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Nutrient Physiology, Metabolism, and Nutrient-Nutrient Interactions

Extensive Gut Metabolism Limits the Intestinal Absorption of Excessive Supplemental Dietary Glutamate Loads in Infant Pigs^1,2

USDA/Agricultural Research Service Children's Nutrition Research Center, Department of Pediatrics, Baylor College of Medicine, Houston, TX 77030

^* To whom correspondence should be addressed. E-mail: dburrin{at}bcm.tmc.edu.

	ABSTRACT

TOP ABSTRACT Introduction Materials and Methods Results Discussion LITERATURE CITED

 
Glutamate (Glu) is a major intestinal oxidative fuel, key neurotransmitter, and may be a useful dietary supplement to augment health of the infant gut. We quantified the metabolic fate of various supplemental dietary Glu intakes in young pigs surgically implanted with vascular, intraduodenal (ID), or intragastric (IG) catheters and a portal blood flow probe. Piglets were acutely fed a range of dietary Glu intakes using a basal milk formula (100%) supplemented with varying amounts of monosodium Glu (up to 400%) via ID or IG routes. We quantified the gastrointestinal metabolic fate of dietary Glu using [U-¹³C] Glu tracer. The Glu net absorption in the basal 100% group was low in both ID and IG groups, ranging from 13 to 17% of intake. Enteral Glu supplementation significantly increased the absolute absorption rate and arterial concentration of Glu. In both the ID and IG groups, enteral [¹³C]Glu absorption was limited (<5% tracer input) at the basal Glu intake (100%) but increased nearly 4-fold (20% input) in the 300% intake group. A substantial fraction (33–50%) of the enteral [¹³C]Glu input was oxidized by the gut to ¹³CO₂ in both the 100 and 300% intake groups. We conclude that extensive gut metabolism limits the absorption of supplemental dietary Glu even at excessive intakes.

	Introduction

TOP ABSTRACT Introduction Materials and Methods Results Discussion LITERATURE CITED

The importance of Glu as a major gut oxidative fuel and key enteric neurotransmitter may have therapeutic potential for improving neonatal gut function. The premature neonatal intestine exhibits a high rate of epithelial growth and cell turnover, but poorly developed gastro-duodenal function limits the ability to provide critically important enteral nutrition (6). However, the use of Glu as an enteral supplement to augment neonatal gut function should be considered in the context of previous reports of Glu-induced neurotoxicity (7–10). Subsequent reviews have concluded that there is no evidence linking monosodium Glu to long-term serious health problems in the general population. These reviews acknowledged the evidence of neurotoxicity in several experimental models, yet this only occurred with extremely high enteral and parenteral Glu loads (11).

Therefore, the aim of the current study was to examine the capacity of the developing gut to metabolize dietary Glu loads in excess of the normal intake. We undertook the study with 2 protocols utilizing ID and IG routes. The initial study was conducted using the ID route to allow for a more uniform delivery of diet and isotopic tracer to the small intestine. We also completed an IG study to more accurately replicate the typical feeding used in neonatal infants and to evaluate the gastric mucosa as a potential area of Glu absorption and metabolism. In this article, we demonstrate that the gut has a substantial capacity to oxidize and metabolize Glu, even when presented in supraphysiologic amounts. This has implications for further clinical studies investigating the effects of dietary Glu supplementation on neonatal gut development and function.

	Materials and Methods

TOP ABSTRACT Introduction Materials and Methods Results Discussion LITERATURE CITED

 
Animals

The following studies used 3-wk-old, female, crossbred piglets (Large White x Hampshire x Duroc) obtained from the Texas Department of Criminal Justice, Huntsville, TX. The pigs arrived at the Children's Nutrition Research Center in Houston at 14 d of age and were then fed a liquid milk replacement formula (Litter Life, Merrick) at a rate of 50 g·kg^–1·d^–1 for 7 d. The formula composition (per kilogram dry matter) was 527 g lactose, 100 g fat, and 250 g protein. The study protocols were approved by the Animal Care and Use Committee of Baylor College of Medicine and were conducted in accordance with the NRC's Guide for the Care and Use of Laboratory Animals.

ID study

    Surgery. At 21 d of age, after overnight food deprivation, piglets were surgically implanted with catheters in the carotid artery, jugular vein, portal vein, and duodenum under general anesthesia, as described previously (12). Piglets also were implanted with an ultrasonic flow probe (8–10 S model; Transonics) around the portal vein. After surgery, pigs were administered i.v. fluids and nutrients for 24 h as described previously (12). Pigs were then fed liquid milk replacer formula and recovered for 7 d before starting the infusion protocols.

    Infusion protocol 1. This protocol was designed to determine the dose-dependent effect of enteral Glu intake on portal Glu and amino acid absorption. The infusion protocol was performed over 8 h. The piglets were randomly assigned to receive 1 of 3 Glu intakes comprising 250, 350, or 400% of their normal Glu intake. The normal Glu intake (100%) was 510 µmol·kg^–1·h^–1 when the liquid milk formula diet was fed alone. We studied a total of 27 piglets; all pigs received the 100% level first, followed by 1 of 3 higher treatment levels of either 250% (9 pigs), 350% (9 pigs), or 400% (9 pigs) of normal dietary intake. On d 1, pigs were food deprived overnight and received a bolus of formula (15.5 mL/kg) providing 1/12 of their daily intake. Immediately thereafter, pigs received a constant, ID infusion of 7.75 mL·kg^–1·h^–1 formula providing 510 µmol·kg^–1·h^–1 Glu and 2 mL·kg^–1·h^–1 saline for 4 h. After 4 h, the saline infusion was replaced with a monosodium Glu solution and continued for another 4 h, resulting in Glu intakes that were either 250% (510 + 800 µmol·kg^–1·h^–1), 350% (510 + 1250 µmol·kg^–1·h^–1), or 400% (510 + 1600 µmol·kg^–1·h^–1) of the Glu provided by the formula alone. Portal blood flow (PBF) was measured continuously for the entire 8-h period. Arterial and portal venous blood samples (3 mL) were collected at 2, 3, 4, 6, 7, and 8 h of infusion. We measured the hematocrit of each sample and then centrifuged 1.5 mL of each blood sample at 2000 x g for 15 min; at 4°C. The resulting plasma was stored at –80°C until amino acid analysis. After the infusion protocol, pigs resumed their normal feeding schedule and 2 d later (d 3) pigs were randomized to another Glu treatment and subjected to the same 8-h infusion protocol again.

    Infusion protocol 2. This protocol was designed to quantify the whole body flux and intestinal metabolic fate of a normal (100%) and high (350%) ID Glu load. A total of 9 pigs were assigned to either the normal or high enteral Glu group. All pigs were administered separate infusions of [U-¹³C] Glu (99% atom percent excess [APE], 90% [¹³C₅]glutamic acid; Cambridge Isotopes) via the i.v. (30 µmol·kg^–1·h^–1) and ID (150 µmol·kg^–1·h^–1) routes on 2 separate days in random order. Pigs first received an i.v. or ID priming dose of 5 µmol/kg Na¹³HCO₃ followed immediately by a primed (30 or 150 µmol/kg), continuous, i.v. (30 µmol·kg^–1·h^–1) or ID (150 µmol·kg^–1·h^–1) infusion of [U-¹³C]Glu in a volume of 0.5 mL·kg^–1·h^–1. PBF and blood samples were analyzed as in infusion protocol 1, with the additional analysis of ¹³CO₂ as described previously (12).

IG study

    Surgery. Similar to the ID study above, at 21 d of age, piglets were surgically implanted with catheters in the carotid artery, jugular vein, portal vein, and stomach, and a flow probe around the portal vein; postsurgical care and feeding was also similar.

    Infusion protocol 3. The aim of this protocol was to quantify the metabolic fate of dietary [U-¹³C]Glu fed IG at 100, 200, and 300% of the normal intake based on the intakes described above. Each pig was randomly assigned to receive 2 of 3 possible Glu intakes (100, 200, or 300%) during a 7-h infusion protocol administered on 2 separate days. At the start of the protocol, pigs were given an oral feeding of 15.5 mL/kg formula followed by a continuous, IG infusion of 7.75 mL·kg^–1·h^–1 formula for 7 h. PBF measurement began 30 min prior to oral feeding and continued throughout the entire 7-h protocol. Pigs first received a primed (5 µmol/kg), constant, i.v. infusion of sodium-[¹³C]bicarbonate (NaH¹³CO₃, 5 µmol·kg^–1·h^–1) for 2 h to estimate the whole-body CO₂ production rate. Arterial blood samples (1 mL) were collected at 90, 105, and 120 min to measure hematocrit, hemoglobin, blood gases, and ¹³CO₂ enrichment. Following the 2-h NaH¹³CO₃ infusion, pigs received a constant IG infusion of 140 µmol·kg^–1·h^–1 [U-¹³C]-Glu for the remaining 5 h of the experiment. Concurrent with the [U-¹³C]-Glu tracer infusion, pigs received an IG infusion of either 2 mL·kg^–1·h^–1 saline (9 g/L NaCl; 100% Glu group) or monosodium Glu at either 650 µmol·kg^–1·h^–1 (200% Glu group) or 1300 µmol·kg^–1·h^–1 (300% Glu group) for the remaining 5 h of the infusion protocol. A 3-mL arterial blood sample was taken before the start of the enteral feeding and tracer protocol (baseline), then we collected 3-mL arterial and portal blood samples at 5, 6, and 7 h of the [U-¹³C]-Glu infusion. From each sample, we used 1 mL of whole blood to measure hematocrit, hemoglobin, blood gases, and ¹³CO₂ enrichment; from the remainder, plasma was obtained and frozen in liquid nitrogen for further analysis. After the infusion protocol, pigs resumed their normal feeding schedule, and 2 d later (d 3), pigs were randomized to another Glu treatment and subjected to the same 7-h infusion protocol again, so that each pig was studied twice.

At the conclusion of d 2 of infusion, pigs were killed with an i.v. injection of pentobarbital sodium (50 mg/kg body weight) and sodium phenytoin (5 mg/kg; Beuthanasia-D; Schering-Plough Animal Health). The abdomen was opened and the entire small intestine distal to the ligament of Treitz, stomach, and liver were quickly removed. The small intestine was immediately flushed with ice-cold saline and tissue samples from the jejunum and ileum were snap-frozen in liquid nitrogen. Concurrently, samples from stomach, liver (left lobe), and brain (cerebrum in anterior temporal lobe and region of hypothalamus) were rapidly dissected and snap-frozen in liquid nitrogen. All tissues were transferred and stored at –80°C until further analysis.

Sample preparation and analysis

Blood gasses, hematocrit, and isotopic enrichment (IE) of ¹³CO₂ in whole blood were analyzed as previously described (12). Plasma was obtained from blood after centrifugation (3000 x g; 10 min at 4°C) and analyzed by HPLC (PicoTag System; Waters) as described previously (13); we determined tissue free amino acid concentrations similarly. The plasma and tissue free isotope enrichment of Glu were measured by GC-MS as described previously (2,13). The IE was determined by monitoring ions at mass-to-charge ratio 407 and 412 corresponding to unlabeled Glu (M+0) and [U-¹³C]Glu (M+5). For each measurement, the baseline-corrected enrichment in mole percent excess (MPE) was determined. Blood ¹³CO₂ enrichment was measured as described previously (12) using continuous flow gas isotope ratio mass spectrometer (Thermo Finnigan Gasbench-II coupled with Delta^plusXL Isotope Ratio MS).

Calculations

    Whole body [¹³C]Glu kinetics. Whole body kinetics were calculated using Glu IE during both the i.v. and ID tracer infusion protocols as described previously (2).

where whole body flux is expressed as µmol·kg^–1·h^–1 and IE_infusate is IE (MPE) of Glu infusate during i.v. or ID infusion and IE_plasma is IE (MPE) of Glu isotopomer in arterial plasma during i.v. or ID infusion. Tracer infusion rate is expressed in µmol·kg^–1·h^–1.

    Portal plasma flow. PBF as measured by the ultrasonic flow probe was converted to portal plasma flow (PPF), as the amino acid concentrations were measured in the plasma of portal and arterial blood samples. Using the hematocrit measurements (Hct), PPF was calculated as follows:

    Portal mass balance and portal tracer balance.

where conc_port and conc_art are amino acid concentrations (µmol/L) in portal and arterial plasma samples, respectively.

Isotopic enrichments of [U-¹³C]Glu were converted to tracer-to-tracee ratios (mol% of [U-¹²C]Glu) and expressed as MPE compared with the enrichment of Glu in baseline samples taken from each pig before the tracer infusion.

where MPE_port and MPE_art are [U-¹³C]Glu enrichments in portal and arterial plasma samples, respectively.

Throughout this article, a positive portal balance signifies the addition of a compound to the portal blood and a negative balance signifies the removal of the compound from the arterial input.

    Utilization. Glu utilization refers to the quantity of Glu administered enterally that was not absorbed into the portal blood but utilized by the intestine.

[U-¹³C]Glu utilization was calculated in the same manner.

    ¹³CO₂ production from [¹³C]Glu. ¹³CO₂ enrichment was expressed as APE compared with the enrichment in baseline samples taken from each pig before the tracer infusion. The ¹³CO₂ production rate by the portal-drained viscera (PDV) was calculated.

Statistical analysis

The mean kinetic measurements of whole body and PDV substrate mass and tracer balance represent mean values derived from analysis of the 3 replicate samples obtained at the end of an infusion protocol. The means for each pig were then used to calculate the mean ± SEM values in each treatment group. The statistical differences among Glu treatment groups for each infusion protocol were compared using the ANOVA general linear model and then subjected to Tukey's post hoc analysis (Minitab). Differences in arterial and portal concentrations and IE of Glu and other amino acids were tested using a 1-tailed t test. The effect of Glu treatment or intake level on mass and tracer balances were also analyzed by regression. Differences were considered significant at P < 0.05.

	Results

TOP ABSTRACT Introduction Materials and Methods Results Discussion LITERATURE CITED

 
ID study

    Infusion protocol 1. Neither the body weights nor PBF of the pigs differed among the treatment groups (Table 1). Arterial and portal Glu concentrations, the portal-arterial difference, and the net portal Glu absorption and utilization rates all increased dose dependently with increasing dietary Glu infusion. However, when expressed as a percentage of the Glu infusion rate, the fractional net portal balance did not differ among the treatment groups, ranging from 14 to 19%. Similarly, the fractional net Glu utilization did not differ and ranged from 86 to 81%.

IG study

    Infusion protocol 3. The piglet body weights were 9.2, 9.4, and 9.1 kg and the PBF were 3.3, 3.2, and 3.4 L·kg^–1·h^–1 in the 100, 200, and 300% treatment groups, respectively. Neither differed among the groups. Net portal Glu balances in the 3 treatment groups increased dose dependently (linear effect; P < 0.01) with Glu intake, increasing from 108 to 276 to 545 µmol·kg^–1·h^–1 at the 100, 200, and 300% intakes, respectively (Fig. 1); these balances all differed significantly from one another. In contrast to the results from infusion protocol 1, when expressed as a percentage of Glu intake, the net portal Glu absorption increased from 17 to 21 to 28% with increasing Glu intake (P < 0.05). The net PDV Glu utilization rate increased as well in the 3 treatment groups from 542 to 1024 to 1404 µmol·kg^–1·h^–1 (P < 0.05). Also in contrast to infusion protocol 1, the fractional PDV utilization rate decreased from 83 to 79 to 72% with increasing Glu intake (P < 0.05) (Fig. 1).

View larger version (19K): [in this window] [in a new window]   FIGURE 1  Glu net absorption and utilization in IG-fed infant pigs given 100, 200, or 300% of their enteral Glu intake (protocol 3). Bars represent means ± SEM, n = 7–8. Means without a common letter differ, P < 0.05 (Tukey's multiple comparison test).

View larger version (17K): [in this window] [in a new window]   FIGURE 2  [U-13C] Glu absorption, utilization, and 13CO2 production in IG-fed infant pigs given 100, 200, or 300% of their enteral Glu intake (protocol 3). Bars represent means ± SEM, n = 7–8. Means without a common letter differ, P < 0.05 (Tukey's multiple comparison test).

View larger version (13K): [in this window] [in a new window]   FIGURE 3  Relationships between Glu absorption and Glu intake during ID and IG Glu infusion. Relationship between net PDV Glu absorption and dietary Glu intake in pigs fed ID (protocol 1) or IG (protocol 3) routes. Each point represents the mean ± SEM, n = 6–10. Linear regression equations best described the relationship between Glu intake and portal absorption in each group and were significant, P < 0.01. They are as follows: ID Y = 0.205 x –40.9, R2 = 0.623; IG Y = 0.339 x –130, R2 = 0.822.

	Discussion

TOP ABSTRACT Introduction Materials and Methods Results Discussion LITERATURE CITED

Our results showed that, in absolute terms (i.e. µmol·kg^–1·h^–1), the net portal Glu absorption rate increased in a dose-dependent manner with increasing enteral Glu intake. In both the ID and IG infusion protocols, increasing the Glu intake to 300 or 400% resulted in an approximate 4-fold increase in net Glu absorption. The increased portal Glu absorption rates translated into higher circulating arterial Glu concentrations in both the ID and IG infusion protocols. The increased net Glu absorption after IG infusion (protocol 3) at the 200 and 300% intake levels also significantly increased arterial concentrations compared with the fasted level (P < 0.05). Despite the absolute increases in absorption, the fractional Glu absorption rates (expressed percent intake) were not (13 vs. 19%) changed when the Glu intake increased from 100 to 400%. In the IG protocol, fractional Glu absorption rates significantly increased from 17% in pigs fed the 100% Glu to 28% in pigs fed the 300% Glu (P < 0.05). Thus, in infant pigs, a majority (70–80%) of the dietary Glu is metabolized by the gut even during a 2- to 3-fold increase in intake.

We examined the metabolic fate of dietary Glu when given via both the IG and ID routes. The ID infusion protocol bypassed the stomach and allowed for a more uniform delivery of diet and isotopic tracer directly to the small intestine. However, the IG protocol more accurately replicated the typical feeding route used in neonatal infants and also enabled us to evaluate the gastric mucosa as a potential area of Glu absorption and metabolism. When comparing the 2 protocols, net portal Glu absorption rate was similar when pigs were fed the 100% intake. Yet, with increasing dietary Glu intake >100%, the net portal Glu absorption rate was higher in the IG than ID protocol. This finding implies that IG Glu infusion resulted in Glu absorption across the gastric mucosa into the portal blood. The direct evidence for amino acid transport and absorption across the gastric mucosa is limited, although several amino acid transporters are expressed in gastric epithelial cells (14,15), including some involved in Glu transport (16,17). The physiological importance of gastric Glu transport and absorption under normal and excessive dietary Glu loads warrants further study.

Consistent with our previous studies (2), we found that much of the dietary Glu metabolized by the gut was oxidized to CO₂. In pigs fed the basal glutamate intake (100%), 49% of the [¹³C]glutamate infused was oxidized to ¹³CO₂ in the ID infusion protocol and 37% was oxidized in the IG protocol. This value was 38% and 35% when the dietary Glu intake increased to 350 and 300%. This result indicates that the fractional intestinal oxidation of Glu is relatively constant despite the large increase in the dietary load. Moreover, it reveals a substantial reserve in gut oxidative capacity, because the absolute rate of [¹³C]Glu oxidation increased from 217 µmol·kg^–1·h^–1 in pigs fed 100% Glu to 608 µmol·kg^–1·h^–1 in pigs fed 300% Glu (P < 0.05). Based on our previous studies (2,5), we suspect that the remaining Glu metabolized by the gut, but not oxidized to CO₂, was converted into other nonessential amino acids, namely aspartate, glutamine, and ornithine. The arterial concentration and net portal absorption of aspartate, glutamine, and ornithine significantly increased in pigs fed the 200 and 300% Glu intake compared with the basal 100% intake (P < 0.05). The portal absorption rates of other metabolic by-products of Glu metabolism, namely proline, arginine, as well as branched-chain amino acids tended (P < 0.10) to be higher in supplemented groups, but the circulating arterial concentrations did not differ. In the 300% Glu group in protocol 3, we could account for 90% of gut Glu metabolism based on the production of CO₂, aspartate, glutamine, ornithine, and proline.

An especially interesting observation was that the net portal absorption of Glu was higher than the unidirectional absorption of [¹³C]Glu tracer. Thus, in protocol 2, the net portal Glu absorption rate in the 100% group was 86 µmol·kg^–1·h^–1, which represents 13% of the total intake (654 µmol·kg^–1·h^–1) and the rate of absorption of [¹³C]Glu tracer was 3.8 µmol·kg^–1·h^–1, which is <3% of the total infusion rate (154 µmol·kg^–1·h^–1). However, in the 350% group in protocol 1, there was a comparatively small difference between the fractional net portal Glu absorption (17%) and [¹³C]Glu tracer absorption (14%) rates. There are various possible explanations for this observation. The first possibility is that dietary Glu ingested in a free form (i.e. [¹³C]Glu) is metabolized by the gut differently than protein-bound Glu present in the milk protein of the formula. The vast majority of the Glu normally consumed is found in protein, as Glu comprises 20% of dietary protein. The lower rate of [¹³C]Glu absorption in the 100 vs. 350% group can be explained by a higher fractional rate of mucosal oxidation. We postulate that the relatively close agreement between the net tracee and tracer rates of Glu absorption at the high Glu intake is because 70% of the Glu infused was in a similar free form, which is more rapidly absorbed and readily oxidized to CO₂ (18,19). The other, more likely explanation for the discrepancy between net tracee and tracer rates of Glu absorption is due to incorporation into protein and net synthesis and release of Glu from the gut tissues. A fraction of [¹³C]Glu infused into the gut is sequestered in the first pass and incorporated into mucosal protein and would not appear in the portal blood, whereas unlabeled Glu appears in portal blood derived from endogenous synthesis and release via proteolysis. Regardless of the origin of Glu released into portal blood, it represents only a relatively small fraction (10%) of the normal intake.

Our study has shown that even when it is administered in higher than normal dietary quantities, the majority of enterally fed Glu is utilized by the gut, mainly as either an oxidative fuel by the mucosa or metabolized into other nonessential amino acids. We also showed that, at high dietary intakes, the fractional rate of Glu absorption is higher when given via the IG compared with ID route. We also found the tissue concentrations of Glu in the brain were unaffected by a demonstrable increase in both intestinal absorption and circulating concentrations of Glu in piglets given high dietary loads of Glu.

	FOOTNOTES

 
¹ Supported in part by a grant from the International Glutamate Technical Committee and by federal funds from NIH-HD33920 (D.G.B.) and the USDA-ARS under Cooperative Agreement Number 58-6250-6-001. The contents of this publication do not necessarily reflect the views or policies of the USDA, nor does mention of trade names, commercial products, or organizations imply endorsement by the U.S. Government. Michael Janeczko was supported by a NICHD Training Grant (T32 HD07445).

² Author disclosures: M. J. Janeczko, B. Stoll, X. Chang, X. Guan, and D. G. Burrin, no conflicts of interest.

³ Abbreviations used: APE, atom percent excess; ID, intraduodenal; IE, isotopic enrichment; IG, intragastric; MPE, mole percent excess; PBF, portal blood flow; PDV, portal-drained viscera; PPF, portal plasma flow.

Manuscript received 21 May 2007. Initial review completed 13 June 2007. Revision accepted 27 August 2007.

	LITERATURE CITED

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