tian N, Zou Y (2005) Uncoupling protein 2 involved in protection of glucagon-like peptide 2 in small intestine with ischemia-reperfusion injury in mice. Digestive Diseases & Sciences 50, 554–560.
| Uncoupling protein 2 involved in protection of glucagon-like peptide 2 in small intestine with ischemia-reperfusion injury in mice.Crossref | GoogleScholarGoogle Scholar |
Heo JM, Opapeju FO, Pluske JR, Kim JC, Hampson DJ, Nyachoti CM (2013) Gastrointestinal health and function in weaned pigs: a review of feeding strategies to control post-weaning diarrhoea without using in-feed antimicrobial compounds. Journal of Animal Physiology and Animal Nutrition 97, 207–237.
| Gastrointestinal health and function in weaned pigs: a review of feeding strategies to control post-weaning diarrhoea without using in-feed antimicrobial compounds.Crossref | GoogleScholarGoogle Scholar |
Isbil-Buyukcoskun N, Cam B, Gulec Suyen G, Ozluk K (2018) Effects of intracerebroventricularly injected glucagon-like peptide-2 on ethanol-induced gastric mucosal damage in rats. Endocrine Research 43, 220–227.
| Effects of intracerebroventricularly injected glucagon-like peptide-2 on ethanol-induced gastric mucosal damage in rats.Crossref | GoogleScholarGoogle Scholar |
Ivory CPA, Wallace LE, McCafferty D-M, Sigalet DL (2008) Interleukin-10-independent anti-inflammatory actions of glucagon-like peptide 2. American Journal of Physiology-Gastrointestinal and Liver Physiology 295, G1202–G1210.
| Interleukin-10-independent anti-inflammatory actions of glucagon-like peptide 2.Crossref | GoogleScholarGoogle Scholar |
Jeppesen PB (2005) Teduglutide (ALX-0600), a dipeptidyl peptidase IV resistant glucagon-like peptide 2 analogue, improves intestinal function in short bowel syndrome patients. Gut 54, 1224–1231.
| Teduglutide (ALX-0600), a dipeptidyl peptidase IV resistant glucagon-like peptide 2 analogue, improves intestinal function in short bowel syndrome patients.Crossref | GoogleScholarGoogle Scholar |
Jeppesen PB, Pertkiewicz M, Messing B, Iyer K, Seidner DL, O’keefe SJD, Forbes A, Heinze H, Joelsson B (2012) Teduglutide reduces need for parenteral support among patients with short bowel syndrome with intestinal failure. Gastroenterology 143, 1473–1481.e3.
| Teduglutide reduces need for parenteral support among patients with short bowel syndrome with intestinal failure.Crossref | GoogleScholarGoogle Scholar |
Lai SW, de Heuvel E, Wallace LE, Hartmann B, Holst JJ, Brindle ME, Chelikani PK, Sigalet DL (2017) Effects of exogenous glucagon-like peptide-2 and distal bowel resection on intestinal and systemic adaptive responses in rats. PLoS ONE 12, e0181453
| Effects of exogenous glucagon-like peptide-2 and distal bowel resection on intestinal and systemic adaptive responses in rats.Crossref | GoogleScholarGoogle Scholar |
Lallès J-P, Bosi P, Smidt H, Stokes CR (2007) Weaning – a challenge to gut physiologists. Livestock Science 108, 82–93.
| Weaning – a challenge to gut physiologists.Crossref | GoogleScholarGoogle Scholar |
Lei Q, Bi J, Chen H, Tian F, Gao X, Li N, Wang X (2018) Glucagon-like peptide-2 improves intestinal immune function and diminishes bacterial translocation in a mouse model of parenteral nutrition. Nutrition Research 49, 56–66.
| Glucagon-like peptide-2 improves intestinal immune function and diminishes bacterial translocation in a mouse model of parenteral nutrition.Crossref | GoogleScholarGoogle Scholar |
Ørskov C, Hartmann B, Poulsen SS, Thulesen J, Hare KJ, Holst JJ (2005) GLP-2 stimulates colonic growth via KGF, released by subepithelial myofibroblasts with GLP-2 receptors. Regulatory Peptides 124, 105–112.
| GLP-2 stimulates colonic growth via KGF, released by subepithelial myofibroblasts with GLP-2 receptors.Crossref | GoogleScholarGoogle Scholar |
Pedersen NB, Hjollund KR, Johnsen AH, Ørskov C, Rosenkilde MM, Hartmann B, Holst JJ (2008) Porcine glucagon-like peptide-2: structure, signaling, metabolism and effects. Regulatory Peptides 146, 310–320.
| Porcine glucagon-like peptide-2: structure, signaling, metabolism and effects.Crossref | GoogleScholarGoogle Scholar |
Qi K-K, Wu J, Xu Z-W (2014) Effects of PEGylated porcine glucagon-like peptide-2 therapy in weaning piglets challenged with lipopolysaccharide. Peptides 58, 7–13.
| Effects of PEGylated porcine glucagon-like peptide-2 therapy in weaning piglets challenged with lipopolysaccharide.Crossref | GoogleScholarGoogle Scholar |
Qi KK, Wu J, Deng B, Li YM, Xu ZW (2015) PEGylated porcine glucagon-like peptide-2 improved the intestinal digestive function and prevented inflammation of weaning piglets challenged with LPS. Animal 9, 1481–1489.
| PEGylated porcine glucagon-like peptide-2 improved the intestinal digestive function and prevented inflammation of weaning piglets challenged with LPS.Crossref | GoogleScholarGoogle Scholar |
Qi KK, Wu J, Wen Jun Z, Bo D, Xu ZW (2020) Catch-up growth in intrauterine growth-restricted piglets associated with the restore of pancreatic and intestinal functions via porcine glucagon-like peptide-2 microspheres. Archives of Animal Nutrition 74, 462–475.
| Catch-up growth in intrauterine growth-restricted piglets associated with the restore of pancreatic and intestinal functions via porcine glucagon-like peptide-2 microspheres.Crossref | GoogleScholarGoogle Scholar |
Sigalet DL, Wallace L, De Heuval E, Sharkey KA (2010) The effects of glucagon-like peptide 2 on enteric neurons in intestinal inflammation. Neurogastroenterology & Motility 22, 1318–e350.
| The effects of glucagon-like peptide 2 on enteric neurons in intestinal inflammation.Crossref | GoogleScholarGoogle Scholar |
Sigalet DL, de Heuvel E, Wallace L, Bulloch E, Turner J, Wales PW, Nation P, Wizzard PR, Hartmann B, Assad M, Holst JJ (2014) Effects of chronic glucagon-like peptide-2 therapy during weaning in neonatal pigs. Regulatory Peptides 188, 70–80.
| Effects of chronic glucagon-like peptide-2 therapy during weaning in neonatal pigs.Crossref | GoogleScholarGoogle Scholar |
Thymann T, Le Huërou-Luron I, Petersen YM, Hedemann MS, Elinf J, Jensen BB, Holst JJ, Hartmann B, Sangild PT (2014) Glucagon-like peptide 2 treatment may improve intestinal adaptation during weaning. Journal of Animal Science 92, 2070–2079.
| Glucagon-like peptide 2 treatment may improve intestinal adaptation during weaning.Crossref | GoogleScholarGoogle Scholar |
Washizawa N, Gu LH, Gu L, Openo KP, Jones DP, Ziegler TR (2004) Comparative effects of glucagon-like peptide-2 (GLP-2), growth hormone (GH), and keratinocyte growth factor (KGF) on markers of gut adaptation after massive small bowel resection in rats. Journal of Parenteral and Enteral Nutrition 28, 399–409.
| Comparative effects of glucagon-like peptide-2 (GLP-2), growth hormone (GH), and keratinocyte growth factor (KGF) on markers of gut adaptation after massive small bowel resection in rats.Crossref | GoogleScholarGoogle Scholar |
Wu J, Qi K, Xu Z, Wan J (2015) Glucagon-like peptide-2-loaded microspheres as treatment for ulcerative colitis in the murine model. Journal of Microencapsulation 32, 598–607.
| Glucagon-like peptide-2-loaded microspheres as treatment for ulcerative colitis in the murine model.Crossref | GoogleScholarGoogle Scholar |
Wu J, Qi KK, Xu ZW (2016) Porcine glucagon-like peptide-2 microspheres ameliorate inflammation in lipopolysaccharide-challenged weaning piglets. Journal of Animal Science 94, 5286–5294.
| Porcine glucagon-like peptide-2 microspheres ameliorate inflammation in lipopolysaccharide-challenged weaning piglets.Crossref | GoogleScholarGoogle Scholar |
Yu C, Jia G, Jiang Y, Deng Q, Chen Z, Xu Z, Chen X, Wang K (2014) Effect of glucagon-like peptide 2 on tight junction in jejunal epithelium of weaned pigs though MAPK signaling pathway. Asian-Australasian Journal of Animal Sciences 27, 733–742.
| Effect of glucagon-like peptide 2 on tight junction in jejunal epithelium of weaned pigs though MAPK signaling pathway.Crossref | GoogleScholarGoogle Scholar |