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

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.

Figure 1

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

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

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

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

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.