PMCY 4020: Digestive System

Intro to Digestive System

• Macromolecules too large to cross intestinal epithelium so must be broken down into monomers to be absorbed (through HYDROLYSIS reactions)

  • Hydrolysis reactions: carbs are hydrophilic, lipids are hydrophobic and form large fat droplets (requires bile emulsification)

• Digestive enzymes confined to lumen of GI tract - avoid digesting your own tissues

• CLINICAL: pancreatitis - inflammation of pancreas due to premature activation of digestive enzymes → leads to autodigestion, abdominal pain, and tenderness

Digestive System: Important Concepts

• Lumen opens at both ends (mouth/anus) → continuous w/ environment

• Digestion occurs OUTSIDE the body → harsh environment

• Permit one-way transport: different regions of GI tract are specialized in different functions

• Indigestible materials pass from one end to the other w/o crossing epithelial lining of GI tract

• CLINICAL: Acute Oral Intoxications (activated charcoal to clean stomach)

  • Mechanism: porous form of carbon that binds toxins in GI tract to prevent absorption (toxin charcoal stays in gut and excreted)

  • Limitations: most effective within 1 hr of toxin ingestion, not effective for all substances, risk of vomiting and aspiration

Digestive System Parts

Two functional parts: tubular alimentary/gastrointestinal (GI) tract and accessory digestive organs

GI tract (30 ft): oral cavity, pharynx, esophagus, stomach, small intestine, large intestine, anus
Accessory digestive organs: teeth, tongue, salivary glands, liver, gallbladder, and pancreas

Digestion requires sufficient time of contact between food and active digestive enzymes

• Mastication and oral deglutition phase: secs to mins

  • Salivary amylase (active)

  • Lingual lipase (active, no bile)

• Pharyngeal: 1 sec

• Esophageal: 5 secs

• Stomach: hours

  • Salivary amylase (inactive)

  • Lingual lipase (active, no bile)

Layers of GI Tract

• 4 layers/tunics

  • Each layer contains a dominant tissue type that performs specific functions in the digestive system

  • Inner to outer: mucosa, submucosa, muscularis, serosa

layers not identical or complete in all regions of GI tract

Layer of GI Tract (Mucosa)

• Protection, digestion, and absorption

• Lines the lumen, contains villi and lacteals, has 3 sublayers:

• 1) Epithelium: adjacent cells sealed together by tight junctions w/ channels for selected ideas (can be 2 types)

  • Stratified squamous: mouth, esophagus, anus → protection against friction

  • Simple columnar: rest of GI tract → secretion of mucus and digestive enzymes

• 2) Lamina propria: thin layer of connective tissue contains lymph nodules and capillaries

• 3) Muscularis mucosae: thin layer of smooth muscle that moves the mucosa to enhance contact with contents

Layer of GI Tract (Submucosa)

• Structure, flexibility, and vessel supply

• Dense irregular connective tissue

• Highly vascular layer that serves the mucosa

• Absorbed molecules that pass through the columnar epithelium enter the blood and lymphatic vessels of the submucosa

• Contain the submucosal plexus (Meissner’s plexus), part of enteric nervous system that provides nerve supply to Muscularis mucosae

Layer of GI Tract (Muscularis)

• Major movements

• Composed of inner circular and outer longitudinal layers of smooth muscle

• Responsible for segmental contractions (pulverization and mixing) and peristallic movement (propelling)

• Myenteric plexus (Auerbach’s plexus) located b/w 2 muscle layers provides nerve supply

  • Includes fibers and ganglia from both sympathetic/parasympathetic systems

Layer of GI Tract (Serosa)

• Protection, structure, and lubrication

• Composed by a thin layer of loose connective tissue covered by simple squamous epithelium (mesothelium)

• Mesothelial cells are specialized to secrete watery (serous) fluid into peritoneal cavity

Oral Cavity

• Mechanical and chemical processing of food

• Formation of food bolus

• Teeth:

  • Incisors: sharp; cutting/slicing food

  • Canines: pointed; tearing/ripping food

  • Premolars/molars: flat surface; crushing/grinding food

• Tongue:

  • Moves food around for effective mastication (chewing) and to create food bolus (mix w/ saliva)

  • Pushes food toward oropharynx (voluntary phase of swallowing)

  • Ebner’s glands = secretion of lingual lipase → begins lipid digestion (very limited action)

• Salivary glands:

  • Parotid glands: produces 25% of saliva, watery and rich in salivary amylase (ptyalin) → starch digestion

  • Submandibular glands: produce 70% of saliva, mixed (watery and mucous) secretion

  • Sublingual glands: produce 5% of saliva, rich in mucins for thick/lubricating saliva

  • Tastants must be dissolved in saliva to interact w/ taste receptors

Mastication and Food Bolus

• Mechanical breakdown of food in mouth into small pieces, mixing w/ saliva to form soft food bolus reading for swallowing

• Food bolus: round mass to be swallowing

• Saliva composition:

  • Salivary amylase: starch digestion

  • Lingual lipase: fat digestion (limited)

  • Mucins: lubricate food

  • Lysozyme and IgA: antimicrobial defense

Pharynx and Esophagus

Transportation to right place

Pharynx:

• Connects nasal and oral cavities to larynx and esophagus

• 3 parts:

  • Nasopharynx: air only

  • Oropharynx and laryngopharynx (hypopharynx): air and food

Esophagus:

• Conduction tube that transport food and liquids from pharynx to stomach

• Esophageal peristalsis (involuntary):

  • Muscle contraction behind bolus

  • Muscle relaxation ahead of bolus to allow passage

  • Secondary peristalsis

• Peristaltic reflex:

  • Stretch receptors of sensory neurons in wall detect distension and send signals to myenteric plexus that coordinates movement

• Upper esophageal sphincter (UES) and lower esophageal sphincter (LES)

  • Contracted to prevent air from entering gastric reflux

  • Relax during swallowing

Swallowing/Deglutition

• 3 phases: oral, pharyngeal, and esophageal

• Oral phase = voluntary control

• Pharyngeal, esophageal = automatic, controlled by swallowing center in brain stem

• Receptors in posterior portion of oral cavity and oropharynx stimulate pharyngeal phase of swallowing reflex:

  • Soft palate lifts to close nasopharynx

  • Epiglottis covers windpipe

  • Upper esophageal sphincter relaxes

GI Tract - Stomach

Processes food with HCl and enzymes, forming chyme

• J shaped organ b/w esophagus and duodenum

• Functions: store food, digest proteins, kill pathogens w/ acidity of gastric juice, move food to small intestine as material called chyme

  • Chyme = semi-fluid very acidic mixture

• 3 layers:

  • Longitudinal muscle: propels contents forward toward duodenum

  • Circular muscle: mixes food w/ gastric juice

  • Oblique muscle: generates twisting force for grinding food

• Gastric rugae = visible folds of mucosa and submucosa that line inner stomach

  • Empty vs filled w/ food: great expansion capacity w/o rise in pressure

• Gastric pits = microscopic indentations in mucosal surface

  • Each pit leads to gastric glands that contain several types of cells to secrete different products

    • Chief cells: secrete pepsinogen (inactive precursor of pepsin) and produce gastric lipase

    • Parietal cells: secrete HCl (maintains stomach acidity, kills pathogens, activates pepsinogen into pepsin → begins protein digestion (partial))

      • Secrete intrinsic factor (glycoprotein), essential for vitamin B12 absorption

    • Mucous cells: secrete mucus (+bicarbonate) to protect gastric lining from pepsin and acidic environment

    • Enterochromaffin-like (ECL) cells: secrete histamine (stimulates HCl secretion from parietal cells) and serotonin (inc gut motility)

    • G cells: secrete hormone gastrin - acid secretion and gastric motility

    • D cells: secrete hormone somatostatin - inhibits acid secretion and motility

    • PD1 cells: secrete hormone ghrelin - stimulates appetite

  • Secretion of gastric cells together w/ large amounts of water form highly acidic solution known as GASTRIC JUICE

Parietal Cells HCl Secretion

• Specialized apical region

• High levels of carbonic anhydrase (CA)

• Basolateral membrances take in Cl- (bicarbonate leaves cell) that diffuses to lumen

• H+ secreted into gastric lumen by active transport using H+/K+ ATPase pumps

• Potassium recycling: K+ leaks out through K+ channels to prevent depletion in gastric lumen

Digestion in Stomach

• Proteins partially digested in stomach by pepsin

• Starch digestion begins in mouth w/ salivary amylase but enzyme becomes inactivated by strong acidity of gastric juice

• Bile salts not present in stomach to help w/ digestion of fats

GI Tract - Small Intestine

Extensive digestion and absorption of nutrients from chyme

Divided into duodenum, jejunum, and ileum

Components released:

• Pancreatic juice from pancreas:

  • Sodium bicarbonate to neutralize stomach acid

  • Several digestive enzymes: pancreatic amylase, trypsinogen, nucleases, pancreatic lipase → activated by enterokinases

• Bile salts produced in liver and stored in gallbladder:

  • Functions as detergents for fat emulsification

Brush border enzymes

• Enzymes located on membrane of microvilli in small intestine

• Not secreted into lumen, remain attached to plasma membrane

• Ex:

  • Peptidases -digest peptides into amino acids

  • Enterokinase/Enteropeptidase - activates trypsinogen into trypsin to digest peptides

  • Maltase, sucrase, and lactase - digest carbohydrates

• Enzyme and substrate must get in contact

Intestinal motility

• Slow - for proper digestion and absorption of nutrients

• Peristalsis much weaker in small intestine compared to esophagus/stomach

• Segmentation:

  • Alternating contractions of circular muscle segments at different sites

  • Contents pushed back and forth, creating local mixing w/o net forward movement

• Contractions of intestinal smooth muscle (automatic and rhythmic)

  • Rhythmicity generated by pacemaker cells known as interstitial cells of cajal (ICCs)

    • ICCs produce electrical “slow waves” that spread only short distance and must be regenerated by next pacemaker reigon

    • ANS modulates muscle depolarization

Fat Emulsification

• Lipases can only act on surface of fat droplets (not inside)

• Bile salts are amphipathic (hydrophilic/phobic) molecules - stabilize fat droplets in aq soln (surround them)

• Emulsification → large surface area

• Lipase digests triglycerides → monoglycerides and fatty acids which diffuse into epithelial cells

• Once absorbed, fatty acids recombine and mix with cholestrol and lipoproteins = chylomicrons (large)

  • Reassembled back into triglycerides and packaged

• Fat absorbed into intestinal lacteals (lymphatic vessels), not into blood capillaries (too tight for chylomicrons)

  • Lacteals have more permeable endothelium (special lymph vessels in intestine) and accepts large particles

Gallbladder Removed

Gallstones: solid particles formed from excess cholesterol and/or bilirubin in bile

• Severe abdominal pain and inc risk for infection

Intestine receives steady trickle of dilute bile rather than large bursts during meals

• Makes fat digestion less efficient, especially after large or fatty meals

• Deficiencies of fat-soluble vitamins

GI Tract - Large Intestine

Absorption of water and electrolytes from chyme

Divided into cecum, ascending colon, transverse colon, descending colon, sigmoid colon, rectum

Colon:

• Epithelium has transporters for Na, Cl, H2O

• Diarrhea vs constipation

• Gut microbiome/Microflora

  • Microorganisms w/ biomass greater than 1.5 kg

Rectum:

• Feces storage until elimination

• Stretch receptors in rectal walls detect distension from fecal mass and send signals to brain, initiating urge to defecate

Gut Microbiome/Microflora

Gut microorganisms:

• Produce vitamin K, some B, and short chain fatty acids (SCFAs)

• Break down dietary fibers that humans can’t digest (pectins, beta glucans)

• Compete w/ harmful bacteria

• Support immune system

When does microbiome form?

• At birth (delivery method dependent)

  • Vaginal birth: newborn immediately colonized by vaginal and intestinal microbes from mother

  • C-section: colonization comes mainly from skin and hospital environment microbes → altered metabolic and immune profiles

• Breastfeeding vs formula feeding

• Early childhood diet and exposure to pets, rural environments, and antibiotics affect microbial diversity and immune tolerance

• 0-3 years CRITICAL PERIOD

GI Tract - Anus

Defecation control

Controlled by 2 sphincters:

• Internal anal sphincter - involuntary, smooth muscle

• External anal sphincter - voluntary, skeletal muscle

• Ensures defecation when appropriate

Accessory Organ - Liver

• Heaviest internal organ, upper right abdomen

• Nutrient rich blood from gut passes through liver first → portal system

• Metabolization and detoxification of compounds

• Risk of liver damage

• Liver lobule - basic structural and functional unit of liver:

  • Hepatocytes: main functional cells → removes toxins, process medications, store nutrients, secrete bile salts

• Bile canaliculus → bile duct

• Other cells: Kupffer cells (immune system), stellate cells (vitamin A storage)

Core roles: metabolism, detoxification, exocrine secretion

1) Metabolism

• Stores glucose and releases when needed

• Synthesizes, breaks down, packages fats for transports

• Converts ammonia into urea

• Bilirubin metabolism

• Produces essential plasma proteins (albumin and most clotting factors)

2) Detoxification

• Uses CYP450 enzymes to modify drugs, toxins, hormones

• Converts nonpolar molecules into polar for kidney excretion (blood toxification)

• Kupffer cells clear pathogens and debris

3) Exocrine function

• Bile production

First-Pass Metabolism of Drugs

Orally taken drugs encounter CYP450

• Bioavaliability is fraction of administered drug dose that reaches the systemic circulation in an unchanged form

• Can be altered by liver diseases and enzyme inhibitors or inducers (drug interactions)

• Route of administration can bypass it (sublingual, transdermal, rectal, inhaled, IV, IM, SC)

Bile Production

• Made of bile pigment (bilirubin), bile salts, phospholipids, cholesterol, inorganic ions

• Essential for digestion of fats

Accessory Organ - Liver (2)

• Regenerative capacity

• Injury → hepatocytes re-enter cell cycle → divide to restore liver mass

• Require mass gained → proliferation stops (functional sufficiency and spatial constraints)

• Tumor removal, living-donor transplants

• Chronic injury leads to fibrosis and cirrhosis

  • Alcohol, hepatitis, toxins

  • Stellate cells transform into myofibroblast like cells: produce collagen and create scar tissue

Pancreas: Amphicrine Gland

Exocrine pancreas (98%): composed by acinar cells (amylases, proteases, lipases, nucleases) and ductal cells (bicarbonate)

Endocrine pancreas (2%): mainly alpha and beta cells → islets of langerhans

• Alpha cells (25%) secrete hormone glucagon → inc blood glucose

• Beta cells (70%) secrete hormone insulin → dec blood glucose

Cells Take Up Glucose

• Glucose requires GLUT transporters to enter cells

• Skeletal muscle and adipose tissue contain GLUT4: insulin-dependent

• Liver and pancreas use GLUT2: insulin-independent (allowing sensing of glucose)

• Brain and smooth muscle use GLUT 1/3: insulin-independent

Insulin

• Secreted in response to high blood glucose (after meals)

• Translocates GLUT4 transporters from cytoplasm to membrane of cells

• Promotes storage and anabolism

  • Glycogen synthesis

  • Inhibits hepatic glucose production (gluconeogenesis and glycogenolysis)

  • Stimulates fat storage (lipogenesis) and inhibits lipolysis in adipose tissue

Glucagon

• Secreted when glucose is low (fasting, sleeping)

• Raises blood glucose by mobilizing stored energy

  • inc glycogenolysis and gluconeogenesis

• 2 ways to regulate glucagon release:

  • In fed state, insulin suppresses alpha cells and when glucose drops, removal of inhibition of alpha cells

  • Over depolarization inhibits glucagon release

Clinical App: Diabetes Mellitus

• Disease where body does not produce enough amount of insulin or doesn’t respond normally to insulin

• Type 1 diabetes: destruction of pancreatic beta cells, insulin deficiency

• Type 2 diabetes: desensitization of insulin receptors

  • Accumulation of glucose in blood (hyperglycemia) while lacking in cells