Role In Intestinal Adaptation Research Articles

Does the colon play a role in intestinal adaptation in infants with short bowel syndrome? A multiple variable analysis

Purpose We sought to examine in a multiple variable model the impact of residual colonic length on time to intestinal adaptation in a cohort of infants with short bowel syndrome. Method Infants with a surgical diagnosis of short bowel syndrome who underwent operation 90 days or younger were included in this analysis. Univariate Cox proportional hazards models for time to full-enteral feeds were developed. Predictors significant at the .2 level were entered into a stepwise multiple variable Cox proportional hazards model. Results A total of 106 infants were included in the cohort (70 adapted). Predictors meeting the criteria for the multiple variable model were as follows: multidisciplinary management ( P = .045), Serial Transverse Enteroplasty Procedure ( P = .057), percent small bowel ( P < .001), percent large bowel ( P < .001), preserved ileocecal valve ( P = .001), number of septic ( P < .001), and central line complications ( P < .001). The final model included the following: multidisciplinary management (hazard ratio [HR], 1.932; 95% confidence interval [CI], 1.137-3.281), percent small bowel (HR, 1.028; 95% CI, 1.02-1.04), and septic events (HR, 0.695; 95% CI, 0.6-0.805). Conclusions The colon does not seem to play a significant role in intestinal adaptation. However, in addition to highlighting the importance of residual small bowel length, our model highlights the benefit of multidisciplinary intestinal rehabilitation and reduction of septic complications in achieving intestinal adaptation.

Teduglutide in intestinal adaptation and repair: light at the end of the tunnel

Background: Malabsorption of nutrients, fluids and electrolytes is a key finding in patients with short bowel syndrome. If not compensated for by increased intake, it leads to diminished body stores and subclinical, and eventually clinical, deficiencies. Until recently, management options were limited to interventions aimed at provision of adequate macro- and micronutrients and fluids to prevent malnutrition, nutrient deficiencies and dehydration, treatment of associated infections and correction and prevention of acid-base disturbances. Identification of novel gut hormones, combined with the growing understanding of their pivotal role in intestinal adaptation, has provoked interest in developing more specific therapies. Aim: To provide an update on the recent advances on the use of teduglutide in patients with short bowel syndrome. Methods: A comprehensive Medline search using the terms teduglutide, ALX-0600, dipeptidyl peptidase IV (DPP-IV) and glucagon like peptide-2 (GLP-2). Results: Teduglutide (GATTEX™, ALX-0600; NPS Allelix Corp) is a synthetic DPP-IV-resistant recombinant human GLP-2 analog that differs from GLP-2 only by an N-terminus substitution of glycine for alanine in position 2 of the peptide that renders the component resistant to enzymatic degradation. Based on the results of the few Phase II studies and the preliminary results of a Phase III trial, teduglutide at doses of 0.05 or 0.10 mg/kg/day may improve many clinical, laboratory and histologic abnormalities in short bowel syndrome patients. It appears to be safe and well tolerated. Conclusion: Teduglutide is a first-in-class therapy with the potential to create a new standard of care for patients suffering from short bowel syndrome. Future studies to address the appropriate initial and maintenance dosage and optimal duration of treatment are needed.

Zinc-deficient diet impairs adaptive changes in the remaining intestine after massive small bowel resection in the rat.

An investigation was conducted on the influence of the presence of zinc in an elemental diet on the mucosa of residual intestine after massive small bowel resection. A total of 34 male Sprague-Dawley rats were divided into five groups: control animals (n = 10) were killed after overnight fasting; a second group (n = 14) underwent massive small bowel resection preserving 10 cm of terminal ileum, and the third group (n = 10) underwent sham operation. Animals in the second and third groups were fed either a commercially available elemental diet or a zinc-deficient diet for 2 weeks; they were then killed. In animals receiving the zinc-deficient diet, a significant decrease (P < 0.05) was noted in plasma zinc and total protein, and in mucosal wet weight (duodenum), thickness (duodenum and ileum), and protein (duodenum) and DNA (duodenum) content. Mucosal sucrase and maltase specific activities in the duodenum and ileum fell but diamine oxidase levels did not. These results suggest that zinc plays an important role in intestinal adaptation in the rat, and indicate that this trace element is essential for intestinal mucosal preservation in this animal.

Nutritional and other postoperative management of neonates with short bowel syndrome correlates with clinical outcomes

Objective: To determine correlates of clinical outcomes in patients with short bowel syndrome (SBS). Methods: Retrospective medical record review of neonates treated between 1986 and 1998 who met our criteria for SBS: dependence on parenteral nutrition (PN) for at least 90 days after surgical therapy for congenital or acquired intestinal diseases. Results: Thirty subjects with complete data were identified; 13 (43%) had necrotizing enterocolitis, and 17 (57%) had intestinal malformations. Mean (SD) residual small bowel length was 83 (67) cm. Enteral feeding with breast milk (r = –0.821) or an amino acid–based formula (r = –0.793) was associated with a shorter duration of PN, as were longer residual small bowel length (r = –0.475) and percentage of calories received enterally at 6 weeks after surgery (r = –0.527). Shorter time without diverting ileostomy or colostomy (r = 0.400), enteral feeding with a protein hydrolysate formula (r = –0.476), and percentage of calories received enterally at 6 weeks after surgery (r = –0.504) were associated with a lower peak direct bilirubin concentration. Presence of an intact ileocecal valve and frequency of catheter-related infections were not significantly correlated with duration of PN. In multivariate analysis, only residual small bowel length was a significant independent predictor of duration of PN, and only less time with a diverting ostomy was an independent predictor of peak direct bilirubin concentration. Conclusions: Although residual small bowel length remains an important predictor of duration of PN use in infants with SBS, other factors, such as use of breast milk or amino acid–based formula, may also play a role in intestinal adaptation. In addition, prompt restoration of intestinal continuity is associated with lowered risk of cholestatic liver disease. Early enteral feeding after surgery is associated both with reduced duration of PN and less cholestasis. (J Pediatr 2001;139:27-33)

Epidermal growth factor and the short bowel syndrome.

Because epidermal growth factor (EGF) has multiple effects on the intestinal epithelium and endogenous EGF plays an important role in maintaining normal intestinal structure and the response to injury, EGF should be important in the intestinal adaptive response to resection. The accumulated data in the literature support a role for endogenous EGF in the intestinal adaptive response. Endogenous EGF is increased in saliva and diminished in urine after intestinal resection. This suggests increased tissue utilization of endogenous EGF during adaptation. Intestinal EGF receptor activity is increased after resection. Intestinal adaptation is impaired in animals with defective EGF receptors. Thus EGF receptor activity also is important during adaptation. The results of experimental studies suggest that EGF administered at the time of resection enhances the intestinal adaptive response. Both structural and functional adaptation are augmented. The route, dose, and timing of EGF administration are important factors. EGF has additive effects with glutamine and growth hormone on adaptation. Several observations from these reports have relevance to the potential clinical application of EGF therapy: (1) EGF should be given soon after resection; (2) early transient administration may lead to a substantial effect on adaptation; (3) both systemic and enteral therapy may be effective; (4) luminal nutrients are important but not essential in mediating EGF-stimulated adaptation; and (5) combined therapy with other nutrients and growth factors may have merit. In conclusion, endogenous EGF plays an important role in intestinal adaptation. Furthermore, experimental results suggest the potential clinical usefulness of EGF to stimulate intestinal adaptation after massive intestinal resection. There is currently no evidence to support the use of EGF in patients with well-adapted short bowel syndrome.

Increased expression of mineralocorticoid receptor in human ileum after total colectomy: immunohistochemical and immunoblotting studies.

Aldosterone is known to regulate transmembrane ion transport and water absorption through its binding to mineralocorticoid receptor (MR) in the mammalian colon. A possible roles of aldosterone has been suggested in increased water absorption from remnant ileum in the patients with total colectomy. We, therefore, studied immunolocalization of MR in remnant ileal mucosa in the patients with total colectomy in order to study the role of aldosterone in water and sodium absorption in these patients. Immunohistochemical localization of MR was performed in ileal mucosa of 7 patients with total colectomy and 5 cases of normal ileum obtained from the resection of ascending colon due to carcinoma by using a polyclonal antibody raised against a mineralocorticoid receptor fusion protein as a primary antibody and a biotinstreptavidin system for immunostaining. Immunoblotting was also performed. Positive MR immunoreactivity was observed in both cytoplasm and nucleus of absorptive cells of ileum of total colectomy patients but not in control normal ileum. Immunoblotting revealed the presence of an approximately 100 kDa immunoreactive product corresponding to mineralocorticoid receptor. Aldosterone is considered to act on ileal mucosa following total colectomy and the aldosterone dependent sodium transport and water absorption may be accelerated in ileal mucosa after total colectomy, which is consistent with the postoperative decrease in the stool volume observed in these patients. In conclusion, increased expression of the mineralocorticoid receptor in remnant ileum may play an important role in intestinal adaptation in total colectomized patients.

7 Humoral regulation of intestinal adaptation

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 alpha 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.

Effect of Short‐Chain Fatty Acids on Colonic Function and Structure

Short-chain fatty acids (SCFA), fermentation products of fiber, are believed to play a role in intestinal adaptation. Although the administration of fiber or the infusion of SCFA has been shown to cause colonic growth, studies have been done primarily in enterally fed animals. In addition, the effects of SCFA on absorptive function have not been determined. Adult male rats were maintained on total parenteral nutrition (TPN) and, in addition, received either 150 mmol/L of saline or 150 mmol/L of SCFA mixture (60:25:15, acetate:propionate:butyrate) into the proximal colon. One week later, the in vivo absorption of water, electrolytes, and 20 mmol/L of butyrate was measured. After the rats were killed, parameters of colonic mass were determined. SCFA infusion into the colon had no significant effect on absorptive function. However, significantly greater mucosal height (p less than .01) and mucosal DNA (p less than .05), were observed. Although SCFA has a modest effect on colonic structure, they do not influence absorptive function in TPN rats.

Hyperenteroglucagonaemia and small intestinal mucosal growth after colonic perfusion of glucose in rats.

Beside intraluminal factors, humoral agents play an important role in intestinal adaptation. Enteroglucagon, the mucosal concentration of which is maximal in the terminal ileum and colon, is the strongest candidate for the role of small intestinal mucosal growth factor. The present experiment was designed to study the role of colonic enteroglucagon in stimulating mucosal growth in rats with a normal small intestine. After eight days of glucose large bowel perfusion, enteroglucagon plasma concentrations were 120.7 +/- SEM 9.2 pmol/l, versus 60.1 +/- 6.8 in mannitol perfused control rats (p less than 0.001). Gastrin, cholecystokinin, neurotensin, pancreatic glucagon, and insulin plasma concentrations were unchanged. Crypt cell proliferation, measured by the vincristine metaphase arrest technique, increased significantly in the small intestine of glucose perfused animals (p less than 0.005-0.001) in comparison with the controls. This resulted in a greater mucosal mass in both proximal and distal small bowel: mucosal wet weight, DNA, protein and alpha D-glucosidase per unit length intestine were all significantly higher (p less than 0.05-0.001) than in mannitol perfused rats. Our data, therefore, support the hypothesis that enteroglucagon is an enterotrophic factor and stress the possible role of the colon in the regulation of small bowel trophicity.

Does Enteroglucagon Play a Trophic Role in Intestinal Adaptation?

Does Enteroglucagon Play a Trophic Role in Intestinal Adaptation?