Early but not late administration of glucagon-like peptide-2 following ileo-cecal resection augments putative intestinal stem cell expansion
University of North Carolina at Chapel Hill, Department of Surgery, G140 Physician's Office Bldg., CB #7223, Chapel Hill, NC 27599-7223, USA. AJP Gastrointestinal and Liver Physiology
(Impact Factor: 3.8).
01/2009; 296(3):G643-50. DOI: 10.1152/ajpgi.90588.2008
Expansion of intestinal progenitors and putative stem cells (pISC) occurs early and transiently following ileo-cecal resection (ICR). The mechanism controlling this process is not defined. We hypothesized that glucagon-like peptide-2 (GLP-2) would augment jejunal pISC expansion only when administered to mice immediately after ICR. Since recent reports demonstrated increases in intestinal insulin-like growth factor (IGF)-I following GLP-2 administration, we further hypothesized that increased intestinal IGF-I expression would correlate with pISC expansion following ICR. To assess this, GLP-2 or vehicle was administered to mice either immediately after resection (early) or before tissue harvest 6 wk following ICR (late). Histological analysis quantified proliferation and intestinal morphometrics. Serum levels of GLP-2 were measured by ELISA and jejunal IGF-I mRNA by qRT-PCR. Expansion of jejunal pISC was assessed by fluorescent-activated cell sorting of side population cells, immunohistochemistry for phosphorylated beta-catenin at serine 552 (a pISC marker), percent of crypt fission, and total numbers of crypts per jejunal circumference. We found that early but not late GLP-2 treatment after ICR significantly augmented pISC expansion. Increases in jejunal IGF-I mRNA correlated temporally with early pISC expansion and effects of GLP-2. Early GLP-2 increased crypt fission and accelerated adaptive increases in crypt number and intestinal caliber. GLP-2 increased proliferation and intestinal morphometrics in all groups. This study shows that, in mice, GLP-2 promotes jejunal pISC expansion only in the period immediately following ICR. This is associated with increased IGF-I and accelerated adaptive increases in mucosal mass. These data provide clinical rationale relevant to the optimal timing of GLP-2 in patients with intestinal failure.
Available from: Jason R Spence
- "The length of remaining healthy tissue is a key determinant of patient outcomes in SBS. After surgery, the intestine adapts and increases in circumference and length in an attempt to compensate for the loss of tissue (Dekaney et al., 2007; Garrison et al., 2009; McDuffie et al., 2011; Seetharam and Rodrigues, 2011). Surgical lengthening procedures have been explored to exploit this phenomenon but result in far less than a 2-fold increase in length (Chang et al., 2006; Khalil et al., 2012; Oliveira et al., 2012; Scott et al., 2015). "
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ABSTRACT: Short bowel syndrome (SBS) is characterized by poor nutrient absorption due to a deficit of healthy intestine. Current treatment practices rely on providing supportive medical therapy with parenteral nutrition; while life saving, such interventions are not curative and are still associated with significant co-morbidities. As approaches to lengthen remaining intestinal tissue have been met with only limited success and intestinal transplants have poor survival outcomes, new approaches to treating SBS are necessary. Human intestine derived from embryonic stem cells (hESCs) or induced pluripotent stem cells (iPSCs), called human intestinal organoids (HIOs), have the potential to offer a personalized and scalable source of intestine for regenerative therapies. However, given that HIOs are small three-dimensional structures grown in vitro, methods to generate usable HIO-derived constructs are needed. We investigated the ability of hESCs or HIOs to populate acellular porcine intestinal matrices and artificial polyglycolic/poly L lactic acid (PGA/PLLA) scaffolds, and examined the ability of matrix/scaffolds to thrive when transplanted in vivo. Our results demonstrate that the acellular matrix alone is not sufficient to instruct hESC differentiation towards an endodermal or intestinal fate. We observed that while HIOs reseed acellular porcine matrices in vitro, the HIO-reseeded matrices do not thrive when transplanted in vivo. In contrast, HIO-seeded PGA/PLLA scaffolds thrive in vivo and develop into tissue that looks nearly identical to adult human intestinal tissue. Our results suggest that HIO-seeded PGA/PLLA scaffolds are a promising avenue for developing the mucosal component of tissue engineered human small intestine, which need to be explored further to develop them into fully functional tissue.
Biology Open 10/2015; DOI:10.1242/bio.013235 · 2.42 Impact Factor
Available from: Maria Andrea Azcárate-Peril
- "Post-ICR samples were collected at 7, 14 and 28 days following surgery as indicated. We selected day 7 after ICR because at this time point we have previously reported that the expansion of crypts that contribute to long term adaptation is initiated along with acute changes in proliferation and crypt depth and villus height [24,27,42]. At later time points of 14 and 28 days, the acute increases in proliferation, crypt depth and villus height are decreasing whereas sustained increases in the overall number of jenunal cypts persist . "
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ABSTRACT: Ileocecal resection (ICR) is a commonly required surgical intervention in unmanageable Crohn's disease and necrotizing enterocolitis. However, the impact of ICR, and the concomitant doses of antibiotic routinely given with ICR, on the intestinal commensal microbiota has not been determined. In this study, wild-type C57BL6 mice were subjected to ICR and concomitant single intraperitoneal antibiotic injection. Intestinal lumen contents were collected from jejunum and colon at 7, 14, and 28 days after resection and compared to non-ICR controls. Samples were analyzed by16S rRNA gene pyrosequencing and quantitative PCR. The intestinal microbiota was altered by 7 days after ICR and accompanying antibiotic treatment, with decreased diversity in the colon. Phylogenetic diversity (PD) decreased from 11.8 ± 1.8 in non-ICR controls to 5.9 ± 0.5 in 7-day post-ICR samples. There were also minor effects in the jejunum where PD values decreased from 8.3 ± 0.4 to 7.5 ± 1.4. PCoA analysis indicated that bacterial populations 28 days post-ICR differed significantly from non-ICR controls. Moreover, colon and jejunum bacterial populations were remarkably similar 28 days after resection, whereas the initial communities differed markedly. Firmicutes and Bacteroidetes were the predominant phyla in jejunum and colon before ICR; however, Firmicutes became the vastly predominant phylum in jejunum and colon 28 days after ICR. Although the microbiota returned towards a homeostatic state, with re-establishment of Firmicutes as the predominant phylum, we did not detect Bacteroidetes in the colon 28 days after ICR. In the jejunum Bacteroidetes was detected at a 0.01% abundance after this time period. The changes in jejunal and colonic microbiota induced by ICR and concomitant antibiotic injection may therefore be considered as potential regulators of post-surgical adaptive growth or function, and in a setting of active IBD, potential contributors to post-surgical pathophysiology of disease recurrence.
PLoS ONE 08/2013; 8(8):e73140. DOI:10.1371/journal.pone.0073140 · 3.23 Impact Factor
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ABSTRACT: The medical management of short bowel syndrome frequently requires lifelong parenteral nutrition. Methods of increasing intestinal absorption and reducing parenteral nutrition dependence, by improving postresection intestinal adaptation, are increasingly being explored. Glucagon-like peptide-2 (GLP-2) is an important intestinotrophic growth factor and mediator of intestinal adaptation. This review summarizes our current understanding of GLP-2 physiology and provides an update on clinical trials in short bowel syndrome and related conditions.
There is growing understanding how the effects of GLP-2 are mediated by downstream effectors such as insulin-like growth factor-1. In the treatment of short bowel syndrome, GLP-2 and the long-acting GLP-2 analogue teduglutide (Gattex) are effective in improving fluid absorption. A recent multicentre, placebo-controlled study demonstrates that this can translate into meaningful reductions in parenteral nutrition requirements. Treatment dose and timing of treatment initiation might influence the mucosal growth response. Most of the small intestine has to be preserved to facilitate the previously documented benefits of GLP-2 on bone metabolism. Therapeutic uses of GLP-2 in other gastrointestinal conditions are being explored. GLP-2 treatment appears well tolerated, although concerns about the long-term use of this growth-promoting agent remain.
GLP-2 therapy holds promise as an adjuvant treatment modality for short bowel syndrome and other gastrointestinal disorders.
06/2009; 12(5):526-32. DOI:10.1097/MCO.0b013e32832d23cd
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