Received: 10 August 2018 | Revised: 29 November 2018 | Accepted: 16 December 2018

DOI: 10.1111/nmo.13546

REVIEW ARTICLE

Advances in the physiology of gastric emptying

Raj K. Goyal | Yanmei Guo | Hiroshi Mashimo

Department of Medicine, VA Boston

Healthcare System, Harvard Medical School, Abstract
Boston, Massachusetts There have been many recent advances in the understanding of various aspects of
Correspondence the physiology of gastric motility and gastric emptying. Earlier studies had discov-
Raj K. Goyal, Department of Medicine, VA ered the remarkable ability of the stomach to regulate the timing and rate of empty-
Boston Healthcare System, Harvard Medical
School, Boston, MA. ing of ingested food constituents and the underlying motor activity. Recent studies
Email: [email protected] have shown that two parallel neural circuits, the gastric inhibitory vagal motor circuit
(GIVMC) and the gastric excitatory vagal motor circuit (GEVMC), mediate gastric in-
Funding information
This study was supported by (a) Merit
hibition and excitation and therefore the rate of gastric emptying. The GIVMC in-
Award from the VA Medical Research cludes preganglionic cholinergic neurons in the DMV and the postganglionic
Service, Department of Veterans Affairs,
Washington, DC (RKG); and (b) William S
inhibitory neurons in the myenteric plexus that act by releasing nitric oxide, ATP, and
Middleton Award from the Department peptide VIP. The GEVMC includes distinct gastric excitatory preganglionic choliner-
of Veterans Affairs, Office of Research
and Development, Biomedical Research
gic neurons in the DMV and postganglionic excitatory cholinergic neurons in the
Laboratory, and Development Service (RKG). myenteric plexus. Smooth muscle is the final target of these circuits. The role of the
intramuscular interstitial cells of Cajal in neuromuscular transmission remains debat-
able. The two motor circuits are differentially regulated by different sets of neurons
in the NTS and vagal afferents. In the digestive period, many hormones including
cholecystokinin and GLP‐1 inhibit gastric emptying via the GIVMC, and in the inter‐
digestive period, hormones ghrelin and motilin hasten gastric emptying by stimulat-
ing the GEVMC. The GIVMC and GEVMC are also connected to anorexigenic and
orexigenic neural pathways, respectively. Identification of the control circuits of gas-
tric emptying may provide better delineation of the pathophysiology of abnormal
gastric emptying and its relationship to satiety signals and food intake.

KEYWORDS
digestive and inter‐digestive periods, gastric emptying, gastric motility, intestinal hormones,
neural control, satiety and food intake, the interstitial cell of Cajal, vagal circuits

1 | I NTRO D U C TI O N residues. Over the years, advances in understanding the different

physiological components of gastric emptying have been facilitated
The gastric emptying rate is a measure of the speed of delivery by the development of reliable, noninvasive techniques in humans.1
of gastric contents into the duodenum. Gastric contents to be The understanding of the biomechanics of the stomach helped to
delivered include liquids, digestible solids, and indigestible food understand the relationship between gastric motility and gastric

Goyal R.K. Advances in the physiology of gastric emptying. First Wylie J Dodds and Sushil K Sarna Endowed Lecture of the American Neurogastroenterology and Motility Society, pre-
sented at 13th Postgraduate Course on Gastrointestinal Motility, and Neurogastro‐enterology in Clinical Practice, July 29, 2018, Milwaukee, Wisconsin

This is an open access article under the terms of the Creative Commons Attribution‐NonCommercial License, which permits use, distribution and reproduction
in any medium, provided the original work is properly cited and is not used for commercial purposes.
© 2019. This article is a U.S. Government work and is in the public domain in the USA. Neurogastroenterology & Motility published by John Wiley & Sons Ltd.

Neurogastroenterology & Motility. 2019;e13546.  wileyonlinelibrary.com/journal/nmo | 1 of 14

https://doi.org/10.1111/nmo.13546
2 of 14 | GOYAL et al.

emptying. 2,3 These advances began with the appreciation that gas-
tric emptying is regulated by the physical and chemical nature of
Key Points
the food 4,5 through neuro‐hormonal control mechanisms. Recent,
ongoing studies have shown that inhibitory and excitatory vagal • There have been major recent advances in the under-
motor circuits and their regulatory neurons located in the solitary standing of the role neural circuits, gastrointestinal hor-
tract nucleus (nucleus tractus solitarius [NTS]) are responsible for mones, interstitial cells of Cajal and smooth muscles in
the precise control of gastric emptying.6 The NTS neurons have the regulation of gastric emptying.
widespread connections with neurons in the other parts of the • This review presents an integrated model of the control
CNS. Gastric inhibitory and gastric excitatory hormones released systems in gastric emptying and its link with satiety,
from the intestine and pancreas also actively regulate gastric emp- hunger and energy metabolism.
tying. Many of these hormones are also involved in immediate sa- • This information will be valuable in understanding the
tiety signals, and long‐term food intake, energy metabolism, and relationship between gastric emptying and diabetes
bodyweight, thereby linking these metabolic changes to gastric mellitus, developing strategies for control of hypergly-
emptying. cemia, pathogenesis of type 2 DM, and obesity.
The precise regulation of the rate of gastric emptying of chyme
(semifluid mass of partly digested food) into the duodenum is criti-
cal for further digestion and absorption in the small intestines. This
regulation is provided by feedback from the intestines via a variety over a short period. In humans, the stomach can expand 10‐15 times
of gastrointestinal hormones. The rate of gastric emptying of carbo- its empty state volume without a significant increase in intragastric
hydrates and sugars is particularly an important determinant of post- pressure (called accommodation). Water may leave the stomach
prandial glycemia. Slow gastric emptying may cause postprandial promptly.10 Digestible solids empty after they are pulverized to form
hypoglycemia, whereas fast gastric emptying may cause postpran- chyme, which contains particles less than 2‐3 mm in size. 5 Liquids
dial hyperglycemia. However, fast gastric emptying also upsets the and digestible solids are emptied in the digestive period that lasts
release of intestinal hormones and has complex effects on glucose 2‐3 hours after a meal. However, stomach retains large food parti-
homeostasis. Fast gastric emptying is now recognized as a major cles that escape mincing during the digestive period, and then force-
factor in postprandial hyperglycemia and in the pathogenesis and fully dumps them into the small bowel during the inter‐digestive
management of diabetes mellitus (DM).7-9 period11 (Figure 1A).
The purpose of the present review is to synthesize the advances Hunt and others in the1950s and early 1960s also showed that
in the understanding of gastric motility and its neurohormonal con- the gastric emptying rate in the digestive period is highly dependent
trol into an integrated model of gastric emptying. on volume, osmolality, the chemical composition, and caloric density
of the food.4 The average stomach empties approximately 1‐4 kcal/
min12 (Figure 1B).
2 | G A S TR I C E M P T Y I N G Because of the complex regulation of gastric emptying, proper
assessment of all phases of gastric emptying requires separate
The stomach performs a remarkable function of accepting large studies of liquids and digestible solids of defined caloric density
quantities of foods of different physical and chemical compositions in the digestive period and of large indigestible particles in the

F I G U R E 1 Gastric emptying rates vary with the physical characteristic and caloric density of food. (A) Effect of physical characteristics
of food on the rate of gastric emptying. Note that water or 5% glucose leaves the stomach at a fast rate, and digestible solids begin to leave
after a lag period and leave the stomach slowly. Large pieces of indigestible solids are retained in the stomach during the digestive period
and are then rapidly emptied. (B) Effect of caloric density of the liquid meal. Note that water leaves the stomach very fast and only 50%
remains in the stomach at 10 min. High‐calorie liquids empty at a slower rate with 50% remaining in the stomach at 2 h. Low‐calorie liquids
empty at an intermediate rate so the 50% leave the stomach by 1 h
GOYAL et al. | 3 of 14

inter‐digestive period. Moreover, earlier tests of gastric empty- measurements at 0, 1, 2, and 3 or 4 hours has been used. Gastric
ing were invasive and not repeatable. Development of noninva- retention of <30 at 1 hour is indicative of fast gastric emptying,
sive imaging and isotope techniques has now facilitated studies and retention of >30% at 4 hours suggests slow gastric empty-
of gastric emptying in animals and humans. 3 Scintigraphy using ing.14 More recently, the 13
C breath test that indirectly measures
technetium (99m)‐sulfur colloid‐ or technetium (99m)‐diethylen- gastric emptying has been developed. In the absence of liver
etriaminepentaacetic acid‐labeled food remains the “gold stan- or kidney disease, the results of these tests correlate well with
dard.” Time taken to empty 50% of the ingested contents (t1/2) the results of the scintigraphy. These developments have facili-
has often been used to describe gastric emptying rate for the tated the assessment of gastric emptying in disorders of gastric
purposes of comparison.13 Recently, low‐fat egg white meal with emptying.1

F I G U R E 2 Anatomic and functional parts of the human stomach, the gastric tunnel (Magenstrasse), and the pylorus. (A) Anatomic and
functional parts of the stomach. The stomach includes three multifunctional, interconnected structures: pressure pump, peristaltic pump,
and a grinder. The pressure pump includes anatomic fundus and proximal corpus. The peristaltic pump includes anatomic distal corpus
and pyloric antrum. The pressure and peristaltic pumps form the propulsive unit. The anatomic correlate of the grinder is the pylorus that
includes the anatomic pyloric canal and pyloric sphincter. Modified from Adler.15 (B) A functional tunnel along the lesser curvature of the
stomach, called Magenstrasse, that may allow liquids to bypass the slower movement of the solid food through the stomach to accomplish
a very fast gastric emptying. The figure identifies the initial location of particles emptied during 10 min, gray shaded with the time period
of emptying, temptying. From Pal et al10 (C) Details of the pyloric complex which includes the proximal muscle loop and the distal muscle loop
formed by the pyloric sphincter. The proximal and distal muscle loops are ~2 cm away from each other on the greater curvature but merge
together on the lesser curvature of the stomach. The loops enclose a triangular cavity with the merged muscle loops forming a torus at
the lesser curve. The pyloric torus fits into the groove left between the proximal and distal muscle loops along the greater curvature, like a
pastel and mortar, to form a perfect grinder. Pylorus provides mechanical grinding and food that has been tenderized by acid‐pepsin, to form
chyme. The proximal muscle loop and the pyloric sphincter are separately regulated and can work independently
4 of 14 | GOYAL et al.

3 | B I O M EC H A N I C S O F G A S TR I C pulverization, and an anterograde jet of chyme into the duode-

EMPT YING num. On intraluminal manometry, these events correspond with
the antropyloric pressure waves (APPW) that are intimately as-
Earlier studies also defined how a single‐chamber stomach can sociated with a pulsatile flow into the duodenum18 and “sieving
serve multiple functions such as flexible storage, grinding of food, function”.16 Closure of the pyloric sphincter that causes complete
and controlled delivery of chyme into the duodenum. In humans, closure of gastroduodenal communication corresponds with the
the anatomic fundus and proximal corpus of the stomach serve isolated pyloric pressure waves (IPPW) on intraluminal manometry
as a flexible reservoir and a pressure pump. The distal corpus and in humans.19
proximal antrum constitute the peristaltic pump that primarily Enhanced or impaired relaxation of the pressure pump leads to
serves as a mixer. The terminal antrum and the pyloric sphincter slow or fast gastric emptying, respectively. Loss of strength or orga-
form the functional grinder and filter2,15,16 (Figure 2). The gastric nization of contractions of the peristaltic pump leads to poor mixing
emptying during the digestive and inter‐digestive periods is differ- and slow gastric emptying, while the increased strength of peristal-
ently regulated. tic contractions leads to the fast gastric emptying of the digestible
solids20 (Table 1).
The pyloric sphincter and the duodenum work in a well‐coordi-
4 | G A S TR I C E M P T Y I N G D U R I N G TH E nated way to regulate gastric emptying. As the pyloric complex acts
D I G E S TI V E PE R I O D as both a grinder and a variable filter, it can facilitate or inhibit gas-
tric emptying in the digestive period. The duodenum relaxes during
As the food is ingested and fills the stomach, fundic compliance antral contractions—a phenomenon called “antroduodenal coordina-
increases so that a large volume of food is accommodated without tion.” After accepting injections of chyme, the duodenal bulb con-
an increase in pressure. In this filling phase, the pressure and peri- tracts to expel the chyme in a steady flow into the second portion
staltic pumps remain inhibited and show no contractions. The filling of the duodenum. Studies have shown that slow gastric emptying
phase is followed by a pumping phase, which is associated with a with a high‐fat test meal was associated with decreased antral and
slow tonic contraction of the fundus and increased peristaltic con- increased duodenal contractile activity. 21 Moreover, duodenal con-
tractions in the peristaltic stomach. This allows mixing of ingested tractions may cause closure of the pyloric sphincter that in turn
food with gastric acid and pepsin and its transfer to the pylorus. The corresponds with the isolated pyloric pressure waves (IPPW) on in-
peristaltic pump also accepts food that escapes proper pulverization traluminal manometry.19,22
for recycling. The antrum fills to a certain level before food begins to
enter the duodenum. This is reflected as the lag phase on the whole
stomach‐emptying curve. 5 | G A S TR I C E M P T Y I N G I N TH E I NTE R‐
The stomach forms a functional tunnel named “Magenstrasse,” D I G E S TI V E PE R I O D
along with the lesser curvature of the stomach, that shunts liq-
uids directly into the duodenum and bypasses the main stomach10 In the inter‐digestive (fasting) period, gastric motility designed
(Figure 2). to clear the stomach of undigestible residues. It is characterized
The tenderized food is propelled into the pyloric grinder by by a cyclical motor activity called the migrating motor complex
contractions that become forceful in the antrum. The pylorus (MMC). 23 The MMC is divided into four phases. Phase I lasts ap-
17
relaxes to receive food from the proximal antrum. Pyloric con- proximately 45‐60 minutes, during which the peristaltic pump ex-
tractions generate a powerful retrograde jet of food that escapes hibits electrical slow waves that are not associated with muscle

TA B L E 1 Anatomic parts, muscle type, the presence of ICC‐MY, type of contraction, and effect of inhibition or excitation on different
functional parts of the stomach

Pressure pump Peristaltic pump Grinder

Anatomic parts Fundus + proximal Distal corpus and proximal antrum Terminal antrum + pyloric sphincter.
corpus Pylorus
Muscle type Tonic Phasic Phasic + tonic
ICC‐MY Absent Present Present
Type of contractions Tonic Phasic, peristaltic Strong, phasic, nearly simultaneous
Effect of increased inhibition/ Slow gastric Impaired mixing Impaired grinding
decreased excitation emptying Slow gastric emptying of solids Duodeno‐gastric reflux
Effect of reduced inhibition/ Impaired accommo- Fast gastric emptying of solids Outlet obstruction
increased excitation dation and fast
gastric emptying
GOYAL et al. | 5 of 14

contractions. Motor quiescence is due to tonic inhibition of the

Increasing compliance
motor activity. Phase II is associated with slow waves associated

Increased inhibitory/
reduced excitatory
with frequent phasic contractions. Phase III (also called “activity

Reduced phasic
front”) is characterized by a front of large amplitude contractions,

contractions
Contraction
lasting 5‐15 minutes that march toward the pyloric sphincter.

Phase IV
The phase III of the MMC is neurally mediated and is indepen-
dent of the slow waves. 24 During the migrating front, the pylorus
and duodenum remain relaxed and open to allow phase III activity
to sweep food residues out of the stomach. 25 Loss of pyloric re-

Migrating motor complex

Increased tonic pressure
laxation leads to gastric outlet obstruction and gastric stasis. 26,27
Non‐vagal, peripheral

However, enhanced relaxation of the pylorus may facilitate duo-

neuro‐hormonal

deno‐gastric reflux. 27 Phase IV includes inhibition of contractile

activity that merges with the next phase of digestive period activ-

Relaxation
Phase III

ity. Vagal stimulation immediately abolishes the gastric motor and

Motilin

neurohormonal activity during the digestive and inter‐digestive

periods23 (Table 2).
Increased tonic pressure
increased excitatory

6 | R EG U L ATI O N O F G A S TR I C M OTI LIT Y

Reduced inhibitory/

AND EMPT YING

Increased phasic
contractions
Relaxation

Gastric motility is regulated by the neural circuits that affect the ac-
Phase II

Ghrelin

tivity of its final target, the smooth muscles. The interstitial cells of
Cajal (ICC) may also be involved in the control of gastric emptying in
multiple ways, including afferent mechanosensing, 28 certain types
Inter‐digestive period

Increased inhibitory/

of neuromuscular transmissions (NMT), 29,30 and phasic contractions

reduced excitatory

in the antrum.31,32 However, the multifunctional role of ICC has been

Reduced phasic
contractions

questioned.33
No pressure
Phase I
Neuro‐hormonal activity during the digestive and inter‐digestive periods

7 | N EU R A L CO NTRO L O F G A S TR I C
M OTI LIT Y
Decreasing compliance
increased excitatory
Reduced inhibitory/

It is now generally accepted that autonomic nerves regulate gas-

Increased phasic

tric motility.34-36 Traditionally, parasympathetic and sympathetic

contractions

motor nerves were thought to exert an excitatory and inhibitory

Relaxation

effect on the stomach, respectively. However, studies showed that

Later

sympathetic nerves do not have an important role in physiological

Leptin, cholecystokinin, GLP‐1

regulation of gastric motility, while the vagus nerves exert both in-
hibitory and excitatory effects on the stomach via the gastric inhibi-
tory vagal motor circuit (GIVMC) and a gastric excitatory vagal circuit
Increasing compliance
Increased inhibitory/
reduced excitatory

(GEVMC).37-39
Digestive period

Reduced phasic

Gastric inhibitory vagal motor circuit consists of preganglionic

contractions
Contraction
Immediate

cholinergic and postganglionic non‐cholinergic inhibitory neurons.

The GEVMC consists of preganglionic cholinergic and postgangli-
onic cholinergic neurons. Moreover, the GIVMC and GEVMC are
regulated by other connected neurons and, together, they constitute
the gastric inhibitory vagal circuit (GIVC) and a gastric excitatory
Hormonal activity

vagal circuit (GEVC), respectively. Because the neurons of the same

Vagal activity

chemical nature may be present at different locations of the circuit

TA B L E 2

and even in two opposing circuits, we have identified them by their

Antrum

Pylorus
Fundus

location, chemical nature, and the functional circuitry in the descrip-

tive table (Table 3).
6 of 14 | GOYAL et al.

TA B L E 3 Abbreviated identity of
Triangular parameters
neurons involved in gastric emptying as
Neuron identity Location Chemical nature Neural circuit identified by three parameters, namely,
NG‐GLUT‐i Nodose Ganglion Glutaminergic Gastric inhibitory anatomic location, chemical nature, and
their participation in the gastric inhibitory
NTS‐CC‐i Nucleus tractus Catecholaminergic Gastric inhibitory
or gastric excitatory and hunger or satiety
solitarius
neural circuits
NTS‐GLUT‐e Nucleus tractus Glutaminergic Gastric excitatory
solitarius
NTS‐GABA‐e Nucleus tractus Gamma‐aminobutyric Gastric excitatory
solitarius acid‐ergic
NTS‐PPG‐i Nucleus tractus Pre‐proglucagon Gastric inhibitory
solitarius
NTS‐POMC‐s Nucleus tractus Pro‐opiomelanocortin Satiety
solitarius
DMV‐C‐e Dorsal motor Cholinergic Gastric excitatory
nucleus of vagus
DMV‐C‐i Dorsal motor Cholinergic Gastric inhibitory
nucleus of vagus
DMV‐GABA‐e Dorsal motor Gamma‐aminobutyric Gastric excitatory
nucleus of vagus acid‐ergic
MP‐C‐e Myenteric Plexus Cholinergic Gastric excitatory
MP‐NANC‐i Myenteric Plexus Non‐cholinergic, Gastric inhibitory
non‐adrenergic
H‐POMC‐s Hypothalamus Pro‐opiomelanocortin Satiety
H‐NPY/GABA‐h Hypothalamus Neuropeptide Y/ Hunger
Gamma‐aminobutyric
acid
H‐Gh‐h Hypothalamus Ghrelin Hunger
H‐OREX‐h Hypothalamus Orexigenic Hunger
H‐ANOREX‐s Hypothalamus Anorexigenic Satiety

8 | G A S TR I C I N H I B ITO RY VAG A L M OTO R Vagal motor fibers to different regions of the stomach assemble
C I RCU IT (G I V M C) in different branches of the vagus that innervate the gastric fun-
dus, corpus, and antrum and the pyloric sphincter.46 Various types of
Gastric inhibitory vagal motor circuit consists of preganglionic cho- vagotomy performed for the treatment of peptic ulcer disease have
linergic neurons in the DMV (DMV‐C‐i) and postganglionic, non‐adr- provided important information on vagal control of motility of differ-
energic non‐cholinergic (NANC) inhibitory neurons in the myenteric ent parts of the stomach. Proximal gastric vagotomy leads to vagal
plexus (MP‐NANC‐i) (Figure 3A). The DMV‐C‐i neurons are distinct denervation of the fundus and the proximal corpus and impairs re-
from the DMV‐C‐e neurons and are located in rostro‐lateral and ceptive relaxation and accommodation of the fundus. These changes
caudomedial areas of the DMV.40 Moreover, DMV‐C‐i neurons are increase the fundic tone and lead to a fast emptying of liquids.43
segregated into distinct groups and may have different chemical Because proximal vagotomy spares the distal stomach, a regular pat-
markers, so that they regulate the different regions of the stomach tern of trituration, sieving, and solid emptying is preserved. Truncal
separately.41 vagotomy and selective vagotomy denervate most of the stomach
Motor axons of the DMV‐C‐i neurons travel in the vagus nerve including the pylorus. Denervation of the pylorus causes a decrease
and exert a tonic inhibitory effect on the lower esophageal sphinc- in compliance and loss of relaxation that leads to pyloric obstruction
42 43,44
ter and the stomach. The tonic inhibitory neural effect is also and gastric stasis.44 On the other hand, stimulation of vagal motor
evidenced by the observation that an isolated guinea pig stomach is fibers has been shown to decrease pyloric resistance.47 Clinically,
spontaneously contracted so that small gastric distension causes a truncal or selective vagotomy is always combined with pyloroplasty
steep increase in intragastric pressure and increases the amplitude in the surgical treatment of peptic ulcer, to prevent gastric stasis.
of pressure waves. The resting tonic contraction may be due to the The vagal motor axons of DMV‐C‐i neurons synapse onto the
removal of tonic gastric inhibitory vagal influence. In contrast, larger postganglionic, MP‐NANC‐i neurons via nicotinic (N) and muscarinic
distension volumes cause a decrease in the intragastric pressure in- (M1) receptors.48 Stimulation of the MP‐NANC‐i neurons relaxes
dicating that the response is mediated by a local inhibitory reflex. 45
the smooth muscle by releasing NO, ATP, and VIP.49,50 NO. causes
GOYAL et al. | 7 of 14

F I G U R E 3 A simplified gastric inhibitory vagal circuit (GIVC) and the gastric excitatory vagal circuit (GEVC). (A) The GIVC includes
GIVMC and its inputs. GIVMC consists of preganglionic DMV‐C‐i neuron and postganglionic, NANC inhibitory neuron in the myenteric
plexus (MP‐NANC‐i). See text for details of the neurotransmission. The DMV‐C‐i neurons receive excitatory input directly from the NTS‐
CC‐i neurons via the α1‐receptors and through NTS‐PPG neurons via GHSR or GLP‐1 receptors. The NTS‐CC‐i neurons receive glutaminergic
input from low‐threshold vagal afferents whose neurons are in the nodose ganglion (NG). (Arrow—stimulation; flat—inhibition). (B) The
GEVC includes GEVMC and its inputs. GEVMC consists of preganglionic DMV‐C‐e neurons and postganglionic, cholinergic excitatory
myenteric plexus (MP‐C‐e) neurons. DMV‐C‐e neurons receive strong inhibitory input from NTS‐GABA‐e neurons and NTS‐CC‐e neurons,
and excitatory input from NTS‐GLUT‐e neurons. The NTS‐GABA‐e, NTS‐CC‐e, and NTS‐GLUT‐e neurons are interconnected and send
integrated inhibitory input to the DMV‐C‐e neurons. NTS‐CC neurons also send inhibitory input to DMV‐C‐e neurons via the α2‐receptors.
The inhibitory inputs from the NTS to DMV‐C‐e suppress spontaneously active DMV‐C‐e and cause gastric relaxation. On the other hand,
suppression of the NTS‐GABA neurons NTS‐CC‐i disinhibits the spontaneously active DMV‐C‐e neurons leading to gastric excitation and
fast gastric emptying as in acute hypoglycemia. See text for other details. (Arrow—stimulation; flat—inhibition)

smooth muscle relaxation in part by causing membrane hyperpolar- that release glucagon‐like peptide‐1 (GLP‐1) onto the DMV‐C‐i neu-
ization (nitrergic IJP) via sGC‐cGMP signaling; ATP causes relaxation rons.64 Stimulation of NTS‐CC‐i neurons also inhibits DMV‐C‐e neu-
mainly by causing membrane hyperpolarization via P2Y1 receptors‐ rons via α2‐catecholaminergic receptors and further enhances the
SK channel signaling (purinergic IJP); VIP acts by increasing intracel- gastric inhibitory effect.63 It has been estimated that the GIVMC
51
lular cAMP. Out of these different inhibitory transmissions, muscle mediates fundic relaxation in the esophagogastric reflex.53
. 52-54
relaxant effect of NO is most prominent.
Stimulation of nitrergic neuromuscular transmission (NMT) in the
pressure and peristaltic pumps causes slow gastric emptying, while 9 | G A S TR I C E XC ITATO RY VAG A L M OTO R
its suppression causes fast gastric emptying in the digestive pe- C I RCU IT (G E V M C)
riod.55,56 On the other hand, loss of nitrergic NMT in the tubular py-
lorus causes delayed gastric emptying in the inter‐digestive period. 27 Gastric excitatory motor circuit (GEVMC) consists of pregangli-
ICC‐IM and PDGFRα+ fibroblasts have been proposed to be nec- onic cholinergic neurons (DMV‐C‐e) and postganglionic cholinergic
essary for nitrergic and purinergic NMT, respectively. 29,57 However, (MP‐C‐e) neurons (Figure 3B). The DMV‐C‐e neurons of the GEVMC
this proposal is open to question.56,58 are distinct from the DMV‐C‐i neurons of the GIVMC.37 The DMV‐C‐e
The regulatory part of the GIVC includes vagal afferents and neurons are located in the more rostral and medial divisions of the
second‐order neurons in the NTS for vagovagal reflex and other DMV and are spontaneously active and may cause tonic excitation
neurons that provide input to the NTS neurons. Esophagogastric re- of the stomach muscle.40 Their motor axons are carried in the vagus
laxation and gastric accommodation reflexes are well‐studied gastric nerve in the company of the fibers of the GIVMC and vagal afferents.
inhibitory vagovagal reflexes.40,52-54 The vagal afferents have their The preganglionic efferent fibers synapse on the MP‐C‐e neurons in-
cell bodies in the nodose ganglion. Originally, neural input to the volving nicotinic receptors. The postganglionic excitatory myenteric
DMV‐C‐i was thought to be from vagal afferents leading to mono- neuron releases acetylcholine to contract the smooth muscles via
synaptic vagovagal reflexes. However, it is now clear that the vagal M3 receptors. ICC‐IM has also been proposed to be included in the
afferents do not directly synapse on the DMV‐C‐i neurons but proj- transduction of cholinergic neural signals to smooth muscles.29,30,32,65
ect onto second‐order neurons in the NTS (Figure 3A). However, the role of ICC‐IM in cholinergic NMT is questionable.33,58,66
The vagal afferents provide glutaminergic excitatory input to the The vagal excitatory circuits are a dominant regulator of gastric acid
NTS‐CC‐i neurons. 59 The afferent terminals are a site of action of secretion and hormonal release, but GEVMC plays a less dominant role
multiple hormones that act presynaptically to modulate these syn- in gastric motility.36 Cholinergic excitatory motor responses are usually
60,61
apses. The NTS‐CC‐i neurons inhibit gastric motility by multi- masked by the stronger inhibitory responses.67 Moreover, cholinergic
62
ple pathways, including direct stimulation of DMV‐C‐i neurons via responses are highly dependent on the sensitivity of the smooth mus-
α1‐receptors63 and indirectly via stimulation of NTS‐PPG neurons cle that is related to the activity of the RhoA/ROCK signaling.51,68
8 of 14 | GOYAL et al.

The regulatory part of the GEVC includes GABAergic neurons of the pressure pump, fundus, and proximal corpus is primarily of tonic
that exert a tonic inhibitory influence on the DMV‐C‐e neurons and phenotype. In response to cholinergic stimulation, fundic smooth mus-
neutralize their excitatory tonic effect.69,70 Stimulation of the NTS‐ cle elicits a strong tonic contraction.51,68 The muscles of the peristaltic
GABA‐e neurons suppresses the activity of DMV‐C‐e leading to a pump, distal corpus, and the proximal antrum are primarily of phasic
decrease in the gastric tone and the motility of the gastric corpus phenotype, and cholinergic stimulation elicits phasic contractions.82
and antrum.71 A recent study using optogenetic stimulation sug- Muscle of the pyloric complex possesses both phasic and tonic muscles.
gested that somatostatin‐positive GABA neurons in the DMV are re- The phasic muscles are paired with the myenteric type of inter-
sponsible for the gastric inhibitory effect of vagus‐mediated gastric stitial cells of Cajal (ICC‐MY). ICC‐MY generate propagates electri-
antral motility.72 However, further studies are needed to elucidate cal slow waves in the distal stomach at a rate of 3‐5 per minute. That
the distinct roles of GABA neurons in NTS and DMV in gastric mo- serve to set the pace for the phasic contraction and have been called
tility. NTS‐GABA and NTS‐non‐GABA inhibitory neurons and NTS‐ pace‐setter potentials. The pylorus exhibits nearly simultaneous and
GLUT excitatory neurons exert an inhibitory and excitatory effect, strong slow waves that are associated with forceful contractions.83
73
respectively, on the DMV‐C‐e neurons. Slow waves recorded by surface electrodes in vivo have often
Moreover, within the NTS, the GABA, non‐GABA, and GLUT been assumed to represent phasic contractions. However, it has been
neurons are interconnected.74 NTS‐CC‐e neurons may also act to in- reported that (a) extracellularly recorded slow waves in vivo may not
hibit DMV‐C‐e neurons via the α2‐receptors.62,75 Thus, NTS neurons represent true slow waves recorded intracellularly,84 (b) slow waves
exert a precise inhibitory regulation of the GEVC. DMV‐C‐e neu- recorded by surface electrodes are strongly influenced by neural
76
rons also receive GABAergic inhibitory input from area postrema. stimuli and may not represent mechanical contractions,85,86 and (c)
Interestingly, vagal afferent input to GEVMC has not been described. Klotho‐deficient progeric mice that have a profound loss of ICC and
A variety of neurotransmitters and endogenous chemicals may reduced amplitude of slow waves manifest no change in gastric emp-
exert different effects on vagal circuits, based on the receptor type tying of solids.87 Therefore, the role of ICC‐MY and the slow waves
and the neural input. For example, dopamine may use either stimula- recorded by surface electrodes remains unclear.
tory effect via the dopamine 1 (DA1) receptors or inhibitory effect via
the dopamine 2 (DA2) receptors on the DMV neurons of the GEVC.
Moreover, DA2 receptor‐mediated effect is more prominent 11 | H O R M O N A L CO NTRO L O F G A S TR I C
than the DA1 receptor‐mediated effects. 77
Thus, stimulation of do- M OTI LIT Y
paminergic projections of substantia nigra pars compacta (SNpc)
causes some gastric excitation due to stimulation of DA1 receptors One of the most characteristic features of normal gastric empty-
on the DMV‐C‐e neurons.77 However, gastric inhibitory effect and ing is its large variability, depending on the chemical composition of
delayed gastric emptying in Parkinson's disease associated with loss the food (Figure 1). The effect of different foods on gastric emptying
of dopamine in substantia nigra may not be due to loss of DA1 recep- is in large part due to the hormones released from the gastrointesti-
tor‐mediated excitatory effect on the DMV‐C‐e neurons but may be nal tract that provides feedback regulation of gastric emptying. These
due to the increase in dopaminergic input from other neurons that hormones are released from the stomach, intestines, pancreas, and
77
primarily act to stimulate inhibitory DA2 receptors. Moreover, in other tissues and act at various levels of the neural circuits including
animal models of Parkinson's disease a decrease in DA1 and increase vagal afferents, NTS, area postrema (AP), preganglionic vagal neurons
in DA2 receptors in the DMV have been reported.78 Thus, degener- in the DMV, and myenteric plexus and the smooth muscle. It is note-
ation of SNpc‐DMV dopaminergic pathway neurons in Parkinson's worthy that the dorsal vagal complex (DVC, including NTS, AP, and
disease may cause delayed gastric emptying primarily due to a gain DMV) is located outside the blood‐brain barrier, has a large network
of DA2 receptor‐mediated neurotransmission in the DMV.79 It is in- of fenestrated capillaries, and contacts specialized neurons lining the
triguing to consider that prokinetic agents such as DA2 receptor an- ependymal layer of the central canal and fourth ventricle.81 Some of
80
tagonists may accelerate gastric emptying in Parkinson's disease. these hormones, along with other mediators, act on other control cen-
Although domperidone does not readily cross blood‐brain barrier, it ters to coordinate gastric motility with satiety, food intake, and energy
may act on areas that have deficient blood‐brain barrier.81 balance. Some GI hormones serve as a brake to slow gastric emptying
and are called “braking hormones,” while others serve to accelerate
gastric emptying and are called “accelerating hormones” (Table 4).
10 | M OTO R B E H AV I O R O F D I FFE R E NT
S EG M E NT S O F TH E S TO M AC H
12 | G A S TR I C “ B R A K I N G ” H O R M O N E S
The different segments of the stomach may be regulated by distinct
sub‐circuits of the GIVC and GEVC, the nature of their smooth mus- Ingestion of a meal causes a release of a large number of hormones
cles and presence of the ICC‐MY. that act to put “brakes” on gastric emptying.88 These hormones are
The smooth muscles of the pressure pump, the peristaltic pump, and active during the digestive period and include cholecystokinin (CCK),
the grinder‐filter have distinct mechanical behaviors. Smooth muscle GLP‐1, and leptin.
GOYAL et al. | 9 of 14

TA B L E 4 Hormones that cause slow gastric emptying and that using multiple pathways including the projections of the NTS‐CC‐i
cause fast gastric emptying neurons via the α1‐receptor 89,94 and projections of the NTS‐PPG

Fast gastric neurons via GLP‐1. CCK also exerts its gastric inhibitory effect by
Slow gastric emptying emptying stimulating the myenteric non‐adrenergic non‐cholinergic (NANC)
inhibitory neurons95 (Figure 4A).
Cholecystokinin Ghrelin
CCK also interacts closely with GLP‐1 and bile salts. CCK re-
Leptin Motilin
leases GLP‐1 that is an important gastric inhibitory hormone. It has
Glucagon‐like peptide‐1
been reported that entry of chyme in the gut releases nesfatin‐1 that
Glucagon
stimulates CCK secretion that causes gallbladder emptying and rise
Oxyntomodulin
in bile salts.96 Bile salts stimulate Takeda G‐protein‐coupled recep-
Peptide YY tor‐5 (TGR5) on the basolateral aspect of the enteric endocrine L
Gastrin‐releasing peptide cells to elicit GLP‐1 secretion.97 CCK activation of NTS‐CC‐i neurons
Enterostatin may also inhibit DMV‐C‐e via the α2‐adrenergic receptors. All these
Pancreatic amylin actions of CCK lead to robust gastric inhibition and slowed gastric
Pancreatic polypeptide emptying.
Gastric emptying is also slowed by the products of posttransla-
tional modifications of pre‐proglucagon, which act to slow gastric
Cholecystokinin is a prototype of gastric braking hormones. It emptying and serve as braking hormones.98 In the pancreatic alpha
is released from neuroendocrine cells in the duodenum by stim- cells, these products include glucagon, proglucagon 1‐61, and the
uli such as hydrochloric acid, amino acids, and fatty acids. CCK so‐called major proglucagon factor (MPGF, ie, fused GLP‐1 and
acts to stimulate the GIVC at multiple levels. CCK stimulates GLP‐2). Following ingestion of a meal, the L cells of the intestinal
vagal afferent endings of the vagal inhibitory circuit in a paracrine wall and PPG neurons in the NTS produce pre‐proglucagon gene
fashion, 89,90 may act on nodose ganglion,91 and may enhance syn- products including GLP‐1 and its amide, GLP‐2, oxyntomodulin, and
aptic neurotransmission at the vagal afferent second‐order NTS‐ glicentin. GLP‐1 is the most studied in this group. However, GLP‐1 is
CC‐i neurons by enhancing release of glutamate in the NTS. 89,92 rapidly degraded by N‐terminal degradation by dipeptidyl peptidase
Furthermore, intraperitoneal application of CCK‐8 induces c‐FOS IV (DPP IV, CD26). DPP IV inhibitors and DPP IV‐resistant incretin
immunoreactivity in the catecholaminergic (CC), pro‐opiomelano- analogs have been used to prolong its activity.99
93
cortin (POMC), and pre‐proglucagon (PPG) neurons. CCK stimu- GLP‐1 released from the intestines acts to stimulate vagal affer-
lation of the NTS‐CC‐i neurons may, in turn, stimulate NTS‐POMC ents that stimulate the second‐order NTS‐CC‐i neurons that acti-
and NTS‐PPG neurons. Thus, CCK may excite DMV‐C‐i neurons vate DMV‐C‐i neurons. GLP‐1 released from NTS‐PPG neurons also

F I G U R E 4 Main sites of action of CCK and ghrelin. (A) Cholecystokinin (CCK) is a prototype breaking hormone. It acts to stimulate
vagovagal circuit at multiple levels. CCK stimulates vagal afferents endings by paracrine effect and enhances glutamate release from the
vagal afferent endings projecting onto NTS‐CC‐i neurons. CCK also directly or indirectly stimulates NTS‐CC‐i neurons, PPG‐i neurons,
and NTS‐POMC‐S neurons. CCK stimulation of NTS‐CC‐i neurons activates DMV‐C‐i via the α1‐adrenergic receptor; stimulation of the
NTS‐PPG‐i neurons via the GLP‐1 receptor on the DMV‐C‐i. CCK has also been shown to directly stimulate MP‐NANC‐i neurons, and may
also stimulate DMV‐C‐i neurons. Thus, CCK acts at multiple sites to stimulate GIVC. Stimulation of NTS‐CC‐i neurons also inhibits DMV-
C-e neurons via the α2‐adrenergic receptors. Thus, CCK also acts to inhibit GEVC. All these actions further augment the inhibitory effect
of CCK on the gastric muscle. CCK also stimulates NTS‐POMC‐s neurons to generate satiety signals. (Arrow—stimulation; flat—inhibition).
(B) Ghrelin is a gastric accelerating hormone. Ghrelin acts at multiple central and peripheral sites to stimulate gastric motility. Centrally,
ghrelin inhibits NTS‐CC‐i neurons thereby inhibiting DMV‐C‐i. Ghrelin also inhibits NTS‐CC‐e to disinhibit DMV‐C‐e neurons. Ghrelin also
disinhibits DMV‐C‐e neurons by inhibiting AP‐GABA‐e neurons that project onto DMV‐C‐e neurons. Ghrelin also acts on myenteric plexus
and the smooth muscle. All these actions lead to strong gastric excitation. (Arrow—stimulation; flat—inhibition)
10 of 14 | GOYAL et al.

stimulates DMV‐C‐i neurons.89 By stimulating NTS‐CC‐e, GLP‐1 may of DMV‐C‐e neurons. Ghrelin also disinhibits DMV‐C‐e neurons by
also inhibit DMV‐C‐e neurons. These multiple actions account for a activating AP‐GABA neurons109,110 and facilitates excitatory trans-
89,100
strong inhibitory effect of GLP‐1 on gastric motility. In func- mission to DMV‐C‐e neurons.111 Moreover, ghrelin also directly
tional studies, intravenous GLP‐1 has been shown to retard gastric stimulates MY‐C‐e neurons. These actions lead to the gastric stimu-
emptying and decrease the number and volume of flow pulses in latory effect of ghrelin. Functional in vitro studies have shown that
the trans‐pyloric flow. This was associated with an inhibition of an- ghrelin augments electrically stimulated contractions of fundic strips
tropyloric pressure waves, but stimulation of isolated pyloric pres- in mice.112 In vivo, ghrelin increases gastric myoelectrical activity
101
sure waves, and an increase in basal pyloric tone. Interestingly, and gastric emptying in the rats.113 Ghrelin activates phase II activ-
decreased gastric contraction but increased intestinal contractions ity in the antrum of the fasting stomach by a central action.111 The
have been reported to cause delayed gastric emptying in response peripheral action of ghrelin facilitates motilin to induce the activity
to nutrients. 21 in front of the MMC.114 By inhibiting the vagal afferents, ghrelin also
Other pancreatic hormones such as insulin and islet amyloid pep- suppresses anorexigenic signals and stimulates hunger at the NTS
tide (amylin) are co‐secreted from the beta cells. Both these hor- and hypothalamic levels.107,115
mones act to slow gastric emptying and reduce appetite. Pancreatic Motilin is released from M cells during the inter‐digestive
polypeptide (PP) is secreted by PP cells of the pancreas during the phase.114 Motilin release is due to duodenal alkalization that oc-
cephalic phase of gastric acid secretion via cholinergic excitatory curs as a compensatory response to duodenal acidification during
pathway.102 PP has been shown to act on the area postrema and the digestive phase. Acidification of the duodenum causes a release
stimulate a gastric inhibitory vagovagal reflex and slow gastric of prostaglandin E2 (PGE2) and 5HT. PGE2 inhibits further acid se-
emptying.76 cretion and contributes to duodenal alkalization. 5HT acts on 5HT4
Gastric leptin is released from the chief cells along with pepsin receptors to cause a release of duodenal bicarbonate that further
in the gastric juice by protein load and vagal stimulation. It is repro- alkalinizes the duodenal mucosa. 5HT4 receptor stimulation also
cessed in the small bowel to be released as a hormone. Leptin may causes duodenal contractions that activates a gastro‐stimulatory
produce its peripheral effect via the CCK1 receptors. However, the ascending vagal reflex.19
primary source of leptin is white fat cells (adipokine leptin). Gastric Motilin acts on multiple sites including the myenteric neurons and
leptin slows gastric emptying in response to a protein meal. Secretion smooth muscles in a species‐dependent fashion.116 Its action on my-
of adipokine leptin is constitutive and exerts its primary effect on enteric plexus neurons initiates phase III of the gastric MMC that pro-
hypothalamic nuclei to inhibit food intake and gastric emptying.103 motes gastric emptying of indigestible food residues. Phase III of the
It is interesting to note that intragastric infusion of nutrient rapidly MMC is strongly inhibited by the gastric inhibitory vagovagal reflex
inhibits hunger‐promoting, agouti‐related peptide/neuropeptide that is activated upon ingestion of food. It is worth pointing out that
Y (AgRP/NPY, orexigenic) neurons in awake mice. This inhibition is rodents do not exhibit typical MMC pattern because they lack motilin
proportional to the number of calories but independent of the type owing to a defective motilin gene.117 However, dogs and the house
of food and is mediated by CCK, peptide YY, and 5‐hydroxytrypt- musk shrew (Suncus murinus) exhibit MMC pattern similar to that
amine (5HT). Leptin induces a slow modulation that develops over seen in humans. Therefore, these animal species have been used to
104
hours and is required for the inhibition of feeding. investigate the mechanism of action of ghrelin and motilin in MMC.114

13 | G A S TR I C “ACC E LE R ATI N G ” 14 | LI N K I N G G A S TR I C E M P T Y I N G TO
HORMONES SATI E T Y S I G N A L S , FO O D I NTA K E , A N D
G LU COS E M E TA B O LI S M
Ghrelinand motilin act to accelerate gastric emptying and are released
in the inter‐digestive (fasting) period.105 No gastric accelerating hor- Gastric emptying is linked to sensations of satiety, appetite, and hun-
mones are released in the digestive period. Ghrelin is released from G ger and their hedonic aspects as well as to chronic food intake and
cells in the stomach and the ghrelin‐containing neurons in the hypo- energy homeostasis. This linkage involves connections of the GIVC
thalamus. Ghrelin acts on the growth hormone secretagogue receptor and GEVC with the NTS‐CC‐i and NTS‐CC‐e neurons connected
(GHSR) to stimulate the release of growth hormone. Ghrelin increases with satiety‐ and hunger‐associated neural pathways, respectively,
food intake, fat deposition, and weight gain.106 It is a primary stimu- in the hypothalamic, limbic, and cortical areas of the brain118 and
lant of appetite and is called the “hunger hormone” (Table 4). the NTS.94,119
Ghrelin serves as a neurotransmitter as well as a hormone, exerts
its effects centrally as well as peripherally, and acts on afferent as
well as efferent pathways (Figure 4B). Ghrelin inhibits vagal afferent 15 | CO N C LU S I O N
activity at the level of the sensory endings,107 nodose ganglion,108
and the afferent terminal to NTS‐CC synapses.59,61 Suppression of The primary function of the stomach is to prepare ingested food into
NTS‐CC neurons leads to inhibition of the DMV‐C‐i and disinhibition chyme and provide regulated delivery into the small bowel that is
GOYAL et al. | 11 of 14

measured as gastric emptying. Earlier studies had identified two re- ORCID
markable characteristics of gastric emptying: (a) ability to regulate
Raj K. Goyal https://orcid.org/0000-0002-0066-6932
the timing and rate of emptying of ingested food of different physi-
cal compositions; and (b) ability to regulate emptying based on the Yanmei Guo https://orcid.org/0000-0001-8711-0699

caloric density of food. Studies on the biomechanics of gastric emp- Hiroshi Mashimo https://orcid.org/0000-0002-6132-6771
tying revealed that activity of different anatomic parts of the stom-
ach was integrated to form functional “pressure” and “peristaltic”
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