Intestinal adaptation after small bowel resection in human infants

McDuffie, Lucas A.; Bucher, Brian T.; Erwin, Christopher R.; Wakeman, Derek; White, Francis; Warner, Brad W.

doi:10.1016/j.jpedsurg.2011.03.027

Cited by 64 publications

(48 citation statements)

References 13 publications

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“…Finally, it is possible that the enterocytes in the p38-IKO mice are less mature, but compensated by the expanded mucosal surface area. Our laboratory has recently demonstrated adaptive mucosal growth in human infants (30). This observation validates the use of our animal model for understanding the regulation of structural features of adaptation after intestinal resection.…”

Section: Discussionsupporting

confidence: 76%

p38 MAPK regulates Bax activity and apoptosis in enterocytes at baseline and after intestinal resection

Wakeman

Guo

Santos

et al. 2012

American Journal of Physiology-Gastrointestinal and Liver Physi

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Increased apoptosis in crypt enterocytes is a key feature of intestinal adaptation following massive small bowel resection (SBR). Expression of the proapoptotic factor Bax has been shown to be required for resection-induced apoptosis. It has also been demonstrated that p38-α MAPK (p38) is necessary for Bax activation and apoptosis in vitro. The present studies were designed to test the hypothesis that p38 is a key regulator of Bax activation during adaptation after SBR in vivo. Enterocyte expression of p38 was deleted by tamoxifen administration to activate villin-Cre in adult mice with a floxed Mapk14 (p38-α) gene. Proximal 50% SBR or sham operations were performed on wild-type (WT) and p38 intestinal knockout (p38-IKO) mice under isoflurane anesthesia. Mice were killed 3 or 7 days after operation, and adaptation was analyzed by measuring intestinal morphology, proliferation, and apoptosis. Bax activity was quantified by immunoprecipitation, followed by Western blotting. After SBR, p38-IKO mice had deeper crypts, longer villi, and accelerated proliferation compared with WT controls. Rates of crypt apoptosis were significantly lower in p38-IKO mice, both at baseline and after SBR. Levels of activated Bax were twofold higher in WT mice after SBR relative to sham. In contrast, activated Bax levels were reduced by 67% in mice after p38 MAPK deletion. Deleted p38 expression within the intestinal epithelium leads to enhanced adaptation and reduced levels of enterocyte apoptosis after massive intestinal resection. p38-regulated Bax activation appears to be an important mechanism underlying resection-induced apoptosis.

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Section: Discussionsupporting

confidence: 76%

p38 MAPK regulates Bax activity and apoptosis in enterocytes at baseline and after intestinal resection

Wakeman

Guo

Santos

et al. 2012

American Journal of Physiology-Gastrointestinal and Liver Physi

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“…We, and others have consistently measured increases in villus height and crypt depth in the adaptive state [7, 24]. Individual growth factors have been investigated in SBS models, with conflicting results.…”

Section: Discussionmentioning

confidence: 99%

Short bowel syndrome results in increased gene expression associated with proliferation, inflammation, bile acid synthesis and immune system activation: RNA sequencing a zebrafish SBS model

et al. 2017

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BackgroundMuch of the morbidity associated with short bowel syndrome (SBS) is attributed to effects of decreased enteral nutrition and administration of total parenteral nutrition (TPN). We hypothesized that acute SBS alone has significant effects on gene expression beyond epithelial proliferation, and tested this in a zebrafish SBS model.MethodsIn a model of SBS in zebrafish (laparotomy, proximal stoma, distal ligation, n = 29) or sham (laparotomy alone, n = 28) surgery, RNA-Seq was performed after 2 weeks. The proximal intestine was harvested and RNA isolated. The three samples from each group with the highest amount of RNA were spiked with external RNA controls consortium (ERCC) controls, sequenced and aligned to reference genome with gene ontology (GO) enrichment analysis performed. Gene expression of ctnnb1, ccnb1, ccnd1, cyp7a1a, dkk3, ifng1-2, igf2a, il1b, lef1, nos2b, saa1, stat3, tnfa and wnt5a were confirmed to be elevated in SBS by RT-qPCR.ResultsRNA-seq analysis identified 1346 significantly upregulated genes and 678 significantly downregulated genes in SBS zebrafish intestine compared to sham with Ingenuity analysis. The upregulated genes were involved in cell proliferation, acute phase response signaling, innate and adaptive immunity, bile acid regulation, production of nitric oxide and reactive oxygen species, cellular barrier and coagulation. The downregulated genes were involved in folate synthesis, gluconeogenesis, glycogenolysis, fatty-acid oxidation and activation and drug and steroid metabolism. RT-qPCR confirmed gene expression differences from RNA-Sequencing.ConclusionChanges of gene expression after 2 weeks of SBS indicate complex and extensive alterations of multiple pathways, some previously implicated as effects of TPN. The systemic sequelae of SBS alone are significant and indicate multiple targets for investigating future therapies.Electronic supplementary materialThe online version of this article (doi:10.1186/s12864-016-3433-4) contains supplementary material, which is available to authorized users.

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“…In animal models, adaptation is characterized by taller villi, deeper crypts, increased bowel diameter and length, and increased proliferation and apoptosis in the remaining bowel 1, 2, 3, 4, 5. However, these changes have been inconsistently found in human intestine after resection 6, 7, 8, 9. Further investigation is necessary to understand regulatory mechanisms that direct adaptation in human intestine.…”

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confidence: 99%

Prolonged Absence of Mechanoluminal Stimulation in Human Intestine Alters the Transcriptome and Intestinal Stem Cell Niche

Wieck

Schlieve

Thornton

et al. 2017

Cellular and Molecular Gastroenterology and Hepatology

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Background & AimsFor patients with short-bowel syndrome, intestinal adaptation is required to achieve enteral independence. Although adaptation has been studied extensively in animal models, little is known about this process in human intestine. We hypothesized that analysis of matched specimens with and without luminal flow could identify new potential therapeutic pathways.MethodsFifteen paired human ileum samples were collected from children aged 2–20 months during ileostomy-reversal surgery after short-segment intestinal resection and diversion. The segment exposed to enteral feeding was denoted as fed, and the diverted segment was labeled as unfed. Morphometrics and cell differentiation were compared histologically. RNA Sequencing and Gene Ontology Enrichment Analysis identified over-represented and under-represented pathways. Immunofluorescence staining and Western blot evaluated proteins of interest. Paired data were compared with 1-tailed Wilcoxon rank-sum tests with a P value less than .05 considered significant.ResultsUnfed ileum contained shorter villi, shallower crypts, and fewer Paneth cells. Genes up-regulated by the absence of mechanoluminal stimulation were involved in digestion, metabolism, and transport. Messenger RNA expression of LGR5 was significantly higher in unfed intestine, accompanied by increased levels of phosphorylated signal transducer and activator of transcription 3 protein, and CCND1 and C-MYC messenger RNA. However, decreased proliferation and fewer LGR5+, OLFM4+, and SOX9+ intestinal stem cells (ISCs) were observed in unfed ileum.ConclusionsEven with sufficient systemic caloric intake, human ileum responds to the chronic absence of mechanoluminal stimulation by up-regulating brush-border enzymes, transporters, structural genes, and ISC genes LGR5 and ASCL2. These data suggest that unfed intestine is primed to replenish the ISC population upon re-introduction of enteral feeding. Therefore, the elucidation of pathways involved in these processes may provide therapeutic targets for patients with intestinal failure. RNA sequencing data are available at Gene Expression Omnibus series GSE82147.

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Intestinal adaptation after small bowel resection in human infants

Cited by 64 publications

References 13 publications

p38 MAPK regulates Bax activity and apoptosis in enterocytes at baseline and after intestinal resection

p38 MAPK regulates Bax activity and apoptosis in enterocytes at baseline and after intestinal resection

Short bowel syndrome results in increased gene expression associated with proliferation, inflammation, bile acid synthesis and immune system activation: RNA sequencing a zebrafish SBS model

Prolonged Absence of Mechanoluminal Stimulation in Human Intestine Alters the Transcriptome and Intestinal Stem Cell Niche

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