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e-mail: hisayuki_uneyama＠ajinomoto.comThis Review is based on the content of Symposia 15(S15) of the 131st Annual Meeting of the PharmaceuticalSociety of Japan.

1699YAKUGAKU ZASSHI 131(12) 1699―1709 (2011) 2011 The Pharmaceutical Society of Japan

―Review―

Nutritional and Physiological Signiˆcance of Luminal Glutamate-sensingin the Gastrointestinal Functions

Hisayuki UNEYAMA

Umami Wellness Research Group, Frontier Research Laboratories, Institute for Innovation,Ajinomoto Co., Inc., 11 Suzuki-cho, Kawasaki-ku, Kawasaki 2108681, Japan

(Received August 23, 2011)

Recent evidence indicates that free amino acids are nutrients as well as acting as chemical transmitters within thegastrointestinal tract. Gut glutamate research is the most advanced among 20 amino acids. Free glutamate carries theumami taste sensation on the tongue and a visceral sensation in the gut, especially the stomach. In the ˆeld of taste physi-ology, the physiological meaning of the glutamate-derived chemical sense, the umami taste, has been proposed to be amarker of protein intake. Experimental evidence in gut glutamate physiology strongly supports this hypothesis. Freeglutamate is sensed by the abdominal vagus and regulates gastrointestinal functions such as secretion and emptying toaccelerate protein digestion. Clinical application of glutamate has also just begun to treat gastrointestinal disorders suchas dyspepsia, ulcer, dry mouth and functional dyspepsia. In this review, we introduce recent advances in gut glutamateresearch and consider the possible contribution of glutamate to health.

Key words―glutamate; umami taste; serotonin; taste receptor; gut nutrient sensing

AMINO ACID-SENSING RECEPTORS DISTRIB-UTED IN THE TASTE AND GUT ORGANS

During the past 20 years, a wide variety of aminoacid-sensing receptors have been identiˆed to distrib-ute in non-neuronal peripheral tissues beyond thebrain. For example, neuronal glutamate receptorssuch as metabotropic glutamate type 1 (mGluR1)and type 4 (mGluR4) are expressed in the taste cellson the tongue13) as well as mucosal cells in thestomach and duodenum4,5). Sweet taste receptors(T1R2/T1R3) and umami taste receptors (T1R1/T1R3) for sensing amino acids on the tongue havealso been indicated to be distributed in the intes-tine.610) The calcium-sensing receptor (CaSR),which was originally discovered as a blood calciumsensor in the kidney, can also be activated by aminoacids.11) CaSR was reported to distribute in the gas-trointestinal tract, including in the oral cavity.12)

Professor Hans Br äauner-Osborne recently reportedthat the GPRC6A receptor could act as lysine and ar-ginine sensors.13) This receptor is widely distributed inthe gut organs, but the expression of GPRC 6A ontaste tissue has not been identiˆed.

ROLE OF TASTE AND VISCERAL INFORMA-TION IN NUTRIENT HOMEOSTASIS

The abdominal vagus is extensively distributed inthe digestive tract from the esophagus to the uppergastrointestinal tract, and functions as the primaryneuroanatomical substrate in the gut-brain axis totransmit meal-related signals in the gastrointestinalmucosa to the brain, which mediates neuronal gas-trointestinal functions (e.g., food digestion, em-ptying and absorption) and conscious sensations(e.g., satiety, nausea, and discomfort)1416). Nutri-tional information from the gastrointestinal tractaŠects the regulation of food digestion and nutrientabsorption as well as eating behavior, eventually con-tributing to the formation of dietary habits. A moredetailed knowledge of the physiological signiˆcanceof the gut nutrient perception would contribute to thedevelopment of new medicines to treat medical pro-blems which have recently attracted a lot of attention,such as obesity, functional dyspepsia and irritablebowel syndrome, because these problems can also becalled ``eating habit style-related diseases.''

Several lines of evidence suggest that visceral infor-mation mediated by vagal aŠerents play an importantrole in feeding behaviors. For example, rats fed an es-sential amino acid (lysine)-deˆcient diet showed ap-petite loss, lower growth and hypersensitivity to

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Hisayuki Uneyama

Associate General Manager and Group Manager.Umami Wellness Research Group, Forntier ResearchLabs., Institute for Innovation, Ajinomoto Co., Inc.1989 Graduated from Tohoku University School ofPharmaceutical Sciences, 1989 Life Science Labs.,Central Research Labs., Ajinomoto Co. Inc. 1998Basic Research Labs., Central Research Labs.Ajinomoto Co. Inc. 2002 Chief Researcher, Institutefor Life Sciences, Ajinomoto Co. Inc. Researchˆelds: physiology of taste sense and body amino acidhomeostasis.

Fig. 1. Taste Preference and Body Nutrient ConditionA: EŠect of lysine deˆciency on taste preference in rats. Normal rats

preferred umami (glutamate) and sweet (glycine) amino acids, but lysine-deˆcient rats also preferred the bitter (lysine) amino acid. Data is quotedfrom Tabuchi et al.18) B: Relationship between protein intake and umamitaste preference. Changes in taste preference for umami taste (150 mMmonosodium glutamate; MSG), salty taste (150 mM NaCl) and sweet taste(500 mM Glycine) in rats fed with various contents of protein diets (020％). Data is quoted from Torii et al.19)

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stressors.17) In the normal diets, rats did not preferthe taste of lysine, due to its bitter taste. However,lysine-deˆcient rats showed a high preference for ly-sine solution because their palatability for it changed,due to the deˆciency (Fig. 1(A)).18) Nerve recordingstudies of taste and vagal aŠerents showed that the ly-sine sensitivity of the taste aŠerents was not changedin rats who were lysine deˆcient but the sensitivity forvagal aŠerent sensitivity for lysine was dramaticallyincreased up to one hundred times.19) These resear-chers proposed the hypothesis that lysine deˆciencychanged the vagal aŠerent sensitivity for lysine, lead-ing rats to selectively drink lysine-containing solutionvia brain coordination of taste and visceral informa-tion.

Regarding the preference for glutamate, an animalexperiment has shown that a preference for the uma-mi taste derived glutamate is somehow linked to thebody's requirement to metabolize ingested dietaryprotein (Fig. 1(B)). In this experiment, rats received

a diet containing stepwise increasing doses of puriˆedegg protein for the indicated periods, and the prefer-ences to three taste solutions (NaCl, glycine andglutamate) were determined. When the protein con-tent in diet is restricted to deˆcient levels around 05％, rats favor a salty taste (NaCl solution) and sweettaste (glycine solution) rather than the umami taste(monosodium glutamate solution). However, as theprotein content in the diet increases, the taste prefer-ence for these solutions gradually changes. Interest-ingly, at a 20％ protein diet, rats favor an umami so-lution rather than a NaCl solution or glycine solu-tion.20,21) This palatable change is explained by the re-quirement of glutamate as triggering molecules forgastric protein digestion. Thus, some lines of evidencestrongly suggest that taste and visceral amino acid gutamino acid sensing can change feeding behavior toregulate the nutrient intake and help the maintenanceof the body amino acid homeostasis.

TASTE FUNCTIONS VIA ORAL GLUTAMATESENSING

As previously described, the sense of taste is thechemical sense to intake essential nutrients, and thesense helps us to trigger oral digestion masticationwith saliva as well as to prepare the gastric and pan-creatic digestions via the cephalic phase response.22)

The sense of Umami taste occurs by the binding ofglutamate to umami taste receptors expressed on thetaste cells within taste buds on the tongue. Many can-didate receptors for umami taste receptors have re-cently been revealed, such as G-protein coupledreceptors (T1R1/T1R3 heterodimers, metabotropicglutamate 1 and 4 and their truncated receptors).23)

The sense of umami taste evokes a series of auto-nomic re‰exes related to food ingestion. First, umamitaste stimulation induces salivation, as observed inthe other four basic tastes. It was reported that thepotency in salivation of parotid glands in healthyvolunteers is in the order of sour＞umami＞salty＞sweet＞bitter.24) We studied the e‹cacy of the umami

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Fig. 2. Proˆles of Amino Acid-sensing in the Rat Abdominal VagusA: Typical vagal aŠerent response of mechanical (gastric aŠerent) and glutamate (branches of abdominal vagus) in rats. B: EŠects of 20 amino acids on the

gastric vagal aŠerents. Each amino acid aqueous solution was introduced directly into the stomach at a concentration of 150 mmol/l. Data are modiˆed from Un-eyama et al.31)

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taste for inducing human whole saliva compared tothat of the sour taste with healthy volunteers. Thesour taste stimulation evoked a transient increase insalivation, but umami taste stimulation induced long-lasting salivation of more than 10 min. Interestingly,the total amount of saliva for 10 min with the umamitaste was signiˆcantly larger than with the sour.25) Incontrast, there is no human evidence on the cephalicphase response induced by the umami taste, but it isestimated in animal experiments that the cephalicphase response with the umami taste can induce acephalic phase response to activate vagal eŠerent ac-tivities of the gastric, pancreatic and celiac branches,and increase gastric and pancreatic exocrine (gastricand pancreatic juice) and endocrine (insulin) secre-tions.26,27)

GLUTAMATE SIGNALING IN THE GUT

Since Iggo et al. for the ˆrst time measured thenerve activity of the vagal aŠerent pathway with elec-trophysiological recordings,28) a variety of nutrientssuch as glucose, amino acids and fatty acids havebeen found to activate the vagus from the gut, and achemical perception system for nutrients has been as-sumed in the gastrointestinal mucosa, the so called``gut nutrient-sensing.'' For years, scientiˆc knowl-edge about the mechanism and physiological sig-

niˆcance of gut nutrient-sensing has not been ad-vanced. However, identiˆcation of a series of aminoacid-sensing receptors expressed in the gut as well ason the tongue elucidates the contribution of thesereceptors to the gut nutrient-sensing. Given this, whatare the vagal sensing proˆles for amino acids? I wouldlike to introduce our recent research work. Niijimaˆrst reported that the injection of glutamate solutioninto the stomach, duodenum and portal vein in-creased nerve ˆrings of aŠerent ˆbers of the gastric,celiac and hepato-portal vagal branches (Fig.2(A)).29) He suggested that the chemical perceptionin those organs by the vagus may act as nutrient infor-mation to the brain. We also investigated the aminoacid sensing proˆle by the vagus in the gastrointesti-nal tract.

The results are shown in Fig. 2(B). In the duode-num, all 20 amino acids could modulate the aŠerentactivities of the celiac aŠerents. Glycine suppressedand glutamate, aspartate and tryptophan stimulatethe aŠerent activities.30) However, in the stomach,glutamate alone clearly increased the gastric aŠerentactivities.31) This strongly suggests that the intestinalmucosa has a mechanism that can recognize all the in-dividual amino acids formed during protein diges-tion, but the gastric mucosa has a unique mechanismthat can detect only free glutamate contaminated in

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Fig. 3. Neuronal Pathways of Gut Glutamate and Glucose Perceptions within Rat BrainfMRI image after intra-gastric administrations of glutamate and glucose. Almost all gastric glutamate-mediated signaling was diminished by the total

vagotomy, but gastric glucose (120 mmol/l)-mediated signaling was not aŠected by the vagotomy. The data are from Tsurugizawa et al.32)

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proteins because the gastric proteolytic enzyme can-not digest protein to each amino acid.

Using the fMRI technique, we revealed that brainnuclei linked to feeding behaviors and gut functionsare activated in response to the application of gluta-mate into the stomach.3234) Intra-gastric administra-tion of 1％ glutamate activated the brain nuclei in-cluding the dorsal vagal nucleus (DVN) and thenucleus of solitary tract (NTS), which is the outputand input of the vagal nerve, and the insula cortex in-tegrated with taste and visceral information. At thesame time, each nucleus of the hypothalamus con-veying feeding behavior and body temperature con-trol was activated. Since the brain activation wasdiminished by cutting the vagus nerve, it was con-ˆrmed that most of the brain response induced by lu-minal glutamate was carried through the vagal aŠer-ent pathway (visceral sensation). On the other hand,intra-gastric application of another nutrient, glucose,brought the activation of some brain nucleus, but theactivation was not aŠected by cutting the vagus nerve

(Fig. 3). Glucose-induced brain activation seems tobe mediated by humoral factors (gut-pancreatic hor-mones). Interestingly, the brain mechanisms for gut-nutrient sensing seem to vary depending on nutrients.We need to conduct further experiments to identifythe brain-gut communication for individual nutrients.

What is the mechanism involved in the gastricglutamate sensing by the vagus? As an example of sig-nal transduction cascade of gut amino acid-sensing,we examined gastric glutamate-sensing cascade withinmucosa, using electrophysiological and pharmacolog-ical techniques (Fig. 4).35) Vagal aŠerent activationinduced by luminal glutamate was abolished by thetreatment with type 3 serotonin receptor inhibitor,granisetron, serotonin synthesis inhibitor, and p-nitrophenylalanine (PCPA). This indicates that theglutamate response was mediated by serotonin.Moreover, the response was also abolished by thetreatment with nitric oxidase inhibitor, L-NAME. Inthe case of gastric aŠerents, a NO donor, sodiumnitroprusside, is known to activate the aŠerent ˆbers

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Fig. 4. Mechanisms of Luminal Glutamate-sensing in the Rat Gastric MucosaA: EŠect of 5-HT3 antagonist, granisetron, on the gastric vagal excitation induced by luminal glutamate. B: 5-HT Proˆles at the endings of gastric aŠerents.

Each 5-HT agonist was intravenously applied (ug/kg., i.v.). C: EŠect of mucosal 5-HT depletion on the glutamate responses. D: EŠect of nonselective NOS block-ade on the glutamate responses. Data are quoted from Uneyama et al.31)

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via the serotonin/5-HT3 cascade.36) Taking theseresults together, it is indicated that luminal glutamatestimulates the mucosal receptors (perhaps mGluRs orT1Rs), which in turn stimulates mucosal NO/5-HTsecretion couplings, and activates the 5-HT3 recep-tors at the nerve endings of gastric vagal aŠerents.However, we need further study to clarify whetherthis cascade is a common pathway in mucosal aminoacid sensing or not.

Other experiments support the possibility thatmucosal serotonin is involved in the gastric glutamatesensing.31) In Fig. 5, the serotonin content within thegastric mucosa, and the contents of serotonin and itsmetabolite, 5-hydroxy acetic acid (5-HIAA) in theportal vein after 150 mmol/l glutamate was in-troduced into the stomach are shown. The data clear-ly indicate that the mucosal serotonin was increasedbut the blood serotonin never increased. 5-HT meta-bolites were increased in the portal vein. The mucosalserotonin might be mobilized and then metabolizedwithin the mucosa to prevent the penetration of thebioactive substance, serotonin, directly into the

bloodstream. In fact, gastric mucosa is known tohave dense monoamine oxidases (MAOs).37,38)

Mucosal serotonin might be cleared by the enzyme orblood platelet uptake. Zhu et al. reported thatglucose-sensing in the duodenum also mediatedmucosal serotonin.39) To date, more than 90％ bodyserotonin is known to be localized within gastrointes-tinal mucosa, but its physiological role is unclear,despite involvement in emergency reactions such asvomiting and diarrhea. We think that the physiologi-cal role of gut mucosal serotonin is as a mediator ofgut nutrient sensing. In Fig. 6, we summarize the pos-sible mechanism involved in the gastric glutamatesensing.

PHYSIOLOGICAL SIGNIFICANCE OF GLUTA-MATE-INDUCED VISCERAL INFORMATION

We showed that gastric glutamate signaling poten-tiates gastric exocrine secretion such as gastric acid,pepsinogen and gastric juice, using Pavlov pouchdogs. In this experiment, we examined the eŠect offree glutamate on gastric acid secretion when injected

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Fig. 5. 5-HT Secretion and Metabolism within Rat Gastric MucosaA: 5-HT release within the rat gastric mucosa in response to luminal glutamate loading. 5-HT was measured by the micordialysis technique. B: Portal plasma

levels of 5-HT and 5-HAA after gastric glutamate loading. Data are quoted from Uneyama et al.36)

Fig. 6. Hypothesis of Gastric Glutamate SensingLuminal glutamate is sensed by the epithelial cells within gastric mucosa, leading to activation of the mucosal NO/5-HT cascade, and ˆnally activation of the

5-HT3 receptor at the nerve endings of gastric aŠerent ˆbers.

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directly into the main stomach of Pavlov pouchdogs.40,41) We used an enteral liquid diet (ElentalTM)

as a nutrient, which is mainly composed of a mixtureof amino acids, ˆnal nutrients digested from protein.

ElentalTM is composed of 17 amino acids (Ile, Leu,Lys, Met, Phe, Thr, Trp, Val, His, Arg, Ala, Asp,Gln, Gly, Pro, Ser, Tyr), vitamins, carbohydratesand micronutrients, and this amino acid diet com-

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Fig. 7. Gastric Secretions Induced by Luminal Glutamate in Pavlov Pouch DogsSupplementation with 10100 mmol/l monosodium glutamate enhanced gastric secretion induced by amino acid-rich diet (Elental) in Pavlov pouch dogs. Data

are quoted from Uneyama et al.41)

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pletely lacks glutamic acid in its composition. As aresult, injection of the amino acid diet (1 kcal/ml, 20ml) into the main stomach could induce slight gastricsecretion. Surprisingly, in the presence of theElentalTM diet, intra-gastric application of free gluta-mate induced powerful gastric secretion in a dose-dependent manner (Fig. 7). The intra-gastric ad-ministration of glutamate aqueous solution withoutElentalTM failed to induce the gastric acid secretion atall. Interestingly, the glutamate eŠect seemed to ap-pear speciˆcally in the amino acid diet. Moreover, thegastric eŠects of glutamate markedly decreased byabout 80％ after cutting the vagus nerve innervationsto the stomach.41) That is, it was revealed in the dogexperiments that glutamate directly acts in thestomach and helps the digestion of dietary protein inthe stomach through stimulating vagal nerve depen-dent gastric exocrine secretion.

There is evidence in humans of food digestion viagut glutamate signaling. Dr. Zai and his colleague dis-covered that the addition of free glutamate to a high

protein diet improved delayed gastric emptying andpost-ingestive abdominal unpleasantness such as aheavy stomach (Fig. 8(A)).42) With a breath test us-ing stable isotope-labeled (13C) sodium acetate, theystudied the supplemental eŠects of free glutamate to ahigh protein liquid diet (a mixture of 50％ casein cal-cium and 50％ dextrin, 1 kcal/ml, 400 kcal) and a 100％ pure dextrin diet (1 kcal/ml, 400 kcal) on the hu-man gastric emptying rate in 10 healthy adults. Theaddition of free glutamate (0.5％) to the pure 100％dextrin diet failed to increase the gastric emptyingrate, but the supplementation of free glutamate to thehigh protein diet signiˆcantly promoted the delayedgastric emptying. In the post-ingestive sensory evalua-tion study, free glutamate supplementation showedno eŠect on abdominal discomfort in young adults(between 2039 years old), but in adults more than 40years old, the post-ingestive abdominal discomfortsuch as a heavy stomach and fullness was much im-proved (Fig. 8(B)).43) This result might suggest thatthe addition of free glutamate to a protein-rich diet

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Fig. 8. EŠects of Glutamate on Human Gastric Emptying and Post-ingestive Abdominal FeelingsA: EŠects of glutamate supplementations to the protein-rich and pure dextrin liquid diets on the gastric emptying rates in healthy adult volunteers. Gastric em-

ptying rate was measured by the breath test using a stable isotope (13C labeled acetate). B: EŠect of glutamate supplementation to the protein-rich liquid diet on ab-dominal discomfort in healthy adult volunteers. Data are quoted.42,43)

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enhanced gastric secretion, improving gastric proteindigestion and accelerating the gastric emptying, lead-ing to improvement of post-ingestive abdominal un-pleasantness.

Hospitalized elderly often have advanced gastricatrophy with a decreased appetite and protein diges-tion, which cause a low-protein nutritional status witha plasma albumin level below 3.6 g/dl (proteinenergy malnutrition: PEM). Based on the resultsmeasuring the free glutamate contents of typicalhospital meals for the elderly, Toyama and Tomoereported that the free glutamate intake of thehospitalized elderly was about half that of the averageglutamate intake of healthy Japanese elderly.44)

Therefore, to conˆrm the beneˆts of free glutamateintake in the hospitalized elderly, they conducted aclinical study of glutamate fortiˆcation to hospitalmeals. They obtained evidence that free glutamatesupplementation to the daily main dish (porridge) ofabout 2.7 g/day improved elderly QOL measuressuch as the level of consciousness and some nutrition-al parameters (numbers of peripheral circulating lym-phocytes and plasma albumin levels).4446)

POSSIBLE CLINICAL APPLICATION AS ATARGET OF GUT GLUTAMATE SIGNALING

Improvement in Enteral Nutrition Somekawaet al. reported that glutamate supplementation to anenteral liquid diet could prevent diarrhea induced bytube feedings in rats (Fig. 9).47) Repetitive injection(bolus injection of 5 ml/every h) of puriˆed proteinliquid diet through a gastric tube could induce diar-rhea after 7 injections. 0.5％ free glutamate sup-plementation to this protein liquid diet could suppressthe incidence of the diarrhea after the 7th repetitiveinjection. Moreover, taking advantage of glutamateuse for a clinical diet, a clinical physician, Dr. Ohura,pointed out many beneˆts for nutritional manage-ment of enteral liquid diets containing 0.5％ monoso-dium glutamate, which can reduce the incidence of di-arrhea and gastro-esophageal re‰ux.48) To date, thephysiological importance of taste substances such asfree glutamate (umami taste) contained in naturalfoods has been ignored, since historically, enteral liq-uid diets have been developed with the ˆrst priority ofdelivering simple puriˆed nutrients to patients. Wenow believe that free glutamate supplementation toenteral liquid diets can improve the digestion, absorp-

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Fig. 9. Application of Glutamate for Improving Enteral Nutrition TherapyA: Incidence of diarrhea induced by repetitive feedings through gastric tube in the glutamate fortiˆed (G) and non-fortiˆed (C) liquid diets. B: EŠect of gluta-

mate on total incidence of diarrhea (7 h). Data are modiˆed from Somekawa et al.47)

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tion and utilization of the diets through initiatingvisceral glutamate information from the stomach tothe brain.

Dyspepsia Another report describing the possi-ble contribution of free glutamate in protein digestionwas reported from the Russian Academy of Sciencesin 1992.49) They studied the free glutamate fortiˆca-tion of hospital meals served to patients with chronicatrophic gastritis. Supplementation of about 23grams of free glutamate per day for a month marked-ly improved basal acid output (BAO) and maximalacid output (MAO) and appetite in the hospitalizedpatients

Functional Dyspepsia Functional dyspepsia(FD) was deˆned as a clinical syndrome character-ized by chronic or recurrent symptoms centered in theupper abdomen, in the absence of underlying histo-chemical disturbances.50) The symptoms complex in-cludes epi-gastric pain, bloating, postprandial full-ness, early satiety, nausea, vomiting, belching andanorexia. Recently, it was reported that postprandialsymptoms, especially postprandial fullness, is themost severe symptom in patients reporting aggrava-tion by a meal.51) There are three main possiblemechanisms related to gastric disorders52): 1) delayedgastric emptying, 2) impaired gastric accommodationto a meal, and 3) hypersensitivity to gastric disten-

tion. Delayed gastric emptying was initially consi-dered to be the main etiology of symptoms in FD.Therefore, Kusano et al. proposed the therapeuticpossibility of glutamate in the FD patients by increas-ing gastric emptying. Delayed gastric emptying is afocal point of debate about anorexia caused by dys-pepsia, and prokinetic agents are often administeredin Japan for symptom therapy.53)

Gastrointestinal Ulcer Luminal glutamate in-duced mucosal secretions. Focusing on this glutamateeŠect, Professor Takeuchi proposed the possibility ofpreventing and treating drug-induced gastrointestinalulcers. He clearly showed that glutamate-supplement-ed foods could protect non-steroid anti-in‰ammatorydrug (NSAID)-induced gastric and duodenal ulcersin rat models.54) The protective eŠects of glutamatewere observed in H. pylori infected-gastric ulcers inthe gerbil.55)

Oral care Saliva is essential for the mainte-nance of oral mucosa circumstances as well as oralfunctions such as speech, mastication, swallowingand taste sensation. Patients who visited hospitalswith complaints of oral dryness in many cases havehypo-saliva secretion.56) These patients also suŠerfrom secondary symptoms such as di‹culty speakingand swallowing, masticatory disturbance, mucosalpain and taste disorder. The patients' symptoms were

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relieved following increased salivation. Saliva alsocontains anti-bacteria, anti-viral and anti-fugal sub-stances (i.e., IgA, defensins, mucin), and tissuerecovery factors such as epidermal and transforminggrowth factors. Sever hypo-salivation after strokeand cancer radio and chemotherapy induced oralmucosa injury and bacterial outgrowth, leading tooral pain and aspiratory pneumonia. Sasano et al. at-tempted to treat dry mouth using umami taste stimu-lation instead of drug therapy (muscarine agonists),because umami taste induces long-lasting salivationfrom large salivary glands as well as minor salivaryglands.57)

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