Gastrointestinal Hormones

Overview of the GI Tract

Digestion and Absorption

Regulation of Digestive Functions

GI Hormones and Paracrine Factors

Integration of Neural and Endocrine Signals

Signaling Mechanisms

Functions of the GI Tract

Ingestion: Taking in foodDigestion: Chemical and MechanicalAbsorption: moving nutrients from the lumen of

the GI tract into the cells of the bodyExcretion: getting rid of undigested and

unabsorbed materialMovement: movement of ingested food

throughout the GI tract

Organs of the Digestive System

Accessory Digestive Organs:Salivary glandsLiver, gall bladderPancreas

Digestive Tract:Oral CavityPharynxEsophagusStomachSmall IntestineLarge Intestine

The Oral Cavity

Boundaries are:- lips (anteriorly)- cheeks (laterally)- palate (superiorly)

The oral cavity is important in:- mastication (chewing): mechanical

digestion- secretion of saliva for digestion (amylase;

digests starch), coating food (mucus)- no significant absorption of nutrients

occurs in the oral cavity

The Pharynx

The pharynx is the passageway from the nose and mouth to the esophagus and respiratory tract

Boundaries: uvula to epiglottisDuring swallowing, food is directed from pharynx

to esophagus (away from respiratory tract).

Esophagus

The esophagus is a passageway from the pharynx to stomach

Contains two sphincters: upper and lower esophageal sphincters (controls flow)

Upper sphincter is skeletal (voluntary), lower sphincter is smooth muscle (involuntary)

Peristaltic waves move food from pharynx to stomach.

The Stomach

The stomach stores food, and mixes and mechanically and chemically digests it

The stomach also secretes digestive juices pepsin: digests proteinhydrochloric acid (acidic pH, required for

pepsin activity, and to kill ingested bacteria)

Mucus: protects the stomach wallPartially digested food: chymeLittle absorption occurs in the stomach

(exceptions: alcohol, aspirin…)

Histology of the Stomach

Cell types:Chief cells: produce pepsinogen (inactive

precursor to pepsin)Parietal cells: produce HCl and intrinsic factor

(absorption of vitamin B12; important in RBC maturation)

“Endocrine” cells: G cells: gastrinD cells: somatostatin (paracrine)Enterochromaffin-like cells: histamine (paracrine)

Small Intestine

Connects the stomach with the large intestineIt is the major site of digestion It is also the major site of absorptionSpecialized structures (villi, microvilli) increase

the surface area of the small intestine, aiding absorption.

The small intestine has three parts (duodenum, jejunum, and ileum)

The bile duct (from liver) and pancreatic duct (digestive juices) empty into the duodenum.

Histology of the Small Intestine

Absorptive cellsGoblet cells (mucus)Enteroendocrine cells:

secretincholecystokinin

Digestion & Absorption: Carbohydrates

Carbohydrates: small amount of digestion begins in oral cavity (amylase). Most digestion in small intestine:Enzyme Digestspancreatic amylase polysaccharides to

disaccharidesdisaccharidases disaccharides into (small intestine) monosaccharides

What’s absorbed: monosaccharides

Proteins: Digestion begins in stomach (pepsin), continues in small intestine:

Enzyme Digeststrypsin, chymotrypsin, polypeptides intocarboxypeptidase small peptides(from pancreas)aminopeptidase dipeptidases small peptides

into smaller peptides

What’s absorbed: mono-, di-, and tri-peptides

Digestion & Absorption: Proteins

Lipids: Digestion begins in the small intestine (minor amount in oral cavity)

Note: Lipids are not soluble in water. Thus, it is hard for enzymes to act on them.

The first step in lipid digestion is emulsification of lipids with bile (secreted from the liver).

Emulsification: transformation of large lipid droplets into small lipid droplets.

This increases the surface area of lipid that can be acted on by the digestive enzyme, pancreatic lipase.

Digestion & Absorption : Lipids

Emulsification of Lipids by Bile

Bile acts on lipids in a way similar to detergent acting on greasy water:

bile

large lipid droplet

lipase

Absorption of Lipids

Bile also helps absorption of products of lipid digestion, forming micelles (free fatty acids, glycerol, cholesterol).

Absorption of lipids is required for absorption of fat-soluble vitamins (vitamins A, D, E, K)

Digestion and Absorption: Nucleic Acids

Food also contains RNA and DNA (also from shed cells of the GI tract).

The pancreas releases nucleases into the small intestine.

Nucleases digest RNA and DNA into components.

Digestion and absorption of dietary nucleic acids probably not important for DNA/RNA synthesis.

Absorption in the Small Intestine: Water

About 9 liters of water enters the digestive tract each day.

About 8 liters of this is absorbed by the small intestine (by osmosis, following movement of ions).

Large Intestine

Last portion of the digestive tract.No digestion occurs in the large intestine.In the large intestine, there is absorption of

water (about 1 liter/day) and salts from feces (undigested, unabsorbed food).

Bacteria produce vitamin K, B vitamins.Secretion of mucus (lubrication of feces)Contractions move feces along large intestine

and rectum, to be expelled out of the anal canal.

Accessory Digestive Organs

Pancreas: exocrine portion produces digestive enzymes, bicarbonate

Liver: Produces bile, stores glycogen, interconverts nutrients (gluconeogenesis), detoxifies toxic substances (alcohol, drugs, ammonia…), makes blood proteins (albumin, fibrinogen, clotting factors)

Gallbladder: concentrates and stores bile

Regulation of Digestion

Allow communication between different parts of the digestive tract

Ensure the presence of sufficient secretions when food present

Help avoid overabundance of secretions in absence of food

Two types of mechanisms: neural and endocrine

Neural Control of DigestionNeural control of digestion is controlled largely by the

parasympathetic nervous system, and local (enteric) reflexes.

Activation of the parasympathetic system results in secretion of digestive juices, increased motility of the stomach, and slowing down movement of food from the stomach to small intestine.

Stimuli: Thought, sight, taste of smell of food; distension of GI tract; chemoreceptors detecting nutrients, pH.

Example: Thought, chewing, or taste of food activates parasympathetic system, resulting in increased release of mucus, HCl, and pepsin in the stomach.The goal of this is to prepare the stomach for oncoming food.

Intestinal Phase of Gastric Secretion

(~ 10% of total)

(due to some G cells extending from antrum into the duodenum)

Important aspect of intestinal phase is feedback regulation and inhibition

Involves interactions between duodenal contents and duodenal hormones, including their actions on pancreas, liver, gall bladder, and stomach

G

gastrin

circulation

HCl

vagus nerve

FOODFOOD

DistensionPeptides

2. Gastric Phase of Gastric Secretion (approx 60% of total)

(initiated by gastric events)

G

gastrin

circulation

HCl

vagus nerve

1. Cephalic Phase of Gastric Secretion (approx.

30% of total)

(initiated by brain)

B. Functional Phases of Gastric Secretion

C. G.I. HORMONESC. G.I. HORMONES

Structure of Structure of SecretinSecretin (27 AA) (27 AA) (comparison with other GI hormones)(comparison with other GI hormones)

Gastrin (17 AA)Gastrin (17 AA)

Cholecystokinin (CCK (33 AA))Cholecystokinin (CCK (33 AA))

+ + HH++

++ psnognpsnogn++ motil.motil.++ LESLES++ growthgrowth

+ + panc enz panc enz ++ G.B.G.B.++ growthgrowth- OddiOddi- gastr emptying gastr emptying - synrg w/ Secretinsynrg w/ Secretin

+ + HCO3 outputHCO3 output++ psnogn psnogn++ synrg w/ CCK synrg w/ CCK- gastr emptyinggastr emptying-- HH++

Endocrine Control of DigestionGastrin:

- produced from the stomach (G cells)- release increased by stomach

distension, peptides, amino acids, alcohol, caffeine, parasympathetic innervation

- release inhibited by highly acidic pH (< 2.0)

- functions: increases gastric (stomach) secretions (primarily HCl); increases histamine release; increases gastric motility; opens pyloric sphincter (between stomach and small intestine), relaxes ileocecal sphincter, stimulates growth of gastric mucosa.

Endocrine Control of Digestion

Histamine:Produced by enterochromaffin-like cells (ECL

cells) of the stomach.Release is stimulated by gastrin.Action: increase HCl secretion from parietal

cells (major factor in HCl secretion).

H/KP

H/KP

histamine-secreting cell

Acetylcholine neural input neurocrineneurocrine

Gastrin hormonal input

endocrineendocrine

PARIETAL cell

paracrineparacrine release of histamine

histamine receptor

ACh receptor

gastrin receptor

transduction-activation events

HCl

secretion

Combined neurocrine, endocrine and paracrine events in the activation of gastric HCl secretion

ECL cell

G cellG cellcirculationcirculation

ECL cell = enterochromaffin-like cell

G cell = G cell = gastrin-secreting cellgastrin-secreting cell

HOW IT WORKS AT THE RECEPTOR LEVEL

neural inputneural input

chemical inputchemical input

H/KP

H/KP

histamine-secreting cell

Acetylcholine neural input neurocrineneurocrine

Gastrin hormonal input

endocrineendocrine

PARIETAL cell

paracrineparacrine release of histamine

histamine receptor

ACh receptor

gastrin receptor

transduction-activation events

HCl

secretion

Combined neurocrine, endocrine and paracrine events in the activation of gastric HCl secretion

ECL cell

G cellG cellcirculationcirculation

ECL cell = enterochromaffin-like cell

G cell = G cell = gastrin-secreting cellgastrin-secreting cell

HOW IT WORKS AT THE RECEPTOR LEVEL

H-2 receptor blockers

H/K ATPase pump inhibitors

Tagamet ZantacPepcid

Prilosec Nexium Aciphex

neural inputneural input

chemical inputchemical input

Turning the G-cell On and Off

ACh ACh

ACh GRP

(Somatostatin)cell

(Gastrin)cellSS

GRPneuron

digestedprotein

H+

vagusnerve

CirculatingGastrin

GD

+-

++

cholinergic neurongastric

mucosa

Gastric LumenGastric Lumen

Turning the G-cell On and Off

ACh ACh

ACh GRP

(Somatostatin)cell

(Gastrin)cellSS

GRPneuron

digestedproteinH+

vagusnerve

CirculatingGastrin

GD

+

++

cholinergic neurongastric

mucosa

Gastric Lumen

SS = somatostatin

-

Endocrine Control of Digestion

SomatostatinProduced by D cells of the stomachSecretion is stimulated by activation of the

sympathetic nervous system and by acidic pH, and is inhibited by activation of the parasympathetic nervous system, continuously released, overridden by gastrin and nerves.

Actions: inhibit gastrin and histamine secretion (decreased acid release and gastric motility); also directly inhibits acid release from parietal cells.

Secretin:

- Produced by duodenum (enteroendocrine cells of the small intestine); crypts of Lieberkühn

- stimulated by arrival of acidic chyme in duodenum.

- functions: stimulates bicarbonate secretion from pancreas; inhibits gastric secretion (decreases HCl production by inhibiting gastrin release); decreases gastric motility (slowing rate of gastric digestion and delivery to the small intestine), increases hepatic bile production, increases CCK, promotes growth and maintenance of the pancreas.

Endocrine Control of Digestion

Cholecystokinin (CCK):- produced by enteroendocrine cells of

the duodenum- release stimulated by fatty acids in

duodenum (also amino acids, acidic chyme)- functions: causes gallbladder

contraction (bile to small intestine); stimulates release of pancreatic enzymes; decreases gastric motility and secretion (increases somatostatin release).

Endocrine Control of Digestion

Endocrine Control of Digestion

Gastric Inhibitory Peptide (GIP):Secretion: Enteroendocrine cells in the small intestine mucosa Crypts of Lieberkuhn

Stimulus: Chyme rich in triglycerides, fatty acids, and glucose enter the small intestine.

Actions: Stimulates release of insulin by beta cells Inhibits gastric secretion and motility Stimulates lipogenesis by adipose tissue Stimulates glucose use by skeletal muscle cells

Endocrine Control of Digestion

Vasoactive Intestinal Peptide (VIP):Secretion: Enteroendocrine cells in the small intestine mucosa Crypts of Lieberkuhn

Stimulus: Chyme entering the small intestine.

Actions: Stimulates buffer secretion Inhibits gastric secretion Dilates intestinal capillaries

Control of Gastric Acid Secretion

How does a parietal cell secrete hydrochloric acid?

CO2 + H20 H2CO3 H+ + HCO3-

Cl-

Cl-H+

HCO3-

Control of Gastric Acid Secretion

ECLparietal

cellG Cell

HCl

Gastrin

histamine

D Cell

somatostatin (-)SECRETIN

CCK

Integration of Neural and Endocrine Functions: Central Effects

CNS: Thoughts, taste, smell of food; chewing – activates parasympathetic nervous system (neurotransmitter: acetylcholine).

ACh acts directly on parietal cells to increase acid secretion.

Ach increases gastrin release, inhibits somatostatin release (increased gastric secretion and motility).

Sympathetic input (activity, stress): increased somatostatin release (inhibiting gastrin secretion – decreased gastric secretion and motility)

Integration of Neural and Endocrine Functions

ECLparietal

cellG Cell

HCl

Gastrin

histamine

D Cell

somatostatin (-)SECRETIN

CCK

ACh(-)

(+) (+)

Vagus N.

Digested protein

(+)

Integration of Neural and Endocrine Functions: Local Reflexes

Mechanoreceptors in the walls of the GI tract detect movement of food into an organExample: In the stomach distension causes

activation of the parasympathetic system, increasing gastrin secretion and acid release, and decreasing somatostatin secretion.

Chemoreceptors detect nutrients and pH.Example: Presence of amino acids, alcohol, or

caffeine in the stomach increases gastrin release. Presence of fatty acids in the duodenum causes

release of CCK.

Signaling Mechanisms

Histamine: Receptor coupled to Gs – increases cyclic AMP production and acts via PKA. Results in phosphorylation and increased transport of proton pumps to cell membrane.

Gastrin: Receptor coupled to Go/IP3/DAG; increased intracellular calcium, and activation of PKC (PKC also phosphorylates proton pumps).

Somatostatin: Receptor coupled to Gi – inhibits cyclic AMP production, decreasing PKA signaling.

Signaling Mechanisms

CCK: Receptor coupled to Go (increased calcium causes somatostatin release)

Secretin: Receptor couple to Gs (increased cyclic AMP, causes increased secretion of bicarbonate from the pancreas)

Integration of Gastric SecretionIntegration of Gastric Secretion

++

++

++++

++

++

Integration of Gastric SecretionIntegration of Gastric Secretion

++ ++

++

--

-- --

++

++++

++

++

D. Duodenal Integration & Control: 1. Response to Acidity

Regulation by Secretin

HCl + NaHCOHCl + NaHCO33 NaCl + CO NaCl + CO22 + H + H22OO

+

+

-

+

gallbladder

liver

HCl

HClmotility

NaCl+ H2O

HCO3HCO3

HCl

NaHCO 3

NaHCO3

Secretin

Secretin

Regulation by CCK (Cholecystokinin)

CCKCCKCCKCCK

gall

bladder

Bile

FOOD

+

-

liver

+

fats & peptides

bile & enzymes

fat & protein digestion

- HCl

2. Duodenal Response to Food