Verdaaung (1), full

Main task of the gastrointestinal (GI) system

To get food ready for absorption into blood and the lymphatic system while excreting non-digestible components.

What is the basic mechanism of digestion?

• Attack of large molecules by specific enzymes

• Enzymes are either:

  • Secreted by the stomach, small intestine, or accessory glands

  • Bound to the luminal surface of epithelial cells of the small intestine

How is fat processed during digestion?

• Fat is degraded to simpler fatty acids

• Or is absorbed as droplets

How is digestion regulated hormonally and what is its historical significance?

• Regulation of digestion by hormones is an example of positive and negative hormonal feedbacks

• The first hormone discovered (in 1902) was secretin

• Secretin is a gastrointestinal hormone produced in the small intestine

Standard daily energy uptake for an adult

Approximately 2,100 kcal per day.

Energy needs of professional endurance athletes

Up to 10,000 to 13,000 kcal per day, which often leads to muscle loss during races.

Standard percentage breakdown of food components

Carbohydrates (50-60%), proteins (10-15%), and fat (25-30%).

Basic mechanism of digestion

Large or insoluble molecules are attacked by specific enzymes to become simple, soluble compounds.

The two mechanical ways food is broken down

Chewing [Kauen] and peristalsis.

Approximate length of the GI tract

Approximately 4.5 metres long.

Unidirectional movement direction in the GI tract

From the mouth to the rectum, assisted by adjusted contractions of muscular layers.

Total daily fluid volume entering the GI system

Approximately 9 litres per day (2L from intake and 7L from endogenous secretions).

Amount of fluid excreted in feces daily

Approximately 100 ml, meaning the system reabsorbs almost 99% of the fluid.

Surface area of the gastrointestinal tract

Approximately 140 to 200 square metres, roughly the size of a tennis court.

Main functions of the GI system beyond digestion

Absorption, hormone secretion, and protection against toxins and bacteria.

The four general layers of the GI wall

Mucosa, submucosa, muscularis (circular and longitudinal), and serosa.

The nervous system specifically innervating the GI tract

The enteric nervous system, which is part of the autonomic nervous system.

Plexus myentericus (Auerbach plexus) function

Innervates smooth muscles (longitudinal/circular) and is responsible for muscle tone and motility.

Plexus submucosus (Meissner plexus) function

Regulates the secretory function of the mucosa.

Major functions of the stomach

Reservoir, protein denaturation via HCl, protein hydrolysis via pepsin, killing bacteria, and Vitamin B12 protection via secretion of intrinsic factor and haptocorrin (the two are essential for the uptake of vitamin B12 in the small intestine).

How much acid is secreted per day in digestion and what concentration gradient must hydrogen ions overcome?

• Total acid secretion per day equals about 25 ml of concentrated (12 molar) HCl

• Because plasma pH is 7.4, hydrogen ions must be secreted against a concentration ratio of about 1 : 1,000,000

What is constant mucosal repair in the gastrointestinal tract?

• Small damaged areas can be restored independent of cell division

• Several growth factors modulate this repair

• Larger defects require cell proliferation

Where is mucus produced and what is its function?

• Produced in the gastrointestinal system and in many other organs (e.g. respiratory tract, lungs, eyes, vagina)

• Serves as a protectant

What protective functions does mucus have in the gastrointestinal tract?

• Protection against mechanical damage by food lumps; acts as a lubricant

• Protection against chemical damage by HCl and digestive enzymes

• In the stomach, mucus gel prevents pepsin from reaching the epithelial cell surface

Why is mucus alone or bicarbonate alone insufficient to maintain epithelial surface pH near 7?

• Mucus alone cannot neutralize acid because it mainly acts as a physical barrier and diffusion layer, not a strong buffering system

• Bicarbonate alone cannot maintain protection because it would be rapidly washed away or diluted in the lumen

• Therefore, both systems are needed together:

  • Mucus creates a protective gel layer at the epithelial surface

  • Bicarbonate is trapped within this mucus layer to locally neutralize acid

• This combined system is required to keep the pH at the epithelial surface close to 7, protecting cells from acid damage

How does mucin glycosylation determine its properties and function?

• Glycan chains clustered in central regions

• Makes mucins polyanionic

• Causes major structural expansion (~3× larger than globular proteins)

• Provides:

  • Protease resistance

  • Pathogen sequestration

  • Ion and water binding

• Glycan heterogeneity varies between species and tissues → adaptation to changing pathogens

How do secreted mucins form mucus gel and where are they processed?

• Secreted mucins (polymeric mucins) have cysteine-rich N- and C-termini

• Form disulfide bonds → polymerization → gel formation

• Synthesized in epithelial secretory pathway

• Glycosylation occurs in ER and Golgi apparatus

How does HCl secretion affect the morphology of parietal cells?

• Before secretion: extensive secretory network (canaliculi) contains many vesicles in the cytoplasm

• Upon stimulation: vesicles fuse within seconds with the apical (luminal) membrane

• Result:

  • Strong increase of apical membrane surface area (50–100 fold)

  • Formation of a highly infolded membrane

How is HCl secreted by parietal cells and what is the role of omeprazole?

• Cl⁻ is then expelled from the parietal cell on the apical/luminal side by Cl⁻ channels

• H⁺ is secreted into the lumen via the H⁺/K⁺-ATPase in exchange for K⁺

• The increase in intracellular K⁺ is balanced by apical K⁺ channels, which export K⁺ into the lumen of the stomach

• Thus, this process increases the concentration of HCl on the apical/luminal side and causes an increase in pH on the basolateral/interstitial side

• Omeprazole blocks the H⁺/K⁺-ATPase and thus inhibits secretion of HCl

What are peptic ulcers, what causes them, and how are they treated?

• Major forms of peptic ulcer: gastric ulcer and duodenal ulcer

• Both are chronic diseases

• Often caused by the bacterium Helicobacter pylori

• Not all infected individuals develop peptic ulcers

• All infected individuals develop chronic gastritis (cellular infiltrate in gastric mucosa), which may be asymptomatic

• H. pylori can be eradicated in one week using:

  • 2 antibiotics

  • A proton pump inhibitor (e.g. omeprazole)

What are the age patterns and a proposed mechanism in the pathogenesis of gastric and duodenal ulcers?

• Gastric ulcer peaks around 60 years of age

• Duodenal ulcer peaks around 50 years of age

• α-adrenergic agonists decrease bicarbonate secretion

• Chronically elevated adrenaline (epinephrine) may suppress bicarbonate secretion sufficiently to reduce protection

• This mechanism may contribute to the pathogenesis of stress ulcers

What is the role of E-type prostaglandins in gastric protection?

• Stimulate gastric mucus secretion

• Stimulate bicarbonate secretion

• Inhibit acid secretion

• May protect individuals who are susceptible to gastric ulcers

What are COX-1 and COX-2, and what is the role and outcome of COX-2–selective drugs like Vioxx?

• COX exists in at least two isoforms: COX-1 and COX-2

• COX-1:

  • Protects the stomach

  • Promotes platelet aggregation

• COX-2:

  • Triggers pain and inflammation

• COX-2–selective drugs (“superaspirins”), e.g. Vioxx:

  • Block COX-2 but not COX-1

  • Relieve pain and inflammation without damaging the stomach

  • Were introduced around 1998/1999

  • Reached high sales (up to 2.5 billion $/year in 2003)

  • Were withdrawn in September 2004 due to increased risk of myocardial infarction and stroke (Vioxx scandal)

How is basal gastric acid secretion regulated over the day?

• Basal acid secretion depends on circadian control

• It is minimal in the morning

• It is highest in the evening

Parietal cells (Belegzellen) function

Secretion of hydrochloric acid and intrinsic factor.

Chief cells (Hauptzellen) function

Secretion of pepsinogen, which is the inactive precursor to pepsin.

ECL cells (enterochromaffine-like cells) function

Release of histamine, which acts as a paracrine stimulator for acid production.

Surface and neck mucous cells function

Production of alkaline mucus and bicarbonate to protect the stomach lining.

Daily volume of gastric juice secreted by oxyntic glands

Between 1 to 3 litres per day.

Molecular components of the gastric mucosal barrier

Mucus gel, local bicarbonate buffering, and constant mucosal repair.

Regeneration time for GI epithelial cells

Approximately every three to five days due to high chemical and mechanical stress.

Composition of mucus

Highly-glycosylated proteins called mucins that are viscous and resistant to proteolysis,

Molecular structure of mucins

• Polyanionic.

• Contain more than 70% carbohydrates.

• Form polymers via disulfide bridges.

• Two types: membrane-bound and secreted.

• Highly glycosylated centrail domains –> extended, stiff structure in solution.

Mechanism of the stomach Proton Pump

The H+/K+ ATPase, which actively pumps protons into the lumen in exchange for potassium using ATP.

Enzyme providing protons for gastric acid

Carbonic anhydrase, which catalyses H2O and CO2 into carbonic acid,

Cause of the Alkaline Tide (Alkalose)

When parietal cells produce HCl, they release bicarbonate into the blood as a counter-ion, raising blood pH.

Helicobacter pylori significance

A bacterium responsible for 80-95% of peptic ulcers and a major risk factor for gastric cancer.

Discovery of Helicobacter pylori

Discovered in 1983 by Marshall and Warren (Nobel Prize in 2005),

Survival mechanism of Helicobacter pylori

It uses urease to convert urea into ammonia (NH3) and CO2 to neutralise stomach acid locally.

Effect of NSAIDs (e.g. Aspirin) on the stomach

They inhibit COX-1 enzymes, leading to reduced mucus and bicarbonate production, which can cause bleeding or perforation.

Mechanism of Aspirin at acidic pH

It crosses the gastric barrier and inhibits prostaglandin synthesis from behind.

The three phases of gastric secretion regulation

Cephalic, Gastric , and Intestinal.

Trigger for the Cephalic phase

• The thought, sight, smell, or taste of food, mediated by the Vagus nerve (parasympathetic, peripheral nervous system) BUT is induced by the CNS.

• This phase accounts for approx. 40% of the maximal secretion of acid in the stomach.

Clinical significance of Pavlov's dog experiment

Demonstrated that the brain can associate a conditioned stimulus (bell) with a physiological response (salivation),

Triggers for the Gastric phase

• TRIGGERS: Stomach distension and the presence of protein breakdown products (peptides).

• As the food arrives in the stomach, the secretion of pepsinogen is stimulated by the hormone gastrin.

• Phase is completed within 1 to 2 hours and iS responsible for approx. 50% of the acid production.

What happens during the intestinal phase of gastric regulation?

• Triggered by entry of acidic, partially digested food (chyme) from the stomach into the duodenum

• Initiates the intestinal phase (via hormones)

• Initially causes release of gastrin, which increases acid secretion in the stomach (excitatory phase)

• This excitatory phase accounts for ~10% of total gastric acid secretion

• Later, inhibitory humoral factors are released (e.g. secretin, prostaglandins)

• These inhibitory signals reduce HCl secretion in the stomach

Consequence of islet cells malfunctions.

Can cause diabetes mellitus (Type 1 diabetes)

Three main stimulators for maximal HCl secretion

• Gastrin, Histamine (H2 receptors), and Acetylcholine.

• Binding of the three emdiators to their receptors activates specific signaling cascades in the parietal cells (cAMP in case of histamine; IP3 in case of gastrin and acetylcholine) that then trigger the release of HCL.

Synergistic effect of HCl stimulators

The three stimulators potentiate each other, and removing one (like histamine) abolishes most secretion.

Enterogastric inhibitory reflex

Triggered in the intestinal phase when the duodenum detects low pH, high osmolarity, or fat, slowing gastric emptying.

Pharmacological intervention for reflux and heart burn

Antacids (alkaline buffers), H2 receptor antagonists (ranitidine), and proton pump inhibitors (omeprazole).

Two fundamentally different tasks of the pancreas

Endocrine (glucose regulation via Islet cells) and Exocrine (secretion of alkaline digestive liquid).,

Percentage of pancreatic tissue dedicated to endocrine vs exocrine

Endocrine is only 1-2%, while the rest is dedicated to exocrine functions.

Components of the exocrine pancreas

Acinar cells (produce enzymes) and Duct cells (secrete bicarbonate and liquid).

• note: approx. 90% of the proteins in pancreatic juice are proteolytic enzymes (mostly end- and exopeptidases).

What is the role of pancreatic polypeptide and somatostatin in the pancreas?

• Pancreatic polypeptide (from PP cells) and somatostatin (from δ-cells)

• Modulate the secretory activity of other pancreatic cell types

What does the pancreatic juice contain in order to prevent premature activation of proteases in the pancreas?

A high concentration of Trypsin inhibitors.

Pancreatic islet cell types and functions

Alpha cells (Glucagon), Beta cells (Insulin), PP cells (Polypeptide), and Delta cells (Somatostatin).

Main proteolytic enzymes from the pancreas

Trypsin, chymotrypsin, and carboxypeptidase.

Inactive forms of pancreatic enzymes (zymogens)

Trypsinogen, chymotrypsinogen, and procarboxypeptidase.

Activation of Trypsinogen

Specifically activated by Enteropeptidase (enterokinase) in the duodenum.

Role of Trypsin in the duodenum

It serves as the master endopeptidase that activates all other pancreatic zymogens.

Regulators of the pancreatic intestinal phase

CCK (released by I-cells due to fats/peptides) and Secretin (released by S-cells due to acid).

• Fun fact: the gastric phase is mediated by the relase of gastrin that binds to the same receptor like CCK.

CCK

• Released from I-cells in the duodenum

• Lipids, peptides and amino acids induce its release.

• Increases the release of proteins in the acinus cells (they secrete zymogens) of the pancreas.

Secretin

• Released from S-cells in the duodenum and jejunum.

• Production triggered by HCL, bile salts and lipids.

How is bicarbonate secretion in the pancreas linked to CFTR and cystic fibrosis?

• Bicarbonate secretion pathways involve the chloride channel CFTR (cystic fibrosis transmembrane conductance regulator)

• CFTR is therefore part of the bicarbonate secretion process

• Patients with cystic fibrosis have impaired CFTR function

• As a result, they also have problems with pancreatic secretion

Cystic Fibrosis (Zystische Fibrose) and the pancreas

A mutation in the CFTR chloride channel prevents proper bicarbonate secretion, causing thick mucus and malabsorption,

Pancreatitis definition and causes

Inflammation of the pancreas, often caused by alcohol abuse or gallstones, which can lead to self-digestion.

Pancreatic cancer characteristics and symptoms

• High mortality rate, often affects the endocrine system, and is difficult to treat if removal causes severe diabetes.

• Symptoms: loss of appetite, weight loss, abdominal pain and eventually yellow skin if the cancer obstructs the duct of the pancreas.

What is the functional “reserve” capacity of the small intestine?

• The small intestine has an excess functional capacity

• More than 50% of the organ can be removed without being lethal

Does intestinal absorption regulate caloric intake?

• Intestinal absorption is not thought to regulate caloric input

• Therefore, caloric intake is controlled by the amount of food eaten

• This is important for dietary restriction (e.g. diets)

Main sections of the small intestine

Duodenum, Jejunum, and Ileum.

Small intestine surface area magnification

A 600-fold increase achieved via Kerckring folds, villi, and microvilli.

Small intestine cell types and where they all develop from.

• Enterocytes (absorption), Goblet cells (mucus), Paneth cells (lysozyme), M cells (immune response) and Argentaffine cells (a collection of different hormonal cells).

• Develop from common stem cells located in the crypts (regenerationszone).

What is the role of the intestine in fluid balance and what happens if absorption is disturbed?

• The intestine reabsorbs most of the liquid

• Disturbation of the absorption machinery can lead to loss of proper homeostasis

What is the role of dietary fibers and α-amylase in carbohydrate digestion?

• Some ingested polysaccharides cannot be digested because not all hydrolytic enzymes are expressed

• These non-digestible carbohydrates are called dietary fibers (Faser- oder Ballaststoffe)

• They may be degraded by bacteria in the lower ileum or colon

• Starch digestion begins in the mouth via salivary α-amylase

• Salivary α-amylase is denatured in the stomach, so its overall contribution is limited

• Main site of α-amylase action is the small intestine (pancreatic α-amylase)

• Both salivary and pancreatic α-amylases hydrolyze 1,4 α-linkages

• They spare 1,6 α-linkages and terminal 1,4 α-linkages

Major sites for sugar and amino acid absorption

Primarily in the upper and mid-small intestine (Jejunum).

Absorption site for Vitamin B12 and Bile acids

Specifically in the lower small intestine (Ileum).

Carbohydrate absorption limit

They can only be absorbed in the form of monosaccharides.

Alpha-amylase function

Hydrolyzes 1,4 alpha-linkages in starch but spares 1,6 linkages, resulting in oligosaccharides.

Brush-border enzymes for carbohydrates

• Isomaltase (hydrolyzes 1,6 linkages)

• Sucrase (hydrolyzes sucrose into glucose and fructose)

• Lactase (cleaves lactose into glucose and galactose)

• Trehalase (hydrolyzes trehalose into two glucose molecules).

How is glucose uptake regulated in different cell types, and what is special about GLUT4?

• Many cells (including skeletal muscle) have glucose transporters to pump glucose into the cell

• Most of these glucose transporters are not regulated by insulin

• GLUT4 is expressed in skeletal muscle and adipocytes

• GLUT4 is highly regulated by insulin

What is malabsorption (maldigestion) of carbohydrates and what are its types?

• Malabsorption (maldigestion) of carbohydrates can be primary or secondary

• Primary:

  • Caused by genetically determined enzyme deficiency

  • Intestinal ultrastructure remains unaffected

• Secondary:

  • Caused by environmental agents (e.g. bacteria, viruses, toxic food, allergens)

  • Leads to changes in normal mucosal morphology

SGLT-1 transporter mechanism

A sodium-dependent symporter that uses the electrochemical gradient of 2 sodium ions to pull 1 glucose or galactose into the cell.

GLUT5 transporter function

A carrier protein dedicated to the facilitated diffusion of fructose.

GLUT2 transporter function

Located on the basolateral membrane to allow glucose, galactose, and fructose to enter the blood.

Lactose intolerance mechanism

Undigested lactose draws water into the gut via osmosis and is fermented by bacteria into gas.

• Note: Lactose intolerant people must ensure adequate calcium intake.

What is glucose-galactose malabsorption?

• Rare inherited disorder

• Caused by a defect in the Na⁺-dependent glucose carrier of the brush border membrane

How much protein is ingested and produced endogenously per day?

• Dietary intake: approximately 70–100 g of protein per day

• Endogenous source: approximately 30–50 g of protein per day

  • From dead intestinal cells

  • From proteins secreted by the gastrointestinal system

What is the role of enteropeptidase in protein digestion and what happens if it is defective or the duodenum is removed?

• Enteropeptidase is mainly expressed in the duodenum

• It activates trypsinogen, enabling trypsin formation and thus protein digestion

• Mutations in enteropeptidase cause severe protein absorption defects

• Removal of the duodenum strongly impairs protein digestion

How are amino acids absorbed and transported across enterocytes?

• Amino acids are imported via several different symporters and antiporters

• On the basolateral side of enterocytes, amino acids are released into the blood

• This release occurs via sodium-dependent transporters