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The paper by Jeppsen et al (see page559) shows that glucagon-like peptide-2 (GLP-2) concentrations are low in patients lacking an ileum and colon. This is not an unexpected finding as the L cells that produce GLP-2 are situated in the ileum and colon. GLP-2 is an enterocyte specific growth hormone that in mice causes small and large bowel villus/crypt growth and increases small and large bowel length and weight. In mice it also reduces body weight loss and restores mucosal integrity after dextran induced colitis. In pigs it reduces gastric antral motility.1 The deficiency of GLP-2 in patients with a jejunostomy may explain why these patients show no evidence of structural or functional intestinal adaptation over time.2-4
A distal ileal/colonic peptide with glucagon-like immunoreactivity has been recognised for many years and termed enteroglucagon. However, the molecular structure of enteroglucagon was originally unknown and serum concentrations were derived by subtracting pancreatic glucagon concentrations from total glucagon-like immunoreactivity.5Enteroglucagon producing tumours were associated with mucosal hyperplasia6 7 and enteroglucagon was thought to be responsible for the ileal adaptation that occurred after a jejunal resection. GLP-2 is likely to be the most important mucosal growth stimulating hormone.8 Its consists of 33 amino acids and its structure is highly conserved throughout all mammalian species (only one amino acid different in the rat). It has been synthesised and its receptor characterised.1 As it stimulates mucosal growth there is the possibility of giving it to patients with a short bowel to promote adaptation, or to adults or children with intestinal damage (e.g. from ischaemia, irradiation, chemotherapy, severe coeliac disease, necrotising enterocolitis or congenital microvillus atrophy).
When the jejunum is resected, the remaining ileum undergoes both structural and functional adaptation. Structural adaptation is apparent as the bowel increases in width, its villi become longer and crypts deeper. Functional adaptation is shown by measuring increases (with time or compared with normal subjects) in the absorption of macro- and/or micronutrients over a given length of bowel. Functional adaptation may be the result of structural changes, a slowing of transit rate or intracellular molecular events (e.g. increased transport and/or enzyme activity).9 Patients with a short bowel commonly encountered in clinical practice do not have a retained ileum; they have either a jejuno-colic anastomosis or a jejunostomy.3 There is no convincing evidence in humans that the remaining jejunal mucosa can adapt structurally in either of these situations4 10; however, patients with a retained colon do show evidence of function adaptation.11-13
The clinical problems experienced by the two types of patient with a short bowel are different. Both have problems with nutrient absorption; however, patients with a jejunostomy also lose large amounts of water and sodium from their stoma.14 This is because of loss of normal daily intestinal secretions (about 4 litres/24 hours), rapid gastric emptying and rapid small bowel transit.15 If a patient has less than 100 cm jejunum remaining and a stoma he/she is likely, as a minimum, to need long term parenteral saline.14 This requirement does not reduce with time.3 Patients with a retained colon do not have these problems and, owing to functional adaptation, nutrient absorption usually improves with time. To explain the differences between the two types of patient, measurements of various gastrointestinal hormones have been made with interest focusing upon those produced by the ileum and colon. Peptide YY, which like GLP-2 is produced by the L cells of the ileum and colon, slows gastric emptying and small bowel transit and may be responsible for the “ileal” and “colonic” brakes. Peptide YY serum values are high in patients with a retained colon and low in patients with a jejunostomy.16 Thus peptide YY may be responsible for part of the functional adaptation that occurs in patients with a retained colon; however, it is unlikely to induce structural changes.17
Data are not yet available about GLP-2 values in patients with a jejuno-colic anastomosis. If high, this may represent an adaptive mechanism by which GLP-2 increases intestinal growth and slows gastric emptying. Thus GLP-2 serum values could become a useful measure of the amount of intestinal adaptation. If GLP-2 values are low, then it will be important to study the therapeutic effects of administering it. There may even be a congenital defect in absorption related to a deficiency of GLP-2.
The importance of GLP-2 is just starting to be recognised. Its role in promoting intestinal growth makes it a potentially useful treatment for patients with a short or damaged bowel. The role of GLP-2 (and peptide YY) in inducing jejunal structural and functional adaptation will only become clearer after they (or analogues) have been infused/injected into patients with a short bowel, and the short and long term effects documented.
See article on page 559
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