Russell G. Taylor

Ileal glucagon gene expression: Ontogeny and response to massive small bowel resection

Massive small bowel resection with re-anastomosis of the residual jejunum and terminal ileum results in marked adaptive responses. Various luminal and humoral factors have been implicated in the adaptive response, which may be analogous to the changes occurring in the ileum in the postnatal growth phase. Enteroglucagon, which is synthesized in the L cells of the intestinal mucosa, is thought to be an important humoral factor in this response. In this study, the levels of glucagon gene expression in the rat ileum both after massive small bowel resection and during development are examined. Glucagon messenger RNA levels are increased threefold as part of the adaptive response; the increase is maximal at 2 days and is at least partly dependent on luminal nutrition. Levels of glucagon messenger RNA in the developing ileum increase in the postnatal period until weaning when they decrease somewhat before gradually reaching adult levels.

Ileal proglucagon gene expression in the rat: Characterization in intestinal adaptation using in situ hybridization

BACKGROUND Proglucagon-derived peptides are potential mediators of the adaptive response of the terminal ileum to massive small bowel resection. Ileal proglucagon messenger RNA (mRNA) levels increase during ileal adaptation. The present study explored the cellular basis of this response. METHODS Sections of control ileum, ileum 4 days after resection, and pancreas were analyzed by in situ hybridization with 35S-labeled complementary RNA (cRNA) probes. RESULTS Both the proglucagon and the peptide YY cRNA probes hybridized to discrete cells in the ileal mucosa, the disposition of which corresponds to that reported for intestinal L cells. Four days after resection there was a marked increase in the intensity of the signal for both probes without an increase in cell number. Insulin and histone H3 probes were used as controls to confirm the specificity of the hybridization seen with the L-cell specific, proglucagon, and peptide YY probes. CONCLUSIONS The increase in proglucagon mRNA levels after massive small bowel resection is caused by an increase in the cellular content. The parallel increase in PYY mRNA levels implies an L cell--rather than a proglucagon gene--specific response.

Long‐term continence after surgery for Hirschsprung's disease

Aim:  Our aim was to examine the long‐term bowel dysfunction that followed surgery for Hirschsprungs disease.

Influence of diet complexity on intestinal adaptation following massive small bowel resection in a preclinical model

Aims: To investigate the effect of dietary complexity on intestinal adaptation using a preclinical model.

7 Humoral regulation of intestinal adaptation

Summary After the loss of small bowel through disease or surgery the residual bowel adapts by increasing its functional capacity. This process of adaptation involves dilatation, hypertrophy and mucosal hyperplasia, particularly distal to the area of bowel loss or disease. The response of the residual bowel is mediated by a complex interplay of factors including luminal nutrition, pancreaticobiliary secretions, luminal or local growth factors and also humoral or endocrine factors. The experimental model commonly used to characterize the adaptive response, massive small bowel resection (MSBR), involves 80% resection of the small bowel in the rat. Of the various putative humoral factors, most work has focused on the products of the ileal L cells: enteroglucagon and peptide YY. Plasma levels of both hormones are increased after MSBR and indeed their mRNA levels are also increased as a result of an increase in the amount of message per L cell. Whilst PYY probably serves as an ‘ileal brake’ to slow the movement of the luminal contents and hence increase their mucosal contact time, the role of the enteroglucagon is unresolved. The molecular cloning of the proglucagon gene has revealed, firstly, that there are a number of biologically active peptides which derive from the propeptide and, secondly, that tissue-specific differential processing occurs. Most studies do not clearly define which of these products of proglucagon is being measured and is termed as glucagon-like or enteroglucagon immunoreactivity. The insulin-like growth factors (IGF) have a potent mitogenic action on the bowel. Their role after MSBR is likely to be largely paracrine. Though IGF-I mRNA levels do not increase after MSBR, the precipitous and early fall in ileal IGF-binding protein-3 (IGFBP-3) mRNA levels suggests a fall in IGFBP-3 levels may increase local IGF-I bioactivity. Polyamine synthesis is a critical component of the adaptive response, although the stimulus to their dramatic increase in synthesis after MSBR remains to be elucidated. Other humoral factors such as cholecystokinin, neurotensin and bombesin probably have minor indirect roles in the adaptive response. Components of the epidermal growth factor/transforming growth factor α response pathway family of growth factors may be involved as paracrine regulators. There is thus strong evidence that humoral factors play an important role in intestinal adaptation; characterization of the nature of the humoral factors and their relationship with other influences such as luminal nutrition and pancreatic biliary secretions may facilitate the development of new therapeutic strategies for the short bowel syndromes.

GLP-2 administration results in increased proliferation but paradoxically an adverse outcome in a juvenile piglet model of short bowel syndrome.

Objective: The objective of the present study was to examine the effect of glucagon-like peptide-2 (GLP-2) administration in a piglet, juvenile model of short bowel syndrome. Materials and Methods: Four-week-old piglets underwent either a sham operation or 75% small bowel resection. Postoperatively, piglets received either polymeric infant formula diet or the diet and subcutaneous human recombinant GLP-2 (1600 μg/day for 7 days, 800 μg/day thereafter). Food intake was monitored throughout the experiment, and stool and serum samples obtained fortnightly. After the piglets were killed, tissues were obtained from the duodenum, jejunum, ileum, and terminal ileum, and used for morphological and functional analysis. Results: Treatment with GLP-2 resulted in significantly increased numbers of proliferating and apoptotic cells in the ileum of sham and small bowel resection piglets (P < 0.05). GLP-2 administration resulted in decreased weight gain, serum albumin, and disaccharidases in both sham and small bowel resection piglets (P < 0.001 compared with polymeric infant formula diet alone). Conclusions: This is the first study to our knowledge to examine the effect of GLP-2 administration in a juvenile short bowel syndrome model. Contrary to adult rodent studies, administration of GLP-2 resulted in adverse outcomes including reduced ability to gain weight; decreased serum albumin, tissue maltase, and sucrase; and villous atrophy. We anticipate this information will have important implications for future paediatric clinical trials.

Colostrum protein concentrate enhances intestinal adaptation after massive small bowel resection in juvenile pigs.

Objectives: Short bowel syndrome (SBS) usually results from the surgical removal of a large segment of small intestine. Patient outcome depends on the extent of intestinal resection and adaptation of the remaining intestine. We evaluated the impact of colostrum protein concentrate (CPC) on intestinal adaptation after massive small bowel resection in a porcine model of infant SBS. Methods: Four-week-old piglets underwent an approximate 75% small bowel resection (R, n = 23) or a control transection operation (C, n = 14). Postoperatively, animals from both groups received either pig chow (R = 6, C = 5), polymeric infant formula (R = 6, C = 3) or polymeric infant formula supplemented with CPC (R = 11, C = 6) for 8 weeks until sacrifice. Clinical outcome measures included weight gain and stool consistency. Morphologic measures were intestinal villus height and crypt depth. Functional outcome measure was mucosal disaccharidase activity. Results: Resected animals fed polymeric infant formula alone had reduced weight gain compared with controls fed the same diet (P < 0.005). Despite massive small bowel resection, animals fed pig chow or polymeric infant formula supplemented with CPC grew at an equivalent rate to controls fed polymeric infant formula alone. Resected animals supplemented with CPC had increased villus length and crypt depth in the jejunum (P < 0.001) and ileum (P < 0.001) compared with resected animals fed either pig chow or polymeric infant formula alone. Conclusion: In an animal model of SBS, CPC supplementation of polymeric infant formula resulted in normal weight gain and features of enhanced morphologic adaptation.

Long‐term continence in patients with Hirschsprung's disease and Down syndrome

Background and Aim:  Hirschsprungs disease is more common in children with Down syndrome, but the outcome for continence in this group is unclear. The aim of the present study was to determine the natural history of bowel function in children with Down syndrome and Hirschsprungs disease.

Plasma GLP-2 levels and intestinal markers in the juvenile pig during intestinal adaptation: effects of different diet regimens.

Adaptation of the residual small bowel following resection is dependent on luminal and humoral factors. We aimed to establish if circulating levels of glucagon-like peptide (GLP-2) change under different dietary regimens following resection and to determine if there is a relationship between plasma GLP-2 levels and markers of intestinal adaptation. Four-week-old piglets underwent a 75% proximal small bowel resection (n=31) or transection (n=14). Postoperatively they received either pig chow (n=14), nonpolymeric (elemental) infant formula (n=7), or polymeric infant formula alone (n=8) or supplemented either with fiber (n=6) or with bovine colostrum protein concentrate (CPC; n=10) for 8 weeks until sacrifice. Plasma GLP-2 levels were measured at weeks 0, 2, 4, and 8 postoperatively. In addition, end-stage parameters were studied at week 8 including weight gain, ileal villus height, crypt depth, and disaccharidase levels. Plasma GLP-2 levels were higher in resected animals compared to transected animals fed the same diet. Plasma GLP-2 levels were significantly increased in the colostrum protein isolate-supplemented animals following resection compared to all other diet groups. The increase in plasma GLP-2 (pM) was greatest in the first 2 weeks postresection (week 0, 15.5; week 2, 30.9), followed by a plateau at weeks 2 to 4 and a decrease in GLP-2 levels from week 4 to week 8. At week 8, no relationships were found between the plasma GLP-2 levels and the measurements of weight gain, villus height, lactase, sucrase, maltase, crypt depth, or villus/crypt ratio. Plasma GLP-2 levels increase in the first weeks following massive small intestinal resection. The increase in plasma GLP-2 levels was enhanced by supplementation of the diet with CPC. The changes in GLP-2 levels observed in this study may suggest that GLP-2 plays a role in the adaptive response in the intestine following resection in this preclinical model.

Colostrum Supplementation Restores Insulin-like Growth Factor -1 Levels and Alters Muscle Morphology Following Massive Small Bowel Resection

BACKGROUND Colostrum protein concentrate (CPC) contains a high level of insulin-like growth factor-1 (IGF-1). IGF-1 and IGF binding protein (IGFBPs) may play an important role during the postresection adaptation response. As smooth muscle is an important site for IGF-1 action in the intestine, this study aims to (1) investigate the effect of CPC supplementation on circulating levels and tissue expression of IGF-1, IGF-1 receptor, and IGFBPs following massive small bowel resection (MSBR), and (2) characterize the effect of CPC on the muscular adaptation response following MSBR. METHODS Four-week-old piglets underwent either a 75% MSBR or sham operation. Piglets received either a polymeric infant formula (PIF) diet or PIF supplemented with CPC for 8 weeks. Serum was analyzed by enzyme-linked immunosorbent assay, and ileal tissue assessed by molecular and histological analysis. RESULTS There was no difference in IGF-1 or IGFBPs mRNA among groups. CPC treatment resulted in significant increases in circulating levels of IGF-1 and IGFBPs and a concurrent increase in muscle width and the number of muscle cells, but did not alter muscle cell size. CONCLUSIONS Strategies aimed at increasing muscular adaptation may decrease Gl transit and allow greater mucosal contact time for absorption. We have shown that CPC supplementation following resection results in increased levels of circulating IGF-1, IGFBP-2, and IGFBP-3 and muscular hypertrophy. Our results suggest that IGF-1 and its mediators may play a role in the muscular adaptation response and warrant further exploration as a treatment option for short bowel syndrome.