Unité Mixte de Recherches sur le Veau et le Porc, Institut National de la Recherche Agronomique, 35590 Saint-Gilles, France
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ABSTRACT |
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Coloileal reflux episodes trigger specialized ileal motor activities and inhibit gastric motility in pigs. The initiation of these events requires the detection by the distal ileum of the invading colonic contents that differ from the ileal chyme primarily in short-chain fatty acid (SCFA) concentrations. In addition to the already described humoral pathway, this detection might also involve ileal vagal afferents. Sensitivity to SCFA of 12 ileal vagal units was investigated in anesthetized pigs with single-unit recording at the left cervical vagus. SCFA mixtures (0.35, 0.7, and 1.4 mol/l) containing acetic, propionic, and butyric acids in proportions identical to that in the porcine cecocolon were compared with isotonic and hypertonic saline. All units behaved as slowly adapting mechanoreceptors (half-adaptation time = 35.4 ± 15.89 s), and their sensitivity to local mechanical probing was suppressed by local anesthesia; 7 units significantly decreased their spontaneous firing with 0.7 and 1.4 but not 0.35 mol/l SCFA infusion compared with hypertonic or isotonic saline. Similarly, the response induced by distension in the same seven units was reduced (5 neurons) or abolished (2 neurons) after infusion of 0.7 (22.8 ± 2.39 impulses/s) and 1.4 (30.3 ± 2.12 impulses/s) mol/l SCFA solutions compared with isotonic saline (38.6 ± 4.09 impulses/s). These differences in discharge were not the result of changes in ileal compliance, which remained constant after SCFA. In conclusion, SCFA, at concentrations near those found during coloileal reflux episodes, reduced or abolished mechanical sensitivity of ileal vagal afferents.
vagal afferents; lipids; coloileal reflux; ileal brake
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INTRODUCTION |
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SHORT-CHAIN FATTY ACIDS (SCFA) are produced during bacterial fermentation of carbohydrates and glycoproteins in the large intestine of animals with simple stomachs. When present at the ileal level as a result of a coloileal reflux episode (9), they trigger local and remote activities. Locally, they are potent stimulants of prolonged propagated contractions and discrete clustered contractions (25). At a distance, they are able to produce an ileal brake toward gastric motility and emptying (10, 11). Whereas the pathways for the ileal brake are mainly of an endocrine nature (8), those modulating ileal motility are still not resolved. Experimental data suggest that activation of vagal afferents sensitive to SCFA might be involved, as proposed by Yajima (47) for the colon. Furthermore, epithelial SCFA-sensitive chemoreceptors were described in the reticulorumen of ruminants (7), and mucosal SCFA-sensitive chemoreceptors were reported in the proximal duodenum of sheep (5). Propionate was also shown to activate some duodenal vagal afferents of nonruminant animals (32). More recently, vagal afferents sensitive to medium-length fatty acids were demonstrated in the rat ileum (36).
The effects of SCFA on vagal afferents are controversial. In the adult sheep duodenum, SCFA exposure produces desensitization of the unit without change in mechanosensitivity (5). An opposite result, that is, increase in basal activity, was observed in the cat duodenum after administration of propionate (32). Similarly, acetate in the esophagus also increased neuronal background activity (15, 41). A region-dependent dose threshold above which desensitization occurred can be hypothesized to explain these differences. However, data from duodenal or esophageal receptors obtained in other species cannot be extrapolated to ileal receptors because ileal concentration of SCFA is ~50 times that at the duodenal level in the pig (14).
The aim of this study was to assess the sensitivity of ileal vagal afferents to SCFA at concentrations close to those occurring during coloileal reflux episodes in pigs. This was achieved by the measurement of single vagal afferent activity at the cervical vagus in vivo. The motility of the ileum was assessed concurrently with the activity of vagal neurons to discriminate the effects related to SCFA on ileal compliance from the direct effects of SCFA on nerve terminals.
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MATERIALS AND METHODS |
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Twelve female Large White pigs (34 ± 3 kg) were used during this study. Experiments conform to European and French legislation and guidelines on experimental animal care (Agreement no. A35-622). Only one receptive unit was recorded in each animal because repetitive administrations of SCFA were suspected to generate long-lasting changes in the unit characteristics (5).
Anesthesia.
The animals were preanesthetized with ketamine (5 mg/kg im; Rhone
Mérieux). Suppression of the pharyngotracheal reflex was obtained
by inhalation of halothane (5% vol/vol by face mask) immediately
before intubation. A venous cannula was inserted into the marginal vein
of the ear to infuse a mixture of -chloralose (60 mg/kg; Sigma) and
urethane (500 mg/kg, Sigma), the primary anesthetic agent. At the
completion of the abdominal and cervical surgical procedures, the
surgical anesthesia level was maintained by continuous intravenous
infusion of pentobarbital sodium (20 mg · kg
1 · h
1; Sanofi
Santé Animale). Motion artifacts were canceled by supplemental slow intravenous bolus injections of D-tubocurarine (0.2 mg/kg; Sigma) every 2 h. The surgical level of anesthesia was
continuously assessed by arterial blood pressure measurements obtained
from a catheter located in the right carotid artery.
Ileal surgery.
Ileal surgery was performed under aseptic conditions because previous
nonaseptic attempts failed to identify ileal receptors, probably as a
consequence of the rapid deterioration of the ileal mucosa caused by a
proliferation of exogenous or/and colonic bacteria. A left retrocostal
laparotomy was performed to access the distal ileum. Two Foley
catheters (CH18; Vygon) were inserted in the ileal lumen and secured in
position with a purse suture to isolate an ileal loop 15 cm in length
located 5 cm proximal to the ileocecal sphincter (Fig.
1). A double-lumen catheter (ID 3.5 mm
for air injection/retrieval and 1 mm for pressure sensing)
incorporating a latex balloon 15 cm in length was placed in the middle
of the ileal loop. The larger-bore opening was used for air injection and retrieval, allowing inflation and deflation of the latex balloon. The smaller-diameter opening was connected to a pressure transducer (PX23; Gould) to record the static air pressure within the balloon in
the absence of artifacts related to dynamic pressure changes during
inflation and deflation. A polyvinyl chloride (PVC) catheter (OD 1 mm)
incorporating one side hole was also placed in the ileal lumen to
record the intraluminal pressure of the ileum (see
Recordings). The oral end of the manometric catheter was
attached to the oral end of the balloon. Distally, at the entrance into
the gut lumen of the balloon and the manometric catheter, both
catheters were secured in position by a purse suture. At the completion
of the abdominal surgery, the laparotomy was closed and the cervical vagal dissection was performed.
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Recordings.
Electrical activity from single vagal afferent neurons was recorded by
classic neurophysiological methods (30) adapted to the
pig. Briefly, the left vagus was made free from surrounding connective
tissue. The skin and cervical muscles were sutured to a metallic frame
to create a pool filled with warm paraffin oil. Monopolar recordings of
vagal bundles were performed after sectioning of the cervical vagus and
microdissection of its distal end. Adequate amplification of the signal
was provided by a homemade amplifier (gain 50,000, impedance 20 M)
placed near the recording electrodes (tungsten, 50 µm; WPI). After
low- and high-pass filtration (300-6,000 Hz), the raw
electroneurogram was stored on a digital tape (Biologic) for
postprocessing at 20 KHz together with lower-frequency pressure and
volume signals (see below). Unitary vagal activity was discriminated
off-line using adaptive shape-matching criteria (19, 33).
Instantaneous and cumulative frequency histograms were constructed
after detection of the adequate ileal unit. The conduction velocity was
measured by a modified peripheral stimulus technique (22).
Briefly, 4 cm distal to the recording site, the entire vagus nerve was
lying on a pair of platinum electrodes connected to a homemade isolated
voltage stimulator. A "Wagner ground" electrode was also inserted
between the recording and stimulating electrodes to reduce stimulation artifact.
Experimental protocol.
Computer-controlled rapid (rise rate 100 mmHg/s) distension of the
ileum was used to identify mechanosensitive ileal units. This was
achieved by connecting the balloon to a compressed air source (750 mmHg) through a computer-controlled valve until the pressure within the
balloon equaled 30 mmHg. Thereafter, the balloon was deflated by
computer-controlled connection of the balloon to a vacuum source (
75 mmHg).
Data analysis. Receptor mechanical threshold was calculated for each solution using firing rate data obtained during the inflation phase of the slow distension episodes as previously described (42). Briefly, a linear fitting between firing rate and pressure was calculated. Threshold was then extrapolated from the pressure required for the firing rate to be nullified. Half-adaptation time (in s) was calculated according to a previously described method (6).
Data are presented as means ± SE. Comparisons between treatments (isotonic and hypertonic saline and the 3 SCFA mixture concentrations) during infusions and during distensions were performed using one-way analysis of variance (StatView 5.0; SAS Institute). P < 0.05 indicated a significant difference. ![]() |
RESULTS |
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Twelve units that responded to rapid ileal distension were
recorded. Six of them were spontaneously active and as a consequence were not taken into account for the calculation of mechanical threshold. Of the 12 neurons, 8 were classified as C fibers (2.5 ± 0.93 m/s) and 4 as A fibers (5.1 ± 0.94 m/s). A
fibers
did not show mechanical or chemical sensitivity significantly different from that of C fibers. In addition, there was no significant difference in conduction velocities between neurons that were desensitized by SCFA
compared with those that were not. Therefore, A
and C neurons were
analyzed together. All units responded to von Frey hair stimulation.
Topically applied lignocaine reversibly inhibited the response to
mucosal probing for all units. The receptive fields of units were of
ellipsoidal shape with an area ranging from 3 to 8 mm2.
All units behaved as slowly adapting receptors with half-adaptation time obtained from the rapid inflation data equal to 35.4 ± 15.89 s. No significant change in half-adaptation time between 1.4 mol/l SCFA infusion and isotonic saline could be noticed (40.6 ± 17.37 vs. 35.4 ± 15.89 s for 1.4 mol/l SCFA vs. isotonic saline; P > 0.05).
Spontaneous activity. All units increased their firing rate or became active during infusion of isotonic or hypertonic saline and SCFA solutions, probably as a result of increased intraluminal pressure during infusion (see below). Those that were classified initially as quiescent became active when the pump was turned on. No significant difference was found in the increased firing rate during isotonic versus hypertonic saline infusions (P > 0.05).
Seven of twelve neurons were found to decrease their firing rate significantly during SCFA infusions compared with isotonic and hypertonic saline (Figs. 2 and 3A). Of these seven neurons, five were spontaneously active and two were quiescent during basal (no perfusion) period. The most potent inhibitor was 1.4 mol/l SCFA. Conversely, 0.35 mol/l SCFA did not significantly modify firing rate compared with isotonic or hypertonic saline. For two neurons spiking activity was abolished during SCFA infusions irrespective of the SCFA concentrations, whereas their mean firing rates were 5.9 ± 0.45 and 5.8 ± 0.52 spikes/10 s during isotonic and hypertonic saline infusions, respectively. No significant difference could be observed in mean intraluminal pressure during SCFA and hypertonic or isotonic saline infusions (15.2 ± 4.12, 15.1 ± 5.27, 15.0 ± 4.92, 14.8 ± 4.92, and 14.8 ± 4.56 mmHg for 0.35, 0.7, and 1.4 mol/l SCFA, hypertonic saline, and isotonic saline, respectively; P > 0.05).
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Distension-elicited activity.
Ileal distension was significantly less effective in increasing firing
rate after SCFA infusions compared with isotonic or hypertonic saline
(Fig. 3B). For the same seven neurons that were inhibited by
SCFA infusions, 0.7 and 1.4 mol/l SCFA were also able to reduce the
firing rate significantly during slow distension (Fig.
4). Furthermore, the reduction in firing
exhibited a dose relationship pattern, the highest SCFA concentration
being the most potent inhibitor of unit activity (22.8 ± 2.39, 30.3 ± 2.12, and 38.6 ± 4.09 spikes/s for 1.4 and 0.7 mol/l
SCFA and saline, respectively). The five remaining neurons that did not
change their firing rate during SCFA infusion were also insensitive to SCFA during slow distension (P > 0.05). The increased
intraluminal pressure recorded during distension was not significantly
modified by SCFA or hypertonic or isotonic saline (44. 2 ± 1.36 vs. 42.8 ± 1.45 mmHg for 1.4 mol/l SCFA vs. isotonic saline;
P > 0.05).
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Ileal compliance. Pressure-volume curves recorded during graded isobaric distension showed a typical S shape irrespective of the solution infused. The larger slope, indicative of ileal compliance, was always found between 14 and 22 mmHg. It was unchanged by the composition of the infused solution (21.9 ± 3.75 vs. 21.4 ± 4.84 mmHg/ml for 1.4 mol/l SCFA vs. isotonic saline; P > 0.05).
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DISCUSSION |
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The results of this study indicate that vagal ileal units are inhibited by SCFAs. Furthermore, the mechanical sensitivity of ileal units was severely impaired after SCFA contact. This desensitization occurred with SCFA concentrations in the range of those occurring during coloileal reflux episodes.
Ileal afferents described in this study are all of the mucosal type because their mechanical sensitivity was reversibly inhibited by topical lignocaine application (20). However, they differed significantly from vagal mucosal afferents described elsewhere in the gut. All units found in our study were slowly adapting to mechanical stimulus, whereas Leek (28) described duodenal mucosal receptors with an on-off response to mechanical distension. In contrast, Cottrell and Iggo (5) showed mucosal afferent fibers in the adult sheep duodenum with persistent responses to mechanical distension. The adaptation time of these duodenal mucosal receptors was within the range of that found for ileal units. More surprisingly, none of the 40 duodenal receptors sensitive to lipids (including propionate) described by Mélone (32) responded to mechanical stimulation. On the contrary, the ileal receptors sensitive to medium-chain fatty acids described by Randich et al. (36) were all sensitive to mechanical stimulus, a feature also found in the in vitro ileal preparation of Cervero and Sharkey (3) and in our in vivo preparation. Hence, it is likely that porcine ileal vagal units sensitive to SCFA had the same sensitivity to mechanical stimulus as rat ileum.
The sensitivity to SCFA demonstrated in our study cannot be called chemosensitivity as such. Indeed, duodenal SCFA-sensitive units increase their firing rate in contact with SCFA and in relation to the molecular weight of the acid (29), whereas we observed reduced basal and stimulated firing after contact with SCFA. However, units sensitive to organic or nonorganic acids are commonly desensitized after the initial application of acids (5). During this period, they are "turned off" for 5-15 min (37) but their mechanical sensitivity is unchanged, unlike the situation observed for ileal units. In contrast, the desensitization observed with SCFA was very similar to that demonstrated after acute application of capsaicin: desensitization to the actual compound itself plus cross-desensitization to mechanical stimuli observed in 37% of the afferents (2).
Unlike nonabsorbed nutrients present within the ileum during pathological conditions that have been shown to trigger the ileal brake (44), SCFA represent a stimulus of physiological relevance, at least for the pig. We previously demonstrated (9) that SCFA were present in the porcine ileum as a result of cecoileal reflux episodes occurring about six times per hour. These reflux episodes last more than 10 min and deliver 10-20 mmol of SCFA into the distal ileum. This amount is within the range delivered by the 0.35 mol/l solution infused at 150 ml/min over 1 min. Using the same logic, the 0.75 mol/l solution supplied about the same amount of SCFA as three ileocecal refluxes and the 1.4 mol/l solution was equivalent to six reflux episodes. It is unlikely that vagal afferent desensitization induced by SCFA was related to a volume, osmolarity, or pH effect of the SCFA solution. Indeed, the pH of the solution was adjusted to neutrality. Distension- and osmolarity-related effects were tested by infusing isotonic and hypertonic saline used as volume and osmotic controls, respectively.
It is unlikely that the inhibitory effect of SCFA infusion was related to changes in the compliance of the ileum wall as already observed at the gastric level during impaired relaxation of the organ wall (13). Indeed, neither the compliance nor the intraluminal ileal pressure was significantly modified by SCFA versus saline. The reduced sensitivity to mechanical distension after SCFA may be related to an increased firing threshold of the unit, whereas the adaptation characteristics remained constant. Indeed, we found a slight reduction (2 mmHg) in the threshold for the two units responsive to SCFA and for which a valid threshold could be calculated. The magnitude of this reduction must be evaluated with care because it is unlikely that the relationship of discharge rate to stimulus intensity was linear at or near the threshold level.
The amount of SCFA required to inhibit mechanical sensitivity is also physiologically relevant for species other than the pig. Indeed, the amount of SCFA able to desensitize ileal afferent is theoretically (for 0.7 mol/l SCFA solution) yielded by the fermentation of 13 g of unabsorbed carbohydrate (such as resistant starch or dietary fiber). Because no quantitative value for the volume of coloileal refluxate exists in the literature aside from the porcine model (9, 10), it is difficult to evaluate the proportion of these SCFA synthesized in the colon that can be found in the distal ileum. Nevertheless, motility data for the Mayo group (16, 25, 27) suggest that, for the dog model, it might be of the magnitude of that found in pig.
About 65% of the ileal neurons were classified as C fibers with
conduction velocities within the range already described in sheep
(6) and ferrets (35). This percentage is more
than double that found in the esophagus (35) but is
similar to that observed in the extensive study of Cervero and Sharkey
(3) in the rat intestine. Because the methods used to
evaluate mechanical threshold were different (42), it is
difficult to draw conclusions about a potential lower threshold of A
fibers (17). However, in our experimental conditions,
mechanical thresholds of C versus A
fibers were not statistically different.
The physiological significance of ileal vagal afferent desensitization by SCFA is still hypothetical. Whereas the pathways for the ileal brake are mainly endocrine (8), those modulating ileal motility are likely of a nervous nature (12). However, the motor response of the distal ileum to mechanical distension and the neuronal network controlling this response are complex. Indeed, a classic peristaltic event will be elicited by distension if it occurs in an oral-to-aboral direction (18). In contrast, a single, broad-based contraction (prolonged propagated contraction) or brief bursts of phasic contractions (discrete clustered contractions) must be triggered after a distension that occurs in an aboral-to-oral direction (26). It is worth noting that two key parameters, the chemical nature of the intraileal contents and the direction of the distension, control the amplitude and velocity but not direction of the contractile events. A similar situation exists at the lower esophageal level with primary and secondary peristalsis associated with gastroesophageal acidic reflux episodes. There are numerous similarities in the chemical sensitivity to acid (HCl and SCFA) of esophageal and ileal vagal afferents. First, acid-sensitive esophageal units are scant (40). Second, in vitro, a second application of acid induces a response that is either greatly reduced or nonexistent (35). Third, there is also a general desensitization to mechanical stimulation after application of HCl (35). Fourth, the chemical sensitivity is not related to the conduction velocity of the neurons (35). All of these similarities suggest that the hypothesis postulated for esophageal vagal afferents is also valid for ileal units, that is, a role in inflammatory processes but a limited contribution in physiological conditions (43). However, it is equally possible that the inhibition of vagal units sensitive to SCFA is a prerequisite for the switch from peristalsis to fast propulsion, the initial stimulus triggering motor events being identical, that is, distension of the distal ileum.
The mechanisms of SCFA-induced desensitization were not evaluated in our study. Nevertheless, it is likely that the mechanisms used by SCFA to interact with vagal afferents differed from those suspected for longer-chain fatty acids because most of the SCFA passage to the blood occurred outside the chylomicron route (39). Hence, it is possible to rule out a direct activation of vagal afferents by chylomicrons (38) or by chylomicron-induced release of other activating substances (24). On the contrary, on the isolated ileal muscle cell, SCFA induce contractions through an acid-sensitive, calcium-dependent mechanism (4) that could also occur at the terminal endings of vagal afferents. Similarly, SCFA in the ileum induce a large peptide YY response (8) that might also activate vagal afferents. Finally, stimulation of vanilloid receptor subtype 1 (VR1) by mild change in acidic concentration (2) induced after the absorption of SCFA was a strong candidate to explain afferent desensitization. Indeed, protons decrease the temperature threshold for VR1 activation such that even moderately acidic conditions (pH = 5.9) activate VR1 at room temperature (45). Together with the already mentioned mechanical stimuli desensitization obtained with capsaicin, it could be possible that SCFA, at the concentration used in our study, activated VR1 receptor without neurotoxic effects (21).
In conclusion, this is the first description of vagal sensory neurons that are desensitized by SCFA. These neurons behave as slowly adapting units and exhibit mechanical desensitization while exposed to SCFA at concentrations within the range occurring during spontaneous reflux episodes.
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FOOTNOTES |
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Address for reprint requests and other correspondence: C. H. Malbert, Unité de Physiopathologie, Physiologie de la digestion et du métabolisme protéique, UMRVP, INRA, 35590 Saint-Gilles, France (E-mail: malbert{at}st-gilles.rennes.inra.fr).
The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
Received 6 July 2000; accepted in final form 20 December 2000.
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