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

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.

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Chronically administered retinoic acid has trophic effects in the rat small intestine and promotes adaptation in a resection model of short bowel syndrome

AJP Gastrointestinal and Liver Physiology ◽

10.1152/ajpgi.00567.2006 ◽

2007 ◽

Vol 292 (6) ◽

pp. G1559-G1569 ◽

Cited By ~ 15

Author(s):

Lihua Wang ◽

Yuzhu Tang ◽

Deborah C. Rubin ◽

Marc S. Levin

Keyword(s):

Extracellular Matrix ◽

Cell Proliferation ◽

Retinoic Acid ◽

Small Bowel ◽

Vitamin A ◽

Short Bowel Syndrome ◽

Crypt Cell ◽

Short Bowel ◽

Trophic Effects ◽

Crypt Cell Proliferation

Following the loss of functional small bowel surface area, the intestine undergoes a compensatory adaptive response. The observation that adaptation is inhibited in vitamin A-deficient rats following submassive intestinal resection suggested that vitamin A is required for this response and raised the possibility that exogenous vitamin A could augment adaptation. Therefore, to directly assess whether chronically administered retinoic acid could stimulate gut adaptation in a model of short bowel syndrome and to address the mechanisms of any such effects, Sprague-Dawley rats were implanted with controlled release retinoic acid or control pellets and then subjected to mid-small bowel or sham resections. At 2 wk postoperation, changes in gut morphology, crypt cell proliferation and apoptosis, enterocyte migration, the extracellular matrix, and gene expression were assessed. Retinoic acid had significant trophic effects in resected and sham-resected rats. Retinoic acid markedly inhibited apoptosis and stimulated crypt cell proliferation and enterocyte migration postresection. Data presented indicate that these proadaptive effects of retinoic acid may be mediated via changes in the extracellular matrix (e.g., by increasing collagen IV synthesis, decreasing E-cadherin expression, and reducing integrin β3 levels), via affects on Hedgehog signaling (e.g., by reducing expression of the Hedgehog receptors Ptch and Ptch2 and the Gli1 transcription factor), by increasing expression of Reg1 and Pap1, and by modulation of retinoid and peroxisome proliferator-activated receptor signaling pathways. These studies are the first to demonstrate that retinoic acid can significantly enhance intestinal adaptation and suggest it may be beneficial in patients with short bowel syndrome.

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

AJP Gastrointestinal and Liver Physiology ◽

10.1152/ajpgi.00426.2005 ◽

2006 ◽

Vol 290 (6) ◽

pp. G1280-G1288 ◽

Cited By ~ 21

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.

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Polyamines and intestinal growth--increased polyamine biosynthesis after jejunectomy

AJP Gastrointestinal and Liver Physiology ◽

10.1152/ajpgi.1983.245.5.g656 ◽

1983 ◽

Vol 245 (5) ◽

pp. G656-G660 ◽

Cited By ~ 3

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.

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

AJP Gastrointestinal and Liver Physiology ◽

10.1152/ajpgi.00242.2004 ◽

2005 ◽

Vol 288 (3) ◽

pp. G431-G438 ◽

Cited By ~ 92

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.

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Interleukin-6 is an important in vivo inhibitor of intestinal epithelial cell death in mice

Gut ◽

10.1136/gut.2008.151175 ◽

2008 ◽

Vol 59 (2) ◽

pp. 186-196 ◽

Cited By ~ 55

Author(s):

Xiaoling Jin ◽

Teresa A Zimmers ◽

Zongxiu Zhang ◽

Robert H Pierce ◽

Leonidas G Koniaris

Keyword(s):

Cell Proliferation ◽

Cell Death ◽

Small Bowel ◽

Interleukin 6 ◽

Crypt Cell ◽

Parp Cleavage ◽

High Dose ◽

Crypt Cell Proliferation ◽

In Vivo Effects

Background and aimsInterleukin-6 (IL-6) is a well-recognised mediator of liver disease and regeneration. However, the in vivo effects of IL-6 on enterocytes and the intestinal tract have not been elucidated. We sought to determine the in vivo effects of IL-6 on enterocytes.MethodsMurine models of increased or absent IL-6 were examined.ResultsSystemic, high-dose IL-6 administration to mice over 7–10 days resulted in intestinal hyperplasia with a ∼40% increase in small bowel mass and in intestinal villus height. No increase in crypt cell proliferation was noted. IL-6 administration was associated with induction of pSTAT3 in enterocytes along the lower and middle regions of villi but not in crypts. IL-6 administration was also associated with induction of anti-apoptotic proteins including pAKT, and FLIP along with decreased executor caspase activity and PARP cleavage. Pulse bromodeoxyuridine labelling demonstrated equivalent crypt cell proliferation rates but prolonged enterocyte lifespan and slowed enterocyte migration rates in IL-6 treated mice. Furthermore, IL-6 treated mice showed less intestinal injury and improved barrier function following ischaemia reperfusion of the small bowel. Conversely, Il6 null mice exhibited impaired recovery following massive enterectomy and increased apoptosis after 5-fluorouracil chemotherapy relative to wild-type controls.ConclusionsIL-6 inhibited both constitutive and induced enterocyte cell death in vivo. Loss of IL-6 in mice resulted in increased activation of pro-apoptotic and necrotic pathways in enterocytes after injury. Therapies that augment IL-6 or its signalling pathways may help manage intestinal disorders associated with increased apoptosis, necrosis and gut injury.

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The effects of dimethylhydrazine and small bowel resection on crypt cell proliferation in the rat colon

Gastroenterology ◽

10.1016/0016-5085(78)93411-x ◽

1978 ◽

Vol 74 (5) ◽

pp. 1105

Author(s):

M.D. Tilson ◽

M. Buck ◽

E.M. Livstone

Keyword(s):

Cell Proliferation ◽

Small Bowel ◽

Bowel Resection ◽

Small Bowel Resection ◽

Crypt Cell ◽

Rat Colon ◽

Crypt Cell Proliferation

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Intestinotrophic Glucagon-Like Peptide-2 (GLP-2) Activates Intestinal Gene Expression and Growth Factor-Dependent Pathways Independent of the Vasoactive Intestinal Peptide Gene in Mice

Endocrinology ◽

10.1210/en.2012-1069 ◽

2012 ◽

Vol 153 (6) ◽

pp. 2623-2632 ◽

Cited By ~ 28

Author(s):

Bernardo Yusta ◽

Dianne Holland ◽

James A. Waschek ◽

Daniel J. Drucker

Keyword(s):

Gene Expression ◽

Cell Proliferation ◽

Small Bowel ◽

Vasoactive Intestinal Peptide ◽

Paneth Cell ◽

Crypt Cell ◽

Colonic Injury ◽

Intestinal Phenotype ◽

Crypt Cell Proliferation ◽

Glucagon Like Peptide

The enteroendocrine and enteric nervous systems convey signals through an overlapping network of regulatory peptides that act either as circulating hormones or as localized neurotransmitters within the gastrointestinal tract. Because recent studies invoke an important role for vasoactive intestinal peptide (VIP) as a downstream mediator of glucagon-like peptide-2 (GLP-2) action in the gut, we examined the importance of the VIP-GLP-2 interaction through analysis of Vip−/− mice. Unexpectedly, we detected abnormal villous architecture, expansion of the crypt compartment, increased crypt cell proliferation, enhanced Igf1 and Kgf gene expression, and reduced expression of Paneth cell products in the Vip−/− small bowel. These abnormalities were not reproduced by antagonizing VIP action in wild-type mice, and VIP administration did not reverse the intestinal phenotype of Vip−/− mice. Exogenous administration of GLP-2 induced the expression of ErbB ligands and immediate-early genes to similar levels in Vip+/+vs. Vip−/− mice. Moreover, GLP-2 significantly increased crypt cell proliferation and small bowel growth to comparable levels in Vip+/+vs. Vip−/− mice. Unexpectedly, exogenous GLP-2 administration had no therapeutic effect in mice with dextran sulfate-induced colitis; the severity of colonic injury and weight loss was modestly reduced in female but not male Vip−/− mice. Taken together, these findings extend our understanding of the complex intestinal phenotype arising from loss of the Vip gene. Furthermore, although VIP action may be important for the antiinflammatory actions of GLP-2, the Vip gene is not required for induction of a gene expression program linked to small bowel growth after enhancement of GLP-2 receptor signaling.

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

British Journal of Surgery ◽

10.1002/bjs.1800790639 ◽

1992 ◽

Vol 79 (6) ◽

pp. 581-583 ◽

Cited By ~ 34

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

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

Endocrinology ◽

10.1210/en.2007-0561 ◽

2007 ◽

Vol 149 (1) ◽

pp. 291-301 ◽

Cited By ~ 56

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 < 0.05) and increased mucosal c-myc and Sox9 mRNA expression by 90 ± 20 and 376 ± 170%, respectively (P < 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 < 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.

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