Effects of exogenous glucagon-like peptide-2 and distal bowel resection on intestinal and systemic adaptive responses in rats

Abstract

ObjectiveTo determine the effects of exogenous glucagon-like peptide-2 (GLP-2), with or without massive distal bowel resection, on adaptation of jejunal mucosa, enteric neurons, gut hormones and tissue reserves in rats.BackgroundGLP-2 is a gut hormone known to be trophic for small bowel mucosa, and to mimic intestinal adaptation in short bowel syndrome (SBS). However, the effects of exogenous GLP-2 and SBS on enteric neurons are unclear.MethodsSprague Dawley rats were randomized to four treatments: Transected Bowel (TB) (n = 8), TB + GLP-2 (2.5 nmol/kg/h, n = 8), SBS (n = 5), or SBS + GLP-2 (2.5 nmol/kg/h, n = 9). SBS groups underwent a 60% jejunoileal resection with cecectomy and jejunocolic anastomosis. All rats were maintained on parenteral nutrition for 7 d. Parameters measured included gut morphometry, qPCR for hexose transporter (SGLT-1, GLUT-2, GLUT-5) and GLP-2 receptor mRNA, whole mount immunohistochemistry for neurons (HuC/D, VIP, nNOS), plasma glucose, gut hormones, and body composition.ResultsResection increased the proportion of nNOS immunopositive myenteric neurons, intestinal muscularis propria thickness and crypt cell proliferation, which were not recapitulated by GLP-2 therapy. Exogenous GLP-2 increased jejunal mucosal surface area without affecting enteric VIP or nNOS neuronal immunopositivity, attenuated resection-induced reductions in jejunal hexose transporter abundance (SGLT-1, GLUT-2), increased plasma amylin and decreased peptide YY concentrations. Exogenous GLP-2 attenuated resection-induced increases in blood glucose and body fat loss.ConclusionsExogenous GLP-2 stimulates jejunal adaptation independent of enteric neuronal VIP or nNOS changes, and has divergent effects on plasma amylin and peptide YY concentrations. The novel ability of exogenous GLP-2 to modulate resection-induced changes in peripheral glucose and lipid reserves may be important in understanding the whole-body response following intestinal resection, and is worthy of further study.

Glucose and Several Mitogenic Agents Modulate the Glucagon-Like Peptide-2 Receptor Expression in Cultured Rat Astrocytes

“…Likewise, in studies with different animal models, the intraperitoneal administration of GLP-2 also showed contradictory results. Thus, the GLP-2R expression was downregulated in the ileum of 21-day-old sows [ 41 ], in the mucosal of TPN-mice [ 39 ], and in the jejunum of rats with short bowel syndrome, but not in rats with a distal bowel resection [ 42 ]. Likewise, the GLP-2R expression was reduced in both the anastomotic segments and in the ileal samples recovered after ileal resection and isolated laparotomy of rats after teduglutide administration [ 11 ].…”

Teduglutide Promotes Epithelial Tight Junction Pore Function in Murine Short Bowel Syndrome to Alleviate Intestinal Insufficiency

“…While the trophic effects on the small intestinal mucosa by GLP-2 stimulation are well described [40][41][42][43], the functional relevance of small bowel villus growth is less clear. The mechanistic implication of villus growth is called into question by translational observations: 1) Villus growth in response to Teduglutide is not in the same order of magnitude as a reduction of parenteral support (PS) [13], and enterocyte mass expansion does not correlate with PS reduction [42].…”

Host-Gut Microbiota Crosstalk in Intestinal Adaptation

“…A recent report showed that rats who underwent SBR showed an increased proportion of myenteric nitrergic neurons that correlated with a thicker muscularis propria and higher crypt cell proliferation in both the jejunum and colon. 117 This study suggested that modulation of the neuronal population potentially could be a compensatory mechanism that reduces motility and improves nutrient/fluid absorption. 117 …”

“… 117 This study suggested that modulation of the neuronal population potentially could be a compensatory mechanism that reduces motility and improves nutrient/fluid absorption. 117 …”