Nutrient-stimulated GLP-2 release and crypt cell proliferation in experimental short bowel syndrome

2005 ◽  
Vol 288 (3) ◽  
pp. G431-G438 ◽  
Author(s):  
G. R. Martin ◽  
L. E. Wallace ◽  
B. Hartmann ◽  
J. J. Holst ◽  
L. Demchyshyn ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Time Course ◽  
Intestinal Adaptation ◽  
Intestinal Resection ◽  
Small Bowel Resection ◽  
Crypt Cell ◽  
Crypt Cell Proliferation ◽  
Proximal Intestine ◽  
The Relationship ◽  
Over Time

Glucagon-like peptide-2 (GLP-2) is an enteroendocrine peptide that is released in response to luminal nutrients and has unique trophic actions in the gastrointestinal tract. These features suggest GLP-2 may be important in controlling intestinal adaptation. We examined the relationship over time of GLP-2 production and adaptation to intestinal resection, the effects of resection-induced malabsorption on GLP-2 production, and the correlation of endogenous serum GLP-2 levels with adaptation as measured by crypt-cell proliferation (CCP). We initially examined the effect of nutrient malabsorption, induced by a 90% resection of the proximal intestine studied on day 4, on the time course and levels of GLP-2 release. Secondly, the degree of malabsorption was varied by performing intestinal transection or 50, 75, or 90% resection of proximal small intestine. Finally, the relationship of GLP-2 levels over time with adaptation to a 90% resection was examined by determining GLP-2 levels on days 7, 14, and 28, and correlating this with intestinal adaptation, as assessed by morphology and CCP rate. A 90% resection significantly increased basal and postprandial GLP-2 levels, with a net increase in nutrient-stimulated exposure over 90 min; GLP-2 exposure (integrated levels vs. time) increased 12.7-fold in resected animals ( P < 0.001). Basal and postprandial GLP-2 levels significantly correlated with the magnitude of intestinal resection ( r2 = 0.71; P < 0.001), CCP ( r2 = 0.48; P < 0.005), and nutrient malabsorption (protein, P < 0.001; fat, P < 0.005). The increase in CCP was maintained to 28 days after small bowel resection and was associated with an ongoing elevation in GLP-2 release. These findings suggest that GLP-2 is important in initiating and maintaining the small intestinal adaptive response to resection.

Polyamines and intestinal growth--increased polyamine biosynthesis after jejunectomy

1983 ◽  
Vol 245 (5) ◽  
pp. G656-G660 ◽  
Author(s):  
G. D. Luk ◽  
S. B. Baylin
Keyword(s):  
Cell Proliferation ◽  
Intestinal Adaptation ◽  
Intestinal Resection ◽  
Crypt Cell ◽  
Mucosal Cell ◽  
Ileal Mucosa ◽  
Cell Hyperplasia ◽  
Polyamine Biosynthesis ◽  
Crypt Cell Proliferation ◽  
Mucosal Cell Proliferation

Transient increases in the activities of ornithine decarboxylase (ODC) and S-adenosylmethionine decarboxylase (SAM-DC), key enzymes in polyamine biosynthesis, may be critical to initiation of cell growth. We now report that such increases in ODC (X170) and SAM-DC (X83) activities, and their synthetic products putrescine (X4) and spermidine (X2), occur in rat ileal mucosa between days 1 and 4 after 50% intestinal resection. This is the time period of initiation of mucosal cell hyperplasia in intestinal adaptation after resection and is characterized by increased mucosal cell proliferation, as measured morphologically and biochemically. Intestinal weight increased by 76% and mucosal thickness by 48%. Mucosal DNA content increased by 67% and mucosal DNA synthesis by 104%. Increased intestinal crypt cell proliferation was manifested by a 120% increase in labeling per crypt and a 152% increase in crypt cell production rate (CCPR). The increase in ODC activity was closely associated with the increases in CCPR and rate of villus lengthening. Rates of mucosal cell proliferation, as measured by CCPR, and villus and crypt lengthening were significantly correlated with ODC activity (r = 0.97, 0.98, and 0.94, respectively; P less than 0.01 for all). Our results indicate that the increase in ODC activity, SAM-DC activity, and polyamine biosynthesis is closely associated with the process of adaptive postresectional crypt cell proliferation.

Increased apoptosis and accelerated epithelial migration following inhibition of hedgehog signaling in adaptive small bowel postresection

2006 ◽  
Vol 290 (6) ◽  
pp. G1280-G1288 ◽  
Author(s):  
Yuzhu Tang ◽  
Elzbieta A. Swietlicki ◽  
ShuJun Jiang ◽  
Kim K. Buhman ◽  
Nicholas O. Davidson ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Small Bowel ◽  
Surface Area ◽  
Intestinal Adaptation ◽  
Critical Role ◽  
Intestinal Resection ◽  
Crypt Cell ◽  
Epithelial Migration ◽  
Crypt Cell Proliferation ◽  
Hh Signaling

The intestinal epithelium undergoes a marked adaptive response following loss of functional small bowel surface area characterized by increased crypt cell proliferation and increased enterocyte migration from crypt to villus tip, resulting in villus hyperplasia and enhanced nutrient absorption. Hedgehog (Hh) signaling plays a critical role in regulating epithelial-mesenchymal interactions during morphogenesis of the embryonic intestine. Our previous studies showed that blocking Hh signaling in neonatal mice results in increased small intestinal epithelial crypt cell proliferation and altered enterocyte fat absorption and morphology. Hh family members are also expressed in the adult intestine, but their role in the mature small bowel is unclear. With the use of a model of intestinal adaptation following partial small bowel resection, the role of Hh signaling in the adult gut was examined by determining the effects of blocking Hh signaling on the regenerative response following loss of functional surface area. Hh-inactivating monoclonal antibodies or control antibodies were administered to mice that sustained a 50% intestinal resection. mRNA analyses of the preoperative ileum by quantitative real-time PCR revealed that Indian hedgehog was the most abundant Hh family member. The Hh receptor Patched was more abundant than Patched 2. Analyses of downstream targets of Hh signaling demonstrated that Gli3 was twofold more abundant than Gli1 and Gli2 and that bone morphogenetic protein ( BMP) 2 was most highly expressed compared with BMP1, - 4, and - 7. Following intestinal resection, the expression of Hh, Patched, Gli, and most BMP genes was markedly downregulated in the remnant ileum, and, in anti-Hh antibody-treated mice, expression of Patched 2 and Gli 1 was further suppressed. In Hh antibody-treated mice following resection, the enterocyte migration rate from crypt to villus tip was increased, and by 2 wk postoperation, apoptosis was increased in the adaptive gut. However, crypt cell proliferation, villus height, and crypt depth were not augmented. These data indicate that Hh signaling plays a role in adult gut epithelial homeostasis by regulating epithelial cell migration from crypt to villus tip and by enhancing apoptosis.

Vitamin A deficiency inhibits intestinal adaptation by modulating apoptosis, proliferation, and enterocyte migration

2003 ◽  
Vol 285 (2) ◽  
pp. G424-G432 ◽  
Author(s):  
Deborah A. Swartz-Basile ◽  
Lihua Wang ◽  
Yuzhu Tang ◽  
Henry A. Pitt ◽  
Deborah C. Rubin ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Small Bowel ◽  
Vitamin A ◽  
Vitamin A Deficiency ◽  
Intestinal Adaptation ◽  
Collagen Iv ◽  
Crypt Cell ◽  
Migration Rates ◽  
Crypt Cell Proliferation ◽  
Extracellular Matrix Components

In a prior study, vitamin A-deficient rats subjected to submassive small bowel resections did not mount a normal intestinal adaptive response by 10 days postoperatively, although adaptive increases in crypt cell proliferation were not attenuated and there were no differences in apoptotic indexes. The present study was designed to address the mechanisms by which vitamin A status effects adaptation by analyzing proliferation, apoptosis, and enterocyte migration in the early postoperative period (16 and 48 h) in vitamin A-sufficient, -deficient, and partially replenished sham-resected and resected rats. At 16 h postresection, apoptosis was significantly greater in the remnant ileum of resected vitamin A-deficient rats compared with the sufficient controls. Crypt cell proliferation was increased by resection in all dietary groups at both timepoints. However, at 48 h postresection, proliferation was significantly decreased in the vitamin A-deficient and partially replenished rats. By 48 h after resection, vitamin A deficiency also reduced enterocyte migration rates by 44%. This occurred in conjunction with decreased immunoreactive collagen IV at 48 h and 10 days postoperation. Laminin expression was also reduced by deficiency at 10 days postresection, whereas fibronectin and pancadherin were unchanged at 48 h and 10 days. These studies indicate that vitamin A deficiency inhibits intestinal adaptation following partial small bowel resection by reducing crypt cell proliferation, by enhancing early crypt cell apoptosis, and by markedly reducing enterocyte migration rates, which may be related to changes in the expression of collagen IV and other extracellular matrix components.

A growth-stimulating activity derived from the proximal small intestine is associated with an adaptive response

1990 ◽  
Vol 68 (5) ◽  
pp. 646-649 ◽  
Author(s):  
V. L. Grey ◽  
C. L. Morin
Keyword(s):  
Cell Proliferation ◽  
Small Intestine ◽  
Thymidine Kinase ◽  
Kinase Activity ◽  
Crypt Cell ◽  
General Mechanism ◽  
Cell Renewal ◽  
Thymidine Kinase Activity ◽  
Crypt Cell Proliferation ◽  
Proximal Intestine

Luminal nutrition is important for the maintenance of small intestinal structure and function. The equilibrium between crypt cell production and villous cell loss in the mucosal epithelium of the small intestine is altered under certain conditions such as after a small bowel resection. Immediately after resection, there is a marked increase in crypt cell proliferation giving rise to an adaptive hyperplasia in the remnant intestine and for this response luminal nutrition is a critical factor. We have previously demonstrated the presence of a growth-stimulating (GS) activity in a heat-stable acidic extract of the rat proximal intestine 24, 48, and 96 h after resection, which is coincidental with an increase in crypt cell proliferation as measured by thymidine kinase activity. Eight days after resection when the GS activity is no longer detectable, the thymidine kinase activity returns to control values. The molecular weights of the peptides associated with this GS activity are 4500 and 1500, as determined by Sephadex gel filtration. Of note is that the oral intake of food is necessary for the appearance of the GS activity postoperatively. The presence of the GS activity has also been demonstrated upon refeeding after a fast, as well as at weaning in the rat, two physiological situations known to be associated with increased proliferation in the small intestine. This GS activity in the proximal intestine first detected in the resection model may represent a general mechanism by which food controls the cell renewal pattern of the small intestine.Key words: stimulating activity, proximal intestine, adaptation.

Reduction of mucosal crypt cell proliferation in patients with colorectal adenomatous polyps by dietary calcium supplementation

1992 ◽  
Vol 79 (6) ◽  
pp. 581-583 ◽  
Author(s):  
G. H. Barsoum ◽  
C. Hendrickse ◽  
M. C. Winslet ◽  
D. Youngs ◽  
I. A. Donovan ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Calcium Supplementation ◽  
Dietary Calcium ◽  
Crypt Cell ◽  
Adenomatous Polyps ◽  
Crypt Cell Proliferation

scholarly journals Glucagon-Like Peptide-2 Activates β-Catenin Signaling in the Mouse Intestinal Crypt: Role of Insulin-Like Growth Factor-I

Endocrinology ◽  
2007 ◽  
Vol 149 (1) ◽  
pp. 291-301 ◽  
Author(s):  
Philip E. Dubé ◽  
Katherine J. Rowland ◽  
Patricia L. Brubaker
Keyword(s):  
Cell Proliferation ◽  
Nuclear Translocation ◽  
Glycogen Synthase ◽  
Crypt Cell ◽  
Acute Administration ◽  
Intestinal Crypt ◽  
Crypt Cell Proliferation ◽  
Igf I ◽  
Glucagon Like Peptide ◽  
Crypt Cells

Chronic administration of glucagon-like peptide-2 (GLP-2) induces intestinal growth and crypt cell proliferation through an indirect mechanism requiring IGF-I. However, the intracellular pathways through which IGF-I mediates GLP-2-induced epithelial tropic signaling remain undefined. Because β-catenin and Akt are important regulators of crypt cell proliferation, we hypothesized that GLP-2 activates these signaling pathways through an IGF-I-dependent mechanism. In this study, fasted mice were administered Gly2-GLP-2 or LR3-IGF-I (positive control) for 0.5–4 h. Nuclear translocation of β-catenin in non-Paneth crypt cells was assessed by immunohistochemistry and expression of its downstream proliferative markers, c-myc and Sox9, by quantitative RT-PCR. Akt phosphorylation and activation of its targets, glycogen synthase kinase-3β and caspase-3, were determined by Western blot. IGF-I receptor (IGF-IR) and IGF-I signaling were blocked by preadministration of NVP-AEW541 and through the use of IGF-I knockout mice, respectively. We found that GLP-2 increased β-catenin nuclear translocation in non-Paneth crypt cells by 72 ± 17% (P &lt; 0.05) and increased mucosal c-myc and Sox9 mRNA expression by 90 ± 20 and 376 ± 170%, respectively (P &lt; 0.05–0.01), with similar results observed with IGF-I. This effect of GLP-2 was prevented by blocking the IGF-IR as well as ablation of IGF-I signaling. GLP-2 also produced a time- and dose-dependent activation of Akt in the intestinal mucosa (P &lt; 0.01), most notably in the epithelium. This action was reduced by IGF-IR inhibition but not IGF-I knockout. We concluded that acute administration of GLP-2 activates β-catenin and proliferative signaling in non-Paneth murine intestinal crypt cells as well as Akt signaling in the mucosa. However, IGF-I is required only for the GLP-2-induced alterations in β-catenin.

Gut adaptation and the insulin-like growth factor system: regulation by glutamine and IGF-I administration

1996 ◽  
Vol 271 (5) ◽  
pp. G866-G875 ◽  
Author(s):  
T. R. Ziegler ◽  
M. P. Mantell ◽  
J. C. Chow ◽  
J. L. Rombeau ◽  
R. J. Smith
Keyword(s):  
Growth Factor ◽  
Small Bowel ◽  
Dna Content ◽  
Bowel Resection ◽  
Synergistic Effects ◽  
Intestinal Adaptation ◽  
Intestinal Resection ◽  
Small Bowel Resection ◽  
Insulin Like Growth Factor ◽  
Igf I

Intestinal adaptation after extensive small bowel resection in rats is augmented by the provision of diets supplemented with the amino acid glutamine (Gln) or by administration of insulin-like growth factor-I (IGF-I). The goal of this study was to investigate potential synergistic effects of Gln and IGF-I on postresection ileal hyperplasia. Rats underwent 80% small bowel resection (SBR) and then were fed low-Gln or L-Gln-enriched diets and subcutaneously given recombinant human IGF-I or vehicle for 7 days. Gln and IGF-I each significantly enhanced adaptive ileal hyperplasia (DNA content) compared with rats receiving vehicle and low-Gln diet. Ileal DNA content was highest when IGF-I was administered together with Gln supplementation. Combined IGF-I plus Gln synergistically increased ileal weight and protein content. This was associated with higher plasma concentrations of IGF-I and Gln than observed when IGF-I or Gln was given individually. Ileal IGF-I mRNA expression rose nearly twofold during gut adaptation after SBR; this response was augmented with IGF-I administration but was unaltered by Gln feeding. In contrast, dietary Gln, but not IGF-I therapy, prevented a decrease in hepatic IGF-I mRNA induced by SBR. We conclude that parenteral IGF-I and enteral Gln have both individual and synergistic effects on ileal adaptation after massive small intestinal resection. These findings support the concept that specific gut-trophic nutrients and growth factors may be combined to enhance intestinal adaptation and possibly reduce the severity of short bowel syndrome after intestinal resection.

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