Glutamate (Glu), either as one of the amino acids of protein or in free form, constitutes up to 8–10% of amino acid content in the human diet, with an intake of about 10–20 g/day in adults. In the intestine, postprandial luminal Glu concentrations can be of the order of mM and result in a high intra-mucosal Glu concentration. Glu absorbed from the intestinal lumen is for a large part metabolized by enterocytes in various pathways, including the production of energy to support intestinal motility and functions. Glu is the most important fuel for intestinal tissue, it is involved in gut protein metabolism and is the precursor of different important molecules produced within the intestinal mucosa (2-oxoglutarate, L-alanine, ornithine, arginine, proline, glutathione, γ-aminobutyric acid [GABA]). Studies in adult humans, pigs, piglets or preterm infants indicate that a large proportion of Glu is metabolized in the intestine, and that for the usual range of Glu dietary intake (bound Glu and free Glu including added Glu as a food additive in normal amounts up to 1 g/day), circulating Glu is tightly maintained at rather low concentrations. Systemic blood levels of Glu transiently rise when high doses monosodium glutamate (> 10–12 g), higher than normal human dietary consumption, are ingested and normalize within 2 h after the offset of consumption. Glu is also involved in oral and post oral nutrient chemosensing that involves gustatory nerves and both humoral and neural (vagal) gut-brain pathways with an impact on gut function and feeding behavior. Glu functions as a signaling molecule in the enteric nervous system and modulates neuroendocrine reflexes in the gastrointestinal tract. The oral taste sensation of Glu involves its binding to the oral umami taste receptors that triggers the cephalic phase response of digestion to prepare for food digestion. Glu is sensed again in the gut, inducing a visceral sensation that enhances additional gut digestive processes through the visceral sense (vago-vagal reflex).
Glutamate (Glu) is a non-essential amino acid, and the most important excitatory neurotransmitter in the central nervous system and in the periphery. In the gut, dietary Glu is extensively metabolized as a major energy substrate, plays a role in amino acid metabolism and in the disposal of dietary protein, and is the precursor of different important biologically active molecules. In the gut and other tissues Glu, including the dietary-derived fraction, also plays a role in sensory, neurotransmission, and different regulatory processes.
Origin of Dietary Glu in the Gut
Glu, either in a bound form (as one of the amino acids of protein sequences) or in a free form, constitutes up to 10% of amino acids content in the average human diet.
Glu is among the most abundant amino acids (8–10%) found in dietary proteins and as such naturally occurs in foods with high protein content (meats, seafood, stews, soups, and sauces) . Free dietary Glu, either naturally present in some products or produced by fermentation by bacteria (coryneform bacteria, lactobacilli bacteria) in fermented foods, also occurs in many foods consumed by humans (seaweeds, cheeses, fermented beans, tomatoes, mushrooms, cured ham, scallops, tuna, green peas, fish and soy sauces, beef, yeast extract, hydrolyzed vegetable proteins and autolyzed yeast extract, human and cow’s milk) [2-6]. In addition, free dietary Glu is provided as salts of sodium, potassium, calcium, or magnesium used in foods, and in particular monosodium glutamate (MSG) with the most prominent flavor enhancing capacity and umami potency is used to enhance the flavor and palatability of foods [7-11].
Total dietary Glu intake that comprises protein-associated Glu and free Glu is about 10–20 g/day in adults with different origins and dietary habits [12-14]. In the total Glu intake from various dietary sources, MSG dietary consumption represents a relatively small fraction (5–10%) . Food intake data in the USA and Europe indicate an average daily consumption of food-added MSG of 0.6 g, with a range of 0.3–1.0 g/day and an intake of about 2.0 g/day for high consumers [12, 16-18]. In East and Southeast Asian countries, MSG intakes are 2–3 times higher when compared to those reported in the USA and Europe with an intake of 1.5–3.0 g/day in Taiwan, 1.1–1.6 g/day in Japan and 1.6–2.3 g/day in South Korea [12, 13, 19]. The health impact of the consumption of free Glu salts has been addressed elsewhere .
In addition to the dietary origin, free Glu is produced by the gut microbiota (lactobacilli bacteria) in the large intestinal lumen . Moreover, both prokaryotes and eukaryotes synthesize γ-aminobutyric acid (GABA), a major inhibitory neurotransmitter of the CNS, through the decarboxylation of Glu by glutamate decarboxylase (GAD) and genes encoding GAD are present in the gut microbiota (Lactobacillus, Bifidobacterium) than can synthesize GABA from Glu in the distal intestinal lumen. Commensal Bifidobacterium dentium produce GABA via enzymatic decarboxylation of glutamate by GadB and daily oral administration of this specific Bifidobacterium strain induced the production of GABA .
Glu Metabolism in the Gut
Glu is an important nutrient in the maintenance of intestinal mucosal activity. Glu is the most important fuel for intestinal tissue, it is involved in gut protein metabolism and is the precursor of different important molecules produced within the intestinal mucosa (2-oxoglutarate, L-alanine, ornithine, arginine, proline, glutathione, GABA) . In the intestine, Glu is taken up from the lumen or is produced in the epithelium from glutamine through glutaminase activity. The gastrointestinal tract is the route for the penetration of ingested dietary Glu into the body. Intestinal mucosal tissue is exposed to a high concentration of Glu from the diet and postprandial luminal Glu concentrations can easily be in the order of millimolars, which may accordingly result in a high intramucosal Glu concentration . However, as the gastrointestinal tract has a very high capacity for using Glu, most of the luminal Glu is metabolized within the gut to other amino acids, such as alanine, or utilized as a source of energy within intestinal epithelial cells, and under the usual conditions of intake, the transfer of dietary Glu in the portal vein is low and Glu concentration in peripheral blood is low (10–50 μM) compared to other amino acids [24-26].
Glu absorbed from the intestinal lumen is for a very large part metabolized by enterocytes in various pathways, including the production of energy to support intestinal motility and functions [27-31]. After transport from the intestinal lumen across the apical membrane of the intestinal enterocyte, Glu catabolism occurs in the cytosol and mitochondria by transamination by aspartate aminotransferase, alanine aminotransferase, branched chain aminotransferase, and glutamate dehydrogenase which are expressed along the intestine [32-34]. These metabolic pathways include transamination of glutamate to alanine and aspartate, as well as the formation of other metabolites (α-ketoglutarate, γ-aminobutyrate, urea, and glutathione). Glu undergoes transamination with pyruvate generating 2-oxoglutarate oxidized in the tricarboxylic acid cycle generating malate, pyruvate, and NADH and FADH2 is used to promote ATP synthesis, and L-alanine exported through the hepatic portal vein to the liver. Glu is a major energy substrate in the gut and approximately 35% of the total energy consumption of intestinal mucosal cells is derived from dietary Glu oxidized to CO2 [27, 35-38]. Most of the glutamine (55–70%), Glu (52–64%), and aspartate (52%) are oxidized to carbon dioxide in the intestine [27, 35, 39, 40]. In the neonate, the GI tract also preferentially uses dietary glutamine and Glu as respiratory fuels and dietary Glu is almost completely oxidized in the mucosal cells of the intestine as an energy source for growth and function . One of the consequences of gut Glu metabolism is that plasma Glu levels are not strongly affected by dietary Glu and circulating Glu is tightly maintained at rather low concentrations .
Studies with adult humans, pigs, piglets or preterm infants indicate that a large proportion of Glu is metabolized in the intestine and that the usual range of Glu dietary intake (bound Glu and free Glu including added Glu as a food additive in normal amounts up to 1 g/day MSG) has a relatively small impact on Glu plasma levels. In healthy adults, about 96% of the enterally delivered L-Glu is removed by the splanchnic bed on the first pass [43, 44]. In premature human infants on enteral feeding, some 74% of Glu is removed in the first pass . In premature infants, splanchnic extraction is the major fate of dietary Glu, which is not a significant gluconeogenic substrate in these infants . These studies in premature infants and adults indicate that about 75–80% of the dietary Glu intake is metabolized in first-pass by splanchnic tissues and that a large proportion above 80% of this Glu is oxidized to CO2. Taken together, the rapid metabolism and use of Glu in the intestine explains why normal dietary consumption of MSG has no major effect on plasma Glu concentration . In young piglets fed a high-protein, milk-based formula, 95% of the dietary glutamine, Glu, and aspartate are used in vivo by the gastrointestinal tract [29, 40] and 5% of enteral Glu appeared in portal blood . In piglets, about 90% of the dietary Glu is metabolized by the gut and 50% of this fraction is converted to CO2 [28, 40].
Under usual levels of intake (1–2 g/day), the majority of ingested MSG is actively metabolized in the intestine and the concentration in blood remains low (about 10–50 μM). Only with high doses of MSG (i.e. >10–12 g), at levels higher than usual human dietary consumption, do systemic blood levels of Glu transiently rise, particularly when ingested without food or if MSG is administered by parenteral routes, and these elevated plasma levels normalize within 2 h after the offset of consumption [24, 26, 47, 48]. The concurrent consumption of sucrose, starch, gelatin, or ingesting MSG with foods, blunts for a part the plasma increase that is reduced by up to several times in relation to an increase in the gut metabolism through transamination of Glu with other metabolites [48-50]. When MSG was added at 15, 40, and 45 mg/kg (total, 100 mg/kg/day) respectively to the breakfast, lunch, and dinner meals, plasma Glu concentrations slightly but significantly increased after lunch and dinner, but the circadian variations of plasma glutamate were small (between 32 and 53 µM) and varied significantly as a function of the time of day, indicating that Glu is actively metabolized in the gut . In adult pigs, transient portal and arterial increase in Glu concentration was observed when the diet was supplemented with 10 g MSG, but the most part of MSG was metabolized in the gut . In post-weaning pigs, dietary supplementation with 4% MSG (2 g MSG/kg BW/day) results in a transient, approximately 75% increase in circulating Glu levels at 1 h after feeding but the resulting concentrations in plasma remain low . In piglets, an increase in Glu concentrations was observed in portal and arterial blood plasma when a basal milk formula, administered enterally at a rate of 510 µmol/kg/h was supplemented with high MSG level (1,250 µmol/kg/h) . In these piglets when the dietary intake is increased 3–4 fold, a main part of the dietary Glu intake is metabolized by the gut, either for the generation of ATP or for conversion into other amino acids. Apart from CO2, most of the end-products of Glu metabolism are predictably non-essential amino acids and when the dietary Glu intake is increased 3-fold, the net intestinal production of glutamine, aspartate, and ornithine increased significantly by 4.8, 4.0, and 2.7-fold, respectively . In freely moving rats, MSG at 4 g/kg (40% solution) given by gavage induced an increase in plasma Glu compared to control rats receiving a 40% sucrose solution (10 mL/kg) .
Role of Glu in Oral and Visceral Sensation and in Regulatory Processes within the Gut
Glu is involved in the oral and post oral nutrient chemosensing that involves gustatory nerves, and both humoral and neural (vagal) gut-brain pathways with an impact on gut function, feeding behavior and food preferences [56, 57].
Glutamate functions as a signaling molecule in the enteric nervous system and modulates neuroendocrine reflexes in the gastrointestinal tract [58, 59]. Multiple glutamate receptors and transporters have been found in the gastrointestinal tract, enteric nervous system, and pancreatic tissues [60-63]. Amino acid taste receptors (T1R1/T1R3) and metabotropic glutamate receptors (mGluR1/mGluR4) are candidates for the umami taste receptor in the mouth . The stomach and intestine have also specific glutamate recognizing systems in the epithelial mucosa. The primary receptor types (T1R1 + T1R3, mGluR4, and mGluR1) are found in the stomach and intestine, and both stomach and duodenal MSG can elicit mucosal responses [56, 64]. There is a large distribution and function of the major glutamate receptors along the brain gut axis . Analysis of Group III mGlu receptor expression shows the presence of mGlu 4, 6, 7, and 8 receptors not only in the brain but also along the gastrointestinal tract where they are involved in several neural function and digestive processes . L-Glu receptors are also involved in sensory and secretory functions of enteroendocrine cells of the gut where both the taste receptor (T1R1/T1R3) and metabotropic mGluR1 and 4 glutamate receptors are identified .
The taste and oral sensations of Glu include its binding to the oral umami taste receptor that participates in the signaling of the cephalic phase response of digestion, which consists of a series of autonomic reflexes, such as salivation related to food mastication and swallowing, to prepare for food digestion. Glu is sensed again in the gut, inducing a visceral sensation that enhances additional gut digestive processes through the visceral sense (vago-vagal reflex). Intragastric Glu inhibits food intake more potently than most other proteinogenic amino acids in rats . Ingestion of MSG induces gastric distension and promotes gastric emptying and greater postprandial elevations of several indispensable amino acids in plasma in humans [69, 70]. Flavor preference conditioning using intragastric MSG infusions in water-restricted rats shows a 70% preference for a conditioned stimuli flavor paired with intragastric self-infusion of 60 mM (1%) MSG over a conditioned stimuli flavor paired with intragastric water [71, 72]. Post-oral MSG sensing is not restricted to gastric sensing for the learned response as flavor preference conditioning using intragastric or intraduodenal MSG infusions in rats shows that both water-restricted and food-restricted rats acquired a significant conditioned stimuli preference for a flavor paired with intragastric or intraduodenal self-infusions of 60 mM MSG . Further evidence for post oral MSG conditioning is provided by the finding that P2X2/P2X3 knockout mice, which do not taste MSG orally, acquired a preference for a flavor mixed into a 150 mM MSG solution [73-75].
There is a vagal transmission of post oral MSG sensing. Gut vagal stimulation by gastric or intestinal Glu appears to mediate post oral MSG learning. Only MSG-induced gastric vagal afferent responses to intragastric amino acids and intragastric infusions of MSG, but not other amino acids or sodium chloride, was reported to stimulate gastric vagal afferent activity . Rats with total abdominal vagotomy, unlike those with hepatic vagotomy or sham surgery, failed to learn a preference for a conditioned flavor stimulus paired with intragastric self-infusions of 60 mM MSG but not with glucose. MSG administration induces a reflex activation of vagal gastric intestinal, hepatoportal and pancreatic nerve activity through oral, gastric, intestinal, and hepatoportal glutamate sensors .
In addition, the high Glu concentration in the intestinal microenvironment and in the microenvironment of Peyer’s patches could participate in the oral tolerance to food antigens by a tonic inhibitory effect on the intestinal naïve T cells that become hypo-responsive to several stimuli and favor Th2/Treg differentiation .
Dietary Glu has numerous roles in the intestine, being involved in energy metabolism, in the synthesis of important bioactive molecules, and in sensory and signaling pathways. It is remarkable to note that although Glu represents close to 10% of amino acid content in the average human diet and that postprandial Glu concentrations in the intestinal luminal can be in the order of millimolars, the largest proportion of ingested Glu is actively metabolized in the intestinal mucosa and under usual levels of Glu intake, Glu concentration in the peripheral blood remains low (about 10–50 μM) and transiently increase only with a high dose of Glu intake. Glu also appears as an important player in taste and oral sensations, and significant progress has been made during the last decades in the identification of Glu receptors in the gut, their signaling pathways, and their role in the control of different functions.
The author has no ethical conflicts to disclose.
The author has no conflicts of interest to disclose.
The Workshop preparation, setting, and attendance were supported by the International Glutamate Technical Committee (IGTC), Brussels. The views of the author are his own, and do not necessarily reflect those of the IGTC.