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© 2005 The American Society for Nutritional Sciences J. Nutr. 135:1491-1495, June 2005

Nutritional Neurosciences

Activation of Vagal Afferents in the Rat Duodenum by Protein Digests Requires PepT11,2

N. P. Darcel*, A. P. Liou, D. Tomé* and H. E. Raybould3

Department of Anatomy, Physiology and Cell Biology, UC Davis School of Veterinary Medicine, Davis, CA 95616 and * UMR INRA 914 Physiologie de la Nutrition et du Comportement Alimentaire, INAPG, 75231 Paris cedex 05, France

3To whom correspondence should be addressed. E-mail: heraybould{at}ucdavis.edu.


   ABSTRACT
TOP
 ABSTRACT
MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 LITERATURE CITED
 
Intestinal infusion of protein digests activates a vago-vagal reflex inhibition of gastric motility. Protein digests release cholecystokinin (CCK) from enteroendocrine cells; however, the precise cellular mechanisms leading to vagal afferent activation is unclear. The hypothesis that the oligopeptide transporter PepT1 plays a major role in the initiation of this vago-vagal reflex was tested by recording activation of duodenal vagal afferent activity and inhibition of gastric motility in response to protein hydrolysates in the presence of 4-aminomethylbenzoic acid (4-AMBA), a competitive inhibitor of PepT1, or 4-aminophenylacetic acid (4-APAA), an inactive 4-AMBA analog. Duodenal infusion of the protein hydrolysate increased vagal afferent discharge and inhibited gastric motility; these responses were abolished by concomitant infusion of 4-AMBA, but not 4-APAA. Duodenal infusion with Cefaclor, a substrate of PepT1, increased duodenal vagal afferent activity; Cefaclor and protein hydrolysates selectively activated CCK-responsive vagal afferents. This study demonstrates that products of protein digestion increase spontaneous activity of CCK-sensitive duodenal vagal afferents via a mechanism involving the oligopeptide transporter PepT1.

KEY WORDS: • nutrient detection • protein • vagal afferents • PepT1 • cholecystokinin

Dietary proteins play a major role in the regulation of motility in the gastrointestinal tract and in the establishment of satiety. For example, infusion of the intestine with hydrolysates of protein inhibits gastric motility and emptying (1,2) and reduces food intake (3,4) in both animals and humans. This response to dietary protein is part of the intestinal feedback regulation of gastrointestinal function and food intake; this homeostatic response matches the digestive and absorptive capacity of the gastrointestinal tract with the entry of nutrients, to ensure efficient digestion and absorption of a meal in the postprandial period. The mechanisms and pathways by which nutrients, including proteins, are detected by the wall of the gut involve local responses of epithelial cells, release of hormones, and activation of neural pathways (5). The vagus nerve conveys information from the gut to the brainstem and plays a major role in the control of postprandial gastrointestinal function and satiety by macronutrients (6,7); the presence of protein hydrolysate in the duodenum effectively releases cholecystokinin (CCK)4 from endocrine cells, resulting in the activation of CCK1 receptors (CCK1R) on vagal afferent nerve terminals (8). Inhibition of gastric motility in response to protein hydrolysates is mediated by a CCK1R and vagal afferent reflex pathway (2,9,10). Stimulation of vagal afferent activity in response to protein digests is blocked by specific antagonists of CCK1Rs (8), and activation of the marker of neuronal activation, fos, in the brainstem is increased by intestinal perfusion of protein hydrolysates via a CCK1R mechanism (11,12).

The precise mechanism and the cascade of events by which a protein hydrolysate is detected by intestinal epithelial cells and causes the release of CCK from endocrine cells remain unclear. A main process for the uptake of protein hydrolysates in the intestine is the proton-coupled oligopeptide transporter PepT1, a member of the family of peptide transporters found in all species from bacteria to humans (13,14). This transporter is the exclusive oligopeptide transporter of the intestinal mucosa and has a requirement for the di- and tripeptide structure. Thus, it has a large range of substrates from oligopeptides derived from dietary protein to synthesized peptides such as the ß-lactam antibiotics and angiotensin-converting enzyme inhibitors. The transporter is localized to the apical membrane of enterocytes. Protein hydrolysates release CCK from the intestinal mucosa, but it is not clear whether this is a direct effect on endocrine cells or whether the effect of protein hydrolysates is mediated indirectly by releasing factors (15–18). The CCK-producing cell line, STC-1, proved to be a useful model for the study of CCK release; in these cells, the peptidomimetic cephalosporin, Cefaclor, stimulates a calcium-dependent release of CCK (19). This suggests a direct effect of substrates of PepT1 to release CCK from endocrine cells. However, whether this occurs in vivo with native endocrine cells is not known. Cefalcor was also reported to inhibit gastric emptying through a vagal and CCK1 receptor–mediated mechanism in awake rats (20).

Given the observation that high-protein diets induce satiety and are used in weight reduction programs, there is substantial interest in understanding how signals arising from the gastrointestinal tract associated with protein digestion initiate feedback inhibition of food intake and gastrointestinal function. In the present study, we tested the hypothesis that PepT1 activation is required for activation of vagal afferent nerve fibers to initiate intestinal feedback in response to protein hydrolysates. This hypothesis was tested by determining the ability of protein hydrolysates to stimulate the activity of duodenal vagal afferent fibers and to inhibit gastric motility in the presence of 4-aminomethylbenzoic acid (4-AMBA), a nontranslocated PepT1 competitive inhibitor (21), or 4-APAA, a translocated 4-AMBA analog that does not inhibit the transport of di- and tripeptides (22). We also tested the effects of Cefaclor, a cephalosporin antibiotic, for its ability to stimulate vagal afferent fiber activity.


   MATERIALS AND METHODS
TOP
 ABSTRACT
 MATERIALS AND METHODS
RESULTS
 DISCUSSION
 LITERATURE CITED
 
    Animals, drugs and chemicals. Sprague-Dawley male rats (Harlan) weighing 200–300 g were housed in a room controlled for temperature (21–23°C). All experimental procedures complied with the UC Davis Institutional Animal Care and Use Committee.

CCK-8 was dissolved in physiological saline to make a 10 nmol/L stock solution, which was stored at –20°C and diluted as required. Peptone (enzymatic hydrolysate Type 1: from meat) was dissolved in physiological saline to the desired concentration. 4-AMBA and 4-APAA were dissolved (10 mmol/L) in physiological saline. Cefaclor was dissolved (100 mmol/L) in physiological saline. Normal rat saline was made as previously described (23) (mmol/L: 140 NaCl, 5 KCl, 1 MgCl2, 1.3 Na2HPO4, 5 Hepes, 2 CaCl2, and 10 D-glucose, pH 7.38 ± 0.02). All chemicals and drugs were obtained from Sigma Chemical unless otherwise specified.

    Measurement of gastric motility. Gastric motility measurement was performed in rats as previously described (24). Briefly, rats (200–250 g) were anesthetized with urethane (1.25 g/kg, i.p.; Sigma), a catheter was placed in the trachea to ensure a clear airway, and a catheter was placed through an incision in the forestomach to measure intraluminal gastric pressure (IGP). A second catheter was placed in the proximal duodenum via the stomach just distal to the pylorus, and a third catheter was placed 4–5 cm distal to the pylorus. The proximal duodenal cannula was used for nutrient and drug perfusion, and the more distal cannula was allowed to drain freely. The stomach was placed under 5–6 cm H2O pressure at the start of the recording period to standardize baseline intraluminal pressure. IGP (cm H2O) was displayed and collected online for the duration of the experiment via an A/D converter (Axon Instruments) connected to a PC.

Rats were divided into 2 groups. One group (n = 20) was perfused with either 4 or 8% peptone. In the other group (n = 12), the duodenum was perfused with an 8% peptone solution for 10 min at a rate of 0.05 mL/min, and then with saline at the same rate for another 10 min to flush duodenal contents. The duodenum was perfused with either a 10 mmol/L solution of the competitive inhibitor of PepT1, 4-aminomethylbenzoic acid (4-AMBA; n = 7), or 4-aminophenylacetic acid (4-APAA; n = 5) for 5 min, followed by 8% peptone + 10 mmol/L 4-AMBA or 8% peptone + 10 mmol/L 4-APAA for another 10 min at 0.05 mL/min.

The decrease in the height of phasic gastric contractions was measured as the mean decrease in height over 2 min of perfusion with peptone or peptone and 4-AMBA or 4-APAA. The decrease in tonic IGP was taken as the nadir of the trace over the same time period compared with baseline.

    Recording of vagal afferent nerve fiber discharge. The method used was published previously (23). Briefly, rats were deeply anesthetized (sodium pentobarbital, Nembutal 100 mg/kg i.p.), decapitated, and a segment of the thoracic esophagus, stomach, and proximal duodenum (~4 cm from the pylorus to the common bile duct) was removed and immersed in oxygenated normal rat saline. The pancreas and stomach were removed, except for the pylorus and adjacent antrum, and the subdiaphragmatic dorsal vagus nerve was identified. A catheter was placed into the gastroduodenal artery and the hepatic, left, and right gastric arteries were tied. The segment was pinned into the main chamber of a sylgard-coated organ bath that was perfused continuously with oxygenated normal rat saline at 2.0–2.5 mL/min flow rate; the temperature of the organ bath was maintained at 33 ± 1°C. The isolated dorsal vagus nerve was placed into the recording chamber.

A thin nerve strand was isolated from the dorsal gastric vagus nerve trunk; the distal cut end was wrapped around one lead of a bipolar platinum recording electrode and a strip of neighboring connective tissue was wrapped around another lead to serve as the indifferent electrode. Action potentials were sent to a preamplifier (Model 1700 differential AC Amplifier AM-System), displayed on a digital storage oscilloscope (model 3012, Tektronix), and recorded online using a digital tape recorder (Sony high-density linear A/D D/A optical digital audio tape deck, DTC-ZE700). In addition, unit potentials were simultaneously sent to a A/D module (Micro 1401 MK2, CED) connected to a PC computer. Electrophysiologic recording from duodenal vagal afferents was started ~30 min after the preparation under stable recording conditions. Units were selected by the presence of spontaneous activity in the nerve strand. Each nerve strand containing spontaneously active units was tested for the response to intra-arterial (i.a.) injection of CCK (10 pmol). In 10 preparations, nerve strands containing CCK-responsive units were tested to determine their response to intraduodenal (i.d.) infusion of protein hydrolysates or protein hydrolysates and 4-AMBA or 4-APAA (100 µmol/L, 0.3 mL). Alternatively, in a further 6 preparations, the response of duodenal vagal afferents to Cefaclor infusion (100 mmol/L, 0.3 mL) was tested.

Using the acquisition module of SPIKE2 impulse analysis software (SPIKE2 version 5, CED), units within the upper and lower threshold settings of the amplifier were acquired online onto the hard drive of a PC. Single units were discriminated offline from the multiunit recordings based on their shape. The response pattern of different units was analyzed and displayed separately. Response magnitudes were normalized by a response quotient (RQ), where RQ = the 5-min spike count after treatment divided by 5 min of spike counts before. A value of RQ > 1.20 was taken to indicate an excitatory response and RQ = 1 ± 0.20 indicates no response.

    Statistical analysis. Differences in the decrease in intragastric luminal pressure in response to 4 and 8% peptone were determined by unpaired t test. Differences in response to 8% peptone with and without AMBA or APAA were determined using a paired t test. In electrophysiologic experiments, the differences in response quotient of individual vagal units in response to 8% peptone with and without AMBA or APAA were determined by paired t test. Data are expressed as means ± SEM and differences were considered to be significant at P < 0.05.


   RESULTS
TOP
 ABSTRACT
 MATERIALS AND METHODS
 RESULTS
DISCUSSION
 LITERATURE CITED
 
    Effects of PepT1 blockade on peptone-induced inhibition of gastric motility. Intraduodenal perfusion of 4% peptone decreased tonic IGP by 0.11 ± 0.11 cm H2O (n = 15), whereas perfusion of 8% peptone decreased tonic IGP by 0.72 ± 0.39 cm H2O (n = 5) (4 vs. 8% peptone, P < 0.05, Fig. 1). The height of phasic contractions decreased by 0.35 ± 0.06 cm H2O (n = 14) with a perfusion of 4% peptone and by 0.90 ± 0.16 cm H2O during perfusion of 8% peptone (n = 5) (4 vs. 8% peptone, P < 0.02; Fig. 1).



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  		FIGURE 1 Reproduction of original trace of intragastric pressure measured in an anesthetized rat showing the decreases in tonic and phasic components of intragastric pressure in response to duodenal perfusion of 8% peptone.

 
The addition of 4-AMBA, a PepT1 competitive inhibitor, significantly attenuated the peptone-induced inhibition of phasic gastric contractions (Fig. 2A,B). The height of phasic gastric contractions decreased by 1.65 ± 0.38 cm H2O during perfusion of 8% peptone (n = 7); this response was attenuated by 71% with the addition of 4-AMBA (P < 0.01). The decrease in tonic IGP was reduced by 74%, but this was not significant (P = 0.07). In contrast, the addition of 4-APAA had no effect on the peptone-induced decrease in baseline IGP or the height of phasic gastric contractions (Fig. 3). Intestinal perfusion with peptone (8%; n = 5) decreased tonic IGP and the height of phasic contractions by 0.79 ± 0.30 and 1.55 ± 0.29 cm H2O, respectively. Administration of peptone with 4-APAA decreased tonic IGP and the height of phasic gastric contractions, but the changes did not differ from those due to perfusion of peptone alone (P = 0.6, n = 5). Infusion of 4-APAA alone inhibited tonic IGP (change in IGP: 0.49 ± 0.18 cm H2O, P < 0.01, n = 5).



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  		FIGURE 2 Effect of duodenal perfusion of protein digests in the presence of 4-AMBA a competitive inhibitor of PepT1 on intragastric pressure in an anesthetized rat, showing a reproduction of an original trace of intragastric pressure from an individual experiment (A) and the mean data (B). (A) Reproduction of original trace of luminal pressure showing no decrease in the height of phasic gastric contractions and no decrease in tonic intragastric pressure during intraduodenal perfusion of peptone (8%) with 4-AMBA (10 mmol/L). (B) Effect of infusion of 4-AMBA on peptone-induced inhibition of gastric motility. Values are means ± SEM, n = 5–7/group. *Different from 8% peptone, P < 0.01.

 


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  		FIGURE 3 Effect of duodenal perfusion of protein digests in the presence of 4-APAA, an inactive 4-AMBA analog acid, on intragastric pressure in an anesthetized rat, showing a reproduction of an original trace of intragastric pressure from an individual experiment (A) and the mean data (B). (A) Reproduction of original trace of intragastric pressure showing a decrease in the height of phasic gastric contractions and a decrease in tonic intragastric pressure with intraduodenal perfusion of 8% peptone in the presence of 4-APAA (10 mmol/L) (B) Effect of infusion of 4-APAA on peptone-induced decrease in the height of phasic gastric contractions and on tonic intragastric pressure. Values are means ± SEM, n = 5–7/group.

 
    Effect of inhibition of PepT1 on peptone-induced increase in vagal afferent fiber discharge. Duodenal infusion of protein hydrolysate (8% peptone) increased spontaneous vagal afferent multiunit activity 64 ± 24% (P < 0.05, n = 9 preparations Fig. 4). Of 13 units responding to protein (RQ > 1.2), 11 units (85%) also responded to CCK (RQ > 1.2). The remaining units may have responded to CCK, but with a smaller response amplitude (RQ < 1.19). When 8% peptone was infused together with 100 µmol/L 4-AMBA, vagal afferent activity did not differ. In contrast, duodenal infusion of 8% peptone in the presence of 4-APAA increased vagal afferent firing 93 ± 49% (P < 0.05, Fig 4).



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  		FIGURE 4 Effect of intraduodenal perfusion of protein digests on vagal afferent nerve fiber discharge. Rate histogram of multiunit vagal afferent fiber discharge innervating the duodenum showing an increase in neural discharge in response to intraduodenal infusion of 8% peptone; this increase is abolished by co-infusion of the PepT1 inhibitor 4-AMBA. Vagal afferent discharge was also increased by close arterial injection of CCK (10 pmol i.a.).

 
Infusion of the intestine with Cefaclor (100 mmol/L), a substrate of PepT1, increased spontaneous vagal afferent activity by 75 ± 15% (Table 1, Fig. 5). Of 12 units responding to Cefaclor (RQ > 1.2), 11 units (91%) responded to CCK (RQ > 1.2).


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  		TABLE 1 Effect of Cefaclor and CCK on the discharge of individual duodenal vagal afferent fibers recorded in an in vitro preparation of the rat duodenum1

 


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  		FIGURE 5 Effect of intraduodenal perfusion of Cefaclor, a cephalosporin antibiotic, on vagal afferent nerve fiber discharge. Rate histogram of single-unit vagal afferent fiber discharge innervating the duodenum showing an increase in fiber discharge to luminal perfusion with Cefaclor. The discharge of this duodenal vagal afferent was also increased by close arterial injection of CCK (10 pmol).

 

   DISCUSSION
TOP
 ABSTRACT
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
LITERATURE CITED
 
There is considerable evidence that the release of CCK by endocrine cells and the subsequent activation of CCK1R on vagal afferent fibers is a main pathway that mediates the ability of protein in the intestine to inhibit gastric emptying (10,25) and to stimulate pancreatic enzyme secretion (26). The data presented in this manuscript provide further evidence that the ability of luminal perfusion of protein hydrolysates to stimulate CCK-responsive vagal afferent fiber discharge and inhibit gastric motility was blocked in the presence of a competitive inhibitor of PepT1. Moreover, Cefaclor, a specific substrate for PepT1, increased CCK-responsive vagal afferent fiber activity. Taken together, these findings are consistent with the hypothesis that entry of di- and tripeptides into cells in the intestinal mucosa via PepT1 is involved in the sensory transduction process by which the protein hydrolysate content of the intestinal lumen is signaled to vagal afferent nerve terminals to induce activation of a neural pathway and a vagal reflex inhibition of gastric motility.

The present study provides direct support for a role for PepT1 in the intestinal sensory transduction process induced by protein hydrolysate by using the competitive inhibitor 4-AMBA. 4-AMBA binds to PepT1 with high affinity (low millimolar range) but is not translocated by PepT1 (21). In contrast, 4-APAA binds to PepT1 and is translocated (22). One feature that distinguishes these 2 molecules is the N-terminus; it is likely at the pH in the intestine, 4-AMBA will be cationic, whereas 4-APAA will be neutral, and cationic dipeptides are generally poorer substrates for the transporter (14). It was interesting to note that 4-APAA is capable of trans-stimulation and cis-inhibition of PepT1 (22). Interestingly, intestinal perfusion of 4-APAA alone also produced a small but significant inhibition of gastric motility, further supporting our hypothesis for a role of PepT1. Moreover, it was shown previously that Cefaclor delays gastric emptying via a CCK1R and vagal afferent pathway (20). The present study supports and extends these findings by showing that Cefaclor stimulates CCK-responsive vagal afferent fiber discharge. This increase in vagal afferent activity will activate vagal efferent outflow to inhibit gastric motility, thus resulting in delayed gastric emptying. This result is consistent with the hypothesis that absorption via PepT1 stimulates release of CCK and activation of vagal afferent fiber discharge. Expression of PepT1 by enterocytes is regulated by a number of factors including diet and leptin, and increased protein in the diet will increase the expression of PepT1 (13,14).

This study provides evidence that PepT1 is involved in the release of CCK, but this could be due to an interaction of PepT1 expressed either on absorptive enterocytes or directly on CCK-secreting endocrine cells (15–18). In the gut, PepT1 is localized to the apical membrane of the enterocytes and is most highly expressed along the whole length of the small intestine (13). No expression was found in the mucus-secreting goblet cells or in crypts (27), although detailed double-labeling to determine colocalization with enteroendocrine cell products has not been reported. In contrast, it remains possible that endocrine cells express PepT1. Recent studies used the STC-1 cell line as a model for release of CCK from endocrine cells (28). These cells, originally isolated from a mouse endocrine tumor, release several gastrointestinal hormones including CCK, glucagon-like peptides (GLP) 1 and 2, and glucose-insulinotropic peptide in response to pharmacologic and physiologic stimuli. Peptidomimetics stimulate the release of CCK and GLP-1 from STC-1 cells, associated with an increase in intracellular calcium (19,29). Peptones were also shown to increase transcription of the CCK and glucagon gene and to stimulate c-fos expression in STC-1 cells (19,29,30). Peptidomimetics also increased phosphorylation of p42/44 mitogen-activated protein (MAP) kinase [extracellular signal-regulated kinase (ERK)-1/ERK-2]; the increase in c-fos expression, but not CCK release, was reduced by a MAP kinase inhibitor (29). Thus, there is good evidence that STC-1 cells express PepT1, but whether native CCK endocrine cells express PepT1 is unclear. The effectiveness of hydrolysates of protein from a number of different sources was tested in a preparation of dispersed rat intestinal mucosal cells (31). Several different sources of protein were effective in releasing CCK including casein, soy protein, egg white, and wheat gluten. Although this study provides some evidence that native endocrine cells secrete CCK in response to protein hydrolysates, the preparation was undoubtedly contaminated with enterocytes; therefore the role of PepT1 expression in native endocrine cells remains to be determined.

In conclusion, this study provides evidence that the oligopeptide transporter PepT1 is a good candidate in the sensory transduction process involved in the intestinal release of CCK and the subsequent increase in spontaneous activity of CCK-sensitive duodenal vagal afferents. This could be due to an interaction of protein hydrolysate–derived peptides with PepT1 expressed either on absorptive enterocytes or directly on CCK-secreting endocrine cells. The possibility that dietary regulation of PepT1 and its putative role in the intestinal feedback regulation of gastric function and also food intake is suggestive of a mechanism by which high-protein diets may alter food intake.


   ACKNOWLEDGMENTS
 
The authors are grateful to Denise Ney for her thoughtful reading of the manuscript.


   FOOTNOTES
 
1 Presented in part at Experimental Biology 04, April 17–21, 2004, Washington, DC [Liou, A., Darcel, N., Tomé, D. & Raybould, H. E. (2004) Vagally-mediated inhibition of gastric motility in response to protein digest is dependent on the oligopeptide transporter PepT1. FASEB J. 18: A230 (abs.)] and [Darcel, N., Liou, A., Tomé, D. & Raybould, H. E. (2004) Proton-coupled oligopeptide transporter PepT1 is required for duodenal vagal afferent activation by protein digest. FASEB J. 18: A456 (abs.)]. Back

2 Supported by National Institutes of Health RO1DK 41004 (H.E.R.) and by Achievement Rewards for College Scientists Foundation scholarship (A.L.). Back

4 Abbreviations used: 4-AMBA, 4-aminomethylbenzoic acid; 4-APAA, aminophenylacetic acid; CCK, cholecystokinin; CCK1R, cholecystokinin 1 receptor; ERK, extracellular signal-regulated kinase; GLP, glucagon-like peptide; i.a., intra-arterial; i.d., intraduodenal; IGP, intragastric pressure; MAP, mitogen-activated protein kinase; RQ, response quotient. Back

Manuscript received 2 December 2004. Initial review completed 12 January 2005. Revision accepted 16 March 2005.


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