Glutamate prevents intestinal atrophy via luminal nutrient sensing in a mouse model of total parenteral nutrition

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

SN - 0892-6638

VL - 28

SP - 2073

EP - 2087

JO - F A S E B Journal

JF - F A S E B Journal

IS - 5

ER -