Publications by Year: 2006

BACKGROUND: Short bowel syndrome (SBS) can lead to intestinal failure and require total or supplemental parenteral nutrition (TPN or PN, respectively). Glucagon-like peptide 2 (GLP-2) is a nutrient-dependent, proglucagon-derived gut hormone that stimulates intestinal adaptation.

OBJECTIVE: Our objective was to determine whether supplemental enteral nutrients (SEN) modulate the intestinotrophic response to a low dose of GLP-2 coinfused with PN in a rat model of SBS (60% jejunoileal resection plus cecectomy).

DESIGN: Rats were randomly assigned to 8 treatments by using a 2 x 2 x 2 factorial design and maintained with either TPN or PN for 7 d. The 3 main treatment effects were the following: transection or resection (TPN alone), +/- SEN (days 4-6), and +/- GLP-2 (100 mug . kg body wt(-1) . d(-1)).

RESULTS: The treatments induced differential growth of duodenal and jejunal mucosa. Significant differences in villus height, crypt depth, dry mass, and concentrations of protein and DNA were observed between the treatments and TPN alone (SEN: 15-59% increase; GLP-2: 14-84% increase; and SEN + GLP-2: 63-160% increase). Plasma concentrations of bioactive GLP-2 were significantly greater with GLP-2 infusion (TPN alone: 25 +/- 9 pmol/L; SEN: 29 +/- 10 pmol/L; GLP-2: 59 +/- 31 pmol/L; SEN + GLP-2: 246 +/- 40 pmol/L) and correlated with mucosal growth. Jejunal sucrase activity (in U/cm) was significantly greater with SEN than without SEN. SEN + GLP-2 induced dramatic mucosal growth and greater plasma concentration of GLP-2 (SEN x GLP-2 interaction, P < 0.0001). Resection significantly increased expression of proglucagon mRNA in colon.

CONCLUSIONS: Combination treatment with SEN and GLP-2 induced a synergistic response resulting in greater mucosal cellularity and digestive capacity in parenterally fed rats with SBS. This shows that SEN improve the intestinotrophic response to exogenous GLP-2, possibly by stimulating enterocyte proliferation and differentiation.

Small bowel resection stimulates intestinal adaptive growth by a neuroendocrine process thought to involve both sympathetic and parasympathetic innervation and enterotrophic hormones such as glucagon-like peptide-2 (GLP-2). We investigated whether capsaicin-sensitive vagal afferent neurons are essential for maximal resection-induced intestinal growth. Rats received systemic or perivagal capsaicin or ganglionectomy before 70% midjejunoileal resection or transection and were fed orally or by total parenteral nutrition (TPN) for 7 days after surgery. Growth of residual bowel was assessed by changes in mucosal mass, protein, DNA, and histology. Both systemic and perivagal capsaicin significantly attenuated by 48-100% resection-induced increases in ileal mucosal mass, protein, and DNA in rats fed orally. Villus height was significantly reduced in resected rats given capsaicin compared with vehicle. Sucrase specific activity in jejunal mucosa was not significantly different; ileal mucosal sucrase specific activity was significantly increased by resection in capsaicin-treated rats. Capsaicin did not alter the 57% increase in ileal proglucagon mRNA or the 150% increase in plasma concentration of bioactive GLP-2 resulting from resection in orally fed rats. Ablation of spinal/splanchnic innervation by ganglionectomy failed to attenuate resection-induced adaptive growth. In TPN rats, capsaicin did not attenuate resection-induced mucosal growth. We conclude that vagal afferents are not essential for GLP-2 secretion when the ileum has direct contact with luminal nutrients after resection. In summary, vagal afferent neurons are essential for maximal resection-induced intestinal adaptation through a mechanism that appears to involve stimulation by luminal nutrients.