Digestive Systems II

Cellular and Organ Physiology: Digestive Systems II

Course Details

Course Name: BIO 203
Instructor: Dr. Robert Watson
Institution: Stony Brook University

Learning Objectives

Describe the anatomy of the stomach - Cell Types of Gastric Glands: Identify and explain their functions in digestion.
- Parietal Cells: Describe their role in secreting hydrochloric acid (HCl).
  - Mechanism of HCl Secretion: Explain the detailed process involving ion pumps and channels.
- HCl and Pepsin: Discuss their roles in protein digestion and their activation.
- Diseases: Discuss peptic ulcer disease and gastroesophageal reflux disease (GERD), including treatment.
Describe the anatomical organization of the small intestine.
Discuss the role of the exocrine pancreas in food digestion and zymogen activation.
Discuss the liver, gall bladder, and bile's role in the digestion and absorption of lipids, including chylomicron formation and transport routes.
Explain the importance of the hepatic portal system and the liver in detoxification.
Describe absorption mechanisms for carbohydrates and amino acids, highlighting specific transporters.
Discuss water absorption by small and large intestines, distinguishing mechanism and capacity, and consequences of imbalance.
Discuss regulation of digestive processes by hormones: GLP-1, gastrin, secretin, and cholecystokinin.

The Human Alimentary Canal

Components: Oral cavity, salivary glands, esophagus, stomach, small intestine, large intestine, liver, gallbladder, pancreas, and rectum.
- Food Bolus Formation (Recap): Chewing food mixed with saliva (mucins for stickiness), salivary amylase begins polysaccharide breakdown.
- Deglutition (Swallowing) Reflex: Initiated by bolus against oral cavity; epiglottis protects trachea; peristaltic contractions move bolus to stomach.

Stomach Functions

Storage: Large distensible organ allows for temporary food storage; prevents constant eating; helps manage food influx to the small intestine.
Chemical Digestion: Initial digestion of proteins (major focus) and some lipids (via gastric lipase).
Mechanical Digestion: Breakdown of food particles occurs through muscular contractions (mixing contents).
Absorption: Absorbs hydrophobic substances and small polar molecules (e.g., ethanol). Not its primary function.
Defense: Low pH (acidic environment) kills many microbes, protecting against invasive pathogens. Thought to be the evolutionary primary function of acid secretion.

Stomach Anatomy

Regions: Antrum, pylorus (connects stomach to duodenum), fundus, and body.
Rugae: Foldings that primarily allow for distention and expansion to accommodate food; also increase surface area.
Histological Layers: Epithelium, lymph vessels, muscularis (including longitudinal, circular, and oblique smooth muscle layers for mechanical mixing; myenteric plexus), and mucosa layers.

Gastric Glands

Cell Types and Secretions:
- Mucous Neck Cell & Surface Mucous Cells: Secrete alkaline mucus (consisting of heavily glycosylated proteins and bicarbonate ion, providing mechanical and chemical defense against HCl).
- Parietal Cells: Secrete gastric acid (HCl) across the apical surface and bicarbonate ion across the basolateral surface (into circulation). Also secrete intrinsic factor.
- Enterochromaffin-like Cells: Secrete histamine.
- Chief Cells: Secrete pepsinogen (an inactive zymogen) and gastric lipase.
- D Cells: Secrete somatostatin.
- G Cells: Secrete gastrin (a peptide hormone, released into the circulatory system via the basolateral surface, endocrine function).
Mixed Glands: Have both exocrine (mucus, bicarbonate, HCl, pepsinogen) and endocrine components (gastrin).

Protein Digestion in the Stomach

Acidic Environment ( $pH \sim 1-2$ ):
- Disrupts extracellular matrices in food, denatures proteins (breaks electrostatic interactions and hydrogen bonds, linearizing protein to expose peptide bonds for enzyme access), increasing surface area for digestion.
- Kills microbes (defensive function).
Hydrochloric Acid Secretion (by Parietal Cells):
- Process:
 1. Bicarbonate ( $ext{HCO}3^-$ ) is produced within the cell via carbonic anhydrase from $ext{H}2 ext{O}$ and $ext{CO}2$ : $ext{H}2 ext{O} + ext{CO}2 ightleftharpoons ext{H}2 ext{CO}3 ightarrow ext{H}^+ + ext{HCO}3^-$
 2. Apical $H^+$ ions are actively transported into the lumen in exchange for $K^+$ ions by the $H^+/K^+-ATPase$ pump (a proton pump, not electrogenic, 1:1 exchange, requires ATP).
 3. Basolaterally, $ext{HCO}3^-$ is exchanged for $ext{Cl}^-$ (moving $ext{HCO}3^-$ into the blood, causing an 'alkaline tide', and importing $ext{Cl}^-$ ).
 4. Apical $ext{Cl}^-$ ions enter the lumen through a chloride channel.
 5. $H^+$ and $ext{Cl}^-$ combine in the lumen to form HCl.
 6. The basolaterally released $ext{HCO}_3^-$ enters the circulation and is later incorporated into the alkaline mucus produced by mucous cells.

Pepsin Activation and Function

Pepsinogen:
- An inactive zymogen released by Chief cells; contains a 44 amino acid inhibitory peptide.
- Converted to active pepsin in the acidic stomach environment.
- Low pH causes a slight conformational change in pepsinogen, allowing it to autocatalytically cleave its own inhibitory peptide to form active pepsin.
- Active pepsin then rapidly catalyzes the further activation of other pepsinogen molecules (positive feedback loop).
- Pepsinogen is an acid-stable enzyme that functions optimally at low pH; higher pH denatures it.

Gastric Juice Composition

Aqueous Mixture: Contains pepsin and acid, effectively digesting proteins due to:
- Denaturation of proteins by acid, exposing peptide bonds.
- Pepsin is highly active in low pH.
Protective Mechanisms for the Stomach:
- Alkaline Mucus Barrier: A thick layer of alkaline mucus (containing bicarbonate from parietal cells) neutralizes acid at epithelial cell surfaces and acts as a physical barrier against pepsin and acid.
- Constant Regeneration: Constant and rapid regeneration of epithelial cells (every 3 days) protects against acid and enzyme damage.
- Gastroesophageal reflux (GERD) and ulcers may result from excessive acid or compromised defense mechanisms.

Peptic Ulcer Disease and GERD

Ulcer Statistics:
- Approximately 70% of ulcers occur in the duodenum, 30% in the stomach (gastric ulcers).
- Mechanism: Occurs when defensive mechanisms (like alkaline mucus) are compromised, allowing stomach acid and pepsin to directly digest the stomach or duodenal wall, creating a wound. Transmural ulcers can erode through the wall, leaking contents into the body cavity.
GERD (Gastroesophageal Reflux Disease) Mechanism:
- Involvement of a dysfunctional lower esophageal sphincter, which allows acidic chyme (acid and enzymes) to reflux back into the esophagus.
- The esophagus is not protected from stomach acid like the stomach is, leading to a burning sensation (heartburn).
Treatment (Omeprazole/Prilosec):
- Omeprazole specifically blocks the $H^+/K^+-ATPase$ pump (proton pump) in parietal cells.
- It forms a covalent, permanent inhibition, requiring the cell to re-synthesize new pumps.
- Blocking the pump raises gastric juice pH to 5-6, directly inhibiting HCl secretion and indirectly inhibiting pepsin activation (as low pH is required for pepsinogen's autocatalytic cleavage) and activity. This allows ulcers to heal.

Small Intestine Functions

Overview: Major organ responsible for digestion and absorption ( $\sim 6$ meters in length).
- Site of enzymatic hydrolysis of macromolecules (chemical digestion).
- Main site of nutrient absorption (monomers), producing hormones.
- Receives acidic chyme from the stomach via the pyloric sphincter.
Surface Area Structures (3 layers of organization for enormous surface area):
- Plicae Circulares (circular folds): Large circular folds that increase surface area for absorption (unlike rugae, which are primarily for distention).
- Villi: Finger-like projections, enhancing absorption area and containing capillaries and lacteals.
- Microvilli: Microscopic projections on individual epithelial cells, forming a 'brush border', which further greatly increases surface area for absorption.

Small Intestine Organization

Sections:
- Duodenum ( $25 ext{ cm}$ ): Relatively short, an important entry point for acidic chyme from the stomach, bile from the liver/gallbladder, and pancreatic zymogens/bicarbonate. It needs protection from the arriving acidic contents.
- Jejunum ( $\sim 3$ meters): The largest segment and primary site for chemical digestion and nutrient absorption.
- Ileum ( $\sim 2$ meters): Further absorption of nutrients not absorbed in the jejunum; length varies among individuals. (Mnemonic: Dow Jones Industrial for order).
Histological Layers: Contains smooth muscle layers (longitudinal and circular) responsible for peristaltic contractions, orchestrated by the enteric nervous system.
Vascularization: Highly vascularized with blood vessels (capillaries for most nutrient absorption) and lymphatic vessels (lacteals for lipid absorption).
Peyer's Patches: Lymphoid tissue with immune function (gut-associated lymphoid tissue).
Villus and Crypt Structure:
- Villus: Finger-like projections containing a rich capillary network and a blind-ended lymphatic vessel called a lacteal (important for lipid absorption).
- Crypts: Invaginations (similar to gastric glands) containing stem cells (source for rapid epithelial cell turnover) and gland cells that produce hormones (released into interstitial compartment, then to circulation).
Enterocytes: Epithelial cells lining the intestine, possessing the microvilli (brush border).

Exocrine Pancreas Functions

Acinar Cells: These glandular cells produce the pancreatic secretions.
Secretions:
- Bicarbonate: Released into the duodenum via the pancreatic duct to neutralize acidic chyme from the stomach, raising pH to $7-8$ for optimal enzyme activity.
- Digestive Enzymes (Zymogens): Produced as inactive precursors to prevent autodigestion of the pancreas/ducts; transported via the pancreatic duct into the duodenum for activation.
  - Peptidases (e.g., trypsinogen, chymotrypsinogen): Digest proteins.
  - Nucleases: Hydrolyze DNA and RNA.
  - Amylases: Digest carbohydrates.
  - Lipases: Digest fats.
Zymogen Activation in Duodenum:
- Enteropeptidase: An enzyme anchored to the brush border of intestinal epithelial cells. It cleaves trypsinogen to active trypsin.
- Trypsin: Once formed, active trypsin then cleaves and activates other pancreatic zymogens (e.g., chymotrypsinogen to chymotrypsin), initiating a cascade of enzyme activation.

Liver and Gallbladder Functions

Bile Role in Digestion:
- Production and Storage: Bile is produced by hepatocytes in the liver and stored in the gallbladder.
- Composition: Contains bile salts (cholesterol + amino acids, forming amphipathic molecules), pigments, and cholesterol.
- Emulsification (Biological Detergent): Bile salts act as biological detergents. Their amphipathic nature allows them to break up large, hydrophobic fat droplets into smaller, more numerous micelles. This greatly increases the surface area for water-soluble digestive enzymes (lipases) to act on fats.
- Release: Released into the duodenum via the common bile duct upon hormonal stimulation (CCK). The Sphincter of Oddi controls this release.

Triglyceride Digestion and Absorption

Initial Problem: Ingested lipids form large droplets in the aqueous GI environment, limiting surface area for digestion.
Emulsification: Bile salts break these large droplets into smaller micelles (small lipid particles containing bile salts, phospholipids, triglycerides, monoglycerides, and cholesterol).
Mechanism of Enzymatic Breakdown: Pancreatic lipase and colipase convert triglycerides (within micelles) into 2-monoglycerides and free fatty acids by cleaving ester linkages.
Absorption Process into Intestinal Cells:
1. Monoglycerides and fatty acids (being hydrophobic enough) diffuse across the apical membrane into intestinal epithelial cells (enterocytes).
2. Inside the enterocytes, monoglycerides and free fatty acids are reassembled into triglycerides.
3. These triglycerides, along with cholesterol and some protein, are packaged into large lipoprotein particles called chylomicrons.
4. Chylomicrons are too large to directly enter the fenestrations of blood capillaries.
5. They are released from the enterocytes via exocytosis and enter the lacteals (blind-ended lymphatic vessels found in the villi). Lacteals have large gaps in their endothelial cells, allowing chylomicron entry.
6. Chylomicrons are transported via the lymphatic system, eventually entering the venous circulation (e.g., vena cava) and thus bypassing the liver initially.

Nutrient Absorption in the Small Intestine

Carbohydrates:
- Breakdown: Polysaccharides (starch, glycogen) are broken down into disaccharides by salivary and pancreatic amylase. Disaccharides are then broken down into monosaccharides (e.g., glucose, fructose, galactose) by brush border enzymes (e.g., lactase, sucrase).
- Monosaccharide Absorption (e.g., Glucose):
  - Across apical membrane: Glucose is absorbed into epithelial cells against its concentration gradient via the $SGLT1$ (sodium-glucose co-transporter 1) protein, which uses the electrochemical sodium gradient established by the basolateral $Na^+/K^+-ATPase$ pump.
  - Across basolateral membrane: Glucose diffuses out of the epithelial cell and into the capillary via $GLUT$ carrier proteins (facilitated diffusion) and is then swept into the circulatory system.
Amino Acids:
- Breakdown: Proteins are initially broken down into smaller peptides by endopeptidases (e.g., pepsin in stomach, trypsin, chymotrypsin from pancreas). These smaller peptides are then broken down into free amino acids by exopeptidases (e.g., aminopeptidases, carboxypeptidases) that cleave from the ends.
- Amino Acid Absorption: Absorbed primarily as free amino acids, but also some dipeptides and tripeptides.
  - Across apical membrane: Free amino acids are absorbed into epithelial cells via sodium-amino acid co-transporters, utilizing the sodium gradient.
  - Across basolateral membrane: Amino acids are transported into the capillaries via amino acid carrier proteins.
Post-Absorption Pathway (for most nutrients excluding chylomicrons): Monosaccharides and amino acids are absorbed into the capillaries of the intestine and are then carried by the hepatic portal vein directly to the liver, then into the systemic circulation.

Explain the importance of the hepatic portal system and the liver

Hepatic Portal System:
- An unusual anatomical organization involving two capillary beds in series: Capillaries of the intestine $\rightarrow$ Hepatic Portal Vein $\rightarrow$ Capillaries of the Liver.
- This system ensures that most absorbed nutrients (except chylomicrons) and any ingested toxins go directly to the liver first.
Liver Functions (Detoxification):
- The liver is rich in enzymes (e.g., cytochrome P450 enzymes) that modify and break down organic toxins ingested in the diet.
- Positioning the liver first in the circulatory path allows for detoxification of potentially harmful substances before they enter the general systemic circulation, protecting the body.

Water Absorption

Absorption Overview (Fluid Balance):
- Total fluid input into the GI lumen is approximately $9 ext{ L/day}$ ( $2 ext{ L}$ ingested, $7 ext{ L}$ secreted from salivary glands, stomach, pancreas, liver, intestine).
- Absorption occurs primarily in the small intestine ( $\sim 7.5 ext{ L}$ ) and in the large intestine ( $\sim 1.4 ext{ L}$ ), with only $\sim 0.1 ext{ L}$ excreted in feces.
- The small intestine has an enormous absorptive capacity ( $\sim 15 ext{ L/day}$ ).
Mechanism of Water Absorption:
- Water absorption follows sodium (osmosis), as sodium is actively transported.
- Basolateral $Na^+/K^+-ATPase$ pumps sodium out of epithelial cells, creating a sodium gradient.
- Apical sodium entry occurs via various mechanisms (channels, co-transporters, antiporters).
- Water moves across the intestinal epithelium primarily through paracellular transport (between cells), not via aquaporins (a key difference from renal water absorption).
Clinical Relevance:
- Diarrhea: Results from too much water being passed into the large intestine, often due to impaired absorption in the small intestine.
- Constipation: Results from insufficient water in the large intestine, leading to hardened feces.
- Hyponatremia (Water Toxicity): Consuming excessive amounts of water ( $\sim 1.7 ext{ gallons}$ at once) can dilute blood sodium and other key electrolytes, leading to serious health consequences.
  - Dilution causes water to move into cells by osmosis, including brain cells.
  - Brain swelling is dangerous due to the rigid skull, leading to increased intracranial pressure, coma, and potentially death.

Regulation of Digestive Processes by Hormones

Overview: The GI tract produces approximately 20 different peptide hormones that regulate digestive functions.
GLP-1 (Glucagon-like Peptide 1):
- Production: Produced by intestinal L cells in response to the presence of food.
- Actions:
  - Promotes insulin release from pancreatic beta cells, helping to manage blood glucose levels (basis for Type 2 diabetes medications like Byetta).
  - Promotes satiety (feeling of fullness), which helps reduce food intake and can contribute to weight loss (basis for medications like Ozempic).
Gastrin:
- Production: Produced by G cells located at the bottom of gastric glands in the stomach.
- Stimulus: Presence of food (especially protein) in the stomach.
- Action: Enters the circulatory system (endocrine) and targets:
  - Parietal cells: Stimulates gastric acid (HCl) secretion.
  - Chief cells: Stimulates pepsinogen release.
- Outcome: Increased protein digestion in the stomach.
Secretin:
- Production: Produced by duodenal cells.
- Stimulus: Low pH (acidic chyme) arriving in the duodenum from the stomach.
- Action: Travels via circulation to the pancreas.
  - Pancreas: Stimulates the release of bicarbonate ion into the pancreatic duct.
- Outcome: Bicarbonate neutralizes the acidic chyme in the duodenum, protecting the intestinal lining and optimizing pH for intestinal enzymes.
CCK (Cholecystokinin):
- Production: Produced by intestinal cells.
- Stimulus: Presence of amino acids and fatty acids in the duodenum.
- Action: Travels via circulation and targets:
  - Gallbladder: Induces smooth muscle contraction, leading to bile release into the common bile duct and then the duodenum.
  - Pancreas: Stimulates the release of various digestive zymogens (proteases, lipases, amylases).
- Outcome: Enhanced digestion of fats (via emulsified bile) and proteins/carbohydrates (via pancreatic enzymes) in the small intestine.