Biomarkers of human gastrointestinal tract regions

Comelli, Elena M.; Lariani, Sofiane; Zwahlen, Marie-Camille; Fotopoulos, Grigorios; Holzwarth, James A.; Cherbut, Christine; Dorta, Gian; Corthésy–Theulaz, Irène; Grigorov, Martin

doi:10.1007/s00335-009-9212-7

Cited by 43 publications

(39 citation statements)

References 51 publications

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“…SI segments were sectioned as duodenum (D), proximal jejunum (Jp), terminal jejunum (Jt), proximal ileum (Ip), and terminal ileum (It). Markers specific for duodenum (Akp3), jejunum (Sis), and ileum (Nox4, Lrp2) were measured by RT-QPCR, and the results were consistent with a previous publication (41).…”

Section: Methodssupporting

confidence: 75%

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Intestinal NCoR1, a regulator of epithelial cell maturation, controls neonatal hyperbilirubinemia

Chen

Lü

Yueh

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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Severe neonatal hyperbilirubinemia (SNH) and the onset of bilirubin encephalopathy and kernicterus result in part from delayed expression of UDP-glucuronosyltransferase 1A1 (UGT1A1) and the inability to metabolize bilirubin. Although there is a good understanding of the early events after birth that lead to the rapid increase in serum bilirubin, the events that control delayed expression of UGT1A1 during development remain a mystery. HumanizedUGT1(hUGT1) mice develop SNH spontaneously, which is linked to repression of both liver and intestinal UGT1A1. In this study, we report that deletion of intestinal nuclear receptor corepressor 1 (NCoR1) completely diminishes hyperbilirubinemia inhUGT1neonates because of intestinalUGT1A1gene derepression. Transcriptomic studies and immunohistochemistry analysis demonstrate that NCoR1 plays a major role in repressing developmental maturation of the intestines. Derepression is marked by accelerated metabolic and oxidative phosphorylation, drug metabolism, fatty acid metabolism, and intestinal maturation, events that are controlled predominantly by H3K27 acetylation. The control of NCoR1 function and derepression is linked to IKKβ function, as validated inhUGT1mice with targeted deletion of intestinal IKKβ. Physiological events during neonatal development that target activation of an IKKβ/NCoR1 loop in intestinal epithelial cells lead to derepression of genes involved in intestinal maturation and bilirubin detoxification. These findings provide a mechanism of NCoR1 in intestinal homeostasis during development and provide a key link to those events that control developmental repression of UGT1A1 and hyperbilirubinemia.

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Section: Methodssupporting

confidence: 75%

“…6C). Upregulation of other maturation markers in ΔIEC UN , including the duodenal-specific Akp3 gene and jejunal-specific Krt20 gene (38)(39)(40)(41), further supports the occurrence of cell maturation in the absence of NCoR1 (Fig. 6C).…”

Section: Developmental Stage-dependent Derepression Of Ugt1a1 Expressionmentioning

confidence: 73%

Intestinal NCoR1, a regulator of epithelial cell maturation, controls neonatal hyperbilirubinemia

Chen

Lü

Yueh

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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“…SLC26A2 mRNA levels are increased severalfold in Crohn's disease and unchanged or strongly decreased in ulcerative colitis (9,43). SLC26A2 and SLC6A14 mRNA levels used as part of a seven gene panel yielded rates of correct prediction, sensitivity, and specificity higher than with previously available diagnostic indices (43).…”

Section: Discussionmentioning

confidence: 96%

Regulated transport of sulfate and oxalate by SLC26A2/DTDST

Heneghan

Akhavein²,

Salas³

et al. 2010

American Journal of Physiology-Cell Physiology

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Nephrolithiasis in the Slc26a6(-/-) mouse is accompanied by 50-75% reduction in intestinal oxalate secretion with unchanged intestinal oxalate absorption. The molecular identities of enterocyte pathways for oxalate absorption and for Slc26a6-independent oxalate secretion remain undefined. The reported intestinal expression of SO(4)(2-) transporter SLC26A2 prompted us to characterize transport of oxalate and other anions by human SLC26A2 and mouse Slc26a2 expressed in Xenopus oocytes. We found that hSLC26A2-mediated [(14)C]oxalate uptake (K(1/2) of 0.65 +/- 0.08 mM) was cis-inhibited by external SO(4)(2-) (K(1/2) of 3.1 mM). hSLC26A2-mediated bidirectional oxalate/SO(4)(2-) exchange exhibited extracellular SO(4)(2-) K(1/2) of 1.58 +/- 0.44 mM for exchange with intracellular [(14)C]oxalate, and extracellular oxalate K(1/2) of 0.14 +/- 0.11 mM for exchange with intracellular (35)SO(4)(2-). Influx rates and K(1/2) values for mSlc26a2 were similar. hSLC26A2-mediated oxalate/Cl(-) exchange and bidirectional SO(4)(2-)/Cl(-) exchange were not detectably electrogenic. Both SLC26A2 orthologs exhibited nonsaturable extracellular Cl(-) dependence for efflux of intracellular [(14)C]oxalate, (35)SO(4)(2-), or (36)Cl(-). Rate constants for (36)Cl(-) efflux into extracellular Cl(-), SO(4)(2-), and oxalate were uniformly 10-fold lower than for oppositely directed exchange. Acidic extracellular pH (pH(o)) inhibited all modes of hSLC26A2-mediated anion exchange. In contrast, acidic intracellular pH (pH(i)) selectively activated exchange of extracellular Cl(-) for intracellular (35)SO(4)(2-) but not for intracellular (36)Cl(-) or [(14)C]oxalate. Protein kinase C inhibited hSLC26A2 by reducing its surface abundance. Diastrophic dysplasia mutants R279W and A386V of hSLC26A2 exhibited similar reductions in uptake of both (35)SO(4)(2-) and [(14)C]oxalate. A386V surface abundance was reduced, but R279W surface abundance was at wild-type levels.

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“…In addition to differentiation along the crypt-villus axis, there are also structural differences along the length of the intestine, such as cell type distribution and expression of proteins with specialized functions [4][5][6]. These differences correlate with the functionality of the different regions of the intestine and are referred to as regional or spatial differences along the cephalocaudal axis.…”

Section: Introductionmentioning

confidence: 99%

Adult Stem Cells in the Small Intestine Are Intrinsically Programmed with Their Location‐Specific Function

et al. 2014

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Differentiation and specialization of epithelial cells in the small intestine are regulated in two ways. First, there is differentiation along the crypt-villus axis of the intestinal stem cells into absorptive enterocytes, Paneth, goblet, tuft, enteroendocrine, or M cells, which is mainly regulated by WNT. Second, there is specialization along the cephalocaudal axis with different absorptive and digestive functions in duodenum, jejunum, and ileum that is controlled by several transcription factors such as GATA4. However, so far it is unknown whether locationspecific functional properties are intrinsically programmed within stem cells or if continuous signaling from mesenchymal cells is necessary to maintain the location-specific identity of the small intestine. Using the pure epithelial organoid technique, we show that region-specific gene expression profiles are conserved throughout long-term cultures of both mouse and human intestinal stem cells and correlated with differential Gata4 expression. Furthermore, the human organoid culture system demonstrates that Gata4-regulated gene expression is only allowed in absence of WNT signaling. These data show that location-specific function is intrinsically programmed in the adult stem cells of the small intestine and that their differentiation fate is independent of location-specific extracellular signals. In light of the potential future clinical application of small intestine-derived organoids, our data imply that it is important to generate GATA4-positive and GATA4-negative cultures to regenerate all essential functions of the small intestine.

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Biomarkers of human gastrointestinal tract regions

Cited by 43 publications

References 51 publications

Intestinal NCoR1, a regulator of epithelial cell maturation, controls neonatal hyperbilirubinemia

Intestinal NCoR1, a regulator of epithelial cell maturation, controls neonatal hyperbilirubinemia

Regulated transport of sulfate and oxalate by SLC26A2/DTDST

Adult Stem Cells in the Small Intestine Are Intrinsically Programmed with Their Location‐Specific Function

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