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Physiology of Taste Processing in the Tongue, Gut, and Brain

Ranier Gutierrez, Sidney A. Simon

10.1002/cphy.c210002

Source: Volume 11, Issue 4, October 2021

Published online: September 2021

Full Article on Wiley Online Library



Abstract

The gustatory system detects and informs us about the nature of various chemicals we put in our mouth. Some of these have nutritive value (sugars, amino acids, salts, and fats) and are appetitive and avidly ingested, whereas others (atropine, quinine, nicotine) are aversive and rapidly rejected. However, the gustatory system is mainly responsible for evoking the perception of a limited number of qualities that humans taste as sweet, umami, bitter, sour, salty, and perhaps fat [free fatty acids (FFA)] and starch (malto‐oligosaccharides). The complex flavors and mouthfeel that we experience while eating food result from the integration of taste, odor, texture, pungency, and temperature. The latter three arise primarily from the somatosensory (trigeminal) system. The sensory organs used for detecting and transducing many chemicals are found in taste buds (TBs) located throughout the tongue, soft palate esophagus, and epiglottis. In parallel with the taste system, the trigeminal nerve innervates the peri‐gemmal epithelium to transmit temperature, mechanical stimuli, and painful or cooling sensations such as those produced by changes in temperature as well as from chemicals like capsaicin and menthol, respectively. This article gives an overview of the current knowledge about these TB cells' anatomy and physiology and their trigeminal induced sensations. We then discuss how taste is represented across gustatory cortices using an intermingled and spatially distributed population code. Finally, we review postingestion processing (interoception) and central integration of the tongue‐gut‐brain interaction, ultimately determining our sensations as well as preferences toward the wholesomeness of nutritious foods. © 2021 American Physiological Society. Compr Physiol 11:2489‐2523, 2021.

Figure 1. Figure 1. Anatomy of the tongue and taste buds. (A) The drawing of a human tongue 275. Slight elevations in the dorsal surface demarcate fungiform papillae. Circumvallate papillae (big arrows), with the exception of the central one, form an inverted V‐shape along the anterior of the sulcus terminalis. (B‐D) Scanning electron micrographs of the mucosal surface of a canine lingual epithelium. (B) A section of the anterior epithelium with three round fungiform papillae (Fu) and numerous pointed filiform papillae (Fi). * Indicates a magnification area shown in (C). (D) A magnified view of a taste pore (TP) opening into the fungiform papillae. Note that the cornified layers are shed in sheets. (E) A longitudinal section of a taste bud from a rabbit foliate papilla. Several nuclei of types I and II cells are shown. A single type III cell appears at the left edge of the TB. Arrows mark afferent nerve fibers. The TB extends from the basal lamina (BL) to the epithelium (E) surface, where the taste pore (TP) is in contact with the external oral environment. CTi, connective tissue. (A) Modified, with permission, from Witt M, 2019 285. (B‐D) Modified, with permission, from Holland VF, et al., 1989 109. (E) Modified, with permission, from Royer SM and Kinnamon JC, 1994 221.
Figure 2. Figure 2. Dorsal surface of a human tongue with taste papillae and taste bud cells. A drawing of the human tongue showing three types of taste papillae containing TBs as well as their associated afferent fibers. In fungiform papillae, TBs are located mainly around the tip of the tongue, while in circumvallate and foliate papillae, they are in trenches on the posterior and lateral areas of the tongue, respectively (middle panel). Right panel shows a schematic representation of a TB, the peripheral end organ responsible for initiating and transmitting signals that arise in taste perception. TBs are composed of four different types, I, II, III, and IV, surrounded by stratified, squamous epithelial cells. The apical and basolateral sides of taste receptor cells (TRCs) are demarked by tight junctions (dashed black lines). The TB shows a small pit with a “crater‐like” shape, called the taste pore (TP), where tastants enter to activate TRCs. Afferent nerve fibers arising from gustatory ganglion neurons are shown in black. Some fibers selectively contact one type of TRC, whereas others can target more than one type (see text and Ref. 114). Other gustatory fibers also contact and terminate in the perigemmal epithelium (black). The chorda tympani (CT) is a branch of the facial nerve (CN VII), and GPN refers to the glossopharyngeal nerve (CN IX). Free ending fibers (red) from the lingual branch (LN) of the trigeminal nerve (CN V) are embedded in the keratinocytes surrounding the TB of fungiform papillae [see red V(LN)]. Not shown is the vagus nerve (CN X) that innervates the root of the tongue, epiglottis, and larynx. Modified, with permission, from Witt M, 2019 285.
Figure 3. Figure 3. 3‐D reconstruction of type I taste cells shows their two apical morphologies and how they embrace type II and III cells. (A) Short type I cells (light green) terminate in an apical microvillus that does not reach the taste pore, whereas Tall type I cells (dark green) have a longer branched apical process penetrating the taste pore. (B) A drawing of a TB depicting how type I cells (blue) wrap‐around type II (green) and III (orange) cells. (C) An electron microscopic section of a type I cell enwrapping a type II cell with a thin lamellae sheet (light green). The type II cell is contacting a nerve fiber (nf, yellow) and contains an atypical mitochondrion (atM) that may serve as a source of ATP. (A,C) Modified, with permission, from Yang R, et al., 2019 289. (B) Modified, with permission, from Witt M, 2019 285.
Figure 4. Figure 4. Reconstruction of a type III taste cell and two associated nerve fibers (nF). (A) Accumulations of synaptic vesicles (Ves) near the point of cell‐nerve contact indicate synapses (see arrows and circles in C). At one of these contacts is an atypical mitochondrion (atM‐red) with irregular cristae close to the cell membrane. (B) Type III cell nuclei are irregular and elongated with deep invaginations (arrows). Also visible are two adjacent type I cell nuclei (nu) with small invaginations. Classical chemical synapses (C) enlarged at the lower left with synaptic vesicles (arrowheads) appear at some contact points between the type III cell and nerve fibers (nf, yellow). C: Enlargements from panel (B) showing electron‐dense synaptic vesicles (arrowheads) at points of contact with the nerve fibers. Modified, with permission, from Yang R, et al., 2019 289.
Figure 5. Figure 5. Type IV basal precursor cells. (A) Type IV (basal) cells have nuclei (magenta) situated in the lower quarter of the TB. In contrast, the nuclei of typical type II (light blue) and type III (red) cells lie higher in the taste bud. (B) Type IV cells have a basal process extending to the basal lamina (Figure 1E; see BL) at the base of the TB. This process frequently contacts the basal plexus of nerve fibers penetrating the base of the bud. Some basal cells also have an apically directed process that may contact type II or type III cells. Modified, with permission, from Yang R, et al., 2019 289.
Figure 6. Figure 6. Thermal transient receptor potential (TRPs) channels. A selected group of thermal TRPs (and their temperature sensitivities) that are activated either indirectly by tastants (TRPM5; sweet, bitter, and umami—see text) or directly by various spices (TRPA1, TRPV1) or other compounds (TRPM8, TRPV2). A ligand for TRPV4 is bisandrographolide A, extracted from the King of Bitter. (inset) Modified, with permission, from Roper SD, 2014 216; Modified, with permission, from Simon SA and Gutierrez R, 2017 240.
Figure 7. Figure 7. Schematic diagram of gustatory and trigeminal afferent nerve fibers. (A) Chorda Tympani (CT) afferent fibers from geniculate ganglion (GG) neurons can innervate adjacent and distal TBs. Some fibers only contact type II cells (blue), whereas others only type III cells (gray). In addition, some fibers can contact both type II and III cells (purple) (see text). The cell bodies of the CT and the greater superficial petrosal (GSP) nerves reside in the GG and project to rNTS (see pictures in C). Some CT fibers do not target fungiform taste bud cells but instead terminate in lingual epithelial tissue (black fibers) (see Figure 8C, cluster M5). The “somatosensory” GG cells innervating the outer ear are not shown. Along with gustatory fibers from the CT run trigeminal innervation. Included in that group are neurons that contain transient receptor potential (TRP) cation channel subfamily M member 8 (TRPM8) neurons that respond to menthol and from the transient receptor potential cation channel subfamily V member 1 (TRPV1), which is a receptor for capsaicin the principal ingredient in chili peppers responsible for its burning sensation (Figure 6). Trigeminal nerve fibers project to the spinal trigeminal nucleus (SpVc) and the rNTS 302. (B) A cresyl‐violet‐stained of a rat GG soma also shown both the CT and GSP fibers (see arrows). (C) Upper picture depicts histology of CT fibers innervating the rNTS, and the lower panel shows fluorescent glossopharyngeal nerve (GPN) in red and GSP fibers in green. 4 denotes the 4th ventricle. (A) Modified, with permission, from Zaidi FN, et al., 2008 302. (C) Modified, with permission, from Martin LJ, et al., 2018 164.
Figure 8. Figure 8. Single‐cell genetic profiling of mouse geniculate ganglion (GG) neurons found two major cell types: those expressing the transcriptional factor Phox2b+ that conveys gustatory information and those expressing Phox2b− fibers that are somatosensory neurons that innervate the outer ear. (A) Labeling the GG. The immunostaining of purinergic receptor P2X3 (a marker for afferent nerve fibers is in red) and purple represents the GG neurons expressing Phox2b+ and P2X3+ are labeled in purple (merge). The nonnuclear “green” signal is an unspecific binding of the mouse antibody. (B) A meta‐analysis of three experiments showing the genetic profiling of individual GG neurons 4,64,304. In the middle panel, a dot represents a single GG neuron classified into seven distinct clusters (M0‐M6) arranged according to its five main genes (see correlation matrix in C). (C) Clusters from M1‐M6 corresponds to gustatory GG neurons (expressing Phox2b+). The somatosensory GG neurons belong to cluster M0 (Phox2b−). The cluster M2 is composed of GG neurons expressing the Spon1 gene, and they are responsive to sweet tastants. The cluster M6 is involved in acid taste transduction and is characterized by the expression of the Penk gene. M5 is an ensemble of GG neurons that may be involved in mechano‐transduction information from the tongue. These cells expressed the gene for Piezo2. Modified, with permission, from Anderson CB and Larson ED, 2020 4.
Figure 9. Figure 9. Primary canonical signaling pathways are shared by sweet and bitter tastants and l‐amino acids. After chemicals are bound to their associated GPCRs, G‐protein βγ subunits then → PLC‐β2 → PIP2 → IP3 and activation of endoplasmic reticulum IP3R3 receptors → increasing intracellular [Ca2+]i → cation influx through TRPM4 and TRPM5 channels → membrane depolarization → opening the CALHM1/3 channels → secretion of ATP that activates P2X2/P2X3 receptors on primary afferent neurons. In parallel, activation of voltage‐gated Na+ channels (Nav) amplifies the membrane depolarization and increases ATP secretion (see text). Some type II cells also express a sodium‐glucose‐linked transporter 1 (SGLT1) that can distinguish glucose from noncaloric artificial sweeteners that can also activate T1R2/T1R3 receptors. Type II cells can also detect and transduce long‐chain fatty acids (FAs). FAs bind to the translocator CD36 to activate specific G protein‐coupled receptors (like GPR120 receptors) to initiate a transduction cascade that in turn produces a second messenger leading to release intracellular [Ca2+]i (see the text on fat for details ). It remains unknown as to whether CD36 serves as a chaperon for GPR120 to transduce FFAs or both works independently. The basal part of the type II cells can also respond in an endocrine, autocrine, or paracrine manner to hormones such as leptin, GLP‐1, and ghrelin (see text for additional details). The TRC in the middle depicts a type II cell that expresses the l‐amino acid receptor, T1R1/T1R3. Shown at the right is a type II cell with three T2R receptors activated by bitter tastants. It remains to determine whether type II bitter cells also express receptors for peptides. Modified, with permission, from Gao N, et al., 2009 84; Liu P, et al., 2011 153.
Figure 10. Figure 10. Morphology of a type II cell and a schematic of the structure of the human “sweet taste” receptor hT1R2/3 with its many binding sites. Reconstruction (3‐D) of a type II cell from a mouse's circumvallate papillae. Red spots indicate the position of atypical mitochondria (atM), which may act as a source of ATP to be released to activate receptors on primary afferent fibers. Also shown is a microvillus that extends through the taste pore (up—not shown) into the oral cavity. Inset. The heterodimer T1R2/T1R3 is composed of an extracellular amino terminal domain (ATD), containing a venus flytrap domain (VFD) and a cysteine‐rich domain (CRD). The VFD has two lobes that change their conformation to “open” or “closed” states, like that seen in the carnivorous plant with the same name. The VFD is connected via the CRD to the seven helical transmembrane domains (TMD). Importantly, sweet‐tasting molecules bind to different receptor sites (arrows), inducing conformational changes eliciting a canonical signaling cascade, shown in Figures 9 and 11. (Left) Modified, with permission, from Yang R, et al., 2019 289. (Right) Modified, with permission, from Laffitte A, et al., 2014 136.
Figure 11. Figure 11. Sweet, umami, and bitter taste responses require the co‐activation of both a narrowly tuned type II cell (left) and a broadly tuned type III cell (right). The integration of information between two types of taste cells could occur in the taste bud (TB) or by those afferent fibers that contact both type II and type III cells. At right is shown a recently identified broadly responsive type III cell (BRtypeIII cell) that responds to acid, sweet, umami, and bitter tastants via not yet identified receptors that activate PLC‐β3 → IP3R1 that then produces an increase of intracellular Ca2+ that probably activate TRPM4 channels (see ?) present in those cells. This leads to the activation of voltage‐gated calcium channels (VGCCs) that cause the release of synaptic vesicles whose transmitters activate primary neurons 10. It is still unknown what transmitter uses the BRTypeIII cell to communicate with afferent nerves (see small ? next to vesicles). Wherever the logic AND circuit occurs (see large ? marks), it should happen between the TB and GG before taste information is sent to the rNTS (light blue somas). From the rNTS, taste information is partitioned into oromotor reticular formation (RF; red neurons), where the central pattern generator for rhythmic licking is located 266 or to a classical taste/visceral pathway in the parabrachial nucleus (PBN; dark blue neurons). Modified, with permission, from Travers JB, et al., 1997 266; Banik DD, et al., 2020 10.
Figure 12. Figure 12. The signaling cascade pathways for acid taste transduction. Type III cells express the proton permeable ion channel, otopetrin‐1 (OTOP1) 265,304. Influx of H+ through OTOP1 acidifies the cytoplasm, which could inhibit potassium Kir2.1 channels that induce a small depolarizing (inward) current sufficient to gate voltage‐gated Ca2+ channels and produce action potentials (Nav), leading to the subsequent release of synaptic vesicles (black circles) containing 5‐HT that may bind to 5‐HT3aR channels on afferent nerves. Alternatively, it perhaps could co‐release ATP that activates the purinergic receptors P2X2/3 (not shown). A parallel pathway for weak acids has been proposed that involves a passive diffusion for weak acids (HA) into the cell and the subsequent dissociation of H+ and cytoplasmic acidification inactivates the Kir2.1 channel. Also depicted is the possibility that the associated anion (A−) binding to OTOP1 may produce an allosteric effect that could account for the weak/strong acid paradox (see text). Type III cells and acid‐activated trigeminal nerves (drawing at right) are both necessary to trigger aversive responses induced by acid stimuli. Modified, with permission, from Zhang J, et al., 2019 304; Teng B, et al., 2019 265.
Figure 13. Figure 13. Cell types involved in low NaCl attraction and high NaCl rejection. Amiloride‐sensitive cells: Left cell displays, the low concentration of salty taste is transduced by an all‐electrical pathway bypassing intracellular calcium signaling to secrete ATP via the CALHM1/3 channel. From left to right, the second cell depicts a benzamil‐inhibitable type I GAD65+ expressing cell whose optogenetic activation (with ChR2) can drive low sodium appetite during salt deprivation. These cells signaling pathways are still unknown but likely involve the β‐ENaC subunit 156. Amiloride‐insensitive cells: High Salt. The third cell on the right is involved in detecting the Cl− anion under high NaCl concentrations. The receptor and signaling pathways that transduce Cl− are currently unknown 211. Another subpopulation of type II cells expressing the bitter receptor T2R32+ is also recruited after applying high sodium concentrations 193. The signaling pathway for this TRC has not been described, although it is expected to be the same canonical pathway used by bitter‐sensitive type II cells. The type III cell expressing Pkdl1+ has also been shown to be involved in high sodium detection 193. Trigeminal nerve: Hypertonic (>1M), salt concentrations diffuse into the perigemmal epithelium and activate trigeminal nerve endings. Modified, with permission, from Lossow K, et al., 2020 156; Oka Y, et al., 2013 193; Roebber JK, et al., 2019 211.
Figure 14. Figure 14. Responses from specialist and generalist taste cells are found throughout the entire rodent gustatory pathway. (A) Results of calcium imaging TRCs in anesthetized mice. Seventy percent of TRCs exhibited narrowly tuned responses to only one taste quality: sweet, bitter, umami, NaCl, and acid. For the remainder, 30% of the cells responded to more than one tastant [upper cylindrical responses 102]. The colors in the TRCs depict the best‐stimulus of narrowly tuned cells. (B) Electrophysiological recordings of tastant‐evoked action potentials from a specialist TRC that is only responsive to HCl and the response to a generalist cell that is activated by MSG, QHCl, HCl, and NaCl. Bar indicates the duration of the stimulus. Note that these responses occurred even in isolated taste buds from Ref. 298. (C) Afferent fibers of the CT have cell bodies in the geniculate ganglion (GG), and segregated GG populations are more sensitive to one taste quality (Penk for acid; Cdh13 for bitter; spon1for sweet; Cdh4 umami; and Egr2 for NaCl 304. The inset: GG neurons selective to one taste quality are spatially intermingled throughout the GG (see Ref. 11). In the rNTS, Pdyn (prodynorphin) expressing neurons convey acid information 304, whereas Sst (somatostatin) neurons respond to bitter, and Calb2 (Calbindin 2) to sweet tastants. All these rNTS neurons are also spatially intermingled (not shown). In contrast, Satb2 expressing neurons in the PBN are broadly tuned and respond to all taste qualities, but their activation enhances sucrose palatability and makes bitter tastants more aversive. CGRP (calcitonin gene‐related peptide) neurons are not involved in taste processing per se. However, they sense aversive and visceral malaise stimuli in general 119. (D) In the Insular cortex (IC), taste responses are spatially distributed and intermixed, with no apparent taste “map” organization (note the color‐coded for tastants is different from panels A and B, S, sucrose; N, NaCl; CA, citric acid; Q, quinine; and W, water). From the gustatory cortex (IC), taste information goes to reaches the orbitofrontal cortex (OFC) that is commonly referred to as the secondary taste cortex. rNTS, rostral nucleus tractus solitarius; PBN, parabrachial nucleus; VPMpc, ventral posterior medial thalamus (parvocellular region); anterior insular cortex (aIC), and posterior (pIC); MCA, medial cerebral artery. (A) Modified, with permission, from Han J and Choi M, 2018 102. (B) Modified, with permission, from Yoshida R, et al., 2009 298. (C) Modified, with permission, from Jarvie BC, et al., 2021 119; Zhang J, et al., 2019 304. (D) Modified, with permission, from Chen K, et al., 2020 40.
Figure 15. Figure 15. Gut nutrient‐sensing can induce food preferences and promote food‐seeking behavior. Across days, trained rodents develop a preference toward instrumental actions such as lever pressing resulting in an intragastric infusion of sucrose over sucralose (Splenda®), an artificial nonnutritive sweet tastant. Modified, with permission, from Fernandes AB, et al., 2020 72.
Figure 16. Figure 16. Schematic representation of the triad tongue, gut, brain interaction. Shown is the dorsal tongue whose taste responsive neurons first project to the rostral rNTS and vagal neurons innervating the gut, which project to ventro‐caudal vcNTS. These two pathways will result in dopamine (DA) release in the dorsal (DS) or ventral striatum (VS) by activating dopaminergic neurons in the substantial nigra par compacta (SNpc) or the ventral tegmental area (VTA), respectively. The ARC nucleus in the hypothalamus contains AgRP neurons that reflect the animals' internal “hunger” state and can be modulated by hormones like CCK, ghrelin, PYY, leptin, and GLP‐1 that signal an internal state of hunger or satiety. The lower right shows EEC cells that are sensitive to free fatty acids (FFA's—left) and l‐amino acids (right). It also shows a neuropod cell the latter forms synapses with vagal nerves activated by glucose via SGLT1 and uses glutamate as a transmitter to rapidly send information to the brain. For noncaloric sweeteners, these neuropod cells release ATP as a transmitter. The tongue, gut, and brain form a closed‐loop feedback system essential to determine the taste, internal state, and nutritive value of food. Multiple populations of neurons and brain circuits integrate the exteroceptive (tongue‐related) and interoceptive (gut‐related) events triggered by food intake to interpret and generate a conscious taste percept and an unconscious preference for food (see text for details). (inset) Modified, with permission, from Kaelberer MM, et al., 2020 127.


Figure 1. Anatomy of the tongue and taste buds. (A) The drawing of a human tongue 275. Slight elevations in the dorsal surface demarcate fungiform papillae. Circumvallate papillae (big arrows), with the exception of the central one, form an inverted V‐shape along the anterior of the sulcus terminalis. (B‐D) Scanning electron micrographs of the mucosal surface of a canine lingual epithelium. (B) A section of the anterior epithelium with three round fungiform papillae (Fu) and numerous pointed filiform papillae (Fi). * Indicates a magnification area shown in (C). (D) A magnified view of a taste pore (TP) opening into the fungiform papillae. Note that the cornified layers are shed in sheets. (E) A longitudinal section of a taste bud from a rabbit foliate papilla. Several nuclei of types I and II cells are shown. A single type III cell appears at the left edge of the TB. Arrows mark afferent nerve fibers. The TB extends from the basal lamina (BL) to the epithelium (E) surface, where the taste pore (TP) is in contact with the external oral environment. CTi, connective tissue. (A) Modified, with permission, from Witt M, 2019 285. (B‐D) Modified, with permission, from Holland VF, et al., 1989 109. (E) Modified, with permission, from Royer SM and Kinnamon JC, 1994 221.


Figure 2. Dorsal surface of a human tongue with taste papillae and taste bud cells. A drawing of the human tongue showing three types of taste papillae containing TBs as well as their associated afferent fibers. In fungiform papillae, TBs are located mainly around the tip of the tongue, while in circumvallate and foliate papillae, they are in trenches on the posterior and lateral areas of the tongue, respectively (middle panel). Right panel shows a schematic representation of a TB, the peripheral end organ responsible for initiating and transmitting signals that arise in taste perception. TBs are composed of four different types, I, II, III, and IV, surrounded by stratified, squamous epithelial cells. The apical and basolateral sides of taste receptor cells (TRCs) are demarked by tight junctions (dashed black lines). The TB shows a small pit with a “crater‐like” shape, called the taste pore (TP), where tastants enter to activate TRCs. Afferent nerve fibers arising from gustatory ganglion neurons are shown in black. Some fibers selectively contact one type of TRC, whereas others can target more than one type (see text and Ref. 114). Other gustatory fibers also contact and terminate in the perigemmal epithelium (black). The chorda tympani (CT) is a branch of the facial nerve (CN VII), and GPN refers to the glossopharyngeal nerve (CN IX). Free ending fibers (red) from the lingual branch (LN) of the trigeminal nerve (CN V) are embedded in the keratinocytes surrounding the TB of fungiform papillae [see red V(LN)]. Not shown is the vagus nerve (CN X) that innervates the root of the tongue, epiglottis, and larynx. Modified, with permission, from Witt M, 2019 285.


Figure 3. 3‐D reconstruction of type I taste cells shows their two apical morphologies and how they embrace type II and III cells. (A) Short type I cells (light green) terminate in an apical microvillus that does not reach the taste pore, whereas Tall type I cells (dark green) have a longer branched apical process penetrating the taste pore. (B) A drawing of a TB depicting how type I cells (blue) wrap‐around type II (green) and III (orange) cells. (C) An electron microscopic section of a type I cell enwrapping a type II cell with a thin lamellae sheet (light green). The type II cell is contacting a nerve fiber (nf, yellow) and contains an atypical mitochondrion (atM) that may serve as a source of ATP. (A,C) Modified, with permission, from Yang R, et al., 2019 289. (B) Modified, with permission, from Witt M, 2019 285.


Figure 4. Reconstruction of a type III taste cell and two associated nerve fibers (nF). (A) Accumulations of synaptic vesicles (Ves) near the point of cell‐nerve contact indicate synapses (see arrows and circles in C). At one of these contacts is an atypical mitochondrion (atM‐red) with irregular cristae close to the cell membrane. (B) Type III cell nuclei are irregular and elongated with deep invaginations (arrows). Also visible are two adjacent type I cell nuclei (nu) with small invaginations. Classical chemical synapses (C) enlarged at the lower left with synaptic vesicles (arrowheads) appear at some contact points between the type III cell and nerve fibers (nf, yellow). C: Enlargements from panel (B) showing electron‐dense synaptic vesicles (arrowheads) at points of contact with the nerve fibers. Modified, with permission, from Yang R, et al., 2019 289.


Figure 5. Type IV basal precursor cells. (A) Type IV (basal) cells have nuclei (magenta) situated in the lower quarter of the TB. In contrast, the nuclei of typical type II (light blue) and type III (red) cells lie higher in the taste bud. (B) Type IV cells have a basal process extending to the basal lamina (Figure 1E; see BL) at the base of the TB. This process frequently contacts the basal plexus of nerve fibers penetrating the base of the bud. Some basal cells also have an apically directed process that may contact type II or type III cells. Modified, with permission, from Yang R, et al., 2019 289.


Figure 6. Thermal transient receptor potential (TRPs) channels. A selected group of thermal TRPs (and their temperature sensitivities) that are activated either indirectly by tastants (TRPM5; sweet, bitter, and umami—see text) or directly by various spices (TRPA1, TRPV1) or other compounds (TRPM8, TRPV2). A ligand for TRPV4 is bisandrographolide A, extracted from the King of Bitter. (inset) Modified, with permission, from Roper SD, 2014 216; Modified, with permission, from Simon SA and Gutierrez R, 2017 240.


Figure 7. Schematic diagram of gustatory and trigeminal afferent nerve fibers. (A) Chorda Tympani (CT) afferent fibers from geniculate ganglion (GG) neurons can innervate adjacent and distal TBs. Some fibers only contact type II cells (blue), whereas others only type III cells (gray). In addition, some fibers can contact both type II and III cells (purple) (see text). The cell bodies of the CT and the greater superficial petrosal (GSP) nerves reside in the GG and project to rNTS (see pictures in C). Some CT fibers do not target fungiform taste bud cells but instead terminate in lingual epithelial tissue (black fibers) (see Figure 8C, cluster M5). The “somatosensory” GG cells innervating the outer ear are not shown. Along with gustatory fibers from the CT run trigeminal innervation. Included in that group are neurons that contain transient receptor potential (TRP) cation channel subfamily M member 8 (TRPM8) neurons that respond to menthol and from the transient receptor potential cation channel subfamily V member 1 (TRPV1), which is a receptor for capsaicin the principal ingredient in chili peppers responsible for its burning sensation (Figure 6). Trigeminal nerve fibers project to the spinal trigeminal nucleus (SpVc) and the rNTS 302. (B) A cresyl‐violet‐stained of a rat GG soma also shown both the CT and GSP fibers (see arrows). (C) Upper picture depicts histology of CT fibers innervating the rNTS, and the lower panel shows fluorescent glossopharyngeal nerve (GPN) in red and GSP fibers in green. 4 denotes the 4th ventricle. (A) Modified, with permission, from Zaidi FN, et al., 2008 302. (C) Modified, with permission, from Martin LJ, et al., 2018 164.


Figure 8. Single‐cell genetic profiling of mouse geniculate ganglion (GG) neurons found two major cell types: those expressing the transcriptional factor Phox2b+ that conveys gustatory information and those expressing Phox2b− fibers that are somatosensory neurons that innervate the outer ear. (A) Labeling the GG. The immunostaining of purinergic receptor P2X3 (a marker for afferent nerve fibers is in red) and purple represents the GG neurons expressing Phox2b+ and P2X3+ are labeled in purple (merge). The nonnuclear “green” signal is an unspecific binding of the mouse antibody. (B) A meta‐analysis of three experiments showing the genetic profiling of individual GG neurons 4,64,304. In the middle panel, a dot represents a single GG neuron classified into seven distinct clusters (M0‐M6) arranged according to its five main genes (see correlation matrix in C). (C) Clusters from M1‐M6 corresponds to gustatory GG neurons (expressing Phox2b+). The somatosensory GG neurons belong to cluster M0 (Phox2b−). The cluster M2 is composed of GG neurons expressing the Spon1 gene, and they are responsive to sweet tastants. The cluster M6 is involved in acid taste transduction and is characterized by the expression of the Penk gene. M5 is an ensemble of GG neurons that may be involved in mechano‐transduction information from the tongue. These cells expressed the gene for Piezo2. Modified, with permission, from Anderson CB and Larson ED, 2020 4.


Figure 9. Primary canonical signaling pathways are shared by sweet and bitter tastants and l‐amino acids. After chemicals are bound to their associated GPCRs, G‐protein βγ subunits then → PLC‐β2 → PIP2 → IP3 and activation of endoplasmic reticulum IP3R3 receptors → increasing intracellular [Ca2+]i → cation influx through TRPM4 and TRPM5 channels → membrane depolarization → opening the CALHM1/3 channels → secretion of ATP that activates P2X2/P2X3 receptors on primary afferent neurons. In parallel, activation of voltage‐gated Na+ channels (Nav) amplifies the membrane depolarization and increases ATP secretion (see text). Some type II cells also express a sodium‐glucose‐linked transporter 1 (SGLT1) that can distinguish glucose from noncaloric artificial sweeteners that can also activate T1R2/T1R3 receptors. Type II cells can also detect and transduce long‐chain fatty acids (FAs). FAs bind to the translocator CD36 to activate specific G protein‐coupled receptors (like GPR120 receptors) to initiate a transduction cascade that in turn produces a second messenger leading to release intracellular [Ca2+]i (see the text on fat for details ). It remains unknown as to whether CD36 serves as a chaperon for GPR120 to transduce FFAs or both works independently. The basal part of the type II cells can also respond in an endocrine, autocrine, or paracrine manner to hormones such as leptin, GLP‐1, and ghrelin (see text for additional details). The TRC in the middle depicts a type II cell that expresses the l‐amino acid receptor, T1R1/T1R3. Shown at the right is a type II cell with three T2R receptors activated by bitter tastants. It remains to determine whether type II bitter cells also express receptors for peptides. Modified, with permission, from Gao N, et al., 2009 84; Liu P, et al., 2011 153.


Figure 10. Morphology of a type II cell and a schematic of the structure of the human “sweet taste” receptor hT1R2/3 with its many binding sites. Reconstruction (3‐D) of a type II cell from a mouse's circumvallate papillae. Red spots indicate the position of atypical mitochondria (atM), which may act as a source of ATP to be released to activate receptors on primary afferent fibers. Also shown is a microvillus that extends through the taste pore (up—not shown) into the oral cavity. Inset. The heterodimer T1R2/T1R3 is composed of an extracellular amino terminal domain (ATD), containing a venus flytrap domain (VFD) and a cysteine‐rich domain (CRD). The VFD has two lobes that change their conformation to “open” or “closed” states, like that seen in the carnivorous plant with the same name. The VFD is connected via the CRD to the seven helical transmembrane domains (TMD). Importantly, sweet‐tasting molecules bind to different receptor sites (arrows), inducing conformational changes eliciting a canonical signaling cascade, shown in Figures 9 and 11. (Left) Modified, with permission, from Yang R, et al., 2019 289. (Right) Modified, with permission, from Laffitte A, et al., 2014 136.


Figure 11. Sweet, umami, and bitter taste responses require the co‐activation of both a narrowly tuned type II cell (left) and a broadly tuned type III cell (right). The integration of information between two types of taste cells could occur in the taste bud (TB) or by those afferent fibers that contact both type II and type III cells. At right is shown a recently identified broadly responsive type III cell (BRtypeIII cell) that responds to acid, sweet, umami, and bitter tastants via not yet identified receptors that activate PLC‐β3 → IP3R1 that then produces an increase of intracellular Ca2+ that probably activate TRPM4 channels (see ?) present in those cells. This leads to the activation of voltage‐gated calcium channels (VGCCs) that cause the release of synaptic vesicles whose transmitters activate primary neurons 10. It is still unknown what transmitter uses the BRTypeIII cell to communicate with afferent nerves (see small ? next to vesicles). Wherever the logic AND circuit occurs (see large ? marks), it should happen between the TB and GG before taste information is sent to the rNTS (light blue somas). From the rNTS, taste information is partitioned into oromotor reticular formation (RF; red neurons), where the central pattern generator for rhythmic licking is located 266 or to a classical taste/visceral pathway in the parabrachial nucleus (PBN; dark blue neurons). Modified, with permission, from Travers JB, et al., 1997 266; Banik DD, et al., 2020 10.


Figure 12. The signaling cascade pathways for acid taste transduction. Type III cells express the proton permeable ion channel, otopetrin‐1 (OTOP1) 265,304. Influx of H+ through OTOP1 acidifies the cytoplasm, which could inhibit potassium Kir2.1 channels that induce a small depolarizing (inward) current sufficient to gate voltage‐gated Ca2+ channels and produce action potentials (Nav), leading to the subsequent release of synaptic vesicles (black circles) containing 5‐HT that may bind to 5‐HT3aR channels on afferent nerves. Alternatively, it perhaps could co‐release ATP that activates the purinergic receptors P2X2/3 (not shown). A parallel pathway for weak acids has been proposed that involves a passive diffusion for weak acids (HA) into the cell and the subsequent dissociation of H+ and cytoplasmic acidification inactivates the Kir2.1 channel. Also depicted is the possibility that the associated anion (A−) binding to OTOP1 may produce an allosteric effect that could account for the weak/strong acid paradox (see text). Type III cells and acid‐activated trigeminal nerves (drawing at right) are both necessary to trigger aversive responses induced by acid stimuli. Modified, with permission, from Zhang J, et al., 2019 304; Teng B, et al., 2019 265.


Figure 13. Cell types involved in low NaCl attraction and high NaCl rejection. Amiloride‐sensitive cells: Left cell displays, the low concentration of salty taste is transduced by an all‐electrical pathway bypassing intracellular calcium signaling to secrete ATP via the CALHM1/3 channel. From left to right, the second cell depicts a benzamil‐inhibitable type I GAD65+ expressing cell whose optogenetic activation (with ChR2) can drive low sodium appetite during salt deprivation. These cells signaling pathways are still unknown but likely involve the β‐ENaC subunit 156. Amiloride‐insensitive cells: High Salt. The third cell on the right is involved in detecting the Cl− anion under high NaCl concentrations. The receptor and signaling pathways that transduce Cl− are currently unknown 211. Another subpopulation of type II cells expressing the bitter receptor T2R32+ is also recruited after applying high sodium concentrations 193. The signaling pathway for this TRC has not been described, although it is expected to be the same canonical pathway used by bitter‐sensitive type II cells. The type III cell expressing Pkdl1+ has also been shown to be involved in high sodium detection 193. Trigeminal nerve: Hypertonic (>1M), salt concentrations diffuse into the perigemmal epithelium and activate trigeminal nerve endings. Modified, with permission, from Lossow K, et al., 2020 156; Oka Y, et al., 2013 193; Roebber JK, et al., 2019 211.


Figure 14. Responses from specialist and generalist taste cells are found throughout the entire rodent gustatory pathway. (A) Results of calcium imaging TRCs in anesthetized mice. Seventy percent of TRCs exhibited narrowly tuned responses to only one taste quality: sweet, bitter, umami, NaCl, and acid. For the remainder, 30% of the cells responded to more than one tastant [upper cylindrical responses 102]. The colors in the TRCs depict the best‐stimulus of narrowly tuned cells. (B) Electrophysiological recordings of tastant‐evoked action potentials from a specialist TRC that is only responsive to HCl and the response to a generalist cell that is activated by MSG, QHCl, HCl, and NaCl. Bar indicates the duration of the stimulus. Note that these responses occurred even in isolated taste buds from Ref. 298. (C) Afferent fibers of the CT have cell bodies in the geniculate ganglion (GG), and segregated GG populations are more sensitive to one taste quality (Penk for acid; Cdh13 for bitter; spon1for sweet; Cdh4 umami; and Egr2 for NaCl 304. The inset: GG neurons selective to one taste quality are spatially intermingled throughout the GG (see Ref. 11). In the rNTS, Pdyn (prodynorphin) expressing neurons convey acid information 304, whereas Sst (somatostatin) neurons respond to bitter, and Calb2 (Calbindin 2) to sweet tastants. All these rNTS neurons are also spatially intermingled (not shown). In contrast, Satb2 expressing neurons in the PBN are broadly tuned and respond to all taste qualities, but their activation enhances sucrose palatability and makes bitter tastants more aversive. CGRP (calcitonin gene‐related peptide) neurons are not involved in taste processing per se. However, they sense aversive and visceral malaise stimuli in general 119. (D) In the Insular cortex (IC), taste responses are spatially distributed and intermixed, with no apparent taste “map” organization (note the color‐coded for tastants is different from panels A and B, S, sucrose; N, NaCl; CA, citric acid; Q, quinine; and W, water). From the gustatory cortex (IC), taste information goes to reaches the orbitofrontal cortex (OFC) that is commonly referred to as the secondary taste cortex. rNTS, rostral nucleus tractus solitarius; PBN, parabrachial nucleus; VPMpc, ventral posterior medial thalamus (parvocellular region); anterior insular cortex (aIC), and posterior (pIC); MCA, medial cerebral artery. (A) Modified, with permission, from Han J and Choi M, 2018 102. (B) Modified, with permission, from Yoshida R, et al., 2009 298. (C) Modified, with permission, from Jarvie BC, et al., 2021 119; Zhang J, et al., 2019 304. (D) Modified, with permission, from Chen K, et al., 2020 40.


Figure 15. Gut nutrient‐sensing can induce food preferences and promote food‐seeking behavior. Across days, trained rodents develop a preference toward instrumental actions such as lever pressing resulting in an intragastric infusion of sucrose over sucralose (Splenda®), an artificial nonnutritive sweet tastant. Modified, with permission, from Fernandes AB, et al., 2020 72.


Figure 16. Schematic representation of the triad tongue, gut, brain interaction. Shown is the dorsal tongue whose taste responsive neurons first project to the rostral rNTS and vagal neurons innervating the gut, which project to ventro‐caudal vcNTS. These two pathways will result in dopamine (DA) release in the dorsal (DS) or ventral striatum (VS) by activating dopaminergic neurons in the substantial nigra par compacta (SNpc) or the ventral tegmental area (VTA), respectively. The ARC nucleus in the hypothalamus contains AgRP neurons that reflect the animals' internal “hunger” state and can be modulated by hormones like CCK, ghrelin, PYY, leptin, and GLP‐1 that signal an internal state of hunger or satiety. The lower right shows EEC cells that are sensitive to free fatty acids (FFA's—left) and l‐amino acids (right). It also shows a neuropod cell the latter forms synapses with vagal nerves activated by glucose via SGLT1 and uses glutamate as a transmitter to rapidly send information to the brain. For noncaloric sweeteners, these neuropod cells release ATP as a transmitter. The tongue, gut, and brain form a closed‐loop feedback system essential to determine the taste, internal state, and nutritive value of food. Multiple populations of neurons and brain circuits integrate the exteroceptive (tongue‐related) and interoceptive (gut‐related) events triggered by food intake to interpret and generate a conscious taste percept and an unconscious preference for food (see text for details). (inset) Modified, with permission, from Kaelberer MM, et al., 2020 127.
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Further Reading
 1. Bigiani A. The origin of saltiness: Oral detection of NaCl. Curr Opin Physiol 19: 156‐161, 2021. DOI: 10.1016/j.cophys.2020.11.006.
 2.Davidenko O, Darcel N, Fromentin G, Tomé D. Control of protein and energy intake—brain mechanisms. Eur J Clin Nutr 67: 455‐461, 2013. DOI: 10.1038/ejcn.2013.73.
 3.Gilbertson TA, Yu T, Shah BP. Gustatory Mechanisms for Fat Detection. CRC Press/Taylor & Francis, 2010.
 4.Gutierrez R, Fonseca E, Simon SA. The neuroscience of sugars in taste, gut‐reward, feeding circuits. and obesity. Cell Mol Life Sci 77: 3469‐3502, 2020. DOI: 10.1007/s00018‐020‐03458‐2.
 5.Kaelberer MM, Rupprecht LE, Liu WW, Weng P, Bohórquez DV. Neuropod cells: The emerging biology of gut‐brain sensory transduction. Annu Rev Neurosci 43: 337‐353, 2020. DOI: 10.1146/annurev‐neuro‐091619‐022657.
 6.Lim J, Pullicin AJ. Oral carbohydrate sensing: Beyond sweet taste. Physiol Behav 202: 14‐25, 2019. DOI: 10.1016/j.physbeh.2019.01.021.
 7.Roper SD. 3.09—Microphysiology of taste buds. In: Fritzsch B, editor. The Senses: A Comprehensive Reference (2nd ed). Oxford: Elsevier, 2020, p. 187‐210.

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Article Title: Physiology of Taste Processing in the Tongue, Gut, and Brain
 

How to Cite

Ranier Gutierrez, Sidney A. Simon. Physiology of Taste Processing in the Tongue, Gut, and Brain. Compr Physiol 2021, 11: 2489-2523. doi: 10.1002/cphy.c210002