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Involvement of the enteroendocrine system in intestinal obstruction.

ABSTRACT: Intestinal atresia, a rare congenital condition, is often associated with intestinal motility disorders despite adequate neonatal surgery. Previous studies have focused on changes in the enteric nervous system (ENS). We hypothesized that other components of the digestive tract could be involved in this condition.In a rat model of surgically-induced intestinal obstruction, a transcriptome analysis was performed to measure the global gene expression. Then, analyzes were focused on genes expressed in ENS and neuroendocrine cells. Rat fetus small intestines at different developmental stages (ED15, ED17, ED19 and ED21, (n = 22)) were studied as controls and compared to the upper and lower segments of small intestines from rat fetuses with surgically-induced obstruction (n = 14; ligature at ED18). The gene expression pattern was confirmed by immunohistochemistry, electron microscopy and RT-qPCR.From ED15 to ED21, there was a physiological decrease in the gene expression of ENS markers and an increase in that of neuroendocrine genes. Regarding operated embryos, the changes in global gene expression were significantly higher in the proximal segment compared to the distal segment (18% vs. 9%). More precisely, a decrease in ENS gene expression and an increase in neuroendocrine gene expression were observed in the proximal segment compared to controls, indicating an accelerated maturation pattern. Immunohistochemistry and electron microscopy confirmed these findings.Fetal intestinal obstruction seems to induce an accelerated maturation in the proximal segment. Moreover, neuroendocrine cells undergo significant unexpected changes, suggesting that ENS changes could be associated with other changes to induce intestinal motility disorders.

SUBMITTER: Ballouhey Q

PROVIDER: S-EPMC5665489 | biostudies-literature | 2017

REPOSITORIES: biostudies-literature

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Involvement of the enteroendocrine system in intestinal obstruction.

Ballouhey Quentin Q Richard Laurence L Fourcade Laurent L Ben Rhaiem Ines I Vallat Jean Michel JM Sturtz Franck F Bourthoumieu Sylvie S

PloS one 20171101 11

<h4>Introduction</h4>Intestinal atresia, a rare congenital condition, is often associated with intestinal motility disorders despite adequate neonatal surgery. Previous studies have focused on changes in the enteric nervous system (ENS). We hypothesized that other components of the digestive tract could be involved in this condition.<h4>Material and methods</h4>In a rat model of surgically-induced intestinal obstruction, a transcriptome analysis was performed to measure the global gene expressio ...[more]

PMID: 29091949

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Project description:ObjectiveGlucagon-like peptide-2 (GLP-2) is co-secreted with GLP-1 from gut endocrine cells, and both peptides act as growth factors to expand the surface area of the mucosal epithelium. Notably, GLP-2 also enhances glucose and lipid transport in enterocytes; however, its actions on control of amino acid (AA) transport remain unclear. Here we examined the mechanisms linking gain and loss of GLP-2 receptor (GLP-2R) signaling to control of intestinal amino acid absorption in mice.MethodsAbsorption, transport, and clearance of essential AAs, specifically lysine, were measured in vivo by Liquid Chromatography triple quadrupole Mass Spectrometry (LC-MS/MS) and ex vivo with Ussing chambers using intestinal preparations from Glp2r+/+ and Glp2r-/- mice. Immunoblotting determined jejunal levels of protein components of signaling pathways (PI3K-AKT, and mTORC1-pS6-p4E-BP1) following administration of GLP-2, protein gavage, and rapamycin to fasted Glp2r+/+ and Glp2r-/- mice. Expression of AA transporters from full thickness jejunum and 4F2hc from brush border membrane vesicles (BBMVs) was measured by real-time PCR and immunoblotting, respectively.ResultsAcute administration of GLP-2 increased basal AA absorption in vivo and augmented basal lysine transport ex vivo. GLP-2-stimulated lysine transport was attenuated by co-incubation with wortmannin, rapamycin, or tetrodotoxin ex vivo. Phosphorylation of mTORC1 effector proteins S6 and 4E-BP1 was significantly increased in wild-type mice in response to GLP-2 alone, or when co-administered with protein gavage, and abolished following oral gavage of rapamycin. In contrast, activation of GLP-1R signaling did not enhance S6 phosphorylation. Disruption of GLP-2 action in Glp2r-/- mice reduced lysine transport ex vivo and attenuated the phosphorylation of S6 and 4E-BP1 in response to oral protein. Moreover, the expression of cationic AA transporter slc7a9 in response to refeeding, and the abundance of 4F2hc in BBMVs following protein gavage, was significantly attenuated in Glp2r-/- mice.ConclusionsThese findings reveal an important role for GLP-2R signaling in the physiological and pharmacological control of enteral amino acid sensing and assimilation, defining an enteroendocrine cell-enterocyte axis for optimal energy absorption.

Project description:BACKGROUND & AIMS:The intestinal epithelium is maintained by intestinal stem cells (ISCs), which produce postmitotic absorptive and secretory epithelial cells. Initial fate specification toward enteroendocrine, goblet, and Paneth cell lineages requires the transcription factor Atoh1, which regulates differentiation of the secretory cell lineage. However, less is known about the origin of tuft cells, which participate in type II immune responses to parasite infections and appear to differentiate independently of Atoh1. We investigated the role of Sox4 in ISC differentiation. METHODS:We performed experiments in mice with intestinal epithelial-specific disruption of Sox4 (Sox4fl/fl:vilCre; SOX4 conditional knockout [cKO]) and mice without disruption of Sox4 (control mice). Crypt- and single-cell-derived organoids were used in assays to measure proliferation and ISC potency. Lineage allocation and gene expression changes were studied by immunofluorescence, real-time quantitative polymerase chain reaction, and RNA-seq analyses. Intestinal organoids were incubated with the type 2 cytokine interleukin 13 and gene expression was analyzed. Mice were infected with the helminth Nippostrongylus brasiliensis and intestinal tissues were collected 7 days later for analysis. Intestinal tissues collected from mice that express green fluorescent protein regulated by the Atoh1 promoter (Atoh1GFP mice) and single-cell RNA-seq analysis were used to identify cells that coexpress Sox4 and Atoh1. We generated SOX4-inducible intestinal organoids derived from Atoh1fl/fl:vilCreER (ATOH1 inducible knockout) mice and assessed differentiation. RESULTS:Sox4cKO mice had impaired ISC function and secretory differentiation, resulting in decreased numbers of tuft and enteroendocrine cells. In control mice, numbers of SOX4+ cells increased significantly after helminth infection, coincident with tuft cell hyperplasia. Sox4 was activated by interleukin 13 in control organoids; SOX4cKO mice had impaired tuft cell hyperplasia and parasite clearance after infection with helminths. In single-cell RNA-seq analysis, Sox4+/Atoh1- cells were enriched for ISC, progenitor, and tuft cell genes; 12.5% of Sox4-expressing cells coexpressed Atoh1 and were enriched for enteroendocrine genes. In organoids, overexpression of Sox4 was sufficient to induce differentiation of tuft and enteroendocrine cells-even in the absence of Atoh1. CONCLUSIONS:We found Sox4 promoted tuft and enteroendocrine cell lineage allocation independently of Atoh1. These results challenge the longstanding model in which Atoh1 is the sole regulator of secretory differentiation in the intestine and are relevant for understanding epithelial responses to parasitic infection.

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Involvement of the enteroendocrine system in intestinal obstruction.

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Involvement of the enteroendocrine system in intestinal obstruction.

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