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Background/aims: Bitter taste receptors are expressed throughout the digestive tract. Data on animals have suggested these receptors are involved in the gut hormone release, but no data are available in humans. Our aim is to assess whether bitter agonists influence food intake and gut hormone release in healthy subjects. Methods: Twenty healthy volunteers were enrolled in a double-blind cross-over study. On two different days, each subject randomly received an acid-resistant capsule containing either placebo or 18 mg of hydrochloride (HCl) quinine. After 60 minutes, all subjects were allowed to eat an ad libitum meal until satiated. Plasma samples were obtained during the experiment in order to evaluate cholecystokinin (CCK) and ghrelin levels. Each subject was screened to determine phenylthiocarbamide (PTC) tasting status. Results: Calorie intake was significantly lower when subjects received HCl quinine than placebo (514±248 kcal vs 596±286 kcal; p=0.007). Significantly higher CCK ΔT90vsT0 and ΔT90vsT60 were found when subjects received HCl quinine than placebo (0.70±0.69 ng/ml vs 0.10±0.86 ng/ml, p=0.026; 0.92±0.75 ng/ml vs. 0.50±0.55 ng/ml, p=0.033, respectively). PTC tasters ingested a significantly lower amount of calories when they received HCl quinine compared to placebo (526±275 kcal vs 659±320 kcal;p=0.005), whereas no significant differences were found for PTC non-tasters (499±227 kcal vs 519±231 kcal;p=0.525). Conclusions: This study showed that intra-duodenal release of a bitter compound is able to significantly affect calorie intake and CCK release after a standardized meal. Our results suggest that bitter taste receptor signaling may have a crucial role in the control of food intake.
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Journal of Neurogastroenterology and Motility
Original Article
2015 The Korean Society of Neurogastroenterology and Motility
J Neurogastroenterol Motil, Vol. 21 No. 4 October, 2015
J Neurogastroenterol Motil, Vol. 21 No. 4 October, 2015
pISSN: 2093-0879 eISSN: 2093-0887
Received: February 18, 2015 Revised: April 20, 2015 Accepted: April 21, 2015
This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.
org/licenses/by-nc/4.0) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work
is properly cited.
*Correspondence: Rosario Cuomo, MD
Department of Clinical Medicine and Surgery, Federico II University Hospital School of Medicine, Via S. Pansini 5, Building 6, 80131
Napoli, Italy
Tel: +39-081-7463892, E-mail:
Financial support: None.
Conflicts of interest: None.
Author contributions: Study concept and design: Paolo Andreozzi, Giovanni Sarnelli, and Rosario Cuomo; Subject enrollment and acquisition of data:
Paolo Andreozzi, Giovanni Sarnelli, Marcella Pesce, Francesco P Zito, Alessandra D’Alessandro, Viviana Verlezza; Biochemical
analysis: Ilaria Palumbo and Fabio Turco; Analysis and interpretation of data: Katherine Esposito, Paolo Andreozzi, Giovanni
Sarnelli, and Rosario Cuomo; and Drafting of the manuscript: Paolo Andreozzi, Giovanni Sarnelli, and Rosario Cuomo.
ORCID: Paolo Andreozzi,; Giovanni Sarnelli,; Marcella Pesce,; Francesco Paolo Zito,; Viviana Verlezza,; Ilaria Palumbo,; Fabio Turco,; Katherine Esposito,; Rosario Cuomo,
The Bitter Taste Receptor Agonist Quinine
Reduces Calorie Intake and Increases the
Postprandial Release of Cholecystokinin in
Healthy Subjects
Paolo Andreozzi,
Giovanni Sarnelli,
Marcella Pesce,
Francesco P Zito,
Alessandra D’Alessandro,
Viviana Verlezza,
Ilaria Palumbo,
Fabio Turco,
Katherine Esposito,
and Rosario Cuomo
Department of Clinical Medicine and Surgery,
Federico II
University, Naples, Italy; and
Department of Clinical and Experimental Medicine,
Second University of Naples, Italy
Bitter taste receptors are expressed throughout the digestive tract. Data on animals have suggested these receptors are involved
in the gut hormone release, but no data are available in humans. Our aim is to assess whether bitter agonists influence food
intake and gut hormone release in healthy subjects.
Twenty healthy volunteers were enrolled in a double-blind cross-over study. On 2 different days, each subject randomly received
an acid-resistant capsule containing either placebo or 18 mg of hydrochloride (HCl) quinine. After 60 minutes, all subjects were
allowed to eat an
ad libitum
meal until satiated. Plasma samples were obtained during the experiment in order to evaluate
cholecystokinin (CCK) and ghrelin levels. Each subject was screened to determine phenylthiocarbamide (PTC) tasting status.
Calorie intake was significantly lower when subjects received HCl quinine than placebo (514 ± 248 vs 596 ± 286 kcal;
0.007). Significantly higher CCK
vs T
vs T
were found when subjects received HCl quinine than placebo (0.70
± 0.69 vs 0.10 ± 0.86 ng/mL,
= 0.026; 0.92 ± 0.75 vs 0.50 ± 0.55 ng/mL,
= 0.033, respectively). PTC tasters ingested
a significantly lower amount of calories when they received HCl quinine compared to placebo (526 ± 275 vs 659 ± 320 kcal;
= 0.005), whereas no significant differences were found for PTC non-tasters (499 ± 227 vs 519 ± 231 kcal;
= 0.525).
Paolo Andreozzi, et al
Journal of Neurogastroenterology and Motility
This study showed that intra-duodenal release of a bitter compound is able to significantly affect calorie intake and CCK release
after a standardized meal. Our results suggest that bitter taste receptor signaling may have a crucial role in the control of food
(J Neurogastroenterol Motil 2015;21:511-519)
Key Words
Cholecystokinin; Food intake; Ghrelin; Quinine; Taste
Taste is a complex sensory modality involved in the detection
of food quality. It is commonly accepted that the so-called “basic”
tastes (ie, bitter, sweet, umami, sour, and salty) have been natu-
rally selected to facilitate nutrient consumption and help avoid the
ingestion of potentially harmful foods.1 For instance, the sweet
taste is perceived as palatable and is classically associated with en-
ergy-dense foods, whereas the bitter taste is innately aversive and
related to toxic compounds.
The mechanisms underlying taste detection in the oral cavity
have been well established; in fact, tastants are recognized by a
number of receptors, including ion channels (salty and sour) and
G protein-coupled receptors (GPCRs) (bitter, sweet, and umami).1
Specifically, the GPCR type 1 taste receptor family (T1R) com-
prises 3 different subunits that heterodimerize to detect sweet
(T1R2 + T1R3) and umami (T1R1 + T1R3) tastants, while
the type 2 taste receptor (T2R) family is responsive to bitter
compounds.2,3 The ability to taste bitter compounds varies greatly
among individuals. The best-known example of this variability is
the genetic ability to taste phenylthiocarbamide (PTC) and 6-N
propylthiouracil (PROP). Based on the ability to recognize
PTC or PROP, individuals can be defined as “tasters” or
In the last decade, several studies have demonstrated the ex-
pression of taste receptors and their downstream signaling mole-
cules in the gut, leading to the hypothesis that gastrointestinal
taste system may play a role in the gut chemosensitivity.5,6 In par-
ticular, studies in model cell lines7,8 and a histochemical study9
have shown that T2R family members are expressed by en-
tero-endocrine cells (EECs), which constitute a first level of in-
tegration of the information coming from the lumen.10 EECs in
the gastrointestinal (GI) tract play a crucial role in the control of
food intake through several ways. Their activation results in the
release of a large array of GI peptides, such as glucagon-like pep-
tide 1 (GLP-1), cholecystokinin (CCK) and ghrelin,11 all in-
volved in the control of food intake. Ghrelin, released by gastric
EECs, is the only known orexigenic gut peptide and its plasma
levels increase during fasting and rapidly fall after the meal.12,13
Other hormones, such as CCK, GLP 1, and peptide YY (PYY),
exert an opposite effect, thus inhibiting food intake. CCK is the
anorexigenic peptide that has been more thoroughly studied14;
this hormone is released by I-cells into the duodenum in response
to intra-luminal lipids and proteins.15,16 The CCK inhibitory ef-
fects on food intake are thought to be mediated via CCK1 re-
ceptors on vagal afferents.17
A previous study has shown that the stimulation of T2R with
bitter compounds induced the release of the anorexigenic hor-
mone CCK from mouse EEC lines.18 Moreover, the intragastric
gavage of bitter compounds induced the release of ghrelin in
mice.19 However, this evidence derives from experiments carried
out in vitro or on animals, but no study has translated these find-
ings to in vivo human models to define the role of the stimulation
of these receptors on food intake.
In the wake of these results, we hypothesized that bitter taste
receptors in the gut could be involved in the control of food
intake. Our study thus aimed to investigate the effect of in-
tra-luminal release of a bitter compound (HCl quinine) on food
intake and gut hormone release in healthy subjects.
Materials and Methods
Twenty healthy adult volunteers (12 women, 8 men; median
age 27 years) were recruited from the personnel and students of
the Federico II University Medical School. Their mean ± SD
body mass index (BMI) was 24 ± 4 kg/m2. Exclusion criteria
were: prior abdominal surgery except for appendectomy, pos-
Bitter Taste and Food Intake
Vol. 21, No. 4 October, 2015 (511-519) 513
Figure 1. Study design. (A) All subjects
randomly received a capsule containing
placebo or 18 mg of hydrochloride
quinine in a randomized, double blind,
cross-over design. (B) The ad libitum test
started 60 minutes after capsule admini-
stration. Blood samples were taken to
assay ghrelin and cholecystokinin at T0,
T60, and T90. Gastrointestinal sensation
assessment was performed at T0, T60,
and at the end of ad libitum test (Tend).
GI, gastrointestinal; HCl, hydrochloride;
PTC, phenylthiocarbamide.
itive history of organic or functional GI diseases, use of medi-
cations able to affect GI motility and binge eating disorders.
Informed written consent was obtained from all the participants
and the study was approved by the Ethics Committee of the
Federico II University of Naples.
Study Protocol
This was a randomized, double blind, placebo-controlled,
cross-over study. Following an overnight fast, approximately at
11:30 AM, all subjects underwent ad libitum test 60 minutes after
they randomly received a capsule containing placebo or 18 mg of
hydrochloride (HCl) quinine (Sigma-Aldrich; Gillingham, UK).
After 1 week, the subjects repeated the same experiment receiv-
ing a capsule containing HCl quinine or placebo, respectively
(Fig. 1A). Randomization was assured by a computer-generated
random list (MS Excel 2007). The experimental dose was chosen
after a preliminary study with different amount of HCl quinine
(18, 36, and 72 mg). Given that no differences were observed in
terms of GI feelings and calorie intake among various doses test-
ed, we decided to use the lower dose (data not shown). The cap-
sule was acid-resistant in order to facilitate the release of bitter
compound or placebo into the duodenum. Considering the avail-
able data on gastric emptying time after an overnight fast,20,21 we
chose a 60-minute interval between capsule administration and
the ad libitum test (see below). During the experiment, a ques-
tionnaire was administered to assess GI sensations and plasma
samples were obtained in order to evaluate GI peptide levels (Fig.
1B). Afterwards, all subjects were screened to determine PTC-
tasting status ("tasters" or "non-tasters").
In addition, 8 out of 20 subjects also underwent 2 sessions of
breath test for gastric emptying study. A standard meal was
served to the subjects 60 minutes after the random administration
of a capsule containing 18 mg of HCl quinine or placebo. Breath
samples were collected during the experiments. After 1- week,
Paolo Andreozzi, et al
Journal of Neurogastroenterology and Motility
the same subjects repeated the emptying study receiving a capsule
containing HCl quinine or placebo, respectively. Similarly, ran-
domization was assured by the computer generated random list.
Ad libitum
A standardized test was used to assess calorie intake.22 A
standard buffet meal was served 60 minutes after capsule admini-
stration. The standard meal was composed of white bread, cheese,
and ham spread (Spuntì, Kraft Foods, Italy). The meal was ad-
ministered by single portions, containing 89 kcal each, until max-
imum satiety was reached. The composition of single portions
was the same: 50% carbohydrate, 31% fat, 19% protein. The food
was served in excess to decrease the awareness of food intake. The
quantity of food eaten, the volume of water drunk and the meal
duration were recorded at the end of the test.
Gastrointestinal Sensations Questionnaire
GI sensations were evaluated immediately before the admin-
istration of the capsule (T0), before beginning of the meal (T60)
and at the end of the meal (T end) (Fig. 1B). GI sensations eval-
uated included fullness, nausea, bloating, epigastric pain, heart-
burn, satiety and desire to eat. Measurements were performed by
a visual analogue scale (VAS) calibrated to 100 mm.23,24
Phenylthiocarbamide Status Assessment
To determine PTC tasting status we invited all subjects to
place, consecutively, 2 paper strips on their tongue: the first one
was a control strip, whereas the second one was a strip of filter pa-
per impregnated with 0.3 mg of PTC (Online science mall;
Florida, USA). “Tasters” were defined as subjects who perceived
the bitter taste when PTC-impregnated blotting paper strip was
placed on the tongue. Furthermore, each subject was asked to
rate the intensity of their bitter perception of PTC strip on a VAS
ranging from 0 mm (no taste) to 100 mm (extremely strong
Gastric Emptying Study
Out of 20 subjects who participated in ad libitum test, 8 (4
women, median age 25 years) underwent a breath test study to
determine gastric emptying in a randomized, double blind, place-
bo-controlled cross-over fashion. Sixty minutes after the admin-
istration of HCl quinine or placebo, they were asked to consume
a test meal consisting of 60 g white bread, 10 g butter, 50 g ham,
an omelet made from 1 egg with egg yolk charged with 74 kBq
13C-octanoic acid (Euriso-top, Saint-Aubin, France) and 100
mL water. The test meal contained 480 kcal (19% protein, 53%
carbohydrate, and 31% fat). Subjects were encouraged to eat the
meal within 10 minutes. Breath samples were collected at
15-minute intervals for 240 minutes postprandially. 13CO2-excre-
tion in breath was subsequently analyzed using isotope-selective
infrared spectroscopy to derive gastric emptying half-time.
Biochemical Analysis
Plasma samples were obtained at 0-60-90 minutes after cap-
sules administration, placed in centrifuge tubes containing apro-
tinin and stored at 80oC immediately after centrifugation.
Total plasma immunoreactive ghrelin and CCK were measured
by enzyme immunoassay. Ghrelin was measured in duplicate us-
ing commercial ELISA kits (Phoenix Pharmaceuticals)25; the in-
ter- and intra-assay coefficients of variance were 10%. The
lower and upper detection limits for this assay were 0.12 ng/mL
and 100 ng/mL. CCK (26-33 octapeptide non-sulfated form)
was measured in duplicate using a commercial ELISA kit
(Phoenix Pharmaceuticals)26; the inter- and intra-assay co-
efficients of variance were 10%, with a lower detection limit of
0.04 ng/mL.
Sample Size Calculation
Preliminary data showed a differences of about 100 kcal in
terms of calorie intake between the 2 sessions of the study with a
standard deviation of differences of 120 kcal. Based on this data
we calculated that a sample size of at least 13 p atients would be re-
quired to test our hypothesis with a power of 0.80 and alpha level
of 0.05 (PS Power and Sample Size Calculations; Version 3.0).
Statistical Methods
To evaluate significant differences in terms of GI sensations,
a paired t test was used to compare the VAS scores of these pa-
rameters in the 2 sessions of the study. The same analysis was per-
formed to evaluate differences in calorie intake, volume of water
drunk, meal duration and gastric emptying half-time between the
2 sessions of the experiment, whereas unpaired t test was used to
compare difference of calorie intake in the 2 study sessions (Δ
Kcal = Kcalquinine-Kcalplacebo) between PTC “tasters” and
“non-tasters”. Linear regression was used to evaluate the associa-
tion between bitter PTC intensity and ΔKcal.
Hormone profiles were evaluated both in terms of absolute
values and as difference of T90 values with T0 (before capsule
administration, ΔT90 vs T0) and T60 values (before test meal,
ΔT90 vs T60). Between 2 sessions, ANOVA with repeated meas-
Bitter Taste and Food Intake
Vol. 21, No. 4 October, 2015 (511-519) 515
Figure 2. Gastrointestinal sensations in the 2 sessions of the study. No significant differences were observed between 2 experiments in terms of satiet
and desire to eat at T0, T60, and Tend.
Figure 3. Calorie intake and meal duration in the 2 sessions of the
study. Calorie intake was significantly lower when subjects received
hydrochloride quinine than placebo (514 ± 248 vs 596 ± 286 kcal; P =
0.007). Meal duration did not statistically differ in the 2 sessions of the
study. *P = 0.007.
Table 1. Ad libitum Test in 20 Subjects After the Administration of
HCl Quinine and Placebo
After HCl quinine After placebo P-value
Calorie intake (kcal) 514 ± 248 596 ± 286 0.007
Meal duration (min) 13.7 ± 4.7 14.7 ± 5.4 0.403
Water intake (mL) 157 ± 57 165 ± 59 0.186
Data are presented as mean ± SD.
ures was used to evaluate differences of absolute values, whereas a
paired t test was used to compare differences of ΔT90 vs T0 and
ΔT90 vs T60 between 2 sessions of the study.
The statistical analysis was performed by the statistical soft-
ware package SPSS for Windows Version 12.0 (SPSS, Chicago,
IL, USA). The results are reported as mean ± SD. Differences
were considered statistically significant when P was 0.05.
Effect of Bitter on Gastrointestinal
No subject experienced any oral bitter or unpleasant percep-
tion after HCl quinine or placebo administration, nor were there
any adverse reactions after the experiment. No significant differ-
ences were observed between the 2 experiments in terms of satiety
and desire to eat at T0, T60, and T end (Fig. 2). No significant dif-
ferences were found regarding other symptoms or GI sensations
(data not shown).
Effect of Bitter on Food Intake
As shown in Figure 3, subjects ingested a significantly lower
amount of calories when receiving the capsule containing HCl
quinine than placebo (514 ± 248 vs 596 ± 286 kcal; P = 0.007).
Conversely, meal duration was not different between the 2 experi-
ments (13.7 ± 4.7 vs 14.7 ± 5.4 minutes, P = 0.403) (Fig. 3),
nor was the amount of water intake different (157 ± 57 mL vs
165 ± 59 mL; P = 0.186). All data are showed in Table 1.
Effect of Bitter on Gut Hormones Release
There were no significant differences in CCK absolute values
when subjects received HCl quinine or placebo at the different
time points (T0: 1.05 ± 0.57 vs 1.50 ± 1.11 ng/mL, P = 0.094;
T60: 0.82 ± 0.35 vs 1.11 ± 0.79 ng/mL, P = 0.090; T90: 1.75 ±
0.84 vs 1.60 ± 1.01 ng/mL, P = 0.464). In order to minimize
Paolo Andreozzi, et al
Journal of Neurogastroenterology and Motility
Figure 4. Cholecystokinin (CCK) release after standard meal. Data are
expressed as difference vs basal level (ΔT90 vs T0) and vs pre-meal level
(ΔT90 vs T60). Significantly higher ΔT90 vs T0 and ΔT90 vs T60 were
found when the subjects received a capsule containing hydrochloride
quinine vs those taking placebo. *P = 0.033 and **P = 0.026.
Table 2. Calorie Intake in Phenylthiocarbamide Tasters and Phenylthiocarbamide Non-tasters After the Administration of HCl Quinine and
Placebo (Number of Subjects)
Calorie intake (mean ± SD, kcal) P-value
After HCl quinine After placebo
PTC tasters (n = 11) 526 ± 275 659 ± 320 0.005
PTC non-tasters (n = 9) 499 ± 227 519 ± 231 0.525
PTC, phenylthiocarbamide.
intra-individual variability, we evaluated the difference in CCK
with respect to basal values. Significantly higher ΔT90 vs T0 and
ΔT90 vs T60 were found when subjects received HCl quinine
compared to placebo (ΔT90 vs T0: 0.70 ± 0.69 vs 0.10 ± 0.86
ng/mL, P = 0.033; ΔT90 vs T60: 0.92 ± 0.75 vs 0.50 ± 0.55
ng/mL, P = 0.026) (Fig. 4).
On the contrary, ghrelin plasma levels were not significantly
different with HCl quinine or placebo, either when considered as
absolute concentrations (T0: 2.48 ± 0.66 vs 2.57 ± 0.52 ng/mL,
P = 0.538; T60: 2.50 ± 0.48 vs 2.43 ± 0.39 ng/mL, P = 0.493;
T90: 2.65 ± 0.69 vs 2.45 ± 0.50 ng/mL, P = 0.239) or delta val-
ues (ΔT90 vs T0: 0.17 ± 0.62 vs -0.13 ± 0.46 ng/mL, P =
0.231; ΔT90 vs T60: 0.15 ± 0.49 vs 0.01 ± 0.37 ng/mL, P =
Effect of Bitter on Gastric Emptying Rate
The evaluation of gastric emptying revealed that in a subset
of 8 subjects (5 tasters) HCl quinine was not able to significantly
modify the rate of emptying in comparison to placebo (87 ± 14
vs 88 ± 12 minutes; P = 0.842).
Phenylthiocarbamide Status Assessment
According to the PTC paper test, 11 out of 20 subjects were
identified as “tasters,” while 9 subjects were not able to identify
any bitter sensation and were classified as “non-tasters.”
Most interestingly, a further analysis revealed that PTC tast-
ers ingested a significantly lower amount of calories when they re-
ceived HCl quinine compared to placebo (526 ± 275 vs 659 ±
320 kcal; P = 0.005), whereas no significant differences were
found for PTC non-tasters (499 ± 227 vs 519 ± 231 kcal; P =
0.525) (Table 2). This finding was even more evident when the
difference of calorie intake between the 2 experiments was con-
sidered, since PTC tasters presented a significantly different Δ
Kcal compared to non-tasters (134 ± 124 vs 20 ± 89 kcal;
P = 0.034) (Fig. 5).
Moreover, the linear regression showed a negative associa-
tion between PTC bitter intensity and ΔKcal (r = 0.579; P =
0.008) (Fig. 6).
Regarding CCK release, in PTC tasters we observed that
ΔT90 vs T0 and ΔT90 vs T60 after the administration of HCl qui-
nine was higher compared to placebo but these differences were
not statistically significant (ΔT90 vs T0: 0.84 ± 0.72 vs 0.12 ±
0.88 ng/mL, P = 0.103; ΔT90 vs T60: 1.08 ± 0.88 vs 0.53 ±
0.57 ng/mL, P = 0.083). Similarly, no significant differences for
ghrelin levels were found between the 2 groups in the 2 sessions
of the study (data not shown).
The gut “senses” the food, although the molecular mecha-
nisms of GI chemosensitivity are not fully understood. This study
showed for the first time that the direct intra-luminal admin-
istration of a bitter taste receptor agonist is able to significantly re-
duce calorie intake in healthy subjects, likely acting on gut bitter
taste receptors and altering gut hormone levels.
Bitter Taste and Food Intake
Vol. 21, No. 4 October, 2015 (511-519) 517
Figure 5. Phenylthiocarbamide (PTC) status assessment. PTC tasters ingested a significantly lower amount of calories when they received
hydrochloride quinine compared to placebo (526 ± 275 vs 659 ± 320 kcal; P = 0.005), whereas no significant differences were found for PTC
non-tasters (499 ± 227 vs 519 ± 231 kcal; P = 0.525). PTC tasters presented a significantly higher difference in calorie intake between 2 experiments
(Δ Kcal) compared to non-tasters (134 ± 124 vs 20 ± 89 kcal; P = 0.034). *P = 0.005 and **P = 0.034.
Figure 6. Correlation between bitter phenylthiocarbamide (PTC)
intensity and ΔKcal (calorie intakeplacebo - calorie intakequinine). Linear
regression showed a negative association between ΔKcal and bitter PTC
intensity (r = 0.579, P = 0.008).
In our hands, the administration of HCl quinine in healthy
subjects was able to significantly reduce calorie intake in an ad
libitum food intake test. In particular, the subjects ingested about
15% less calories when compared to placebo, and this occurred
without a significant change in meal duration. This result is in
agreement with previously published data showing that quinine
per se strongly reduces food intake in rats, independently of its
aversive taste.27,28 In addition, we found that the quinine-medi-
ated reduction of food intake is associated to the individual ability
to percept PTC, since a significantly lower amount of calories was
observed in “tasters” than in “non-tasters” subjects.
We used quinine, an anti-malarial drug extracted from the
bark of the cinchona tree, able to trigger bitter taste by the activa-
tion of several members of T2R family receptors.29 The drug was
administered by an acid-resistant capsule for 2 main reasons: (1)
in order to prevent the activation of the taste receptors of the oral
cavity and (2) to prevent the release of ghrelin, produced by the
X/A-like cells of the oxyntic glands of the stomach and to allow
its release into the duodenum where CCK-releasing EECs are
The role of bitter taste in the control of digestive functions is
controversial: bitter compounds are naturally unpleasant. From a
classical point of view, the bitter taste evolved in order to refuse
potentially toxic compounds, such as plant alkaloids or microbial
toxins. However, bitter compounds are also used to stimulate ap-
petite or digestion in several parts of the world. For example, the
habit of drinking aperitif before a meal is justified by the belief
that the bitter taste stimulates appetite and increases gastric
Gustatory signals likely play a role in the cephalic phase of
food intake to prepare the digestive tract to receive food.30
However, previous studies have shown that the activation of in-
testinal T2R results in the release of gut peptides, suggesting a
role in the post-ingestion phase of food intake.18,19,31 In particular,
the release of ghrelin from gastric EECs may explain, at least par-
tially, that bitter compounds could increase appetite feeling.
The process that limits calorie intake is the result of a coordi-
nated series of neural and humoral signals that originate from the
gut. In particular, hormonal signaling is strongly influenced by
intra-luminal chemicals (lipid, carbohydrates, and amino acids).32
According to our preliminary hypothesis, quinine failed to affect
Paolo Andreozzi, et al
Journal of Neurogastroenterology and Motility
ghrelin release while significant postprandial CCK increase
occurred. These data could explain, at least partially, the lower
calorie intake in comparison to placebo. To the best of our knowl-
edge, this is the first report indicating that quinine, a T2R ago-
nist, is able to modify postprandial CCK-release in humans.
Taking into account that the gastric motility may affect food
intake,33 we studied in a subset of volunteers the effect of quinine
on gastric emptying rate. Our results failed to find any significant
change of quinine compared to placebo, further suggesting that
the reduced calorie intake is independent of gastric motility.
Although bitter compounds in rats were able to delay gastric
emptying, our result is in agreement with a previous study show-
ing that quinine did not affect the rate of gastric emptying in
The sensitivity to bitter compounds is genetically grounded
and individuals can be classified as “tasters” or “non-tasters” be-
cause of their ability to recognize PTC. Chang et al36 have dem-
onstrated a positive relationship between PTC/PROP taster sta-
tus and oral taste sensitivity to sucrose or quinine. To verify that
both oral and gut taste mechanisms are comparable, we also
screened the oral taste status of PTC in each subject. We found
that the effects of quinine on calorie intake affected only subjects
who were able to discriminate PTC, but not PTC non-tasters.
However, only a non-significant trend in CCK increase was ob-
served after the administration of quinine in PTC tasters.
Our results suggest that quinine-mediated CCK release is
likely unable per se to explain the observed effects on food intake
and other mechanisms could be involved in the food intake
reduction. To date, it is known that bitter stimuli trigger the re-
lease of gut hormones in EECs through a mechanism appearing
to involve T2Rs, -subunits of the G protein gustducin, phos-
pholipase and Ca2+ influx.18 Given the complexity of bitter stim-
uli transduction pathways in GI cells, we can speculate that other
mechanisms (ie, via gustducin, calcium or phospholipase) may
play a role in quinine-related effects on food intake, activating
neural reflexes and/or acting in a paracrine or endocrine manner.
Various studies have tried to elucidate the physiological role
of gut taste receptors in humans. Gerspach et al37 demonstrated
that lactisole, a T1R1/T1R3 (sweet) antagonist, induced a sig-
nificant reduction in GLP-1 and PYY but not CCK secretion, in
response to intragastric and intraduodenal glucose administration.
Our study demonstrates, for the first time, that bitter taste re-
ceptors are also involved in the physiological mechanisms that
control appetite in humans. Therefore, while the role of the T2Rs
in the oral cavity would prevent the intake of hazardous chem-
icals, the bitter taste receptors in the GI tract may act as a second
level mechanism which is able to further limit the intake of poten-
tially toxic bitter chemicals. Jeon et al31 showed that T2R signal-
ing stimulates the secretion of CCK from EECs and induces the
expression of ATP-binding cassette B1, a transporter expressed
on the apical membrane of intestinal epithelial cells able to limit
absorption of toxic substrates, both in Caco-2 cells and mouse in-
testine, through a CCK-dependent mechanism.
Summarizing, we showed that the intra-luminal release of
quinine, a bitter taste receptor agonist, significantly reduces the
calorie intake in an ad libitum test in healthy subjects, by a mecha-
nisms likely involving CCK. Furthermore, the reduced calorie
intake was positively associated with bitter PTC status. Our re-
sults suggest that T2R signaling in the human gut may have a
role in energy intake and appetite control, likely through the re-
lease of gut hormones. However, further studies are needed to
elucidate the ability of bitter taste receptors to control food intake.
In particular, it could be of extreme interest to test whether the
stimulation of bitter receptors is able to limit calorie intake, and
whether bitter compounds, other than quinine, are able to exert
similar effects. In conclusion, if our hypothesis will be confirmed,
we can speculate that the modulation of T2R activity could turn
out to be a novel therapeutic approach to over-nutritional diseases
and obesity.
The authors would like to express gratitude to Eleonora
Effice for her help in the administration of the capsule to volun-
teers and Rosanna Scala for her help with the preparation of the
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... These gut peptide hormones play a key role the homeostatic regulation of appetite, energy intake, gut function, hedonic food perceptions, and nutrient metabolism (33)(34)(35)(36)(37). A number of clinical studies using either encapsulation or intragastric and intraduodenal infusion of bitter tastents have demonstrated effects ranging from increased gut peptide secretion, reduced energy intake or rate of gastric emptying, modifications in subjective ratings of hunger and fullness, and altered glycemic regulation (38)(39)(40)(41)(42)(43)(44), although these anorexigenic effects are inconsistent (43,(45)(46)(47), necessitating further investigation of this response. ...
... This is in agreement with a previous study investigating the relation between CCK-8 infusion, nausea, and EI (73) in which the authors concluded that "although feelings of anxiety and nausea may accompany CCK infusions, they are not necessary for the effects of CCK on appetite." The magnitude of total EI suppression (17%) is significant in the context of weight management applications (74) and compares favorably with results from previous studies in humans (0-22%) that have used encapsulation, intragastric, or intraduodenal delivery of a variety of bitter tastants (38,40,42,43,47,75,76). ...
... Although correlations between subjective assessments (e.g., hunger) and behavioral effects (e.g., energy intake) are often observed, they assess fundamentally different things, have been reported to show weak correlations, and do not always concur (68,87). Previous studies using either gastric or duodenal delivery of T2R agonists have shown effects on subjective measures of appetite in both men (88)(89)(90), and women (41,91), although many studies show no response (43,(45)(46)(47). Interestingly, participants in the current study did achieve similar feelings of fullness at the ad libitum test meals after consuming less food when taking both hop treatments compared with the placebo. ...
Background: Gastrointestinal enteroendocrine cells express chemosensory bitter taste receptors (T2Rs) that may play an important role in regulating energy intake (EI) and gut function. Objectives: To determine the effect of a bitter hop extract (Humulus lupulus L.) on acute EI, appetite and hormonal responses. Design: Nineteen healthy-weight men completed a randomized three-treatment, double blind, cross-over study with a 1 week washout between treatments. Treatments comprised either placebo or 500 mg of hop extract administered in delayed release capsules (duodenal) at 1100 h or quick release capsules (gastric) at 1130 h. Ad libitum EI was recorded at the lunch (1200 h) and afternoon snack (1400 h), with blood samples taken and subjective ratings of appetite, gastrointestinal discomfort, vitality, meal palatability and mood assessed throughout the day. Results: Total ad libitum EI was reduced following both the gastric (4473 kJ; 95% CI: 3811, 5134; P = 0.006) and duodenal (4439 kJ; 95% CI: 3777, 5102; P = 0.004) hop treatments compared with the placebo (5383 kJ; 95% CI: 4722, 6045). Gastric and duodenal treatments stimulated pre-lunch ghrelin secretion and post-prandial cholecystokinin, glucagon-like peptide 1 and peptide YY responses compared with placebo. In contrast, postprandial insulin, glucose-dependent insulinotropic peptide and pancreatic polypeptide responses were reduced in gastric and duodenal treatments without impacting glycemia. In addition, gastric and duodenal treatments produced small but significant increases in subjective measures of gastrointestinal discomfort (e.g., nausea, bloating, abdominal discomfort) with mild-severe adverse GI symptoms reported in the gastric treatment only. However, no significant treatment effects were observed for any subjective measures of appetite or meal palatability. Conclusion: Both gastric and duodenal delivery of a hop extract modulates the release of hormones involved in appetite and glycemic regulation, providing a potential "bitter brake" on EI in healthy-weight men. Clinical Trial Registry: ACTRN12614000434695
... The following bitters (Table 4) did not affect gastric opening when administered in the gut: denatonium, 55 naringin 56 and quinine hydrochloride. [56][57][58] In contrast, when the bitter tastant, quinine sulphate, was orally administered (sham feeding) it slowed gastric emptying when compared to the control (strawberry taste). 59 More recently, when 600 mg quinine hydrochloride was administered to either the stomach or the duodenum, both modes of administration reduced both gastric emptying and plasma glucose while increasing plasma insulin. ...
... In a crossover design, quinine hydrochloride delivered in intra-duodenal release capsule form elicited increases in CCK compared to control. 57 Also, in another crossover design, a hops concentrate designed to open either in the stomach or duodenum elicited increases in CCK compared to a control. 61 Other studies with intraduodenal infusions of bitter tastants reported no change in CCK. ...
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This paper reports clinical studies on the effect of agonists of taste and chemethesis receptors in the oropharyngeal cavity and the gut. The peripheral nerve system plays a vital role in our selection or rejection of what we eat and drink. Although the degree to which it is hard-wired has not been determined, it is known that our food and drink choices change with age. Scientific studies on the impact of food and drink on the body have been concerned predominantly with nutritional factors and, more recently, impacts on cholesterol and blood sugar levels. On the other hand, the sensations we experience during eating and drinking have long been regarded, perhaps even dismissed, as purely hedonistic. The idea that foods and drinks may actually influence digestion is a novel one and is based on the discovery 20 years ago of taste buds, innervated by the vagi, in stomach and intestinal tissues. Studies indicate some of our most popular drinks modulate both postprandial hyperaemia and gastric emptying. It is proposed that the bitter taste experienced with some foods and drinks promotes increased blood flow to the splanchnic circulation and slows the flow of chyme to the small intestine. In cases of toxicity, these actions promote emesis whereas at non-toxic levels, bitter substances promote digestion by increasing postprandial hyperaemia and slowing gastric emptying. Additionally, chemethesis agonists can act on the oropharyngeal receptors resulting in a slower gastric emptying. These effects may lead to a learned behaviour and subsequent enjoyment of bitter tastants, rather than their rejection, amongst those with reduced digestive capacity. It provides a rationale for the popularity of certain bitter tasting aperitifs and digestive alcoholic beverages originating in southern Europe.
... It is used clinically to treat malaria, usually in a dose of 500 mg intravenously (10), and has the capacity to induce hypoglycemia, probably by direct stimulation of insulin (11). A small number of studies have reported effects of quinine on the secretion of gut hormones, including suppression of plasma ghrelin, and stimulation of CCK and GLP-1 (12)(13)(14)(15)(16). Intragastric (IG) administration of quinine hydrochloride (QHCl), in a dose of 10 µmol/kg (equivalent to ~270 mg in a 70-kg human), suppressed ghrelin (14,15), while a recent study from the same group found no effect of either intraduodenal (ID) or IG-QHCl, in the same dose, on plasma CCK (17). ...
... A small number of studies have reported effects of quinine on the secretion of gut hormones, including suppression of plasma ghrelin, and stimulation of CCK and GLP-1 (12)(13)(14)(15)(16). Intragastric (IG) administration of quinine hydrochloride (QHCl), in a dose of 10 µmol/kg (equivalent to ~270 mg in a 70-kg human), suppressed ghrelin (14,15), while a recent study from the same group found no effect of either intraduodenal (ID) or IG-QHCl, in the same dose, on plasma CCK (17). In contrast, an IG bolus of 18 mg QHCl was found to increase plasma CCK (although the effect was very small) after a standardized meal (12). Both ID-and IG-QHCl, in a dose of 600 mg (~500 mg quinine), stimulated GLP-1 and insulin, associated with postprandial blood glucose lowering (13,16). ...
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Background: The bitter substance, quinine, modulates the release of a number of gut and gluco-regulatory hormones and upper gut motility. As the density of bitter receptors may be higher in the duodenum than the stomach, direct delivery to the duodenum may be more potent in stimulating these functions. The gastrointestinal responses to bitter compounds may also be modified by sex. We have characterised the effects of intragastric (IG) versus intraduodenal (ID) administration of quinine-hydrochloride (QHCl) on gut and pancreatic hormones and antropyloroduodenal pressures in healthy men and women. Methods: 14 men (26±2 years, BMI: 22.2±0.5 kg/m 2) and 14 women (28±2 years, BMI: 22.5±0.5 kg/m 2) received, 600mg QHCl, on 2 separate occasions, IG or ID as a 10-ml bolus, in randomised, double-blind fashion. Plasma ghrelin, cholecystokinin, peptide-YY, glucagon-like peptide-1 (GLP-1), insulin, glucagon and glucose concentrations and antropyloroduodenal pressures were measured at baseline and for 120min following QHCl. Results: Suppression of ghrelin (P=0.006), stimulation of cholecystokinin (P=0.030), peptide-YY (P=0.017), GLP-1 (P=0.034), insulin (P=0.024), glucagon (P=0.030) and pyloric pressures (P=0.050) and lowering of glucose (P=0.001) were greater after ID-QHCl than IG-QHCl. Insulin stimulation (P=0.021) and glucose reduction (P=0.001) were greater in females than males, while no sex-associated effects were found for cholecystokinin, peptide-YY, GLP-1, glucagon or pyloric pressures. Conclusions: ID quinine has greater effects on plasma gut and pancreatic hormones and pyloric pressures than IG quinine in healthy subjects, consistent with the concept that stimulation of small intestinal bitter receptors is critical to these responses. Both insulin stimulation and glucose lowering were sex-dependent.
... Considering the decrease in prospective and actual food intake, along with their covariation with increased activity of homeostatic and hedonic brain regions involved in the control of appetite and food intake, TAS2Rs may represent important alternative neurohumoral gut-brain signals that can mediate the orexigenic effect of ghrelin [156,157]. Nevertheless, Andreozzi et al. observed that 18 mg QHCl did not affect plasma ghrelin level [158]. This can potentially be explained by insufficiency in the dose of QHCl administered, as well as by the difference in the route of its administration, as enteral application bypasses the stomach, which harbours most X/A-like ghrelin-secreting cells [159]. ...
... Apart from targeting detoxification pathways, bitter taste signalling is functionally linked to the regulation of energy intake and appetite control in not only ghrelin-, but also possibly in a CCK-dependant manner. Androzzi et al. [158] have demonstrated that oral administration of 18 mg QHCl in the form of an acid-resistant capsule significantly increased the level of CCK 60 and 90 min after administration of the compound, resulting in reduced calorie intake (ΔKcal) in an ad libitum test (514 ± 248 vs. 569 ± 286 kcal for placebo; P = 0.007) in young healthy volunteers. PTC tasters ingested a significantly lower amount of calories when they received QHCl than those who received placebo. ...
Full-text available
Bitter taste-sensing type 2 receptors (TAS2Rs or T2Rs), belonging to the subgroup of family A G-protein coupled receptors (GPCRs), are of crucial importance in the perception of bitterness. Although in the first instance, TAS2Rs were considered to be exclusively distributed in the apical microvilli of taste bud cells, numerous studies have detected these sensory receptor proteins in several extra-oral tissues, such as in pancreatic or ovarian tissues, as well as in their corresponding malignancies. Critical points of extra-oral TAS2Rs biology, such as their structure, roles, signaling transduction pathways, extensive mutational polymorphism, and molecular evolution, have been currently broadly studied. The TAS2R cascade, for instance, has been recently considered to be a pivotal modulator of a number of (patho)physiological processes, including adipogenesis or carcinogenesis. The latest advances in taste receptor biology further raise the possibility of utilizing TAS2Rs as a therapeutic target or as an informative index to predict treatment responses in various disorders. Thus, the focus of this review is to provide an update on the expression and molecular basis of TAS2Rs functions in distinct extra-oral tissues in health and disease. We shall also discuss the therapeutic potential of novel TAS2Rs targets, which are appealing due to their ligand selectivity, expression pattern, or pharmacological profiles.
... Furthermore, the subjects who were unable to taste bitterness due to genetic variations of the bitter taste receptor TAS2R38 were supposed to consume more dietary fat and, therefore, might develop obesity [34]. Other studies reported that bitter taste might affect various brain regions implicated in appetite reduction, and functional magnetic resonance imaging (fMRI) studies have shown that bitter taste was associated with stronger recruitment of different cortical areas, whose responses to bitterness may elicit appetite reduction [35]. Likewise, electroencephalographic (EEG) studies have further demonstrated that bitterness reduces appetitive ratings for high-caloric food images. ...
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Background: The sense of taste is involved in food behavior and may drive food choices, likely contributing to obesity. Differences in taste preferences have been reported in normal-weight as compared to obese subjects. Changes in taste perception with an increased sweet-induced sensitivity have been reported in surgically treated obese patients, but data regarding the perception of basic tastes yielded conflicting results. We aimed to evaluate basic taste identification, induced perception, and pleasantness in normal-weight controls and obese subjects before and after bariatric surgery. Methods: Severe obese and matched normal weight subjects underwent a standardized spit test to evaluate sweet, bitter, salty, umami, and sour taste identification, induced perception, and pleasantness. A subset of obese subjects were also studied before and 12 months after sleeve gastrectomy. Results: No significant differences in basic taste-induced perceptions were observed, although a higher number of controls correctly identified umami than did obese subjects. Sleeve-gastrectomy-induced weight loss did not affect the overall ability to correctly identify basic tastes but was associated with a significant increase in taste intensities, with higher scores for sour and bitter, and a significantly reduced bitter-induced pleasantness. Conclusions: The perception of basic tastes is similar in normal-weight and severely obese subjects. Sleeve-gastrectomy-induced weight loss significantly increases basic taste-induced intensity, and selectively reduces bitter-related pleasantness without affecting the ability to identify the tastes. Our findings reveal that taste perception is influenced by body mass index changes, likely supporting the hypothesis that centrally mediated mechanisms modulate taste perception in severe obesity.
... Increased CCK excretion was observed after 500 mg of hop (Humulus lupulus) extract given after oral intestinal-and gastric-targeted administration [33]. However, in three studies with quinine hydrochloride applied either in an acid-resistant capsule in healthy males and females [34] or by intraduodenal infusion in healthy, lean men, an increase in CCK was not observed [35,36]. ...
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The worldwide prevalence of gastrointestinal diseases is about 40%, with standard pharmacotherapy being long-lasting and economically challenging. Of the dozens of diseases listed by the Rome IV Foundation criteria, for five of them (heartburn, dyspepsia, nausea and vomiting disorder, constipation, and diarrhoea), treatment with herbals is an official alternative, legislatively supported by the European Medicines Agency (EMA). However, for most plants, the Directive does not require a description of the mechanisms of action, which should be related to the therapeutic effect of the European plant in question. This review article, therefore, summarizes the basic pharmacological knowledge of synthetic drugs used in selected functional gastrointestinal disorders (FGIDs) and correlates them with the constituents of medicinal plants. Therefore, the information presented here is intended as a starting point to support the claim that both empirical folk medicine and current and decades-old treatments with official herbal remedies have a rational basis in modern pharmacology.
Gastrointestinal functions, particularly pyloric motility and the gut hormones, cholecystokinin and peptide YY, contribute to the regulation of acute energy intake. Bitter tastants modulate these functions, but may, in higher doses, induce GI symptoms. The aim of this study was to evaluate the effects of both dose and delivery location of a bitter hop extract (BHE) on antropyloroduodenal pressures, plasma cholecystokinin and peptide-YY, appetite perceptions, gastrointestinal symptoms and energy intake in healthy-weight men. The study consisted of two consecutive parts, with part A including n = 15, and part B n = 11, healthy, lean men (BMI 22.6 ± 1.1 kg/m2, aged 25 ± 3 years). In randomised, double-blind fashion, participants received in part A, BHE in doses of either 100 mg ("ID-BHE-100") or 250 mg ("ID-BHE-250"), or vehicle (canola oil; "ID-control") intraduodenally, or in part B, 250 mg BHE ("IG-BHE-250") or vehicle ("IG-control") intragastrically. Antropyloroduodenal pressures, hormones, appetite and symptoms were measured for 180 min, energy intake from a standardised buffet-meal was quantified subsequently. ID-BHE-250, but not ID-BHE-100, had modest, and transient, effects to stimulate pyloric pressures during the first 90 min (P < 0.05), and peptide-YY from t = 60 min (P < 0.05), but did not affect antral or duodenal pressures, cholecystokinin, appetite, gastrointestinal symptoms or energy intake. IG-BHE-250 had no detectable effects. In conclusion, BHE, when administered intraduodenally, in the selected higher dose, modestly affected some appetite-related gastrointestinal functions, but had no detectable effects when given in the lower dose or intragastrically. Thus, BHE, at none of the doses or routes of administration tested, has appetite- or energy intake-suppressant effects.
Taste receptors are located on the epithelial surface throughout the alimentary canal to identify nutrients and potential toxins. In the oral cavity, the role of taste is to encourage or discourage ingestion, while in the gastrointestinal (GI) tract, the taste receptors help the body prepare for an appropriate response to the ingested foods. The GI sensing of bitter compounds may alter the secretion of appetite-related hormones thereby reducing food intake, which may have potential use for managing health outcomes. This systematic literature review investigated the acute effects of administering different bitter tasting compounds on circulating levels of selected GI hormones, subjective appetite, and energy intake in humans. A literature search was conducted using Medline, CINAHL and Web of Science databases. Of 290 articles identified, 16 met the inclusion criteria. Twelve studies assessed food intake; four of these found bitter administration decreased food intake and eight did not. Fourteen studies assessed subjective appetite; seven found bitter administration affected at least one measure of appetite and seven detected no significant changes. Nine studies included measures of GI hormones; no significant effects were found for changes in GLP-1, CCK or PYY. Four studies measured motilin and ghrelin and found mostly consistent changes in either food intake or subjective appetite. Overall, the data on food intake and subjective appetite were inconsistent, with only motilin and ghrelin responsive to post-oral bitter administration. There is limited consistent conclusive evidence that bitter compounds influence food intake, appetite or hormones with the reasons for this discussed within. Systematic review registration CRD42021226102.
Auch Zellen und Gewebe außerhalb des Mundraumes verfügen über Chemorezeptoren, die normalerweise mit bitter, süß oder scharf schmeckenden Lebensmittelinhaltsstoffen interagieren. Da wir aber weder mit Organen wie dem Magen oder Darm im eigentlichen Sinne „schmecken“, stellt sich die Frage, welche Aufgaben Chemorezeptoren dort erfüllen.
Nutrients sensing is crucial for fundamental metabolism and physiological functions, and it is also an essential component for maintaining body homeostasis. Traditionally, basic taste receptors exist in oral cavity to sense sour, sweet, bitter, umami, salty and et al. Recent studies indicate that gut can sense the composition of nutrients by activating relevant taste receptors, thereby exerting specific direct or indirect effects. Gut taste receptors, also named as intestinal nutrition receptors, including at least bitter, sweet and umami receptors, have been considered to be activated by certain nutrients and participate in important intestinal physiological activities such as eating behavior, intestinal motility, nutrient absorption and metabolism. Additionally, gut taste receptors can regulate appetite and body weight, as well as maintain homeostasis via targeting hormone secretion or regulating the gut microbiota. On the other hand, malfunction of gut taste receptors may lead to digestive disorders, and then result in obesity, type 2 diabetes and gastrointestinal diseases. At present, researchers have confirmed that the brain-gut axis may play indispensable roles in these diseases via the secretion of brain-gut peptides, but the mechanism is still not clear. In this review, we summarize the current observation of knowledge in gut taste systems in order to shed light on revealing their important nutritional functions and promoting clinical implications.
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The emerging picture of taste coding at the periphery is one of elegant simplicity. Contrary to what was generally believed, it is now clear that distinct cell types expressing unique receptors are tuned to detect each of the five basic tastes: sweet, sour, bitter, salty and umami. Importantly, receptor cells for each taste quality function as dedicated sensors wired to elicit stereotypic responses.
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Ingestion of food affects secretion of hormones from enteroendocrine cells located in the gastrointestinal mucosa. These hormones are involved in the regulation of various gastrointestinal functions including the control of food intake. One cell in the stomach, the X/A-like has received much attention over the past years due to the production of ghrelin. Until now, ghrelin is the only known orexigenic hormone that is peripherally produced and centrally acting to stimulate food intake. Subsequently, additional peptide products of this cell have been described including desacyl ghrelin, obestatin and nesfatin-1. Desacyl ghrelin seems to be involved in the regulation of food intake as well and could play a counter-balancing role of ghrelin's orexigenic effect. In contrast, the initially proposed anorexigenic action of obestatin did not hold true and therefore the involvement of this peptide in the regulation of feeding is questionable. Lastly, the identification of nesfatin-1 in the same cell in different vesicles than ghrelin extended the function of this cell type to the inhibition of feeding. Therefore, this X/A-like cell could play a unique role by encompassing yin and yang properties to mediate not only hunger but also satiety.
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The gastrointestinal system can be considered the gateway for food entry in our body. Rather than being a passive player, it is now clear that gut strongly influence the feeding behavior and contribute to maintain energy balance with different signals. The aim of this review is to summarize the current knowledge about the role of gastrointestinal tract in the control of food intake, by focusing on the interplay existing between the enteric nervous system and gastrointestinal hormones and their ability to modulate digestive motility and sensitivity. Also the latest advances about the contribution of gut microbiota and gastrointestinal taste receptors are described. From the reported data it clearly emerges that gut hormones together with nervous signals likely contribute to the regulation of energy balance and modulate food intake through the control of digestive motility and sensations. The close linkage among gastrointestinal hormones, the gut and the central nervous systems appears very intriguing and has induced the development of a new field of research: the gastroendocrinology.
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There is conflicting data on the effects of carbon dioxide contained in beverages on stomach functions. We aimed to verify the effect of a pre-meal administration of a 300 ml non-caloric carbonated beverage (B+CO2) compared to water or a beverage without CO2 (B-CO2), during a solid (SM) and a liquid meal (LM) on: a) gastric volume, b) caloric intake, c) ghrelin and cholecystokinin (CCK) release in healthy subjects. After drinking the beverages (Water, B-CO2, B+CO2), ten healthy subjects (4 women, aged 22-30 years; BMI 23 ± 1) were asked to consume either an SM or an LM, at a constant rate (110 kcal/5 min). Total gastric volumes (TGV) were evaluated by Magnetic Resonance Imaging after drinking the beverage and at maximum satiety (MS). Total kcal intake at MS was evaluated. Ghrelin and CCK were measured by enzyme immunoassay until 120 min after the meal. Statistical calculations were carried out by paired T-test and analysis of variance (ANOVA). The data is expressed as mean ± SEM. TGV after B+CO2 consumption was significantly higher than after B-CO2 or water (p < 0.05), but at MS, it was no different either during the SM or the LM. Total kcal intake did not differ at MS after any of the beverages tested, with either the SM (Water: 783 ± 77 kcals; B-CO2: 837 ± 66; B+CO2: 774 ± 66) or the LM (630 ± 111; 585 ± 88; 588 ± 95). Area under curve of ghrelin was significantly (p < 0.05) lower (13.8 ± 3.3 ng/ml/min) during SM following B-CO2 compared to B+CO2 and water (26.2 ± 4.5; 27.1 ± 5.1). No significant differences were found for ghrelin during LM, and for CCK during both SM and LM after all beverages. The increase in gastric volume following a 300 ml pre-meal carbonated beverage did not affect food intake whether a solid or liquid meal was given. The consistency of the meal and the carbonated beverage seemed to influence ghrelin release, but were unable, under our experimental conditions, to modify food intake in terms of quantity. Further studies are needed to verify if other food and beverage combinations are able to modify satiation.
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Basic taste qualities like sour, salty, sweet, bitter and umami serve specific functions in identifying food components found in the diet of humans and animals, and are recognized by proteins in the oral cavity. Recognition of bitter taste and aversion to it are thought to protect the organism against the ingestion of poisonous food compounds, which are often bitter. Interestingly, bitter taste receptors are expressed not only in the mouth but also in extraoral tissues, such as the gastrointestinal tract, indicating that they may play a role in digestive and metabolic processes. BitterDB database, available at, includes over 550 compounds that were reported to taste bitter to humans. The compounds can be searched by name, chemical structure, similarity to other bitter compounds, association with a particular human bitter taste receptor, and so on. The database also contains information on mutations in bitter taste receptors that were shown to influence receptor activation by bitter compounds. The aim of BitterDB is to facilitate studying the chemical features associated with bitterness. These studies may contribute to predicting bitterness of unknown compounds, predicting ligands for bitter receptors from different species and rational design of bitterness modulators.
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T2Rs (bitter taste-sensing type 2 receptors) are expressed in the oral cavity to prevent ingestion of dietary toxins through taste avoidance. They are also expressed in other cell types, including gut enteroendocrine cells, where their physiological role is enigmatic. Previously, we proposed that T2R-dependent CCK (cholecystokinin) secretion from enteroendocrine cells limits absorption of dietary toxins, but an active mechanism was lacking. In the present study we show that T2R signalling activates ABCB1 (ATP-binding cassette B1) in intestinal cells through a CCK signalling mechanism. PTC (phenylthiocarbamide), an agonist for the T2R38 bitter receptor, increased ABCB1 expression in both intestinal cells and mouse intestine. PTC induction of ABCB1 was decreased by either T2R38 siRNA (small interfering RNA) or treatment with YM022, a gastrin receptor antagonist. Thus gut ABCB1 is regulated through signalling by CCK/gastrin released in response to PTC stimulation of T2R38 on enteroendocrine cells. We also show that PTC increases the efflux activity of ABCB1, suggesting that T2R signalling limits the absorption of bitter tasting/toxic substances through modulation of gut efflux membrane transporters.
In comparison with a saline infusion, the infusion of the C-terminal octapeptide of cholecystokinin (4 ng/kg/min) decreased food intake by an average of 122 g in a group of 12 lean men without objective evidence of untoward side effects. Shapes of the cumulative intake curves under the two conditions were similar, but subjects ate less and stopped eating sooner when receiving octapeptide than when receiving saline. These results are consistent with the hypothesis that cholecystokinin is an endogenous signal for postprandial satiety. The results offer promise for the possible use of the octapeptide as an appetite suppressant.
The release of gut hormones involved in the control of food intake is dependent on the acute nutritional status of the body, suggesting that chemosensory mechanisms are involved in the control of their release. G protein-coupled taste receptors similar to those in the lingual system, that respond to sweet, bitter, umami, and fatty acids, are expressed in endocrine cells within the gut mucosa, and coordinate, together with other chemosensory signaling elements, the release of hormones that regulate energy and glucose homeostasis. In health, these nutrient sensors are likely to function as inhibitors to excessive nutrient exposure, and their malfunction may be responsible for a variety of metabolic dysfunctions associated with obesity; they may thus be considered as new therapeutic targets.
Food intake is influenced not only by nutritional status but also by diverse environmental factors. Indeed, a unique quality of food reward is its strong modulation by palatability cues, such as taste, with animals generally preferring diets that are sweet and avoiding those that are either bitter or sour. As appetite suppressants (including those currently in development) could alter food intake by modifying taste sensitivity and/or palatability, the aim of the present study was to characterise the influence of taste adulteration on the normal structure of feeding behaviour, i.e., the behavioural satiety sequence (BSS). Adult male rats were initially habituated both to the basic test diet (mash) and the test arena. Following stabilisation of basal intake, a continuous monitoring technique was used to profile behaviour in weekly 1-h sessions during which the animals were presented, in counterbalanced order, with the basic diet (control) or one of four taste-adulterated variants (0.015% quinine, 0.04% quinine, 0.2% saccharin, 0.3% saccharin). Food intake was strongly suppressed by the higher quinine concentration but was not significantly altered by any of the other additives. Behavioural analysis revealed that this anorectic-like response to 0.04% quinine-adulterated food was associated with a significant reduction in the peak feeding response, highly atypical intermittent food sampling/digging and the virtual absence of resting behaviour. Importantly, this pattern of behavioural change is readily distinguishable from those seen in response to other manipulations that reduce intake, including selective anorectics, sedatives and psychostimulants. Despite the lack of significant effect on food intake or the duration of feeding behaviour, dietary adulteration with 0.015% quinine (and, to a lesser degree, 0.3% saccharin) produced some effects on behavioural structure/time course consistent with a mild aversive response, i.e., bouts of midsession food sampling and a delay in the transition from eating to resting. Data are discussed in relation to the specific behavioural signature to quinine-induced anorexia and its potential utility in identifying appetite suppressants that may modify intake via changes in taste sensitivity and/or palatability.
Enteric-coated tablets leave the stomach mainly during the interdigestive phase. Composition as well as time of ingestion of meals may influence their gastric emptying considerably. In 12 normal volunteers gastric emptying of a plastic tablet with a metal core was followed by a metal detector in relation to different compositions and various times of ingestion of meals. With an empty stomach and after ingestion of 250 ml water, the mean time for gastric emptying of the tablet was 3811 min (meanSEM) and 388 min. Two hundred fifty milliliters of milk (652 kJ) and a formula diet (1000 kJ) delayed gastric emptying time to 12814 and 1526 min, respectively (PPr=0.92;PPP