Glutamate prevents intestinal atrophy via luminal nutrient sensing in a mouse model of total parenteral nutrition
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Glutamate prevents intestinal atrophy via luminal nutrient sensing in a mouse model of total parenteral nutrition. / Xiao, Weidong; Feng, Yongjia; Holst, Jens Juul; Hartmann, Bolette; Yang, Hua; Teitelbaum, Daniel H.
In: FASEB journal : official publication of the Federation of American Societies for Experimental Biology, Vol. 28, No. 5, 05.2014, p. 2073-87.Research output: Contribution to journal › Journal article › Research › peer-review
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TY - JOUR
T1 - Glutamate prevents intestinal atrophy via luminal nutrient sensing in a mouse model of total parenteral nutrition
AU - Xiao, Weidong
AU - Feng, Yongjia
AU - Holst, Jens Juul
AU - Hartmann, Bolette
AU - Yang, Hua
AU - Teitelbaum, Daniel H
PY - 2014/5
Y1 - 2014/5
N2 - Small intestine luminal nutrient sensing may be crucial for modulating physiological functions. However, its mechanism of action is incompletely understood. We used a model of enteral nutrient deprivation, or total parenteral nutrition (TPN), resulting in intestinal mucosal atrophy and decreased epithelial barrier function (EBF). We examined how a single amino acid, glutamate (GLM), modulates intestinal epithelial cell (IEC) growth and EBF. Controls were chow-fed mice, T1 receptor-3 (T1R3)-knockout (KO) mice, and treatment with the metabotropic glutamate receptor (mGluR)-5 antagonist MTEP. TPN significantly changed the amount of T1Rs, GLM receptors, and transporters, and GLM prevented these changes. GLM significantly prevented TPN-associated intestinal atrophy (2.5-fold increase in IEC proliferation) and was dependent on up-regulation of the protein kinase pAkt, but independent of T1R3 and mGluR5 signaling. GLM led to a loss of EBF with TPN (60% increase in FITC-dextran permeability, 40% decline in transepithelial resistance); via T1R3, it protected EBF, whereas mGluR5 was associated with EBF loss. GLM led to a decline in circulating glucagon-like peptide 2 (GLP-2) during TPN. The decline was regulated by T1R3 and mGluR5, suggesting a novel negative regulator pathway for IEC proliferation not previously described. Loss of luminal nutrients with TPN administration may widely affect intestinal taste sensing. GLM has previously unrecognized actions on IEC growth and EBF. Restoring luminal sensing via GLM could be a strategy for patients on TPN.
AB - Small intestine luminal nutrient sensing may be crucial for modulating physiological functions. However, its mechanism of action is incompletely understood. We used a model of enteral nutrient deprivation, or total parenteral nutrition (TPN), resulting in intestinal mucosal atrophy and decreased epithelial barrier function (EBF). We examined how a single amino acid, glutamate (GLM), modulates intestinal epithelial cell (IEC) growth and EBF. Controls were chow-fed mice, T1 receptor-3 (T1R3)-knockout (KO) mice, and treatment with the metabotropic glutamate receptor (mGluR)-5 antagonist MTEP. TPN significantly changed the amount of T1Rs, GLM receptors, and transporters, and GLM prevented these changes. GLM significantly prevented TPN-associated intestinal atrophy (2.5-fold increase in IEC proliferation) and was dependent on up-regulation of the protein kinase pAkt, but independent of T1R3 and mGluR5 signaling. GLM led to a loss of EBF with TPN (60% increase in FITC-dextran permeability, 40% decline in transepithelial resistance); via T1R3, it protected EBF, whereas mGluR5 was associated with EBF loss. GLM led to a decline in circulating glucagon-like peptide 2 (GLP-2) during TPN. The decline was regulated by T1R3 and mGluR5, suggesting a novel negative regulator pathway for IEC proliferation not previously described. Loss of luminal nutrients with TPN administration may widely affect intestinal taste sensing. GLM has previously unrecognized actions on IEC growth and EBF. Restoring luminal sensing via GLM could be a strategy for patients on TPN.
KW - Animal Nutrition Sciences
KW - Animals
KW - Atrophy
KW - Cell Proliferation
KW - Disease Models, Animal
KW - Down-Regulation
KW - Epithelial Cells
KW - Epithelium
KW - Food
KW - Glucagon-Like Peptide 2
KW - Glutamic Acid
KW - Intestinal Mucosa
KW - Intestines
KW - Jejunum
KW - Male
KW - Mice
KW - Mice, Inbred C57BL
KW - Mice, Knockout
KW - Parenteral Nutrition, Total
KW - Permeability
KW - Piperidines
KW - Receptor, Metabotropic Glutamate 5
KW - Receptors, G-Protein-Coupled
KW - Signal Transduction
KW - Thiazoles
U2 - 10.1096/fj.13-238311
DO - 10.1096/fj.13-238311
M3 - Journal article
C2 - 24497581
VL - 28
SP - 2073
EP - 2087
JO - F A S E B Journal
JF - F A S E B Journal
SN - 0892-6638
IS - 5
ER -
ID: 117852362