Skip to main content
PMC home page
Gut logoLink to Gut
. 2000 May;46(5):694–700. doi: 10.1136/gut.46.5.695

Growth failure occurs through a decrease in insulin-like growth factor 1 which is independent of undernutrition in a rat model of colitis

A Ballinger 1, O Azooz 1, T El-Haj 1, S Poole 1, M Farthing 1
PMCID: PMC1727919  PMID: 10764714

Abstract

BACKGROUND—Linear growth retardation is a frequent complication of inflammatory bowel disease in children. The precise mechanisms causing growth failure are not known.
AIMS—To determine the relative contribution of reduced calorie intake and inflammation to linear growth delay and to determine the effect of inflammation on the hypothalamic-pituitary-growth axis.
METHODS—Linear growth was assessed in prepubertal rats with trinitrobenzenesulphonic acid (TNBS) induced colitis, in healthy free feeding controls, and in a pair-fed group (i.e. healthy animals whose daily food intake was matched to the colitic group thereby distinguishing between the effects of undernutrition and inflammation).
RESULTS—Changes in length over five days in the TNBS colitis and pair-fed groups were 30% and 56%, respectively, of healthy free feeding controls. Linear growth was significantly reduced in the colitic group compared with the pair-fed group. Nutritional supplementation in the colitic group increased weight gain to control values but did not completely reverse the growth deficit. Plasma interleukin 6 (IL-6) concentrations were sixfold higher in the colitic group compared with controls. Plasma concentrations of insulin-like growth factor 1 (IGF-1) but not growth hormone (GH) were significantly lower in the colitic compared with the pair-fed group. Administration of IGF-1 to the colitic group increased plasma IGF-1 concentrations and linear growth by approximately 44-60%.
CONCLUSIONS—It seems likely that approximately 30-40% of linear growth impairment in experimental colitis occurs as a direct result of the inflammatory process which is independent of undernutrition. Inflammation acts principally at the hepatocyte/IGF-1 level to impair linear growth. Optimal growth in intestinal inflammation may only be achieved by a combination of nutritional intervention and anticytokine treatment.


Keywords: inflammatory bowel disease; TNBS colitis; growth retardation; insulin-like growth factor 1; interleukin 6

Full Text

The Full Text of this article is available as a PDF (154.7 KB).

Figure 1  .

Figure 1  

Open in a new tab

Daily food intake in healthy free feeding controls and in TNBS colitis; n =10/group. Values are mean (SD). Colitis was induced on day 0 (age 26 days). ***p=0.0001 v colitis. By definition, food intake in the pair-fed group (data not shown) was the same as that in the colitic group.

Figure 2  .

Figure 2  

Open in a new tab

Changes in body length during the five day study period in the healthy free feeding controls, TNBS colitis and pair-fed groups; n=10/group. Values are mean (SD). *p<0.02 v pair-fed; ††p<0.002 v healthy free feeding controls. The arrows indicate the relative contribution of undernutrition and inflammation to growth retardation in the colitic group.

Figure 3  .

Figure 3  

Open in a new tab

Relationship between plasma concentrations of growth hormone (GH) and rat insulin-like growth factor 1 (rIGF-1) in the healthy free feeding controls (r=0.49, p=0.15), TNBS colitis (r=−0.49, p=0.15), and pair-fed groups (r=0.71, p=0.02).

Figure 4  .

Figure 4  

Open in a new tab

Effect of nutritional supplementation on linear growth in TNBS colitis. n=6-7/group. *p=0.04, ***p=0.0002 v healthy free-feeding controls; †p=0.05, ††p=0.007 v colitis without nutritional supplementation.

Figure 5  .

Figure 5  

Open in a new tab

Effect of insulin-like growth factor 1 (IGF-1) treatment on linear growth in TNBS colitis; n=10/group. *p=0.05, **p=0.009 v placebo/colitic; ††p=0.006 v controls.

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Aiges H., Markowitz J., Rosa J., Daum F. Home nocturnal supplemental nasogastric feedings in growth-retarded adolescents with Crohn's disease. Gastroenterology. 1989 Oct;97(4):905–910. doi: 10.1016/0016-5085(89)91496-0. [DOI] [PubMed] [Google Scholar]
  2. Ayer-le Lievre C., Ståhlbom P. A., Sara V. R. Expression of IGF-I and -II mRNA in the brain and craniofacial region of the rat fetus. Development. 1991 Jan;111(1):105–115. doi: 10.1242/dev.111.1.105. [DOI] [PubMed] [Google Scholar]
  3. Baker J., Liu J. P., Robertson E. J., Efstratiadis A. Role of insulin-like growth factors in embryonic and postnatal growth. Cell. 1993 Oct 8;75(1):73–82. [PubMed] [Google Scholar]
  4. Barot L. R., Rombeau J. L., Feurer I. D., Mullen J. L. Caloric requirements in patients with inflammatory bowel disease. Ann Surg. 1982 Feb;195(2):214–218. doi: 10.1097/00000658-198202000-00016. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. Berger M., Gribetz D., Korelitz B. I. Growth retardation in children with ulcerative colitis: the effect of medical and surgical therapy. Pediatrics. 1975 Apr;55(4):459–467. [PubMed] [Google Scholar]
  6. Braegger C. P., Torresani T., Murch S. H., Savage M. O., Walker-Smith J. A., MacDonald T. T. Urinary growth hormone in growth-impaired children with chronic inflammatory bowel disease. J Pediatr Gastroenterol Nutr. 1993 Jan;16(1):49–52. doi: 10.1097/00005176-199301000-00010. [DOI] [PubMed] [Google Scholar]
  7. Chan A. T., Fleming C. R., O'Fallon W. M., Huizenga K. A. Estimated versus measured basal energy requirements in patients with Crohn's disease. Gastroenterology. 1986 Jul;91(1):75–78. doi: 10.1016/0016-5085(86)90441-5. [DOI] [PubMed] [Google Scholar]
  8. Cortright R. N., Collins H. L., Chandler M. P., Lemon P. W., DiCarlo S. E. Diabetes reduces growth and body composition more in male than in female rats. Physiol Behav. 1996 Nov;60(5):1233–1238. doi: 10.1016/s0031-9384(96)00222-3. [DOI] [PubMed] [Google Scholar]
  9. De Benedetti F., Alonzi T., Moretta A., Lazzaro D., Costa P., Poli V., Martini A., Ciliberto G., Fattori E. Interleukin 6 causes growth impairment in transgenic mice through a decrease in insulin-like growth factor-I. A model for stunted growth in children with chronic inflammation. J Clin Invest. 1997 Feb 15;99(4):643–650. doi: 10.1172/JCI119207. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. Duchmann R., Schmitt E., Knolle P., Meyer zum Büschenfelde K. H., Neurath M. Tolerance towards resident intestinal flora in mice is abrogated in experimental colitis and restored by treatment with interleukin-10 or antibodies to interleukin-12. Eur J Immunol. 1996 Apr;26(4):934–938. doi: 10.1002/eji.1830260432. [DOI] [PubMed] [Google Scholar]
  11. Farthing M. J., Campbell C. A., Walker-Smith J., Edwards C. R., Rees L. H., Dawson A. M. Nocturnal growth hormone and gonadotrophin secretion in growth retarded children with Crohn's disease. Gut. 1981 Nov;22(11):933–938. doi: 10.1136/gut.22.11.933. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Gonzalez C., Jolin T. Effects of starvation on pituitary and plasma growth hormone in rats. J Endocrinol Invest. 1981 Jan-Mar;4(1):65–69. doi: 10.1007/BF03349417. [DOI] [PubMed] [Google Scholar]
  13. Goulet O., Jan D., Brousse N., Revillon Y., Ricour C. Intestinal transplantation. J Pediatr Gastroenterol Nutr. 1997 Jul;25(1):1–11. doi: 10.1097/00005176-199707000-00001. [DOI] [PubMed] [Google Scholar]
  14. Griffiths A. M., Nguyen P., Smith C., MacMillan J. H., Sherman P. M. Growth and clinical course of children with Crohn's disease. Gut. 1993 Jul;34(7):939–943. doi: 10.1136/gut.34.7.939. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. Heinrichs C., Colli M., Yanovski J. A., Laue L., Gerstl N. A., Kramer A. D., Uyeda J. A., Baron J. Effects of fasting on the growth plate: systemic and local mechanisms. Endocrinology. 1997 Dec;138(12):5359–5365. doi: 10.1210/endo.138.12.5603. [DOI] [PubMed] [Google Scholar]
  16. Hoyt E. C., Van Wyk J. J., Lund P. K. Tissue and development specific regulation of a complex family of rat insulin-like growth factor I messenger ribonucleic acids. Mol Endocrinol. 1988 Nov;2(11):1077–1086. doi: 10.1210/mend-2-11-1077. [DOI] [PubMed] [Google Scholar]
  17. Hunziker E. B., Wagner J., Zapf J. Differential effects of insulin-like growth factor I and growth hormone on developmental stages of rat growth plate chondrocytes in vivo. J Clin Invest. 1994 Mar;93(3):1078–1086. doi: 10.1172/JCI117058. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. Jones J. I., Clemmons D. R. Insulin-like growth factors and their binding proteins: biological actions. Endocr Rev. 1995 Feb;16(1):3–34. doi: 10.1210/edrv-16-1-3. [DOI] [PubMed] [Google Scholar]
  19. Kelts D. G., Grand R. J., Shen G., Watkins J. B., Werlin S. L., Boehme C. Nutritional basis of growth failure in children and adolescents with Crohn's disease. Gastroenterology. 1979 Apr;76(4):720–727. [PubMed] [Google Scholar]
  20. Kirschner B. S. Growth and development in chronic inflammatory bowel disease. Acta Paediatr Scand Suppl. 1990;366:98–105. doi: 10.1111/j.1651-2227.1990.tb11608.x. [DOI] [PubMed] [Google Scholar]
  21. Kirschner B. S., Klich J. R., Kalman S. S., deFavaro M. V., Rosenberg I. H. Reversal of growth retardation in Crohn's disease with therapy emphasizing oral nutritional restitution. Gastroenterology. 1981 Jan;80(1):10–15. [PubMed] [Google Scholar]
  22. Kirschner B. S., Voinchet O., Rosenberg I. H. Growth retardation in inflammatory bowel disease. Gastroenterology. 1978 Sep;75(3):504–511. [PubMed] [Google Scholar]
  23. Koniaris S. G., Fisher S. E., Rubin C. T., Chawla A. Experimental colitis impairs linear bone growth independent of nutritional factors. J Pediatr Gastroenterol Nutr. 1997 Aug;25(2):137–141. doi: 10.1097/00005176-199708000-00002. [DOI] [PubMed] [Google Scholar]
  24. Le Roith D. Seminars in medicine of the Beth Israel Deaconess Medical Center. Insulin-like growth factors. N Engl J Med. 1997 Feb 27;336(9):633–640. doi: 10.1056/NEJM199702273360907. [DOI] [PubMed] [Google Scholar]
  25. Lund P. K., Moats-Staats B. M., Hynes M. A., Simmons J. G., Jansen M., D'Ercole A. J., Van Wyk J. J. Somatomedin-C/insulin-like growth factor-I and insulin-like growth factor-II mRNAs in rat fetal and adult tissues. J Biol Chem. 1986 Nov 5;261(31):14539–14544. [PubMed] [Google Scholar]
  26. Markowitz J., Grancher K., Rosa J., Aiges H., Daum F. Growth failure in pediatric inflammatory bowel disease. J Pediatr Gastroenterol Nutr. 1993 May;16(4):373–380. doi: 10.1097/00005176-199305000-00005. [DOI] [PubMed] [Google Scholar]
  27. McHugh K. J., Weingarten H. P., Keenan C., Wallace J. L., Collins S. M. On the suppression of food intake in experimental models of colitis in the rat. Am J Physiol. 1993 May;264(5 Pt 2):R871–R876. doi: 10.1152/ajpregu.1993.264.5.R871. [DOI] [PubMed] [Google Scholar]
  28. Mitsuyama K., Sada M., Ikeda H., Tsuruta O., Irie A., Arima N., Matsukuma N., Kuboyama S., Sueishi T., Murayama S. [Serum levels of interleukin 6 in patients with inflammatory bowel disease]. Nihon Shokakibyo Gakkai Zasshi. 1990 Mar;87(3):890–890. [PubMed] [Google Scholar]
  29. Morris G. P., Beck P. L., Herridge M. S., Depew W. T., Szewczuk M. R., Wallace J. L. Hapten-induced model of chronic inflammation and ulceration in the rat colon. Gastroenterology. 1989 Mar;96(3):795–803. [PubMed] [Google Scholar]
  30. Motil K. J., Grand R. J., Davis-Kraft L., Ferlic L. L., Smith E. O. Growth failure in children with inflammatory bowel disease: a prospective study. Gastroenterology. 1993 Sep;105(3):681–691. doi: 10.1016/0016-5085(93)90883-e. [DOI] [PubMed] [Google Scholar]
  31. Murch S. H., Lamkin V. A., Savage M. O., Walker-Smith J. A., MacDonald T. T. Serum concentrations of tumour necrosis factor alpha in childhood chronic inflammatory bowel disease. Gut. 1991 Aug;32(8):913–917. doi: 10.1136/gut.32.8.913. [DOI] [PMC free article] [PubMed] [Google Scholar]
  32. O'Donoghue D. P., Dawson A. M. Crohn's disease in childhood. Arch Dis Child. 1977 Aug;52(8):627–632. doi: 10.1136/adc.52.8.627. [DOI] [PMC free article] [PubMed] [Google Scholar]
  33. Rachmilewitz D., Simon P. L., Schwartz L. W., Griswold D. E., Fondacaro J. D., Wasserman M. A. Inflammatory mediators of experimental colitis in rats. Gastroenterology. 1989 Aug;97(2):326–337. doi: 10.1016/0016-5085(89)90068-1. [DOI] [PubMed] [Google Scholar]
  34. Rees G. S., Ball C., Ward H. L., Gee C. K., Tarrant G., Mistry Y., Poole S., Bristow A. F. Rat interleukin 6: expression in recombinant Escherichia coli, purification and development of a novel ELISA. Cytokine. 1999 Feb;11(2):95–103. doi: 10.1006/cyto.1998.0408. [DOI] [PubMed] [Google Scholar]
  35. Rigaud D., Angel L. A., Cerf M., Carduner M. J., Melchior J. C., Sautier C., René E., Apfelbaum M., Mignon M. Mechanisms of decreased food intake during weight loss in adult Crohn's disease patients without obvious malabsorption. Am J Clin Nutr. 1994 Nov;60(5):775–781. doi: 10.1093/ajcn/60.5.775. [DOI] [PubMed] [Google Scholar]
  36. Shimoyama S. [Studies on growth hormone secretion in starved rats under urethane anesthesia (author's transl)]. Nihon Naibunpi Gakkai Zasshi. 1979 Jun 20;55(6):817–830. doi: 10.1507/endocrine1927.55.6_817. [DOI] [PubMed] [Google Scholar]
  37. Siegel S. A., Shealy D. J., Nakada M. T., Le J., Woulfe D. S., Probert L., Kollias G., Ghrayeb J., Vilcek J., Daddona P. E. The mouse/human chimeric monoclonal antibody cA2 neutralizes TNF in vitro and protects transgenic mice from cachexia and TNF lethality in vivo. Cytokine. 1995 Jan;7(1):15–25. doi: 10.1006/cyto.1995.1003. [DOI] [PubMed] [Google Scholar]
  38. Thissen J. P., Ketelslegers J. M., Underwood L. E. Nutritional regulation of the insulin-like growth factors. Endocr Rev. 1994 Feb;15(1):80–101. doi: 10.1210/edrv-15-1-80. [DOI] [PubMed] [Google Scholar]
  39. Thissen J. P., Verniers J. Inhibition by interleukin-1 beta and tumor necrosis factor-alpha of the insulin-like growth factor I messenger ribonucleic acid response to growth hormone in rat hepatocyte primary culture. Endocrinology. 1997 Mar;138(3):1078–1084. doi: 10.1210/endo.138.3.4966. [DOI] [PubMed] [Google Scholar]
  40. Woods K. A., Camacho-Hübner C., Savage M. O., Clark A. J. Intrauterine growth retardation and postnatal growth failure associated with deletion of the insulin-like growth factor I gene. N Engl J Med. 1996 Oct 31;335(18):1363–1367. doi: 10.1056/NEJM199610313351805. [DOI] [PubMed] [Google Scholar]
  41. Yamada Y., Marshall S., Specian R. D., Grisham M. B. A comparative analysis of two models of colitis in rats. Gastroenterology. 1992 May;102(5):1524–1534. doi: 10.1016/0016-5085(92)91710-l. [DOI] [PubMed] [Google Scholar]

Articles from Gut are provided here courtesy of BMJ Publishing Group

RESOURCES