Journal of Pediatric Gastroenterology and Nutrition

Original Article: Nutrition

In the Short-term, Milk Fat Globule Epidermal Growth Factor-8 Causes Site-specific Intestinal Growth in Resected Piglets

Corresponding Author

Justine M. Turner

[email protected]

Department of Pediatrics, University of Alberta, Edmonton, Alberta

Address correspondence and reprint requests to Justine M. Turner, PhD, Department of Pediatrics, University of Alberta, Edmonton Clinic Health Academy, 11405 – 87th Avenue NW, Edmonton, AB, Canada T6G 1C9 (e-mail: [email protected]).Search for more papers by this author

Petro George,

Petro George

Department of Pediatrics, University of Alberta, Edmonton, Alberta

Search for more papers by this author

Marihan Lansing,

Marihan Lansing

Department of Pediatrics, University of Alberta, Edmonton, Alberta

Search for more papers by this author

George Slim,

George Slim

Department of Pediatrics, University of Alberta, Edmonton, Alberta

Search for more papers by this author

Pamela R. Wizzard,

Pamela R. Wizzard

Department of Pediatrics, University of Alberta, Edmonton, Alberta

Search for more papers by this author

Patrick Nation,

Patrick Nation

Department of Laboratory Medicine and Pathology, University of Alberta, Edmonton, Alberta

Search for more papers by this author

Patricia L. Brubaker,

Patricia L. Brubaker

Departments of Physiology and Medicine, Hospital for Sick Children, Toronto, Ontario, Canada

Search for more papers by this author

Paul W. Wales,

Paul W. Wales

Department of Pediatrics, University of Alberta, Edmonton, Alberta

Department of Surgery, University of Toronto, Hospital for Sick Children, Toronto, Ontario, Canada

Group for the Improvement of Intestinal Function and Treatment (GIFT), Hospital for Sick Children, Toronto, Ontario, Canada

Search for more papers by this author

Justine M. Turner,

Corresponding Author

Justine M. Turner

[email protected]

Department of Pediatrics, University of Alberta, Edmonton, Alberta

Petro George,

Petro George

Department of Pediatrics, University of Alberta, Edmonton, Alberta

Search for more papers by this author

Marihan Lansing,

Marihan Lansing

Department of Pediatrics, University of Alberta, Edmonton, Alberta

Search for more papers by this author

George Slim,

George Slim

Department of Pediatrics, University of Alberta, Edmonton, Alberta

Search for more papers by this author

Pamela R. Wizzard,

Pamela R. Wizzard

Department of Pediatrics, University of Alberta, Edmonton, Alberta

Search for more papers by this author

Patrick Nation,

Patrick Nation

Department of Laboratory Medicine and Pathology, University of Alberta, Edmonton, Alberta

Search for more papers by this author

Patricia L. Brubaker,

Patricia L. Brubaker

Departments of Physiology and Medicine, Hospital for Sick Children, Toronto, Ontario, Canada

Search for more papers by this author

Paul W. Wales,

Paul W. Wales

Department of Pediatrics, University of Alberta, Edmonton, Alberta

Department of Surgery, University of Toronto, Hospital for Sick Children, Toronto, Ontario, Canada

Group for the Improvement of Intestinal Function and Treatment (GIFT), Hospital for Sick Children, Toronto, Ontario, Canada

Search for more papers by this author

First published: 02 July 2020

https://doi.org/10.1097/MPG.0000000000002818

Citations: 1

Supplemental digital content is available for this article. Direct URL citations appear in the printed text, and links to the digital files are provided in the HTML text of this article on the journal's Web site (www.jpgn.org).

Disclosures: Research was supported by Empire Biotechnologies, Inc., who supplied MFG-E8 in-kind.

Share a link

Email
Wechat
Bluesky

ABSTRACT

Objectives:

Short bowel syndrome (SBS) remains the leading cause of neonatal intestinal failure. Milk fat globule epidermal growth factor-8 (MFG-E8), present in human milk, has homology with epidermal growth factor (EGF), known to enhance adaptation in SBS. In this pilot study, the role of oral MFG-E8 treatment in SBS was explored in neonatal piglets.

Methods:

Neonatal piglets underwent 75% intestinal resection, either distal (jejunal-colonic [JC] anastomosis) or mid-intestinal (jejunal-ileal [JI] anastomosis). Piglets were randomized to intragastric treatment with MFG-E8 (5 mg/kg per day) or saline and were maintained on parenteral nutrition and enteral nutrition for 7 days. Adaptation was assessed by intestinal length and weight, histopathology, fecal fat analysis and RT-qPCR analysis of mucosal transcripts, including growth factors.

Results:

JI piglets demonstrated intestinal lengthening (P < 0.001), 2-fold greater in ileum than jejunum (P = 0.02), where lengthening was increased by MFG-E8 treatment (P = 0.02). JC piglets did not exhibit jejunal lengthening, regardless of treatment. Fat absorption was greater for JI piglets (P = 0.02), unaffected by treatment. In JI piglets, expression of Egf was increased in the ileum (P < 0.01) and MFG-E8 treatment increased Egfr (receptor) expression (P = 0.02).

Conclusions:

MF-EG8 demonstrated site-specific trophic effects, only with JI anatomy. This may limit the utility of this treatment for SBS, except for rare patients with retained ileum. The mechanisms of these site-specific effects, however, and the role of MFG-E8 in neonatal gut growth and in diseases, such as necrotizing enterocolitis that commonly target ileum, warrant further exploration.

REFERENCES

1.Wagner CL, Taylor SN, Johnson D. Host factors in amniotic fluid and breast milk that contribute to gut maturation. Clin Rev Allergy Immunol 2008; 34: 191–204.
10.1007/s12016-007-8032-3
PubMed Web of Science® Google Scholar
2.Schanler RJ, Atkinson SA. Effects of nutrients in human milk on the recipient premature infant. J Mammary Gland Biol Neoplasia 1999; 4: 297–307.
10.1023/A:1018754014330
CAS PubMed Web of Science® Google Scholar
3.Andorsky DJ, Lund DP, Lillehei CW, et al. Nutritional and other postoperative management of neonates with short bowel syndrome correlates with clinical outcomes. J Pediatr 2001; 139: 27–33.
10.1067/mpd.2001.114481
CAS PubMed Web of Science® Google Scholar
4.Nagy ES, Paris MC, Taylor RG, et al. Colostrum protein concentrate enhances intestinal adaptation after massive small bowel resection in juvenile pigs. J Pediatr Gastroenterol Nutr 2004; 39: 487–492.
10.1002/j.1536-4801.2004.tb00896.x
CAS PubMed Web of Science® Google Scholar
5.Hamosh M, Peterson JA, Henderson TR, et al. Protective function of human milk: the milk fat globule. Semin Perinatol 1999; 23: 242–249.
10.1016/S0146-0005(99)80069-X
CAS PubMed Web of Science® Google Scholar
6.Chatterton DE, Nguyen DN, Bering SB, et al. Anti-inflammatory mechanisms of bioactive milk proteins in the intestine of newborns. Int J Biochem Cell Biol 2013; 45: 1730–1747.
10.1016/j.biocel.2013.04.028
CAS PubMed Web of Science® Google Scholar
7.Giuffrida MG, Cavaletto M, Lamberti C, et al. Proteolysis of milk fat globule membrane proteins in preterm milk: a transient phenomenon with a possible biological role? Int J Immunopathol Pharmacol 2008; 21: 959–967.
10.1177/039463200802100420
CAS PubMed Web of Science® Google Scholar
8.Khaldi N, Shields DC. Shift in the isoelectric-point of milk proteins as a consequence of adaptive divergence between the milks of mammalian species. Biol Direct 2011; 6: 40.
10.1186/1745-6150-6-40
PubMed Web of Science® Google Scholar
9.Bu HF, Zuo XL, Wang X, et al. Milk fat globule-EGF factor 8/lactadherin plays a crucial role in maintenance and repair of murine intestinal epithelium. J Clin Invest 2007; 117: 3673–3683.
CAS PubMed Web of Science® Google Scholar
10.Khalifeh-Soltani A, McKleroy W, Sakuma S, et al. Mfge8 promotes obesity by mediating the uptake of dietary fats and serum fatty acids. Nat Med 2014; 20: 175–183.
10.1038/nm.3450
CAS PubMed Web of Science® Google Scholar
11.Khalifeh-Soltani A, Gupta D, Ha A, et al. Mfge8 regulates enterocyte lipid storage by promoting enterocyte triglyceride hydrolase activity. JCI Insight 2016; 1: e87418.
10.1172/jci.insight.87418
PubMed Web of Science® Google Scholar
12.Larocca D, Peterson JA, Urrea R, et al. A Mr 46,000 human milk fat globule protein that is highly expressed in human breast tumors contains factor VIII-like domains. Cancer Res 1991; 51: 4994–4998.
CAS PubMed Web of Science® Google Scholar
13.Lim DW, Diane A, Muto M, et al. Differential effects on intestinal adaptation following exogenous glucagon-like peptide 2 therapy with and without enteral nutrition in neonatal short bowel syndrome [formula: see text]. JPEN J Parenter Enteral Nutr 2017; 41: 156–170.
10.1177/0148607116665812
CAS PubMed Web of Science® Google Scholar
14.Sham J, Martin G, Meddings JB, et al. Epidermal growth factor improves nutritional outcome in a rat model of short bowel syndrome. J Pediatr Surg 2002; 37: 765–769.
10.1053/jpsu.2002.32273
CAS PubMed Web of Science® Google Scholar
15.Nair AB, Jacob S. A simple practice guide for dose conversion between animals and human. J Basic Clin Pharm 2016; 7: 27–31.
10.4103/0976-0105.177703
PubMed Google Scholar
16.Livak KJ, Schmittgen TD. Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) Method. Methods 2001; 25: 402–408.
10.1006/meth.2001.1262
CAS PubMed Web of Science® Google Scholar
17.Guilloteau P, Zabielski R, Hammon HM, et al. Nutritional programming of gastrointestinal tract development. Is the pig a good model for man? Nutr Res Rev 2010; 23: 4–22.
10.1017/S0954422410000077
PubMed Web of Science® Google Scholar
18.Suri M, Turner JM, Sigalet DL, et al. Exogenous glucagon-like peptide-2 improves outcomes of intestinal adaptation in a distal-intestinal resection neonatal piglet model of short bowel syndrome. Pediatr Res 2014; 76: 370–377.
10.1038/pr.2014.97
CAS PubMed Web of Science® Google Scholar
19.Turner JM, Wales PW, Nation PN, et al. Novel neonatal piglet models of surgical short bowel syndrome with intestinal failure. J Pediatr Gastroenterol Nutr 2011; 52: 9–16.
10.1097/MPG.0b013e3181f18ca0
PubMed Web of Science® Google Scholar
20.Dou Y, Lu X, Zhao J, et al. Morphometric and biomechanical remodelling in the intestine after small bowel resection in the rat. Neurogastroenterol Motil 2002; 14: 43–53.
10.1046/j.1365-2982.2002.00301.x
CAS PubMed Web of Science® Google Scholar
21.Appleton GV, Bristol JB, Williamson RC. Proximal enterectomy provides a stronger systemic stimulus to intestinal adaptation than distal enterectomy. Gut 1987; 28 Suppl: 165–168.
10.1136/gut.28.Suppl.165
PubMed Google Scholar
22.Sigalet DL, Lees GM, Aherne F, et al. The physiology of adaptation to small bowel resection in the pig: an integrated study of morphological and functional changes. J Pediatr Surg 1990; 25: 650–657.
10.1016/0022-3468(90)90356-E
CAS PubMed Web of Science® Google Scholar
23.Thompson JS, Quigley EM, Adrian TE. Factors affecting outcome following proximal and distal intestinal resection in the dog: an examination of the relative roles of mucosal adaptation, motility, luminal factors, and enteric peptides. Dig Dis Sci 1999; 44: 63–74.
10.1023/A:1026697915937
CAS PubMed Web of Science® Google Scholar
24.Benhamou PH, Canarelli JP, Richard S, et al. Human recombinant growth hormone increases small bowel lengthening after massive small bowel resection in piglets. J Pediatr Surg 1997; 32: 1332–1336.
10.1016/S0022-3468(97)90315-8
CAS PubMed Web of Science® Google Scholar
25.Lemmey AB, Ballard FJ, Martin AA, et al. Treatment with IGF-I peptides improves function of the remnant gut following small bowel resection in rats. Growth Factors 1994; 10: 243–252.
10.3109/08977199409010990
CAS PubMed Web of Science® Google Scholar
26.Chaet MS, Arya G, Ziegler MM, et al. Epidermal growth factor enhances intestinal adaptation after massive small bowel resection. J Pediatr Surg 1994; 29: 1035–1038.
10.1016/0022-3468(94)90274-7
CAS PubMed Web of Science® Google Scholar
27.FitzSimmons J, Chinn A. Shepard TH Normal length of the human fetal gastrointestinal tract. Pediatr Pathol 1988; 8: 633–641.
10.3109/15513818809022320
CAS PubMed Google Scholar
28.Marnerides A, Ghazi S, Sundberg A, et al. Development of fetal intestinal length during 2nd-trimester in normal and pathologic pregnancies. Pediatr Dev Pathol 2012; 15: 24–29.
10.2350/11-07-1057-OA.1
PubMed Web of Science® Google Scholar
29.Struijs MC, Diamond IR, de Silva N, et al. Establishing norms for intestinal length in children. J Pediatr Surg 2009; 44: 933–938.
10.1016/j.jpedsurg.2009.01.031
PubMed Web of Science® Google Scholar
30.Montgomery RK, Mulberg AE, Grand RJ. Development of the human gastrointestinal tract: twenty years of progress. Gastroenterology 1999; 116: 702–731.
10.1016/S0016-5085(99)70193-9
CAS PubMed Web of Science® Google Scholar
31.Kimble RM, Breier BH, Gluckman PD, et al. Enteral IGF-I enhances fetal growth and gastrointestinal development in oesophageal ligated fetal sheep. J Endocrinol 1999; 162: 227–235.
10.1677/joe.0.1620227
CAS PubMed Web of Science® Google Scholar
32.Dasgupta S, Arya S, Choudhary S, et al. Amniotic fluid: Source of trophic factors for the developing intestine. World J Gastrointest Pathophysiol 2016; 7: 38–47.
10.4291/wjgp.v7.i1.38
PubMed Google Scholar
33.Park J, Puapong DP, Wu BM, et al. Enterogenesis by mechanical lengthening: morphology and function of the lengthened small intestine. J Pediatr Surg 2004; 39: 1823–1827.
10.1016/j.jpedsurg.2004.08.022
PubMed Web of Science® Google Scholar
34.Brubaker PL. Glucagon-like peptide-2 and the regulation of intestinal growth and function. Compr Physiol 2018; 8: 1185–1210.
10.1002/j.2040-4603.2018.tb00039.x
PubMed Web of Science® Google Scholar
35.Israel EJ. Neonatal necrotizing enterocolitis, a disease of the immature intestinal mucosal barrier. Acta Paediatr Suppl 1994; 396: 27–32.
10.1111/j.1651-2227.1994.tb13238.x
CAS PubMed Web of Science® Google Scholar
36.Dvorak B, Halpern MD, Holubec H, et al. Epidermal growth factor reduces the development of necrotizing enterocolitis in a neonatal rat model. Am J Physiol Gastrointest Liver Physiol 2002; 282: G156–G164.
10.1152/ajpgi.00196.2001
CAS PubMed Web of Science® Google Scholar
37.Shin CE, Falcone RA Jr, Stuart L, et al. Diminished epidermal growth factor levels in infants with necrotizing enterocolitis. J Pediatr Surg 2000; 35: 173–176.
10.1016/S0022-3468(00)90005-8
CAS PubMed Web of Science® Google Scholar
38.Clark JA, Lane RH, Maclennan NK, et al. Epidermal growth factor reduces intestinal apoptosis in an experimental model of necrotizing enterocolitis. Am J Physiol Gastrointest Liver Physiol 2005; 288: G755–G762.
10.1152/ajpgi.00172.2004
CAS PubMed Web of Science® Google Scholar
39.Fagbemi AO, Wright N, Lakhoo K, et al. Immunoreactive epidermal growth factor receptors are present in gastrointestinal epithelial cells of preterm infants with necrotising enterocolitis. Early Hum Dev 2001; 65: 1–9.
10.1016/S0378-3782(01)00164-5
CAS PubMed Web of Science® Google Scholar

Citing Literature

Volume71, Issue4

October 2020

Pages 543-549

In the Short-term, Milk Fat Globule Epidermal Growth Factor-8 Causes Site-specific Intestinal Growth in Resected Piglets

ABSTRACT

Objectives:

Methods:

Results:

Conclusions:

REFERENCES

Citing Literature

References

Information

About Wiley Online Library

Help & Support

Opportunities

Connect with Wiley

In the Short-term, Milk Fat Globule Epidermal Growth Factor-8 Causes Site-specific Intestinal Growth in Resected Piglets

ABSTRACT

Objectives:

Methods:

Results:

Conclusions:

REFERENCES

Citing Literature

References

Related

Information