PHYSIOLOGY OF TASTE
Eating is a pleasure and a need. In nature, gratified needs generate pleasure because they persuade us to meet those needs, whereas anything that can harm us causes pain and aversion. In the case of food, the first aspect we feel is the complex sensations generated by the “good flavor” of a certain food that we like and we therefore introduce into our organism, whereas aversion lies in the “bad flavor” of another food that we have tasted but do not like, and which we therefore refuse to eat. The introduction of food is an important issue that it is subject to intense regulation by brain homeostatic and hedonic systems (1).
What is included in the word “flavor” is the result of a combination of connected sensations that food induces and which we can divide schematically into physical sensations (temperature, consistency, humidity, friction), chemical sensations (taste and smell), and chemesthetic sensations. Each of these sensations is detected by specific receptors, complex molecules, or families of molecules, that act as biological sensors, whose function lies at the base of the system of chemical communications that coordinates the functions of all of the cell groups that we are made of. The sensations also generate and transmit to us a representation of the external world that we live in through our senses: physical properties (hearing, sight, touch) and chemical composition (taste and smell).
The mechanism of action of substances able to elicit gustatory sensations (tastants) has been under investigation for several years. The efforts from so many studies were rewarded significantly at the beginning of the 2000s, when the sequence of the genome became available. This allowed the identification, and subsequently cloning, of the genes that code for taste receptors (Fig. 1). There are 2 types of transmembrane receptors that are important for taste, which differ in the way the signal is transmitted inside the cell and translated into a nervous stimulus: the G protein–coupled receptors and the ionic channels. The first taste-specific receptors to be identified were those of bitterness in 2000 (2–4), consisting of a family of about 30 G protein–coupled receptors called T2Rs (taste receptor 2), followed by those of sweetness and umami in 2001 (5–10). The sweet taste receptor is formed by 2 proteins (T1R2 and T1R3), which are able to respond to all of the sweet substances for which the receptor has been tested when they form a dimer, whereas the umami receptor is formed by the dimer T1R1 and T1R3. Ionic channels include the receptor for salty taste (sensitive to the Na+ ion) and the receptor for sour taste (sensitive to the H+ ion). In the case of saltiness, several possible receptors were suggested, but the identity of the salty receptor is still speculative and controversial (11–13). The situation for sour taste was no less complex, but recent studies have limited the search, indicating an ionic channel of the transient receptor potential type as a possible receptor for sourness (14–16).
The generation of the signal triggered by tastants is followed by transmission to the brain and by its translation into an hedonic response in the brain (17,18).
DEVELOPMENT OF TASTE IN CHILDREN
Taste qualities (the “basic tastes”) are sweet, sour, bitter, salty, and umami. The term umami comes from a Japanese word, “umai,” which means delicious, and it is the taste elicited by the amino acid L-glutamate (and L-aspartate) that can be drastically enhanced by 5′ ribonucleotides (19). Tastes are genetically determined but develop in infants over time. The ability to detect sweet tastes occurs before birth. Preterm infants exhibited more non-nutritive sucking when offered a glucose solution compared with plain water (20). Within days of birth, infants can detect dilute sweet solutions and differentiate different sugars. They prefer extremely sweet sugars such as sucrose and fructose to mildly sweet tastes such as glucose and lactose (21). Sour is recognized at birth and can be demonstrated by lip pursing and facial grimaces (22). The ability to detect salt develops during postnatal life. There is no facial response to a salty taste until approximately 4 months of age (23). When moderate concentrations of urea were offered to newborns to test for a bitter taste, these hours-old infants did not reject the taste; however, when the concentration was increased, grimaces followed exposure to quinine and urea (24). Older infants (14–180 days) rejected even low concentrations of urea. This may explain why older infants reject bitter-tasting foods such as some green vegetables. These foods would need to be introduced again and again so that they may be eventually tolerated and even enjoyed. Neonates responded positively to umami when given soup made with monosodium glutamate as compared with soup made without monosodium glutamate (25). By term, the fetus is swallowing amniotic fluid and has been exposed to glucose, amino acids, lactic acids, and salts. The fact that amniotic fluid can acquire the odor of a spicy meal the mother ingested before giving birth suggests that odorous compounds can be passed through the amniotic fluid and give the fetus experience with those sensations (26). Infants seem to detect and retain information about the chemical characteristics of their environment. Days-old infants will spend more time orienting near a breast pad worn by their mother compared with one worn by an unfamiliar lactating woman (27). Older infants are able to respond differently to scented and unscented objects, conditioned to the previous experience with that odor. Human milk is rich in flavors according to the foods and spices eaten by the mother. Breast-fed infants learn the flavor of the foods of their culture long before solids are introduced. Infants feed more and longer when milk is flavored with either garlic or vanilla. Formula-fed infants also responded by increasing their intake when vanilla was added to the formula. Infants are not passive receptacles for flavored foods. They cannot be expected to develop a sweet tooth or a preference for salty foods through manipulation of their diets. They will avidly accept some flavors and reject others.
CHEMOSENSATION IN THE GUT: WHERE, HOW, WHY?
Gut Sense of Taste
Molecular sensing of luminal content of the gastrointestinal (GI) tract plays a critical role in the control of basic functions related to the digestion of nutrients, such as absorption, motility, and secretory activity of GI glands. Detection of chemical compounds of luminal content is also critical to inducing protective responses to toxic substances, such as vomiting and food aversive behavior.
Although a role for the GI mucosa in molecular sensing has been known for a long time, the molecular mechanism involved remained elusive for decades. A taste-specific pathway of chemoreception was suggested in the gut epithelium since the identification of α-gustducin-expressing cells in rat stomach and intestine (28). Only recently is it becoming clear which are the putative sites of molecular sensing and how the chemosensing machinery works to trigger the appropriate responses to beneficial or harmful substances.
Recent studies demonstrate that multiple transcripts coding members of the T2R and the T1R family of taste receptors and the α-subunit of the G proteins “gustducin” (Gαgust) and “transducin” (Gαt) are coexpressed in specialized GI cells of rats (29) and humans (30), suggesting that taste-sensing pathways may also work in the GI tract.
Taste signaling operates in specific cells interspersed in the epithelium lining the GI system, which appears α-gustducin positive by immunohistochemistry. α-Gustducin immunoreactivity has been demonstrated in subpopulations of enteroendocrine cells, namely in the I, K, and L type, localized in the small intestine and in the colon. Enteroendocrine cells respond to gastric and intestinal luminal contents releasing peptides, which regulate a variety of GI functions. I cells produce the hormone cholecystokinin (CCK) that triggers the release of digestive enzymes from the pancreas and modulates food intake; L cells secrete the YY peptide (PYY) that plays an important role in gastric emptying and intestinal motility and the glucagon-like peptides (GLPs) involved in glucose-dependent secretion of insulin; K cells produce the glucose-dependent insulinotropic peptide.
These subpopulations of enteroendocrine cells, called “open cells,” face the intestinal lumen and are equipped with microvilli, so they are suitable to act as primary chemoreceptors that sense the luminal content at the apical side and release GI peptides at the basolateral side.
Evidence from multiple experimental sources confirm the role of taste receptors in the gut. In mouse secretin tumor cell-1 cells expressing bitter taste receptors of the T2R family, the bitter agonists denatonium benzoate and phenylthiocarbamide, putative ligands of T2R108 and T2R38, respectively, induce a marked increase in intracellular Ca2+-triggering CCK release (31). The functional involvement of gut-expressed taste receptors in the control of food intake and glucose homeostasis has been demonstrated in humans. The sweet receptor antagonist, lactisole, is able to block the GLP-1, PYY, and CCK release in response to intragastric or intraduodenal infusion of nutrients (32). Taken together, these data suggest that the same mechanism of chemosensing used by taste cells of the tongue could be operative in enteroendocrine cells.
A reliable model for the signaling pathways triggered by chemical tastants in GI lumen proposes that the bitter and sweet compounds of the luminal content activate the gustducin-coupled taste receptors of the enteroendocrine cells leading, through second messengers, to intracellular Ca2+ increase and peptide release. The peptides secreted by enteroendocrine cells elicit functional responses acting as classic hormones on peripheral targets or in paracrine fashion on nearby cells. Finally, the cascade of events induced by taste transducers’ signaling is responsible for organizing the physiological responses to nutrients or to toxins (33,34) (Fig. 2). Recent studies using bitter and sweet receptors agonists provided important contributions to test this model in vivo.
In this regard, the characterization of taste receptors minor variants associated with taste insensitivity raises the question of how genetic polymorphisms affecting the ability of initiating taste-specific signaling pathways could be critical for the efficiency of the physiological processes of the GI tract.
Functional implications of taste receptors in GI chemosensing raise the possibility that taste-signaling mechanisms could be regarded as therapeutic targets (35).
It is noteworthy that the peptides involved in the regulation of food intake and glucose homeostasis, namely GLP-1 and PYY from L cells and CCK from I cells, may participate in the pathogenesis of metabolic disorders as obesity and type 2 diabetes mellitus.
Significant implications in the therapeutic field could derive from the modulation in the secretion of GI peptides as a novel approach to treatment of aberrant conditions ranging from feeding disorders to obesity and related metabolic dysfunctions.
Ghrelin, Leptin, and Taste Receptors
Hunger starts in the empty stomach. Ghrelin is the main hunger hormone, but it also has remarkable activity in gastric emptying and motor activity.
Recent experimental work on mice suggests the presence of an unexpected synergy between ghrelin and gustducin. When wild-type mice are gavaged with T2R agonists, plasma ghrelin is increased; the effect is suppressed in the gustducin (−/−) mice (36). Consequently, the local activation of the taste receptor stimulates the search for food and food intake through the action of ghrelin. This effect is obviously temporary. When food fills the stomach, gastric emptying is temporarily inhibited and the search for food limited. Bitter taste receptors influence gastric function through direct action on ghrelin. It is well known that some food grossly influences gastric motility and emptying; some elicit adverse reactions and antiperistalsis. These actions are likely to be mediated through local taste receptors, which have a sensitive function independent from the tongue taste papillae. The food-search impulse generated by ghrelin is centrally counteracted by leptin, and produced by fat cells. Leptin is indeed a strong anorexigenic hormone.
In mice, a subset of sweet-sensitive taste cells possesses leptin receptors. Leptin acts as a modulator of sweet taste sensation in humans with a diurnal variation in sweet sensitivity. Plasma leptin level and sweet taste sensitivity are linked to postingestive plasma glucose level. This leptin modulation of sweet taste sensitivity may influence individual preferences, ingestive behavior, and absorption of nutrients, thereby playing important roles in the regulation of energy homeostasis.
TASTE AND GI FUNCTION IN CHILDREN
Children may be extremely fussy in food selection and acceptance. They often associate the ingestion of a particular food with abdominal pain and general discomfort. Their fantasy may lead to blame a specific food for a sense of antiperistalsis and nausea, difficult digestion, and general malaise. It took several decades to classify these symptoms as “functional” just to be safe that we do not miss a “disease,” but these functional disturbances have no functional pathways, no molecular pattern, no receptor, and no identified molecules or genes. Certainly, there are multiple factors, dozens of receptors, hundreds of genes, which participate to build up a profile of a “functional disturbance.”
There are new targets for research progress. We know the existence of specialized cells (enteroendocrine), taste receptors and their signaling pathway, endocrine and paracrine hormones, and a complex nervous domain resident in the gut. We may begin to understand whether abdominal pain is related to the genetically determined specific reaction to a food or to its derivative, after digestion. We may begin to correlate GI motility not only with adverse effects (eg, infection, inflammation) but also with daily common life events and specifically with foods and nutraceutics.
Forty-three patients with irritable bowel syndrome, well classified by Rome III criteria, showed significant differences in their taste sensitivity compared with age-matched unaffected controls (37). Differences were not clear-cut and olfactory sensitivity appeared to be more involved than taste, but there is scope to explore this field.
Investigators explore why a certain food generates vomiting or nausea, and why some foods increase acid secretion in some children and not in others. The “threshold” of sensitivity or aversion may well have a relevant genetic component, once our approach is translated from organs to cells and molecules.
We may ask ourselves why some foods are so related, in genetically predisposed individuals, to constipation: is it all about the fibers or allergy? Certainly not. Just consider the case of milk proteins—no fibers and an only occasional relation to allergy. Moreover, milk proteins are no doubt a cause of constipation in some predisposed children (38).
The whole domain of functional GI disturbances in children may be completely rewritten in the near future; it will take as long as it did before to define appropriate criteria. The actors are multiple and each individual will be likely have a personal profile, which is extremely difficult to analyze and classify.
This new knowledge will also open the way to a better understanding, to personalized food choices, and, most likely, to new approaches to drug management in patients who cannot tolerate the discomfort. And what about real “diseases”? They have their specific pathogenetic pathways, but actual knowledge is mostly restricted to organs and tissues and much less to cells and molecules. Questions arise rapidly: why might the elemental diet be so effective in inducing the first remission in Crohn-selected cases? Do some foods influence the symptoms of ulcerative colitis? We are committed to investigating the relation between GI functional disturbances in children and the genetic polymorphisms that regulate taste sensations. We have the privilege to explore new fields of science and, possibly, to discover a better approach to the care of our patients.
1. Saper CB, Chou TC, Elmquist JK. The need to feed: homeostatic and hedonic control of eating. Neuron 2002; 36:199–211.
2. Chandrashekar J, Mueller KL, Hoon MA, et al. T2Rs function as bitter taste receptors. Cell 2000; 100:703–711.
3. Adler E, Hoon MA, Mueller KL, et al. A novel family of mammalian taste receptors. Cell 2000; 100:693–702.
4. Matsunami H, Montmayeur JP, Buck LB. A family of candidate taste receptors in human and mouse. Nature 2000; 404:601–604.
5. Kitagawa M, Kusakabe Y, Miura H, et al. Molecular genetic identification of a candidate receptor gene for sweet taste. Biochem Biophys Res Commun 2001; 283:236–242.
6. Li X, Inoue M, Reed DR, et al. High-resolution genetic mapping of the saccharin preference locus (Sac) and the putative sweet taste receptor (T1R1) gene (Gpr70) to mouse distal chromosome 4. Mamm Genome 2001;12:13–6.
7. Max M, Shanker YG, Huang L, et al. Tas1r3, encoding a new candidate taste receptor, is allelic to the sweet responsiveness locus Sac. Nat Genet 2001; 28:58–63.
8. Montmayeur JP, Liberles SD, Matsunami H, et al. A candidate taste receptor gene near a sweet taste locus. Nat Neurosci 2001; 4:492–498.
9. Nelson G, Hoon MA, Chandrashekar J, et al. Mammalian sweet taste receptor. Cell 2001; 106:381–390.
10. Sainz E, Korley JN, Battey JF, et al. Identification of a novel member of the T1R family of putative taste receptors. J Neurochem 2001; 77:896–903.
11. Heck GL, Mierson S, Desimone JA. Salt taste transduction occurs through an amiloride-sensitive sodium transport pathway. Science 1984; 223:403–405.
12. Avenet P, Lindemann B. Amiloride-blockable sodium currents in isolated taste receptor cells. J Membr Biol 1988; 105:245–255.
13. Lyall V, Heck GL, Vinnikova AK, et al. The mammalian amiloride-insensitive non-specific salt taste receptor in a vanilloid receptor-1 variant. J Physiol 2004; 558:147–159.
14. Ishimaru Y, Inada H, Kubota M, et al. Transient receptor potential family members PKD1L3 and PKD2L1 form a candidate sour taste receptor. Proc Natl Acad Sci U S A 2006; 103:12569–12574.
15. LopezJimenez ND, Cavenagh MM, Sainz E, et al. Two members of the TRPP family of ion channels, Pkd1l3 and Pkd2l1, are co-expressed in a subset of taste receptor cells. J Neurochem 2006; 98:68–77.
16. Huang AL, Chen X, Hoon MA, et al. The cells and logic for mammalian sour taste detection. Nature 2006; 442:934–938.
17. Yarmolinsky DA, Zuker CS, Ryba NJ. Common sense about taste: from mammals to insects. Cell 2009; 139:234–244.
18. Chaudari N, Roper SD. The cell biology of taste. J Cell Biol 2010; 190:285–296.
19. Zhanga F, Klebanskyb B, Fineb RM, et al. Molecular mechanism for the umami taste synergism. Proc Natl Acad Sci U S A 2008; 105:20930–20934.
20. Tatzer E, Schubert MT, Timischl W, et al. Discrimination of taste and preference for sweet in premature babies. Early Hum Dev 1985; 12:23–30.
21. Beauchamp GK, Moran MM. Dietary experience and sweet taste preference in human infants. Appetite 1982; 3:139–152.
22. Steiner JE. Facial expressions of the neonate infant indicate the hedonics of food-related chemical stimuli. In: Weiffenbach JM, ed. Taste and Development: The Genesis of Sweet Preference. Washington, DC: US Government Printing Office; 1977.
23. Beauchamp GK, Cowart BJ, Moran M. Developmental changes in salt acceptability in human infants. Dev Psychobiol 1986; 19:17–25.
24. Rosenstein D, Oster H. Differential facial responses to four basic tastes in newborns. Child Dev 1990; 59:1555–1568.
25. Mennella JA, Beauchamp GK. Early flavor experiences: research update. Nutr Rev 1998; 56:205–211.
26. Hauser GJ, Chitayat D, Berbs L, et al. Peculiar odors in newborns and maternal prenatal ingestion of spicy foods. Eur J Pediatr 1985; 44:403.
27. Cernoch JM, Porter RH. Recognition of maternal axillary odors by infants. Child Dev 1985; 56:1593–1598.
28. Höfer D, Püschel B, Drenckhahn D. Taste receptor-like cells in the rat gut identified by expression of alpha-gustducin. Proc Natl Acad Sci U S A 1996; 93:6631–6634.
29. Wu SV, Rozengurt N, Yang M, et al. Expression of bitter taste receptors of T2R family in the gastrointestinal tract and enteroendocrine STC-1 cells. Proc Natl Acad Sci U S A 2002; 99:2392–2397.
30. Rozengurt N, Wu SV, Chen MC, et al. Colocalization of the alpha-subunit of gustducin with PYY and GLP-1 in L cells of human colon. Am J Physiol Gastrointest Liver Physiol 2006; 291:G792–802.
31. Chen MC, Wu SV, Reeve JR, et al. Bitter stimuli induce Ca2+ signalling and CCK release in enteroendocrine STC-1 cells: role of L-type voltage–sensitive Ca2+ channels. Am J Physiol Cell Physiol 2006; 291:726–739.
32. Gerspach AC, Steinert RE, Schönenberger L, et al. The role of the gut sweet taste receptor in regulating GLP-1,PYY and CKK release in humans. Am J Physiol Endocrinol Metab 2011;301:E317–25.
33. Sternini C, Anselmi L, Rozengurt E. Enteroendocrine cells: a site of ‘taste’ in gastrointestinal chemosensing. Curr Opin Endocrinol Diabetes Obes 2008; 15:73–78.
34. Rozengurt E, Sternini C. Taste receptor signaling in the mammalian gut. Curr Opin Pharmacol 2007; 7:557–562.
35. Sprous D, Palmer KR. The T1R2/T1R3 sweet receptor and TRPM5 ion channel taste targets with therapeutic potential. Prog Mol Biol Transl Sci 2010; 91:151–208.
36. Janssen S, Laermans J, Verhulst PJ, et al. Bitter taste receptors and alpha-gustducin regulate the secretion of ghrelin with functional effects on food intake and gastric emptying. Proc Natl Acad Sci U S A 2011; 108:2094–2099.
37. Steinbach S, Reindl W, Kessel C, et al. Olfactory and gustatory function in irritable bowel syndrome. Eur Arch Otorhinolaryngol 2010; 267:1081–1087.
38. Iacono G, Cavataio F, Montalto G, et al. Intolerance of cow's milk and chronic constipation in children. N Engl J Med 1998; 339:1100–1104.