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Does Your Gut Taste? Sensory Transduction in the Gastrointestinal Tract

Helen E. Raybould

H. E. Raybould is at CURE/VA Wadsworth Medical Center, Bldg. 115, Room 209, 11301 Wilshire Blvd., Los Angeles, CA 90073, USA.

	Abstract

 
The primary sensors in the gut are endocrine cells. They release peptides and amines that stimulate intrinsic and extrinsic neural pathways affecting gastrointestinal motor and secretory function. These regulatory mechanisms alter the digestive and absorptive capacity of the intestine to match the entry of a meal from the stomach.

	Introduction

Top Introduction Morphology of visceral afferents Mechanotransduction Chemotransduction Perspectives References

 
The nervous system is electrically wired in "reflex circuits." Each neural circuit contains an afferent neuron that carries electrical activity from the periphery to a center of integration, either a ganglion or a specialized region of the brain. After afferent signals are processed, information flows back to the periphery via motoneurons to modify behavior. Thus afferent neurons were thought to be the sensors of the digestive state. Since the beginning of this century, it has been known that visceral nerves, including those supplying the gastrointestinal tract, contain afferent fibers that transmit information from the viscera to the central nervous system. Although early studies used sensation arising from the viscera as a means to study the afferent innervation, Ranson (11) noted that "the majority of the afferent impulses from the viscera never rise to the level of consciousness at all but expend themselves in the production of reflexes." For example, placing acid in the intestine inhibits emptying of the stomach by activating a neural reflex without any conscious sensation. It is now well recognized that a number of mechanical and chemical stimuli applied to the lining or mucosa of the small intestine can exert feedback inhibition of both secretion and muscle contraction of the gastrointestinal tract. The importance of these regulatory mechanisms is to match the digestive and absorptive capacity of the intestine with the entry of nutrients from the stomach and to modify food intake.

Despite nearly 50 years of neurophysiological recordings from afferent nerve fibers innervating the gastrointestinal tract, the transduction mechanisms in the nerve terminals responding to mechanical and chemical stimuli are largely unknown (7). These terminals are not readily identifiable, since they are unmyelinated, unencapsulated, and lacking in morphological specialization. Functional specificity therefore occurs in the absence of gross morphological differentiation. Gastrointestinal afferents are classified according to their presumed location in the gut wall. Thus mucosal afferents respond to mechanical and chemical stimuli applied to the mucosa or epithelial lining, and their activity is lost if the mucosa is perfused with local anesthetic or is stripped from the overlying muscle layers. Receptors with terminal fields in the smooth muscle generally respond to changes in tension, generated by either active contraction or passive distension of the muscle.

	Morphology of visceral afferents

Top Introduction Morphology of visceral afferents Mechanotransduction Chemotransduction Perspectives References

 
New insights made possible by the use of highly fluorescent carbocyanine dyes have revealed some of the detailed morphology of visceral afferent terminals, primarily those traveling in the vagus nerves (Fig. 1) (1). The dye, after it is injected into the nodose ganglia, which contains cell bodies of vagal afferents, is transported to peripheral terminals. With the use of laser scanning confocal microscopy, the detailed morphology of an individual afferent in the tissue can be revealed in its entirety. Vagal afferents have been shown to terminate in the myenteric plexus (part of the enteric nervous system) and within the longitudinal and circular smooth muscle layers of the stomach and proximal intestine (Fig. 1). These terminals situated in the connective tissue matrix of the smooth muscle are in the location predicted for tension receptors (5, 6). Individual afferent fibers collateralize extensively in the submucosa, producing terminal arborizations in the mucosa that cover large areas with endings around the crypts (which contain secretory epithelial cells) and within the lamina propria of the villi (which contain absorptive and endocrine cells). The densest innervation is in the proximal part of the small intestine into which the stomach empties after a meal. No fibers penetrate between epithelial cells or protrude into the lumen. Therefore, the transduction mechanism must occur after nutrients are taken up by epithelial cells, i.e., postuptake mechanisms.

View larger version (58K): [in this window] [in a new window]   FIGURE 1. Schematic view of the vagal afferent innervation of the duodenal wall based on results from in vivo tracing with 1,1'-dioctadecyl-3,3,3',3'-tetramethyl-indocarbocyanine (DiI). CL, crypts of Lieberkuhn; CM, circular muscle; FC, fibrocyte-like cells; IGLE, intraganglionic laminar ending; LM, longitudinal muscle; LV, lymph vessel; MMA, muscularis mucosa; MP, myenteric plexus; SMA, submucosa; SMP, submucosal plexus. [Reprinted from Berthoud et al., Anat. Embryol. (Berl.) 191: 203–212, 1995, with permission. Copyright of Springer-Verlag.]

	Mechanotransduction

Top Introduction Morphology of visceral afferents Mechanotransduction Chemotransduction Perspectives References

Role of stretch-activated channels.
The role of stretch-activated ion channels in the autonomic nervous system has been studied most extensively in carotid and aortic baroreceptors. Arterial baroreceptors, like gastrointestinal afferents, are activated by increases in transmural pressure. In an isolated carotid sinus preparation, the increase in carotid sinus nerve activity in response to an increase in distension was significantly reduced by perfusion with gadolinium, the trivalent lanthanide that blocks stretch-activated channels. In addition, gadolinium abolished pressure-induced increases in neuronal activity in single nerve fiber preparations from baroreceptor afferents. In whole cell patch-clamp studies of putative aortic baroreceptor neurons in culture, hyposmotic stretch caused an increase in conductance, which was gadolinium sensitive. These observations provide functional evidence for a role for stretch-sensitive channels in mechanoelectrical transduction in baroreceptors and raise the interesting possibility that they function in gastrointestinal afferent transmission as well (8).

We have investigated a similar phenomenon by studying increases in intracellular calcium concentration ([Ca²⁺]_i) in extrinsic afferent neurons in cell culture. Spinal and vagal afferent neurons innervating the colon, duodenum, or stomach were identified by the presence of a retrograde tracer, dextran-conjugated Texas Red, injected into the visceral wall 14–28 days previously. Brief focal mechanical deformation of the cell soma increased [Ca²⁺]_i in 40% of these neurons. The increase in [Ca²⁺]_i returned to baseline levels and was repeatable, suggesting it was not due to damage of the cell membrane. The increase in [Ca²⁺]_i in response to mechanical stimulation was dependent on the entry of extracellular calcium and was blocked by gadolinium. This evidence suggests that gastrointestinal afferents express stretch-activated, gadolinium-sensitive channels that may play a role in mechanoelectrical transduction in visceral afferents innervating both the gastrointestinal and cardiovascular systems (Fig. 2). However, as yet there is no functional evidence that these mechanosensitive calcium transients play a role in mediating responses to mechanical stimuli in the gastrointestinal tract.

View larger version (19K): [in this window] [in a new window]   FIGURE 2. A model of mechanosensitivity in the intestine. Mucosal deformation may open stretch-activated ion channels on an enteroendocrine cell, which causes the influx of cations, opens voltage-gated calcium channels, and triggers secretion of 5-hydroxytryptamine (5-HT) by exocytosis. 5-HT then activates neuronal 5-HT1P receptor (5-HT1PR) on intrinsic afferent nerve terminals in the submucosal or myenteric plexus and results in firing of action potentials. Alternatively, stretch-activated channels may be located on afferent nerve terminals themselves, and activation may result in firing of receptor potentials.

	Chemotransduction

Top Introduction Morphology of visceral afferents Mechanotransduction Chemotransduction Perspectives References

 
Unlike mechanosensitivity, in which similarities exist between species with respect to the characteristics of responses, chemosensitivity of extrinsic afferent neurons presents a more complex picture (7). The existence of modality-specific chemoreceptors responding to the various nutrient components of a meal have been described in the cat. These afferents are insensitive to mechanical stimulation and respond only to a specific chemical modality. Thus glucoreceptors, acid or pH receptors, amino acid receptors, lipid receptors, osmoreceptors, and thermoreceptors have been described. However, others have shown only multimodal responses in mucosal afferents; these endings respond to touch or movement across the mucosa and to solutions of high osmolarity. This apparent discrepancy may be due to the heterogeneity of this class of afferents or to the inherent sampling problems in recording from single afferent nerve fibers. However, it may also be due in part to the difficulty in delivering a quantitatively precise stimulus to the receptor endings, since, in particular for nutrients, the release of hormones may alter neural responses or indeed may be the basis for the responses.

Functional evidence for chemosensitivity.
Whatever disagreement exists for the precise properties and responses of individual afferent neurons, the extent of the chemosensitivity of extrinsic afferents can be inferred from in vivo physiological experiments. Perfusion of the intestine with acid, carbohydrate, lipid, protein, or amino acids, as well as solutions of high osmolarity, has been shown to decrease gastric motility, delay gastric emptying, decrease gastric acid secretion, and produce a reduction in food intake (satiety) in a variety of animal models and in humans. Investigators have used the neurotoxin capsaicin, the ingredient in red chili peppers that stimulates and destroys extrinsic small diameter afferents, to demonstrate a direct involvement of extrinsic afferents in this intestinal feedback inhibition of gastric function (12). Systemic treatment of adult or neonatal rats with capsaicin attenuates inhibition of feedback responses to intestinal nutrients. After application of capsaicin either directly to the vagal nerve trunk or the celiac ganglion (to selectively denervate either vagal or spinal afferents respectively), it was shown that inhibition of gastric emptying in response to intestinal lipid is mediated by a vagal afferent pathway, whereas inhibition of gastric emptying by hexoses is mediated by both vagal and spinal afferent pathways (Fig. 3). Thus there is strong functional evidence for both vagal and spinal afferents having roles in mediating chemoreceptive responses from the intestine.

View larger version (25K): [in this window] [in a new window]   FIGURE 3. Both vagal and spinal afferent pathways are important in mediating nutrient-specific information from the gastrointestinal tract. Vagal afferent pathways transmit information about protein/amino acids (AAs), lipids, and carbohydrates (hexoses); for the latter, the vagal afferents seem to be in the accessory celiac branch of the vagus. In addition, spinal afferents transmit information for hexoses but not lipids. Activation of both spinal and vagal afferent fibers results in alteration of autonomic efferent outflow to alter secretory and motor function of the gastrointestinal tract. DRG, dorsal root ganglion; NTS, nucleus of tractus solitarius.

Role for cholecystokinin.
Several peptide hormones, including cholecystokinin (CCK), secretin, and peptide YY, are released from mucosal endocrine cells by nutrients in the intestine and, when administered exogenously, mimic some of the effects of intestinal nutrients on motor and secretory function. Evidence for a physiological role is best for CCK because of the availability of potent, selective receptor antagonists that block its action. Administration of CCK-A receptor antagonists blocks the ability of intestinal nutrients to inhibit gastric emptying and motility, acid secretion, and food intake. The proposed model predicts that nutrients, such as protein and lipid, release CCK from endocrine cells; CCK subsequently stimulates discharge in afferents resulting in reflex alteration of gastric function (Fig. 4). We made the observation that hexoses, which do not increase plasma levels of CCK, inhibit gastric emptying, and this response is abolished by a CCK-A receptor antagonist (12). This observation suggests a local paracrine action of CCK to stimulate intestinal mucosal afferents. Electrophysiological evidence supports this model. Mucosal afferents in the intestine of the ferret are extremely sensitive to exogenously administered CCK. These afferents are also stimulated by mucosal stroking, acidity, and hypertonic solutions and therefore fit the classification of multimodal mucosal afferents.

View larger version (21K): [in this window] [in a new window]   FIGURE 4. Possible sensory transduction mechanisms for glucose and lipid. Hexoses (glucose) are required to be transported via SGLT-1 into epithelial cells to signal changes in gastric motor function. Alternatively, it is possible that endocrine cells express SGLT-1 and may release cholecystokinin (CCK) or 5-hydroxytryptamine (5-HT) in response to glucose, which then stimulates 5-HT3 and CCK-A receptors on afferent nerve terminals located nearby. These sensory nerve terminals respond via the 5-HT3 or CCK-A receptors that they express. In the case of lipids, it is possible that chylomicron formation and apolipoprotein AIV (apoAIV) stimulate release of CCK that then stimulates afferent nerve terminals.

Another candidate agent in sensory transduction in the intestinal mucosa is 5-HT (Fig. 4). Similar to CCK receptors, 5-HT receptors have been identified on vagal and spinal afferent neurons and are of the 5-HT₃ receptor subtype. 5-HT activates vagal mucosal afferents, and this response is abolished by granisetron, a 5-HT₃ receptor antagonist. Hexose-induced inhibition and protein-induced inhibition of gastric emptying are blocked by 5-HT₃ receptor blockade. Thus, like CCK, there is morphological and functional evidence that 5-HT also plays a role in sensory transduction in the gastrointestinal mucosa.

Nutrient-specific effects.
Although it is now clear that peptide hormones and bioactive amines are involved in sensory transduction, the mechanism by which nutrients release these agents is not clear. To identify the exact mechanism of detection and its anatomic substrate, one can consider the pathway of absorption for each macronutrient. We will consider this for fats and carbohydrates (Fig. 4).

After enzymatic breakdown of ingested fats into fatty acids and monoglycerides, these molecules are taken up by enterocytes, resynthesized into triglyceride, and transported out of enterocytes by exocytosis in the form of chylomicrons, which diffuse into lymph (only medium to long chain fatty acids, which are important for signaling feedback). Chylomicrons have an apolipoprotein coat. Synthesis of one of these, apolipoprotein AIV (apoAIV), and formation of chylomicrons can be very rapid and have been proposed to be involved in signaling intestinal lipid content to other organ systems. For example, intraperitoneal injection of chylous lymph or exogenous apoAIV has been shown to inhibit food intake in rats (10). We have support for this proposal, since intestinal lipid-induced inhibition of gastric emptying was abolished in the presence of Pluronic L-81, a detergent that inhibits chylomicron formation. Because we know that CCK is involved in this response, it is possible that chylomicron formation is necessary to produce CCK release. The mechanism by which nutrients, including fat, release CCK from endocrine cells is not well characterized. For example, it is not known whether chylomicron formation occurs in endocrine cells or whether apoAIV is important in signaling to endocrine cells.

Ingested carbohydrates are digested within the lumen and brush border of the intestine and are absorbed as monosaccharides via sodium-coupled transporters into enterocytes. Glucose and galactose are taken up via the transporter called SGLT-1 located on the apical portion of the membrane and extruded out of the basolateral membrane via the transporter GLUT-2 (Fig. 4). The sensory transduction mechanism lies at or beyond SGLT-1 on the apical membrane and probably resides within the epithelial cell. Evidence for this conclusion comes from several observations, including experiments showing that glucose-induced inhibition of gastric emptying is mimicked only by an analog of glucose that is a substrate for SGLT-1 and is blocked by a competitive blocker of SGLT-1. Thus the transduction mechanism for hexoses requires either rapid accumulation of glucose in the enterocyte or some signal generated by activation of the transporter. Alternatively, it is possible that the endocrine cells themselves express the transporter, take up the hexose, and release CCK or 5-HT.

	Perspectives

Top Introduction Morphology of visceral afferents Mechanotransduction Chemotransduction Perspectives References

 
There is support for the hypothesis that EC cells and other endocrine cells are the "sensors" in the gut that release their contents in response to mechanical and chemical stimulations of the intestinal wall. Extrinsic and intrinsic afferents express functional receptors for a number of peptide hormones and bioactive amines, and activation of these receptors initiates responses of the gastrointestinal tract that mimic nutrient effects in the intestine.

	References

Top Introduction Morphology of visceral afferents Mechanotransduction Chemotransduction Perspectives References

 

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