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

ABSTRACT: 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.

SUBMITTER: Xiao W

PROVIDER: S-EPMC3986837 | biostudies-other | 2014 May

REPOSITORIES: biostudies-other

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

Xiao Weidong W Feng Yongjia Y Holst Jens J JJ Hartmann Bolette B Yang Hua H Teitelbaum Daniel H DH

FASEB journal : official publication of the Federation of American Societies for Experimental Biology 20140204 5

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)-knock ...[more]

PMID: 24497581

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Project description:Hyperglycemia is associated with poor clinical outcomes and mortality in several patients. However, studies evaluating hyperglycemia variation in tumor patients receiving total parenteral nutrition (TPN) are scarce. The aim of this study was to assess the relationship between glycemia and tumor kinds with TPN by monitoring glycemic variation in tumor patients.This retrospective clinical trial selected 312 patients with various cancer types, whose unique nutrition treatment was TPN during the monitoring period. All patients had blood glucose (BG) values assessed at least six times daily during the TPN infusion. The glycemic variation before and after TPN was set as the indicator to evaluate the factors influencing BG.The clinical trial lasted 7.5 ± 3.0 days adjusted for age, gender, family cancer history and blood types. There were six cancer types: Hepatic carcinoma (HC, 21.8%), rectal carcinoma (17.3%), colon carcinoma (CC, 14.7%), gastric carcinoma (29.8%), pancreatic carcinoma (11.5%), and duodenal carcinoma (DC, 4.8%). The patients were divided into diabetes and nondiabetes groups. No statistical differences in TPN glucose content between diabetes and nondiabetes groups were found; however, the tumor types affected by BG values were obvious. With increasing BG values, DC, HC and CC were more represented than other tumor types in this sequence in diabetic individuals, as well as in the nondiabetic group. BG was inclined to be more easily influenced in the nondiabetes group. Other factors did not impact BG values, including gender, body mass index, and TPN infusion duration time.When tumor patients are treated with TPN, BG levels should be monitored according to different types of tumors, besides differentiating diabetes or nondiabetes patients. Special BG control is needed for DC, HC and CC in both diabetic and nondiabetic patients. If BG overtly increases, positive measurements are needed to control BG values. The ClinicalTrials.gov ID is NCT02024321.

Project description:BACKGROUND:Total parenteral nutrition (TPN) provides all nutritional needs intravenously. Although lifesaving, enthusiasm is significantly tempered due to side effects of liver and gut injury, as well as lack of mechanistic understanding into drivers of TPN injury. We hypothesized that the state of luminal nutritional deprivation with TPN drives alterations in gut-systemic signaling, contributing to injury, and tested this hypothesis using our ambulatory TPN model. METHODS:A total of 16 one-week-old piglets were allocated randomly to TPN (n = 8) or enteral nutrition (EN, n = 8) for 3 weeks. Liver, gut, and serum were analyzed. All tests were two-sided, with a significance level of 0.05. RESULTS:TPN resulted in significant hyperbilirubinemia and cholestatic liver injury, p = 0.034. Hepatic inflammation (cluster of differentiation 3 (CD3) immunohistochemistry) was higher with TPN (p = 0.021). No significant differences in alanine aminotransferase (ALT) or bile ductular proliferation were noted. TPN resulted in reduction of muscularis mucosa thickness and marked gut atrophy. Median and interquartile range for gut mass was 0.46 (0.30-0.58) g/cm in EN, and 0.19 (0.11-0.29) g/cm in TPN (p = 0.024). Key gut-systemic signaling regulators, liver farnesoid X receptor (FXR; p = 0.021), liver constitutive androstane receptor (CAR; p = 0.014), gut FXR (p = 0.028), G-coupled bile acid receptor (TGR5) (p = 0.003), epidermal growth factor (EGF; p = 0.016), organic anion transporter (OAT; p = 0.028), Mitogen-activated protein kinases-1 (MAPK1) (p = 0.037), and sodium uptake transporter sodium glucose-linked transporter (SGLT-1; p = 0.010) were significantly downregulated in TPN animals, whereas liver cholesterol 7 alpha-hydroxylase (CyP7A1) was substantially higher with TPN (p = 0.011). CONCLUSION:We report significant alterations in key hepatobiliary receptors driving gut-systemic signaling in a TPN piglet model. This presents a major advancement to our understanding of TPN-associated injury and suggests opportunities for strategic targeting of the gut-systemic axis, specifically, FXR, TGR5, and EGF in developing ameliorative strategies.

Dataset Information

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

Publications

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

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