The Gastrointestinal System (消化系統)

台北醫學大學醫學系生理學科蔡麗雪教授 (Li-Hsueh Tsai, PhD) E-mail: [email protected] 27361661-3181

1 References:

¾ Guyton : Human Physiology and Mechanisms of Disease (16th edition) ¾ Ganong : Review of medical Physiology (22 edition) ¾ William J. German and Cindy L. Stanfield: Principles of Human Physiology (Third edition) ¾ Sherwood L: Human Physiology-From Cells to Systems (Seventh edition).

2 Chapter Outline I. Overview of the gastrointestinal (GI) system II. General Principles of GI Regulation Neural regulation Hormonal regulation III. Functional Anatomy of the Gastrointestinal System (secretion, disgestion, absorption) 1. Mouth, pharynx, and esophagus 2. Stomach 3. Pancreas 4. Liver 5. Small intestine 6. Large intestine 3 Overview of Gastrointestinal System

4 Gastrointestinal System

5 Accessory Glands Secrete products into lumen of digestive tract

– Salivary glands • Saliva – Pancreas • Pancreatic juice – Liver • Bile

6 Sphincter Locations

7 Sphincters of GI Tract

• Consider as traffic control devices • Total of seven – Upper and lower esophageal sphincters – Pyloric sphincter – Sphincter of Oddi - common bile duct entry into duodenum – Ileocecal – Internal and external anal sphincters - think how much you appreciate these! • Resting tone is > in segments above & below

8 9 Digestive System

• Primary function – Transfer nutrients, water, and electrolytes from ingested food into body’s internal environment • Four functions – Motility – Secretion – Digestion

– Absorption 10 General Principles of GI Regulation

11 General Principles of GI Regulation

– Neural and endocrine pathways of gastrointestinal control – Regulation of food intake

12 Wall of GI Tract

13 General Principles of GI Regulation

•Neural Control (神經的控制)

•Gastrointestinal peptides

14 What is the enteric nervous system?

15 Neural Control A. Enteric Neurons Myenteric plexus (腸間肌神經叢) Submucosal plexus (黏膜下神經叢) B. Autonomic Nervous System (自主神經之控制)

16 The Enteric Nervous System

17 Parasympathetic n.s Sympathetic n.s.

Vagal nuclei CNS Preganglionic fibres Preganglionic fibres Sacral spinal cord Sympathetic ganglia Postganglionic fibres

Enteric nervous system

Myenteric Submucosal plexus plexus

Smooth Secretory Endocrine Blood muscle cells cells vessels

18 Gastrointestinal Peptides

19 20 Neurocrines

NO ACh Norepinephrine GRP (bombesin)

Gastrin Releasing Peptide

21 Paracrines

22 23 Hormone

24 Gastrointestinal peptides

25 26 Gastrin family

27 Gastrin 胃泌素 (G cell) 90% in antral tissue 10% in duodenum

G34, G17, G14

28 Cholecystokinin-Pancreozymin (CCK)

膽囊收縮素 (I cell)

29 Digestion - fat in duodenum stimulates CCK release from I cells

FAT CCK

Gall bladder contraction BILE

Sphincter of Oddi relaxes30 Cholecystokinin stomach duodenum CCK I cells

Peptides Amino acids,H+ Fat pancreas

Enzymes

31 32 Secretin family

33 Secretin (S cell) ;腸泌素

In 1902, Bayliss and Starling

34 35 Secretin

Fat H+

S cells - HCO3

Secretin 36 In fasting state Liver Bile stored in gall bladder& concentrated Aqueous secretion

- from duct epithelium HCO3 - rich in HCO3 and stim. by secretin

- HCO3 Cl- Na+ H O 2 Sphincter of Oddi Fluid & electrolytes (closed) absorbed by active 37 transport of Na+ GIP (Glucose-dependent insulinotropic polypeptide) K cell

38 Gastric Inhibitory Peptide 葡萄糖倚賴型胰島素控制胜肽 • Inhibits emptying of the stomach when fats and large amounts of sugar are present • K cells in duodenum and jejunum • Potentiates insulin release and increases anabolic activity in fat cells

39 40 41 Functional Anatomy of the Gastrointestinal System

42 Gastrointestinal motility and its regulation

43 Slow wave 0

Membrane Membrane potential (mV) -60 Tension

Acetylcholine 0

Membrane Membrane potential (mV) -60

Tension 44 The contraction of smooth muscle : Syncytium

Spikes potentials

45 46 Receptive Relaxation of Stomach

Swallowing center also initiates relaxation of stomach smooth muscle as it prepares for receipt of bolus

47 Law of the Gut smooth muscle relaxation downstream (anally) = receptive relaxation

48 MOUTH & ESOPHAGUS

49 Salivary Glands

– Saliva • Bicarbonate • Mucus • Salivary amylase • Lysozyme

50 唾液的分泌

Sublingual gland (舌下腺)

51 • Saliva

– Produced largely by three major pairs of salivary glands – Composition

• 99.5% H2O • 0.5% electrolytes and protein (amylase, mucus, lysozyme) – Functions • Salivary amylase begins digestion of carbohydrates • Facilitates swallowing by moistening food • Mucus provides lubrication • Antibacterial action – Lysozyme destroys bacteria – Saliva rinses away material that could serve as food source for bacteria • Solvent for molecules that stimulate taste buds • Aids speech by facilitating movements of lips and tongue • Helps keep mouth and teeth clean 52 • Rich in bicarbonate buffers Control of Salivary Secretion

53 食道

54 Pharynx and Esophagus

• Swallowing

– Motility associated with pharynx and esophagus – Sequentially programmed all-or-none reflex – Initiated when bolus is voluntarily forced by tongue to rear of mouth into pharynx – Most complex reflex in body – Can be initiated voluntarily but cannot be stopped once it has begun – Process divided into two stages • Oropharyngeal stage • Esophageal stage (moves bolus from mouth through pharynx and into esophagus) 55 Stomach

(胃)

56 Stomach

57 Gastric Motility • Four aspects – Filling • Involves receptive relaxation – Enhances stomach’s ability to accommodate the extra volume of food with little rise in stomach pressure – Triggered by act of eating – Mediated by vagus nerve –Storage • Takes place in body of stomach –Mixing • Takes place in antrum of stomach –Emptying • Largely controlled by factors in duodenum 58 Gastric Emptying • Factors in stomach – Amount of chyme in stomach is main factor that influences strength of contraction • Factors in duodenum –Fat • Fat digestion and absorption takes place only within lumen of small intestine • When fat is already in duodenum, further gastric emptying of additional fatty stomach contents is prevented –Acid • Unneutralized acid in duodenum inhibits further emptying of acidic gastric contents until neutralization can be accomplished – Hypertonicity • Gastric emptying is reflexly inhibited when osmolarity of duodenal contents starts to rise – Distension • Too much chyme in duodenum inhibits emptying of even more gastric contents 59 Gastric Emptying • Factors trigger either – Neural response • Mediated through both intrinsic nerve plexuses (short reflex) and autonomic nerves (long reflex) • Collectively called enterogastric reflex – Hormonal response • Involves release of hormones from duodenal mucosa collectively known as enterogastrones – Secretin – Cholecystokinin (CCK) • Additional factors that that influence gastric motility – Emotions • Sadness and fear – tend to decrease motility • Anger and aggression – tend to increase motility – Intense pain – tends to inhibit motility 60 Gastric Motility

– Functions • Mix chyme • Regulate gastric emptying – Mechanism • Segmentation • Peristalsis Coordinated by enteric nervous system

61 Migrating Motility Complex

– Wave of intense contractions – Travel short distances – Occur between meals to clear stomach

62 胃酸之成分

(Pepsinogen)

63 Oxyntic Gastric mucosa pit

Mucosa

Stomach lumen

Pyloric gland area Submucosa

64 In oxyntic mucosa In pyloric gland area

Surface epithelial cells

Gastric pit Mucosa cells

Gastric G cells gland Chief cells

D cells

Parietal cells

Enterochomaffin- like (ECL) cells 65 Autocatalysis PepsinogenPage 16.11 Pepsin Digestion Page 611Protein Peptide fragments Gastric HCI lumen

66 Stomach acid

67 Parietal cell

Acid production by the parietal cells in the stomach depends on the generation of carbonic acid; subsequent movement of hydrogen ions into the gastric lumen results from primary active transport. 68 1988 Nobel Prize

Cimetidine and propranolol 69 ECL Cells

• Enterochomaffin-like cells

70 One inhibitory and three stimulatory signals that alter acid secretion by parietal cells in the stomach.

71 72 73 74 Regulation of Gastric Secretion

1. Cephalic Phase 2. Gastric Phase 3. Intestinal Phase

75 1. Cephalic Phase 1883 –Beaumont Martin Ivan Paulov (1904 Nobel Prize)

2. Gastric Phase Heindenhain pouch Ivy 3. Intestinal Phase Ivy 76 What Is Helicobacter pylori?

1983, Western Australia

Robin Warren and Barry Marshall

UBT (urea breath test) C13 or C14

CO2 NH3 77 The Nobel Prize in Physiology or Medicine 2005

Barry J. Marshall J. Robin Warren

78 Peptic ulcer (消化性潰瘍）

Risk Factors and Contributing Factors

1. Genetic Factors 2. Psychological Stress 3. NSAIDs (nonsteroidal anti-inflammatory drugs) such as aspirin and ibuprofen. 4. Cigarette smoking 5. Breverages Foods such as caffeine 6. Ethanol

79 Drug treatment

a. antacid drug: Al(OH)3 , Mg(OH)2 , NaHCO3. b. anticholinergic drug : atropine;

H2 blocker: cimetidine, ranitidine c. H+-K+-ATPase inhibitor: omeprazole d. antibiotics

80 Pancreas (胰臟)

81 82 Normal Human Pancreatic Juice

• Cations: Na+, K+, Ca2+, Mg2+ (pH approximately 8.0) - - 2- 2- • Anions: HCO3 , Cl , SO4 , HPO4 • Digestive enzymes (95% proteins in juice) • Other proteins

83 Pancreas – Exocrine and endocrine gland – Pancreatic juice • Bicarbonate • Pancreatic amylase • Pancreatic lipases • Proteases • Nucleases

84 What are zymogens, and why are they present in the pancreas?

85 Zymogens Inactive forms of digestive enzymes

– Stored in zymogen granules of acinar cells – Activated, usually by proteolytic enzymes, in lumen of intestinal tract

86 Pancreatic secretion

- secretion in 3 phases Cephalic phase - only 10-15% of total secretion activation of vagal efferents stimulates enzyme release Gastric phase - only present in some species NOT SIGNIFICANT IN HUMANS Intestinal phase - majority of secretion combination of hormones CCK and secretin results in maximal enzyme and bicarbonate release

87 Enzymes in pancreatic juice Enterokinase= Enteropeptidase Enzyme Zymogen Activator Action

Trypsin Trysinogen Enterokinasee Cleaves internal peptide bonds

Chymotrypsin Chymotrypsinogen Trypsin Cleaves internal peptide bonds

Elastase Proelastase Trypsin Cleaves internal peptide bonds

Carboxypeptidase Procarcoxypeptidase Trypsin Cleaves last amino acid from carboxyterminal end of polypeptide

Phospholipase A2 Prophospholipase A2 Trypsin Cleaves fatty acids from phospholipids such as lecithin88 Enzymes in pancreatic juice

Enzyme Zymogen Activator Action

Lipase None None Digests fat to fatty acids and glycerol Amylase None None Digests starch to maltose and short chains of glucose molecules Cholestrolesterase None None Releases cholesterol from its bonds with other molecules Ribonuclease None None Cleaves RNA from short chains Deoxyribonuclease None None Cleaves DNA from short chains

89 Prevention of Pancreatic Self-digestion

• Digestive enzymes - made in zymogen or precursor form, require activation • Are activated by trypsin • Trypsin activator is enterokinase • Enterokinase is physically separate from pancreas - on brush border of enterocytes • Just-in-case - pancreas also makes a trypsin inhibitor

90 Liver & Bile Secretion (肝臟及膽汁)

91 Liver

• Largest and most important metabolic organ in the body • Body’s major biochemical factory • Importance to digestive system – secretion of bile salts

92 Liver

• Functions not related to digestion – Metabolic processing of the major categories of nutrients – Detoxifying or degrading body wastes and hormones, drugs, and other foreign compounds – Synthesizes plasma proteins – Stores glycogen, fats, iron, copper, and many vitamins – Activates vitamin D – Removes bacteria and worn-out red blood cells

– Excretes cholesterol and bilirubin 93 94 95 Biliary System Liver, gallbladder, and associated ducts – Joins with pancreatic duct to form Ampulla of Vater – Sphincter of Oddi • Regulates flow from pancreas and gallbladder to duodenum

96 Bile

1. Emulsifying function 2. formation of micelles in lipid digestion

97 Small Intestine (小腸)

98 Small Intestine

• About 5 m in length • Chyme takes 2 - 4 hours to traverse • Initial 5 % is duodenum • Next 40 % is jejunum • Last 55 % is ileum • Amost all digestion, most nutrient absorption, fluid & electrolyte occur here

99 Small Intestine • Segmentation – initiated by pacemaker cells in small intestine which produce basic electrical rhythm (BER) – Circular smooth muscle responsiveness is influenced by distension of intestine, gastrin, and extrinsic nerve activity – Functions • Mixing chyme with digestive juices secreted into small intestine lumen • Exposing all chyme to absorptive surfaces of small intestine mucosa • Migrating motility complex – Sweeps intestines clean between meals 100 101 102 103 lysozyme kills bacteria enterokinase 104 Secretions into the lumen- aqueous

Absorption of nutrients and secretion occurs at brush border in mature enterocytes

Secretion moves up and out of the crypts, mixes with chyme and washes over the villi into the lumen.

Water and electrolyte secretion from undifferentiated enterocytes in the bottom of crypts. 105 Small Intestine

• Secretion – Juice secreted by small intestine does not contain any digestive enzymes – Synthesized enzymes act within brush-border membrane of epithelial cells • Enterokinase • Disaccharidases • aminopeptidases

106 = enterokinase

107 Small Intestine

• Digestion – Pancreatic enzymes continue carbohydrate and protein – Brush-border enzymes complete digestion of carbohydrates and protein – Fat is digested entirely within small intestine lumen by pancreatic lipase

108 Small Intestine

• Absorption – Absorbs almost everything presented to it – Most occurs in duodenum and jejunum – Adaptations that increase small intestine’s surface area • Inner surface has permanent circular folds • Microscopic finger-like projections called villi • Brush border (microvilli) arise from luminal surface of epithelial cells – Lining is replaced about every three days – Products of fat digestion undergo transformations that enable them to be passively absorbed • Eventually enter lymph

109 Carbohydrate

– Only monosaccharides absorbed – Disaccharides and polysaccharides must be digested to monosaccharides

110 Category of foodstuffs Intermediate End Products Breakdown of Digestion of Products Absorbable Units

Carbohydrates Monosaccharides Polysaccharides (starch and glycogens) Maltose (glucose, galactose, fructose)

Amylase Maltase Disaccharides Sucrose

Sucrase

Lactose

Lactase

111 SGLT1

GLUT2

112 Protein

113 114 Lumen

Na+-and energy- dependent absorption

Energy required

Epithelial cell of villus Capillary 115 Absorption of Amino Acids

– Cross apical membrane by sodium-linked secondary active transport or facilitated diffusion – Cross basolateral membrane by facilitated diffusion

116 Absorption of Dipeptides, and Tripeptides

– Cross apical membrane by active transport – Broken down inside cell to amino acids – Amino acids cross basolateral membrane by facilitated diffusion

117 Fat

118 Lipid Digestion

– Enzymes of digestion = lipases – Secreted from pancreas – Lipases can only act on molecules near edge of fat droplet – Bile salts increase surface area of droplets by breaking large droplet into several small droplets = emulsification

119 Bile Salts

– Synthesized in liver from cholesterol – Secreted in bile to duodenum – Amphipathic molecule – Emulsify fat

120 121 lipase

Micelles - 20-40 polar bile salt 3-6nm molecules diameter dissolve micelle monoglycerides and fatty acids

Fat absorption into enterocytes by

diffusion 122 Micelles 微膠粒 Chylomicron 乳糜微粒

123 Recycling Bile Salts: Enterohepatic Circulation

124 Absorption of Vitamins – Fat-soluble vitamins (A, D, E, and K) • Absorbed with lipids • (dissolve in lipid droplets, micelles, chylomicrons) – Water-soluble vitamins • Require special transport proteins

– Vitamin B12 • Absorbed only when bound to intrinsic factor

125 126 127 128 129 New Ascending meal colon Gastrin

Ileocecal valve Ileocecal sphincter

Pushes valve open and relaxes sphincter Pushes valve closed and contracts Ileum sphincter

Cecum

Appendix 130 Large Intestine • Primarily a drying and storage organ • Consists of –Colon –Cecum – Appendix – Rectum • Contents received from small intestine consists of indigestible food residues, unabsorbed biliary components, and remaining fluid • Colon – Extracts more water and salt from contents

– Feces – what remains to be eliminated 131 Large intestine

132 133 134 Motility in Colon

– Purpose: mix and propel – Haustrations: mix • Proximal colon • Like segmentation, but slower

135 Motility in Colon

– Mass Movement: propel • Similar to peristalsis • Contraction lasts longer than relaxation • Move bolus toward rectum

• The contraction : more forces about 30 seconds • The relaxation : 2-3 min • Persists 10-30 minutes

136 Regulation of Motility in Colon

– Colonocolonic reflex: : • Distension of colon in one area causes relaxation of other areas of colon – Gastrocolic reflex ；Duodenocolic reflex • Food in stomach (duodenocolic) increases colonic motility

137 Defecation (排便)

138 Defecation

Voluntary and involuntary control Distension of colon

Stretch receptors

Rectum smooth muscle contracts

Increase pressure in rectum

Internal anal sphincter relaxes Both sphincters relax External anal sphincter contracts

Defecation139 Reflexes Composition of the Feces

• ¾water • ¼ solid matter 30% dead bacteria 10-20% fat 10-20% inorganic matter 2-3% protein 30% undigested roughage

140 141 Summary

142