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Peppermint (Mentha piperita L.) is a perennial herb endemic in Europe which has been used for centuries as a digestive aid in traditional medicine. Peppermint oil (PO) is extracted through distillation of various plant parts, and its main active constituent is menthol, among other volatile oils. In vitro animal studies have documented the inhibitory effects of menthol on gastrointestinal (GI) segmentation and motility.[2, 3] Based on recent clinical evidence, PO is widely being used as a spasmolytic agent in the treatment of the irritable bowel syndrome.[4-7]
Although the sites of action and pathways remain controversial,[3, 8, 9] the GI effects of menthol appear to be at least partly mediated by the melastatin8 (M8) member of the transient receptor potential (TRP) cation channel superfamily, which is also activated by cold temperatures and the cooling agent icilin. Transient receptor potential cation channels are increasingly being implicated in multiple cellular functions, including several regulatory aspects of the alimentary tract. Animal studies have detected TRPM8 channels in the dorsal root ganglia, vagal afferent neurons, the gastric fundus, colon, and small intestine.[2, 10-15]
Despite centuries of peppermint use and the recent insights in the TRPM8 channels, only few studies have examined the effects of TRPM8 ligands on GI sensorimotor functions. The effects of PO and menthol demonstrate significant species- and region-related variability.[15, 16] Furthermore, mechanistic studies in humans used combinations of several herbal extracts, rendering inferences about specific PO effects on gastric motor functions impossible.[17, 18] Finally, there is as yet no published data on the influence of PO on meal-induced accommodation, nutrient tolerance, and sensitivity to gastric distension.
Our group has recently implicated proximal gastric tone, through its effects on intragastric pressure (IGP), in the modulation of satiation during meal ingestion. Indeed, through a minimally invasive approach that involves the manometric measurement of IGP during intragastric infusion of a nutrient drink, we were able to demonstrate a close correlation between IGP and satiation changes. Nevertheless, it remains yet unclear how this modality compares to the gastric barostat, the current gold standard for the assessment of gastric accommodation.
Our aim was therefore to investigate the acute effect of an enteric-coated PO formulation on IGP profiles, gastric sensorimotor functions, and nutrient tolerance in health.
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This study explored the acute effects of an enteric-coated PO formulation on IGP, gastric sensorimotor functions and nutrient tolerance, in normal-weight healthy adults. Our results demonstrate significant effects of PO during fasting namely a reduction in IGP levels, phasic contractility, and appetite scores. Peppermint oil did not influence gastric sensitivity/compliance during isobaric distensions. We observed negligible effects of PO on gastric accommodation to a nutrient drink and on IGP profiles during intragastric infusion. Peppermint oil did not affect satiation and epigastric symptoms during the infusion or the liquid meal.
The observed clear-cut effect of PO on fasting IGP could be interpreted as a result of sustained reduction in gastric tone. This is in concordance with studies that demonstrated menthol-induced relaxation of intestinal and colonic muscle strips.[2, 3] Also, relaxation of guinea-pig fundic strips and of the proximal stomach in man were induced by a combination of multiple herbal extracts including PO, although the contribution of PO to these effects remains unclear. Transient receptor potential M8 superfamily channel activation on the other hand has been implicated as the underlying mechanism of cooling-induced contractions in the rat gastric fundus.[15, 16] Adding to the controversy, the barostat data did not indicate any effect of PO on proximal gastric tone. In support and further confirmation of this notion comes the fact that gastric volumes were not significantly altered after intraduodenal administration of PO in a subset of our HVs; thus, a potential interference of the balloon with capsule emptying in the duodenum and PO availability is not a plausible explanation for the lack of effect on proximal gastric tone as measured with the barostat.
Based on our data, the reduction in fasting IGP should thus be attributed to a simultaneous reduction in gastric phasic contractility after PO administration, reflected in decreased MI of the proximal stomach. This finding is in concordance with preliminary or indirect evidence from previous studies namely reduced contraction duration and amplitude in the gastric corpus after direct intraduodenal administration of PO, and following a single oral dose of a herbal combination containing PO. Spraying of L-menthol on the gastric mucosa yielded similar findings, in a controlled trial reporting suppression of endoscopically assessed gastric peristalsis. The temporal correlation between the reduction of IGP and gastric MI further supports our hypothesis. The fact that changes in phasic contractility were shown with IGP measurement, but not with barostat measurements, suggests that IGP monitoring may have superior sensitivity to assess phasic motor events in the proximal stomach. We assume that during fasting conditions the balloon may be influenced by antral activity due to the small intragastric volume, thus masking a potential effect of PO on fundic MI. This is in line with the intended design of the barostat which mainly serves to quantify changes in tone.
Our study was not designed to investigate the receptors and pathways mediating the effects of PO in gastric motility. There is some experimental evidence to support a direct action on gastric smooth muscle, involving reduction in calcium influx. On the other hand, although TRPM8 channel expression has been demonstrated in the fundic muscular layer of certain species, it is still controversial whether menthol affects motility through this receptor.[15, 26] Moreover, most of this evidence comes from studies on isolated muscle strips. Thus, given the expression of TRPM8 channels in vagal afferents projecting to the upper GI, and the well-known dependence of gastric phasic contractility on the vagus nerve, the observed effects may be initiated by TRPM8-receptor coupling in duodenal vagal afferents and mediated through a vagal circuit. Evidently, these hypotheses would require further study employing selective TRPM8-channel inhibition at different levels. These studies would ideally investigate any further effects of TRPM8 ligands on the intestinal peptides that influence gastric contractility and the gastric migratory motor complex (MMC) namely motilin and ghrelin.[28, 29]
Also, while most studies focus on TRPM8 as the primary molecular target for menthol, TRPM8-deficient mice still exhibit a considerable amount of menthol-sensing dorsal root and trigeminal neurons.[30, 31] However, Karashima et al. provided evidence that another member of the TRP superfamily, TRPA1, is also sensitive to menthol, at least at submicromolar to low micromolar concentrations. As TRPA1 is widely expressed throughout the gut and is shown to control visceral sensation and GI motility,[12, 33, 34] it is also possible that some of the effects observed in this study are mediated by TRPA1.
On the other hand, our data argue against a significant influence of PO on proximal gastric sensitivity to distension, as quantified by perception and discomfort thresholds, by area under the pressure–perception curve, and by VAS scoring. It is important to note that these findings do not necessarily exclude efficacy of PO in dyspeptic patients who are hypersensitive to mechanical stimuli; this hypothesis, warrants testing in future clinical studies.
Before this study, the effect of PO on meal-induced accommodation had not been directly addressed. The accommodation response involves relaxation of the proximal gastric muscular layer upon initiation of a meal, and is mediated through a vago-vagal reflex which is integrated in the brainstem. Fundic relaxation is effected primarily through inhibitory nitrergic pathways, although inhibition of cholinergic pathways may also contribute to the reflex. In this study, we did not observe any effects on IGP profiles or in accommodation parameters during a nutrient drink challenge. Although our study was powered to detect a 30% change in postprandial balloon volumes, and clinically important differences in gastric accommodation were previously detected with similar samples,[37, 38] we cannot exclude the possibility that a type II error may have masked a modest effect. Moreover, the omission of a dose–response study of PO represents a potential limitation of our data. On the other hand, there are several lines of evidence that indirectly support our findings. First, animal studies have previously established that menthol-induced relaxation of gastrointestinal muscle strips is independent of cholinergic antagonism or nitrergic pathways.[3, 8, 9, 16] Second, a randomized controlled trial found no significant effect of a 90 mg PO capsule on the gastric emptying rate of liquids, suggesting lack of a robust effect on fundic tone in response to a liquid meal. Similarly, a PO-containing formula minimally increased the retention of liquids between 10 and 50 min postprandially compared with placebo, while no differences were found in the lag phase, T1/2 and AUC for liquid emptying. Third, unaffected satiation/symptom scores and IGP profiles during intragastric infusion in this study also argue against a significant effect of PO on the gastric accommodation reflex.
To the best of our knowledge, this is the first report of an effect of PO on the control of food intake in humans. In our hands PO reduced fasting appetite. Relevant animal data are inconclusive, as a single study failed to detect differences in feeding behavior or weight gain between rabbits fed with peppermint and other herbs. The mechanism of the appetite effect cannot be safely inferred based on our data. It is generally accepted that enteric peptide hormones released during nutrient exposure mediate satiety during the late postprandial period, via local vagal stimulation or through hypothalamic signaling. Given the long pretest fasting period of our protocol, enteric peptides are unlikely to mediate the appetite effect of PO, which does not refer to satiety, but rather to the return of hunger pangs during prolonged fasting. The concomitant reduction of appetite scores and MI, however, raise the question whether decreased appetite is mediated through a reduction in phasic gastric contractility. In this perspective, our group has recently presented preliminary data that generation of hunger pangs requires motilin receptor stimulation and/or a typical phase-III pattern of the MMC. In addition, we found significant correlations between motilin levels, MI during phase III and hunger scores. Whether the specific trigger of hunger pangs in humans is the rise of motilin levels or the emergence of gastric phase-III activity per se still remains to be determined. Therefore, future studies of PO should evaluate motilin levels in addition to gastric motility and hunger ratings.
In conclusion, in this study acute oral administration of PO did not affect gastric sensitivity, compliance, or accommodation reflex to a liquid drink in health. Satiation and meal-related symptoms were also unaffected. During fasting, PO reduced IGP, phasic contractility of the proximal stomach, and appetite ratings. Further studies are warranted to refine the role of TRPM8 channel activation and antagonism on gastric motility, control of food intake and determine the underlying mechanisms.