Neuro-Endocrine Regulation of GI

Question 1

Answer 1

Question 2

Answer 2

Question 3

Submucosal Plexus

Answer 3

• layer of nerves found beneath the mucosa
• nerves within this plexus send out processes which synapse on other nerves within the plexus (inter-neurons), as well as, effecter cells (secretory, endocrine) located within the mucosa and submucosa, and also smooth muscle cells in the circular muscle layer.

Question 4

Myenteric Plexus

Answer 4

• nerves reside between the circular and longitudinal layers of smooth muscle
• Output from these nerves primarily regulate and coordinate the contractility of the muscle layers. The innervation of muscle layers can either inhibit or stimulate muscle activity dependent on the neurotransmitter released. However, visceral smooth muscle contractility is generally under inhibitory control.

Question 5

Inputs to the Enetric (Intrinsic) Neuronal Plexi

Answer 5

• CNS - sympathetic and parasympathetic autonomics
• walls of the alimentary canal itself - proprio- and chemo receptors located within the mucosa and submucosa
• neurons within wach plexus communicate via interneurons - reflex arcs

Question 6

Outputs from the Enteric (Intrinsic) Neuronal Plexi

Answer 6

• Outputs from the neuronal plexi regulate all functions of the alimentary canal, and modulate function of the pancreas, gall bladder, as well as, provide information to the central nervous system.
• Interneurons within the plexi coordinate activities along the canal.
• Cholinergic neurons (acetylcholine) located in the submucosal plexus regulate secretory cell activity while cells in the circular muscle layer are regulated by neurons located within both plexi. This is particularly true for the sphincter regions, which are thickenings of the circular layer.
• On the other hand, the longitudinal muscle layers that drive movements along the canal are regulated primarily by neurons whose cell bodies are located in the myenteric plexus.

Question 7

Extrinsic Regulation - Sympathetic Innervation

Answer 7

• The Salivary glands are innervated by fibers originating in the superior cervical ganglia.
• Thoracic and lumbar cord segments extend neurons to the celiac, superior and inferior mesenteric and hypogastric plexuses (the Sympathetic Chain).
• These ganglia send out axons that innervate the enteric plexi via adrenergic (norepinephrine) synapses, and directly innervate the pancreas, liver, gall bladder and vascular smooth muscle of feed arterioles.
• The primary consequence of sympathetic stimulation is a general inhibition of motor and secretory function that includes enhanced contraction of the alimentary sphincters via activation through the submucosal plexus.

***Possibly the most important response to sympathetic output is vasoconstriction through the direct innervation of blood vessels.

Question 8

Extrinsic Regulation - Parasympathetic Innervation

Answer 8

• The 7th and 9th cranial nerves innervate the salivary glands.
• Vagal branches innervate from the esophagus through the ascending colon, and include the liver, pancreas and gall bladder.
• The descending colon to anus is innervated by pelvic nerves.
• All parasympathetic fibers synapse on neurons within the enteric plexi. The response to parasympathetic stimulation is a general increase in motor and secretory function within the alimentary canal, and ancillary organs.

Question 9

Extrinsic Regulation - Central Afferents

Answer 9

•Afferents to the spinal cord travel primarily in vagus nerves, with fewer in sympathetic tracts.

-However, visceral pain signals, originating in nerve endings (receptors) located in the wall of the alimentary canal, are carried via sympathetic nerve fibers whose cell bodies reside in the “sympathetic chain” ganglia.

• Most afferent signals arise from proprio- and chemo-receptors located in the mucosa with their cell bodies located in the myenteric and submucosal plexi.
• Afferent signals are transmitted from the plexi to either the sympathetic chain or spinal cord where these signals are assimilated. Thus afferent sensory signals can elicit local responses within segments of the canal via direct enteric reflex, and can coordinate responses between different segments of the canal via long central reflex arcs.
• In addition, parasympathetic afferent fibers provide information to hypothalamus regarding moment-to-moment feeding behavior.

Question 10

Reflex Arcs

Answer 10

• In general, reflex arcs are described by their point of origin and termination.
• For example, an enteric reflex that initiates in the intestine to regulate gastric acid secretion is referred to an entero-gastric (or -oxyntic) reflex.
• A classic reflex that originates from stretch of the stomach to enhance motility of the colon is called the gastro-colic reflex. This reflex travels from the stomach via the vagus nerve to the spinal cord, then back to the colon also via the vagus. Therefore, this is in the general class of a vago-vagal reflex.

Question 11

Intergration of Signals

Answer 11

Signal integration occurs primarily within the enteric nervous system, but also through long reflexes coordinated in prevertebral ganglia and spinal cord.

Question 12

Extrinsic Intergration

Answer 12

• Afferents signals originating from enteric receptors are relayed through the enteric neuronal network then feed into the parasympathetic and sympathetic arms of the ANS.
• These fibers synapse centrally where they integrate with incoming signals from other areas of the alimentary canal, as well as, with higher centers.
• The summation of signals at this level modifies subsequent feedback to the digestive tract. Since the pancreas and biliary tract receive no direct innervation from the alimentary canal, all sensory feedback is via these “spinal reflexes.”

Question 13

Intrinsic Integration

Answer 13

• Integration within the canal is coordinated through enteric neurons.
• The strongest input comes from local alimentary receptors, but these intrinsic signals are influenced by long reflexes from central autonomics.
• When food resides in a specific region of the tract, local signals to the enteric plexi to drive local alimentary function.
• Long reflexes coordinate activity, but rarely are strong enough to override strong local signals such as distension or lumenal acidity.

Question 14

Hormone

Answer 14

Chemical messenger produced and secreted by a specialized gland, released into the blood where it “circulates” to distant organs to elicit a physiological response. Effects are exerted relatively slowly, but for prolonged periods The GI tract is the largest endocrine organ in the body. It produces a wide variety of hormones and biologically active peptides

Question 15

Gastrin Family

Answer 15

• Increases Intracellular Ca²⁺
• Gastrin
• CCK (neurotransmitter and hormone)

Question 16

Secretin Family

Answer 16

• Activates adenylate cyclase, increasing cAMP
• Secretin
• VIP (neurotransmitter and hormone)
• GIP
• Glucagon

Question 17

Gastrin

Answer 17

• Gastrin is released by G-cells located primarily in the pyloric antrum portion of the stomach in response to vagal (neural) stimulation, peptides in the stomach, and stretch of the stomach.
• Gastrin’s primary actions are to stimulate HCl secretion from oxyntic glands and stimulate growth of mucosa in the stomach and pancreas.
• At high levels gastrin stimulates contractility (mixing) of the stomach and closure of the pyloric sphincter.

Question 18

Secretin

Answer 18

• Secretin is secreted by duodenal and jejunal S-cells in response to increased H+ (pH < 4) and to lesser degree free fatty acids in the small intestine.
• Secretin stimulates secretion of bicarbonate and water by the pancreas and biliary tract

Question 19

CCK

Answer 19

• Cholecystokinin (also called Pancreozymin CCK–PZ); is secreted by duodenal and jejunal I-cells.
• CCK release is stimulated by certain essential amino acids and long-chain fatty acids in the small intestine.
• CCK stimulates pancreatic secretion of enzymes and gall bladder contraction.
• CCK also promotes growth of pancreatic acinar cells.
• hormone and a neurotransmitter (NANC)
• At high levels CCK, like Gastrin, activates motility of the stomach and closure of the pyloric sphincter.

Question 20

GIP and Glucagon

Answer 20

• The ‘Incretin’s’ Glucose-dependent insulinotropic peptide (GIP) and Glucagon like peptide-1 (GLP-1).
• These peptides are released from duodenal K-cell and L-cells respectively, primarily in response to luminal glucose, and their primary action(s) is to enhance secretion of insulin from Beta-cells and reduce glucagon secretion from alpha-cells of the pancreas.
• Glucose in the small intestine (with subsequent absorption to blood) elicits a much greater release of insulin than does injection of glucose intravenously due to incretin release from the intestine by the alimentary glucose load.
• At physiological levels, GLP-1 also inhibits gastric emptying, and has significant satiety effects.

Question 21

Distribution of Cells that Secrete GI Hormones

Answer 21

• Mucosal endocrine cells distributed throughout the mucosa and at the base of the crypts of the intestine and distal stomach.
• The mucosal endocrine cells structurally resemble mucosal epithelial cells involved in digestion and absorption in having brush borders. These cells contain “receptors’ for digestive products or other lumenal factors which promote the release of GI hormones, though little is known about the mechanisms for sensing nutrients.
• Since these cells reside within the canal itself, and their secretion is stimulated by factors within the lumen, the rate of secretion of a hormone is dependent upon the length of small intestine lumen that contains the stimulatory factor; i.e.; the length of lumen that is active.

-Full secretory rates are observed only when the entire proximal small intestine is active, and wanes as the chyme is moved distally.

Question 22

Answer 22

Question 23

Other (Candidate) Hormones

Answer 23

• There are several peptides that regulate specific GI functions, which may be considered as GI hormones, however either the mechanism of action or stimulus for release of these peptides is not known.
• Pancreatic Polypeptide
• Ghrelin
• Motilin
• Enteroglucagon (GLP-1)
• Entero-oxyntin
• Enteropastrone

Question 24

Pancreatic Polypeptide

Answer 24

• Candidate hormone
• produced in pancreas islets of Langerhans, and its release is likely stimulated by nutrients in the intestine.
• PP inhibits pancreatic enzyme and HCO3 - secretion, and may act as a “break” on secretion, since maximal secretory rates are rarely observed.

Question 25

Motilin

Answer 25

• Candidate hormone
• Motilin clearly plays a physiological role, since there is a direct correlation between elevated blood motilin and onset of a pattern of alimentary motility during periods of fasting.
• However, the stimulus for motilin release and its mechanism of action are not known, so it is considered a “candidate hormone”

Question 26

Ghrelin

Answer 26

• Candidate hormone
• Ghrelin is secreted from the gastric mucosa, which stimulates hunger during inter-digestive periods.
• Stomach resection leads to decreased blood ghrelin that may be related to “loss of appetite” in these individuals.

Question 27

Enterogastrone and Entero-oxyntin

Answer 27

• Candidate hormone
• There are two other purported hormones, which have been observed only through functional studies- no structural information exists. Both peptides are secreted from the small intestine and feed back onto the acid secreting glands to either stimulate or inhibit gastric acid secretion. Since little is known about these peptides, they are given generic names of enterogastrone (inhibitor of gastric secretion) and entero-oxyntin (stimulator of gastric secretion).

Question 28

Not Adrenergic Nor Cholinergic Transmitters - Peptide Modulators of GI Function

Answer 28

• VIP and Guanylin
• GRP or bombesin
• Enkephalins
• Substance P
• CCK

Question 29

Peptide Modulators of GI Function

Answer 29

Many peptides are active modulators of GI function. These peptides can exert their actions in several ways.

1) They can act in an endocrine fashion by being released into the general circulation and acting at sites remote from their site of release.
2) They can function in a paracrine fashion by acting at sites near their site of release.
3) They can serve as neurotransmitters by being released from nerve endings

Question 30

Paracrine Peptide Modulators of GI Function

Answer 30

• Somatostatin
• Histamine

Question 31

VIP and Guanylin

Answer 31

• NANC
• mucosa and muscle of gut, colon
• Relaxation of smooth muscle. Elevates cAMP in intestinal mucosa, activates NaCl and water secretion.

Question 32

GRP or bombesin

Answer 32

• NANC
• gastric mucosa
• gastrin release

Question 33

Enkephalins

Answer 33

• NANC
• mucosa and muscle of gut
• sphincter muscle contraction

Question 34

Substance P

Answer 34

• NANC
• salivary glands
• secretion, blood flow enhanced

Question 35

Somatostatin

Answer 35

• Paracrine
• Released by cells within the submucosa where they directly regulate function of adjacent cells; blood levels are not significantly elevated.
• decreases gastrin secretion

Question 36

Histamine

Answer 36

• Paracrine
• Released by cells within the submucosa where they directly regulate function of adjacent cells; blood levels are not significantly elevated.
• Stimulates acid secretion (secreted from “Enterochromaffin cells”) Activates crypt fluid secretion in intestine and colon (originating from Mast cells?)

Question 37

Regulation of Gastrin Secretion

Answer 37

• The primary regulator of Acid Secretion is the hormone gastrin.
• Secretion of gastrin into the blood is also closely regulated.
• Described here are the primary mechanisms for regulating the release of Gastrin from the G cells located within glands residing in the sub-mucosa of the pyloric region of the distal stomach.
• G cells have receptors on their lumenal surface, which can sample the contents of the gastric lumen (amino acids).
• In addition to this primary sensory information, Gastrin secretion is modulated by somatostatin released from cells located within the pyloric glands (paracellular regulation), as well as, neural input from the submucosal plexus.