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Gastrointestinal Physiology

(4) GI SECRETION

1. Salivary Secretion

2. Gastric Secretion

3. Pancreatic Secretion

4. Bile Secretion by the Liver

5. Secretions of the Small Intestine

6. Secretions of the Large Intestine

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SECRETORY GL ANDS IN THE DIGESTIVE TRACT

• Goblet cells in digestive epithelium Lubrication of surface

• Crypts of Lieberkühn Enzyme secreting cells • Tubular glands Oxyntic or Parietal cells (acid production) Peptic or Chief cells (pepsinogen)

•Complex glands Salivary, pancreas, liver

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1. Salivary Secretion

a. Structure of the salivary glands

b. Formation of saliva

c. Regulation of salivary secretion

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a. Structure of the salivary glands

serous

mixed serous + mucous

Three major salivary glands:

Parotid glands

Submandibular glands

Sublingual glands

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b. Formation of saliva

Step 1 - The acinar cells secrete the initial saliva. - The initial saliva is isotonic. - It has the same electrolyte composition as plasma.

Step 2 - The ductal cells modify the initial saliva.

- Absorption of Na+, CI- > secretion of K+ and HCO3-

- The final saliva is hypotonic.

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c. Regulation of salivary secretion

• Salivary secretion is exclusively under neural control.

• Both PSNS and SNS stimulate saliva production. PSNS is primary.

• Conditioning, food, thought, and nausea etc. also stimulate salivary secretion.

• Dehydration, fear, and sleep inhibit salivary secretion.

PSNS:

SNS:

Primary controller of salivation, large amount of watery saliva containing enzymes

Small volume of saliva, thick with mucus

Because sympathetic stimulation accompanies frightening or stressful situations, the mouth may feel dry at such times.

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• lubrication• Protection

thiocyanate ions, proteolytic enzymes (lysozyme), IgA etc.• α-amylase, lingual lipase • Kallikrein cleaves kininogen to produce bradykinin (a strong

vasodilator, accounts for high salivary blood flow)

Summary of Salivary Secretion

Characteristics of saliva secretion:

• high volume (approx. 1 L/day)• high K+ and HCO3

- concentrations• low Na+ and Cl- concentrations• hypotonicity• The composition of saliva varies with flow rate(next slide)• pH of 6.0 – 7.0

Functions of saliva:

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• The composition of saliva varies with flow rate

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THE DIGESTIVE SYSTEMMotility

Chewing occurs in the mouth

Swallowing initiates primary peristalsis in the esophagus

Stretch of the esophageal wall initiates secondary peristalsis

Motility in esophagus :- Primary and secondary peristalsis.

- Function of peristalsis is toPropel a bolus of food to stomach.

Clinical correlaton-

-Peptic Ulcer.

-Gastroesophageal reflux disease(GERD)

-Achalasia-Chagas disease

Barium swallow showing bird's beak“ or "rat's tail" appearance in achalasia.

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2. Gastric Secretion

a. Structure and cell types of the gastric mucosa

b. HCL secretion

c. Pepsinogen secretion and activation

d. Intrinsic factor secretion

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Stomach Motility After A Meal

1. Fasting state

2. Meal enters stomach

3. Peristalsis begins4. Antral systole

Food bolus

receptive relaxation

accommodation

retropulsion

MMC *(90 mins)

Vago-vagal reflex

↑ gastric pressure

* migrating myoelectric complexes

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a. Structure and cell types of the gastric mucosa

Oxyntic glands-cardia,fundus and body(80%) surface epithelium

mucous neck cells (mostly mucus but also pepsinogen)

peptic or chief cells (pepsinogen)

parietal or oxyntic cells (HCl and intrinsic factor)

paracrine cells (histamine)

Pyloric glands(20%) surface epithelium

mucous cells (pepsinogen, mucus)

G cells (gastrin)

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histamine

[ Enterochromaffin-like (ECL)]

Gastric pit

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b. HCI secretion

Alkaline tide

Omeprazole

(-)

Figure 8-7 Mechanism of HCl secretion by gastric parietal cells. ATP, Adenosine triphosphate.

(in gastric venous blood)

K+ channel

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Summary of HCI Secretion

1. Intracellular fluid: Carbonic anhydrase

2. Apical membrane H+-K+ ATPase, inhibited by omeprazole CI- channel

3. Basolateral membrane

Cl-—HCO3- exchanger

alkline tide

4. Net secretion of HCl, net absorption of HCO3-

20Release of histamine by gastrin is a major pathway viawhich gastrin stimulates acid production.

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Stimulation Of Acid Production During The

Cephalic PhaseConditioned reflexes

sight, smell, taste

hypoglycemia etc.

gastrin

G-cell

GRP

Ach

Gastrin + Ach

= ECL cell to give histamine release

Vagus nerve

parietal cell

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Stretch

Amino acids

gastrin

GRP

Ach

Vagus nerve

G-cell

Parietal cell

Stimulation Of Acid Production

During The Gastric Phase

ENS ANS

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Negative Feedback Of Acid Secretion By H+

Has Several Mechanisms.

D G

Lumen H+

Antrum

BodySST-

DECL

SST-

P

-

-Lumen

H+

+

PGE2 -

SST-

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Feedback Inhibition From

The Small Intestine:

Enterogastrones

Acid, hyperosmolarity, fats, proteins

CCK

Secretin

GIP

Peptide YY

Neurotensin

SST

VIP (via ENS)

-

Diagram source unknown

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STIMULATION OF GASTRIC H+ SECRETION

1. Vagal stimulation

Vagus nerve innervates G cells gastrin H+ secretion GRP is the neurotransmitter

Direct path:

Vagus nerve innervates parietal cells Ach is the neurotransmitter

Indirect path:

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3. Histamine

• is released in response to eating a meal.

• the second messenger for gastrin on the parietal cell is IP3/Ca2+

2. Gastrin

• is released from enterochromaffin-like (ECL) cells in the gastric mucosa and diffuse to the nearby parietal cells.

• stimulates H+ secretion by activating H2 receptor on the parietal cell membrane.

STIMULATION OF GASTRIC H+ SECRETION

H2 receptor-blocking drugs such as cimetidine (famotidine, ranitidine) inhibit H+ secretion by blocking the stimulatory effect of histamine.

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• Potentiation occurs when the response to stimultaneous administration of two stimulants is greater than the sum of response to either agent given alone.

• Histamine potentiates the actions of Ach and gastrin;

Ach potentiates the actions of histamine and gastrin.

4. Potentiating effects of Ach, histamine, and gastrin on H+ secretion

STIMULATION OF GASTRIC H+ SECRETION

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INHIBITION OF GASTRIC H+ SECRETION

1. Low pH (< 3) in the stomach

inhibits gastrin secretion by negative feedback, thus inhibits further H+ secretion.

2. Somatostatin

direct pathway:

indirect pathway:

3. Prostaglandins

via Gi protein cAMP

inhibit histamine release from ECL cells inhibit gastrin release from G cells

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c. Pepsinogen secretion and activation

pepsinogen pepsinH+

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Gastric Mucosal Protection

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Normal Gastric Antrum

o

Antral gastritis

with erosions

GASTRIC AND PEPTIC ULCERSPeptic ulcers• Erosions of the gastric and duodenal mucosa produced by action of

HCl• Results from

– Excessive acid secretion (i.e., Zollinger-Ellison syndrome - ↑ secretion of gastrin)

• ↓ protective properties of the mucosal barrier (i.e., Helicobacter pylori -bacterium that resides in GI tract that liquefy and penetrate the barrier)

• Treatment: Antibiotics, proton pump inhibitors, inhibitors of gastric secretion, selective vagotomy

Gastritis• Bacterial infection of gastric mucosa• Histamine released by tissue damage and inflammation stimulate

further acid secretion• Ingested irritant substances (i.e., alcohol, NSAID), smoking

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d. Intrinsic factor secretion

Intrinsic factor (IF): a mucoprotein, secreted by parietal cells along with HCl.

• Vitamin B12 requires IF to be absorbed.

• IF combines with vitamin B12 to form a complex that is absorbed in the terminal ileum.

• Vitamin B12 is essential for maturation of red blood cells. The absence of IF prevent absorption of B12 and leads to abnormal production of RBCs, which causes pernicioius anemia.

.

IF-B12

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~ 1.5 L is secreted per day, pH: 0.8 – 3.5

A Summary of Gastric Secretion

Gastric juice:

Thick alkaline mucus by surface epithelium

Thin watery mucus by neck cells

HCl by parietal cells

Pepsinogen by chief cells

Intrinsic factor by parietal cells

Gastric mucosal epithelium is made entirely of secretary cells including exocrine, endocrine, and paracrine cells.

3. Pancreatic Secretion

a. Structure of the pancreatic exocrine glands

b. Formation of pancreatic secretion

c. Regulation of pancreatic secretion

Most chemical digestion and absorption occur in the small intestine-

• The secretions that initiate chemical digestion in the small intestine come from the exocrine (acinar) pancreas

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Structure of the pancreatic exocrine glands

b. Formation of pancreatic secretion

Exocrine pancreas

Acinar cells

Ductal cells

enzymes

amylase

lipases

proteases

trypsinogenchymotrypsinogenprocarboxypeptidaseproelastase

aqueous alkaline secretion (HCO3-)

Trypsin inhibitor is secreted by acini to prevent activation of trypsin. If the pancreas is damaged, large quantities of pancreatic secretion pools in the damaged areas, and trypsin inhibitor is overwhelmed. Pancreatic secretions can digest the pancreas, which is known as acute pancreatitis.

Enzymes often secreted in an inactive form, and activated near the wall of gastrointestinal tract - so food is broken down where it can be transported into the blood stream.

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Figure 8-21 Mechanism of pancreatic secretion. The enzymatic component is produced by acinar cells, and the aqueous component is produced by centroacinar and ductal cells. ATP, Adenosine triphosphate.

Figure 8-23 Regulation of pancreatic secretion. ACh, Acetylcholine; cAMP, cyclic adenosine monophosphate; CCK, cholecystokinin; IP3, inositol 1,4,5-triphosphate.

c. Regulation of pancreatic secretion

The Cl channel is encoded by the cystic fibrosis gene product CFTR.

Thus patients with cystic fibrosis, who lack a functional Cl channel have defective duct transport. The ducts get clogged with precipitatedenzymes and mucus and the pancreas undergoes a fibrosis (hence the name of the disease). The physiological significance of this model is twofold, first the HCO3

delivered to the duodenal lumen neutralizes gastric acid and allows the digestive enzymes to operate at their pH optimum, close toneutral. Second, H+ which are produced in the duct cells when HCOis generated for secretion leave via Na-H exchange into the blood. The net effect is to neutralize the alkaline tide in the blood that was generated by gastric acid secretion.

A Summary of Pancreatic Secretion

HCO3- : neutralize the contents from the stomach

Enzymes: digestion of protein, carbohydrate, and fats Pancreatic juice is characterized by: - high volume (1 L/day) - virtually the same Na+ and K+ concentrations as plasma

- much higher HCO3- concentration than plasma

- much lower Cl- concentration than plasma - isotonicity - pancreatic lipase, amylase, and proteases - pH of 8.0 – 8.3

4. Bile Secretion

a. Overview of the biliary system

b. Composition and functions of bile

c. Formation of bile and function of the gallbladder

d. Regulation of bile excretion from the gallbladder

e. Enterohepatic circulation of bile salts

f. Clinical correlation

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Hepatocytes secrete bile into the bile canaliculi and bile ductules.

bile ductule

46Figure 8-24 Secretion and enterohepatic circulation of bile salts. Light blue arrows show the path of bile flow; yellow arrows show the movement of ions and water. CCK, Cholecystokinin.

a. Overview of the biliary system

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Bile salts including bile acids (50%)

Phospholipids (Lecithin, 40%)

Bile pigments (2%): bilirubin

Cholesterol (4%)

Electrolytes (Na+, K+, Ca++, Cl-, HCO3-)

Water

emulsifying fat

eliminating metabolic wastes

Composition Functions

aids in fat digestionaids in fat absorption

b. Composition and functions of bile

amphipathic molecules

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c. Formation of bile and functions of the gallbladder

Hepatocytes secrete: Bile ducts secrete:

Organic constituents are highly concentrated

(5 – 20 fold).

Watery components are reabsorbed by the gallbladder mucosa.

organic components (bile acids, cholesterol, bilirubin)

watery solution, Na+, HCO3-

Bile

Gallbladder

stores bile,

concentrates bile, empties bile.

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CCK• is released in response to small peptides and fatty acids in the duodenum.• tells the gallbladder that fats need to be emulsified and absorbed – in other words, bile is needed.• causes contraction of the gallbladder smooth muscle.• causes relaxation of the sphincter of Oddi.

ACh• also causes contraction of the gallbladder.

d. Regulation of bile excretion from the gallbladder

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Figure 8-24 Secretion and enterohepatic circulation of bile salts.

94%

active transport

diffuse

Na+-bile salt cotransporter

e. Enterohepatic circulation of bile salts

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f. Clinical correlation

Gallstone formation: precipitated cholesterol

high-fat diet, prone to the development of gallstones

too much absorption of water from bile

inflammation of epithelium

Ileal resection

IF-Vitamin B12 complex cannot be absorbed.

Steatorrhea: recirculation of bile via enterohepatic circulation is reduced. Most secreted bile acids are lost in feces. Oil droplets in the stool.

Diarrhea: bile acids cAMP-dependent Cl- secretion in colonic epithelium, Na+ and water follow Cl- into the lumen

GALLSTONESMechanisms of stones formation• absorption of water in the gallbladder• absorption of bile acids ( solubility of

cholesterol)• cholesterol concentration (fatty diet)• Inflammation of the epithelium

Mechanisms the risk of stones formation• Secretion of H+ by the mucosa (acidification

of bile) Ca 2+ precipitation• Absorption of large amounts (about 50%) of

Ca 2+• Release of the inhibitors of Ca2+ and

cholesterol precipitation• Secretion of water and electrolytes during

digestion which intermittently dilute the gallbladder content

• Combination of cholesterol with lecithin and bile salts (micelles) water solubility of cholesterol

• Contractions prevent accumulation of microcrystal

2 types of stones:Cholesterol stones Calcium bicarbonate stones

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Brunner’s glands

Crypts of Lieberkühn

5. Secretions of the Small Intestine

An extensive array of compound mucus glands

Located in the wall of duodenum.

Secrete mucus and HCO3

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Located over the entire surface of the small intestine.

Goblet cell: secrete mucus

Enterocytes: secrete and absorb water and electrolytes

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6. Secretions of the Large Intestine

The large intestine has many crypts of Lieberkühn and secrets an alkline mucus solution containing bicarbonate and K+.

The sole function of mucus is protection. It protects the large intestine wall from damage by acids formed in feces from attacking the intestinal wall.

Acid and mechanical stimulation, mediated by both long and short reflexes, increase the secretion of mucus.

the wall of the large intestine

a mucus layer lining the wall

Acid passage of feces

Neural reflexes

(long and short)

Mucus secretion

Case: Zollinger-Ellison Syndrome

Description of Case: A 52-year-old man visits his physician complaining of abdominal pain, nausea, loss of appetite, frequent belching, and diarrhea. The man reports that his pain is worse at night and is sometimes relieved by eating food or taking antacids containing HCO3-. GI endoscopy reveals an ulcer in the duodenal bulb. Stool samples are positive for blood and fat. His serum gastrin level is measured and found to be markedly elevated. A CT scan reveals a 1.5 cm mass in the head of the pancreas. The man is referred to a surgeon. While awaiting surgery, the man is treated with the drug omeprazole, which inhibits H+ secretion by gastric parietal cells. During a laparotomy, a pancreatic tumor is located and excised. After surgery, the man’s symptoms diminish, and subsequent endoscopy shows that the duodenal ulcer has healed.

Explanation of Case: All of the man’s symptoms and clinical manifestations are caused, directly or indirectly, by a gastrin-secreting tumor of the pancreas. In Zollinger-Ellison syndrome, the tumor secretes large amounts of gastrin into the circulation. The target cell for gastrin is the gastric parietal cell, where it stimulates H+ secretion. The physiologic source of gastrin, the gastric G cells, are under negative feedback control. Thus, normally, gastrin secretion and H+ secretion are inhibited when the gastric contents are acidified (i.e., when no more H+ is needed). In Zollinger-Ellison syndrome, however, this negative feedback control mechanism does not operate: gastrin secretion by the tumor is not inhibited when the gastric contents are acidified. Therefore, gastrin secretion continues unabated, as does H+ secretion by the parietal cells.

Case: Zollinger-Ellison Syndrome, explanation (cont.)

The man’s diarrhea is caused by the large volume of fluid delivered from the stomach (stimulated by gastrin) to the small intestine; the volume is so great that it overwhelms the capacity of the intestine to absorb it. The presence of fat in the stool (steatorrhea) is abnormal, since mechanisms in the small intestine normally ensure that dietary fat is completely absorbed. Steatorrhea is present in Zollinger-Ellison syndrome for two reasons. 1) The first reason is that excess H+ is delivered from the stomach to the small intestine and overwhelms the buffering ability of HCO3--containing pancreatic juices. The duodenal contents remain at acidic pH rather than being neutralized, and the acidic pH inactivates pancreatic lipase. When pancreatic lipase is inactivated, it cannot digest dietary triglycerides to monoglycerides and fatty acids. Undigested triglycerides are not absorbed by intestinal epithelial cells, and thus, they are excreted in the stool. 2) The second reason for steatorrhea is that the acidity of the duodenal contents damages the intestinal mucosa (evidenced by the duodenal ulcer) and reduces the microvillar surface area for absorption.

Treatment: While the man is awaiting surgery to remove the gastrin-secreting tumor, he is treated with omeprazole, which directly blocks the H+-K+-ATPase in the apical membrane of gastric parietal cells. This ATPase is responsible for gastric H+ secretion. The drug is expected to reduce H+ secretion and decrease the H+ load to the duodenum. Later, the gastrin-secreting tumor is surgically removed.

Case: Resection of the Ileum

Description of Case: A 36-year-old woman has 75% of her ileum resected following a perforation caused by severe Crohn’s disease (chronic inflammatory disease of the intestine). Her postsurgical management included monthly injections of vitamin B12. After surgery, she experienced diarrhea and noted oil droplets in her stool. Her physician prescribed the drug cholestyramine to control her diarrhea, but she continues to have steatorrhea.

Explanation of Case: The woman’s severe Crohn’s disease caused an intestinal perforation, which necessitated a subtotal ileectomy, removal of the terminal portion of the small intestine. Consequences of removing the ileum include decreased recirculation of bile acids to the liver and decreased reabsorption of the intrinsic factor-vitamin B12 complex. In normal persons with an intact ileum, 95% of the bile acids secreted in bile are returned to the liver, via the enterohepatic circulation, rather than being excreted in feces. This recirculation decreases the demand on the liver for the synthesis of new bile acids. In a patient who has had an ileectomy, most of the secreted bile acids are lost in feces, increasing the demand for synthesis of new bile acids. The liver is unable to keep pace with the demand, causing a decrease in the total bile acid pool. Because the pool is decreased, inadequate quantities of bile acids are secreted into the small intestine, and both emulsification of dietary lipids for digestion and micelle formation for absorption of lipids are compromised. As a result, dietary lipids are excreted in feces, seen as oil droplets in the stool (steatorrhea). This patient has lost another important function of the ileum, the absorption of vitamin B12. Normally, the ileum is the site of absorption of the intrinsic factor-vitamin B12 complex. Intrinsic factor is secreted by gastric parietal cells, forms a stable complex with dietary vitamin B12, and the complex then is absorbed in the ileum. The patient cannot absorb vitamin B12 and must receive monthly injections, bypassing the intestinal absorptive pathway. The woman’s diarrhea is caused, in part, by high concentrations of bile acids in the lumen of the colon (because they are not recirculated). Bile acids stimulate cAMP-dependent Cl- secretion in colonic epithelial cells. When Cl- secretion is stimulated, Na+ and water follow Cl- into the lumen, producing a secretory diarrhea (sometimes called bile acid diarrhea).

Treatment: The drug cholestyramine, used to treat bile acid diarrhea, binds bile acids in the colon. In bound form, the bile acids do not stimulate Cl- secretion or cause secretory diarrhea. However, the woman will continue to have steatorrhea.

• Contraction of the gallbladder is correctly described by which of the following statements?

a. It is inhibited by a fat-rich meal

b. It is inhibited by the presence of amino acids in the duodenum

c. It is stimulated by atropine

d. It occurs in response to cholecystokinin

e. It occurs simultaneously with the contraction of the sphincter of Oddi

D.