The sense of taste provides critical information about the quality and nature of food, leading to specific eating responses (consumption or avoidance). Five basic taste modalities are commonly recognized: sour, salty, sweet, bitter, and umami (the taste of monosodium glutamate), and related tastants are detected by taste buds mainly localized on the tongue epithelium and rarely in the soft palate, pharynx, and upper esophagus. In the lingual epithelium, taste buds are present in three specialized gustatory papillae (i.e., fungiforms, foliates, and circumvallates) displaying different spatial distributions (Figure 1A). Most of the taste buds are found in circumvallate papillae (CVP) that are characterized by a dome-shaped structure with a circular depression connected to von Ebner's glands, which produce and release salivary enzymes (68) and lipocalins (98) (Figure 1B). Taste buds are specialized onion-shaped structures composed of 50-100 TBC clustered in the surrounding stratified epithelium (Figure 1C). Only the apical parts of some TBC are exposed to the saliva, and hence to dietary components, while the basal side of taste buds is connected to afferent fibers from the chorda tympani (CT) and glossopharyngeal (GL) nerves (cranial nerves VII and IX, respectively). This chemoreception system is completed by somatosensory endings from the trigeminal nerve (cranial nerve V) surrounding the taste buds and responsible for thermosensation, mechanoreception, and nociception (Figure 1C). A dense capillary network supplies all the taste buds. Nevertheless, existence of a “blood-bud barrier,” which functions as the blood-brain barrier (BBB), limits the access of taste bud cells (TBC) to some blood molecules (37).

FIGURE 1. Peripheral taste system. A : localization of different types of gustatory papillae onto the human tongue. B : sagittal section of a circumvallate papillae (CVP) showing its typical dome-shaped structure and the anatomical relationship with the von Ebner's glands. C : schematic representation of a taste bud. CA-VI, carbonic anhydrase; rNTS, rostral nucleus of solitary tract; VEGP, von Ebner's gland protein; V, trigeminal endings; VII, afferent fibers of the chorda tympani nerve; IX, afferent fibers of the glosso-pharyngeal nerve.

A. Taste Bud: The Primary Receptor Organ

Studies on taste buds reveal an unexpected complexity. First, each taste bud is a heterogeneous assemblage of three different mature, elongated, cell types (types I to III) and one basal cell type (type IV) (52) (Figure 2A). Type I cells are glial-like supporting cells sharing many features with astrocytes (19). They are thought to participate in sensing sodium (222). Type II cells are the taste receptor cells expressing, in a mutually exclusive manner, the receptors for sweet, bitter, or umami (141). They communicate with afferent gustatory nerve fibers through nonconventional synapses (33) (Figure 2B). Type III cells are presynaptic cells required for sour taste perception (80). They form synapses with primary sensory afferent terminals (VII and/or IX cranial nerves; Figure 2B) (175). Finally, type IV cells are precursor cells responsible for TBC renewal (38, 171).

FIGURE 2.Main cellular and functional characteristics of taste buds. A: functional roles of the different cell types constituting a taste bud. B: role of ATP, as neurotransmitter, in the communication between the different taste bud cells. Ad, adenosine; CALHM1, calcium homeostasis modulator-1; 5-HT, serotonin; 5-HT A1 , serotonin receptor; NTPDase, ectonucleoside triphosphate diphosphohydrolase-2; P 2 X, purinergic (ATP) receptors; VII, chorda tympani nerve; IX, glosso-pharyngeal nerve.

The peripheral coding of taste is still debated, with two proposed theories. In the labeled-line model, the distinct taste qualities are carried by one type of TBC connected to dedicated afferent nerve fibers; while in the combinatorial model, also called the across fiber model, a taste modality is encoded by several broadly tuned neurons (23, 27, 110).

Second, all TBC types appear to be linked through a complex communication network of neurotransmitters, including ATP and acetylcholine (ACh) produced by the type II cells, and serotonin (5-HT), GABA, and norepinephrine (NE) released by the type III cells (for reviews, see Refs. 91, 173, 215). Respective roles of these signal molecules in taste bud function are progressively deciphered. ATP appears to be a major player in this system (Figure 2B). Indeed, ATP are released by type II cells in response to appropriate sweet, bitter, or umami tastants. Moreover, genetic inactivation of the ionotropic ATP receptors P 2 X 2 /P 2 X 3 is associated with a dramatic decrease in basic taste-evoked behaviors, including sour and salty tastes (53). The voltage-gated ATP-permeable ion channel CALHM1, only detected in type II cells, was recently identified as crucial for this taste signal transmission (215) (Figure 2B). CALHM1 knockout abolished taste-evoked ATP release by type II cells, and the gustatory nerve response to taste qualities was dramatically decreased in CALHM1-null mice (216). Once released from type II cells, ATP activates the purigenic receptors (P 2 X 2 /P 2 X 3 ) present both on type II cells themselves, afferent nerve fibers, and adjacent presynaptic cells (type III). Therefore, in the taste bud context, type III cells may be indirectly activated by sweet, bitter, and umami tastants while these presynaptic TBC do not express the related cognate receptors (i.e., T1R and T2R). Nevertheless, type III cells are not absolutely required for transmission of taste information from type II cells to afferent nerves. Indeed, genetic deletion of type III cells is not associated with the abolition of sweet, bitter, and umami tastes (77), in contrast to the outcome of specific deletion of type II cells (124). The fact that type III cells respond, directly (i.e., sour) and indirectly (i.e., sweet, bitter, umami), to a wide range of taste stimuli suggests that the afferent fibers that synapse with these cells might be broadly tuned. Thus, despite the strong evidence in favor of the labeled-line theory (138, 233), it is likely that the peripheral coding of taste is more complex than previously expected. Finally, ATP is quickly degraded to ADP and AMP by the ecto-ATPase NTPDase2 located on the surface of type I cells (6) (Figure 2B).

Purigenic (ATP) stimulation of type III cells triggers the release of 5-HT (79, 81). Whether a direct activation of conventional nerve endings associated with type III cells by 5-HT is questionable (173), accumulative evidences support the involvement of this neurotransmitter in a cross-talk between type III cells and a subset of type II cells expressing the 5-HT A1 receptor (86, 95). By decreasing ATP release from these type II cells during the late transduction phase (Figure 2B), 5-HT contribute to prolong the transmission of taste signals to the brain. Indeed, this transient inhibitory effect of 5-HT prevents the desensitization of P 2 X 2 /P 2 X 3 receptors on afferent gustatory nerve endings, an event ensuring the rapid termination of ATP-mediated action (168).

NE, GABA, and ACh functions in taste buds remain to be fully established (for more details, see Ref. 173). In brief, taste stimulation appears to promote a set of neurotransmitter responses requiring a dialogue between the different cell types constituting the taste buds.

Third, a subset of TBC, mainly type II cells, also expresses multiple gastrointestinal hormones including glucagon-like peptide-1 (GLP-1) (194), cholecystokinin (CCK) (73, 190), neuropeptide Y (NPY) (82, 232), vasoactive intestinal polypeptide (VIP) (119, 190), and ghrelin (195), known to regulate digestive tract function, glucose homeostasis, and appetite/satiety (for an exhaustive review, see Ref. 234) (Figure 3). The fact that cognate receptors are also found in taste buds and, sometimes, in adjacent afferent nerve fibers suggests a local endocrine influence. For instance, GLP-1, primarily identified in enteroendocrine L cells (174), is also expressed in a subset of TBC, whereas its receptor (GLP1-R) is found in afferent gustatory nerves (194). Interestingly, GLP1-R-null mice display a reduced response to sweet tastants during behavioral tests, suggesting that GLP-1 signaling enhances the sweet taste sensitivity (121, 194). In contrast, the active form of the orexigenic hormone ghrelin and of its cognate receptor (GHSR) have been identified in all types of TBC in the mouse (195) (Figure 3). A decreased response to sour and salty tastants was observed in GHSR-null mice (195). In brief, all taste modalities appear to be under endocrine control (234). Hormones produced by taste buds mainly play a role in modulating taste sensitivity. However, other functions are also plausible. For example, expression of NPY in the progenitor type IV cells (232) suggests a possible involvement in the renewal of TBC, as reported for olfactory neurons (41). Gustation is also under the influence of peripheral hormones. Although leptin is not produced by taste buds, the presence of its cognate receptors, ObRb, on the surface of TBC (93) suggests that gustatory papillae are sensitive to variations in plasma leptin levels. The fact that circulating leptin acts as a negative modulator of sweet taste in the mouse is consistent with this suggestion (93). In healthy humans, the recognition threshold for sweet taste correlates with the diurnal variation in plasma leptin levels (140). Therefore, subjects need higher concentration of sugars to detect a sweet quality in the evening than that in the morning. Interestingly, this diurnal rhythm of sweet taste is lacking in overweight and obese subjects, likely because they develop a leptin resistance due to chronically high plasma leptin levels (88). In contrast, the endocannabinoids anandamide and 2-arachidonoyl-glycerol are known to be orexigenic factors and enhance the sweet taste sensitivity through the activation of the CB 1 receptors (CB 1 R) (145). This effect seems to be taste bud dependent because CB 1 R is found in a subset of type II cells expressing the sweet taste receptor T 1 R 3 , and a systemic administration of endocannabinoids increases the activity of gustatory nerves in the mouse (229).

FIGURE 3.Hormone location and functions in taste buds. CB1R, cannabinoid receptor type 1; CCK, cholecystokinin; CCK-A, CCK receptor A; GLP-1, glucagon-like peptide-1; GLP-1R, GLP-1 receptor; ghrelinR, ghrelin receptor; NPY, neuropeptide Y; ObRb, leptin receptor; VIP, vasoactive intestinal peptide; VPAC1&2, VIP receptors; YR, NPY receptor.

Finally, taste buds undergo continuous cellular renewal with an average life span of 10 days (9). Basal cells (type IV) are precursor cells that differentiate into the mature type I, type II, and type III cells (211). Although molecular mechanisms responsible for TBC proliferation and differentiation are actively studied (for a review, see Refs. 51, 91), the regulatory factors responsible for TBC renewal remain poorly known. An endocrine control is likely because type IV cells express several hormone receptors (234) (Figure 3). Extrinsic factors such as bacterial lipopolysaccharides (LPS) can also affect TBC renewal. Indeed, LPS-mediated inflammation reduces the proliferation of taste progenitor cells and shortens the turnover of taste buds in mice (34). Whether an acute or chronic low-grade proinflammatory environment, as reported during obesity, modifies the taste perception, and hence eating preference, is presently unknown.

In summary, the taste bud appears to be a complex sensory entity characterized by a constant cell-to-cell dialogue and able to adapt its renewal and detection levels of sapid molecules to changes in body requirements in response to multiple intrinsic (e.g., neurotransmitters, hormones) and extrinsic (e.g., LPS) influences.