Chapter 65, 66:

1. Chapter 65, 66: Digestion and Absorption in the Gastrointestinal Tract Slides by Thomas H. Adair, Ph.D.

2. Basis for Digestion - Hydrolysis • Digestion involves the breakdown or hydrolysis (addition of water) of nutrients to smaller molecules that can be absorbed in small intestine • Carbohydrates - monosaccharides • Proteins - small peptides and amino acids • Fats - 2-monoglycerides and fatty acids

3. Types of Digestion • Luminal or cavital digestion - • occurs in lumen of GI tract • enzymes from salivary glands, stomach, pancreas • pancreatic enzymes can do all • Membrane or contact digestion - • enzymes on brush border of enterocytes

4. Digestive Enzymes Intestinal Mucosa enterokinase sucrase maltase lactase trehalase -dextrinase (isomaltase) amino-oligopeptidase dipeptidase Salivary glands -amylase lingual lipase Stomach pepsin Pancreas amylase trypsin chymotrypsin carboxypeptidase elastase lipase-colipase phospholipase A2 cholesterol esterase

5. Anatomical Basis for Absorption • Total surface area of small intestine is 250 - 400 m2 • Small intestine - 4 m long • Folds of Kerckring - 3-fold • Villi - 10-fold • Microvilli - 1000-fold

6. Figure 65-5; Guyton & Hall

7. Figure 65-6; Guyton & Hall

8. Figure 65-7; Guyton & Hall

9. Life Cycle of S.I. Enterocytes • Villi house self-renewing population of epithelial cells with a 5-day turnover. • Cell types in villus include: secretory cells, endocrine cells, goblet cells, and mature absorptive epithelial cells. • Cells in enterocyte lineage divide and differentiate as they migrate up crypts, becoming mature absorptive cells. • Enterocytes are shed into lumen to become part of ingesta to be digested and absorbed.

10. Mechanisms of Absorption • Four mechanisms are important in transport of substances across intestinal cell membrane • Active Transport - - primary - secondary (co-transport, counter-transport) • Passive Diffusion • Facilitated Diffusion - carrier mediated • Endocytosis

11. Sodium Electrochemical Gradient • Single most important process in small intestine to make absorption of nutrients possible is establishment of electrochemical gradient of sodium across epithelial cell boundary of lumen (apical membrane).

12. Sites of Absorption • Stomach - ethanol, NSAIDs, aspirin • Duodenum and Jejunum - nutrients, vitamins, various ions, water and electrolytes • Ileum - bile salts and vitamin B12 • - major clinical significance • Colon - water and electrolytes • Rectum - drugs such as steroids and salicylates

13. Absorptive Pathway of Nutrients • A nutrient must cross 8 barriers to be absorbed by blood or lymph 1. Unstirred layer 2. Glycocalyx 3. Apical cell membrane 4. Cytoplasm of enterocyte 5. Basolateral cell membrane 6. Intercellular space 7. Basement membrane 8. Wall of capillary or lymph vessel

14. Digestion • Carbohydrates • Proteins • Fats

15. Digestion of Carbohydrates • Starch digestion - • Begins with -amylase in saliva (5% digestion in mouth, up to 40% in stomach) • Continues in small intestine with pancreatic amylase • Final digestion occurs at brush border • Lactose and sucrose - digestion only occurs at brush border

16. Digestion of Carbohydrates Starches - amylase (saliva) pancreatic amylase Sucrose Lactose Maltose + 3-9 glucose polymers Sucrase Lactase Maltase + -dextinase Fructose Galactose Glucose

17. Monosaccharides are Final Product • The final products of carbohydrate digestion are all monosaccharides, mostly glucose. 1 lactose 1 galactose 1 glucose 1 sucrose 1 fructose 1 glucose 1 maltose & Glu- polymers glucose 80% glucose 10% fructose 10% galactose

18. Absorption of Carbohydrates • Absorption is rate limiting step in carbohydrate assimilation • Glucose and galactose - secondary active transport • compete for membrane carrier (SGLUT-1) • energy from Na+-K+ ATPase • Fructose - facilitated diffusion (GLUT-5) • does not require energy • requires concentration gradient

19. Hexose Transporters • Two distinct groups of hexose transporters are classified based on energy dependence: • Transport hexoses down concentration gradient via facilitated diffusion. (GLUT1, GLUT2, GLUT3, GLUT4 and GLUT5). • Transport hexoses against concentration gradient using sodium electrochemical gradient via secondary active transport. (SGLUT1).

20. Abnormalities of Carbohydrate Assimilation • Lactose Intolerance - most common • Symptoms - abdominal cramps, bloating, diarrhea, and flatulence • Diagnosis - feed lactose - look for glucose in plasma • Cause - absence of brush border lactase • Lack of glucose / galactose carrier - rare • diagnosed at birth • feed fructose

21. Digestion of Proteins • Digestion of proteins to AA occurs in 3 locations - • -Intestinal lumen - • Stomach - pepsin (digests collagen) • Small intestine - endopeptidases - exopeptidases • - Brush border - oligopeptidases, dipeptidases • - Cytoplasm of mucosal cells - dipeptidases

22. Activation/Destruction of Proteases • Proteolytic enzymes are activated and destroyed very rapidly • Enterokinase activates trypsinogen • Trypsin is autocatalytic • Trypsin activates other proenzymes • Proteolytic enzymes digest themselves

23. Protein Digestion and Absorption • Luminal digestion produces 40% amino acids • and 60% small peptides - • Amino acids - - secondary active transport (Na+ dependent) - facilitated diffusion • Di- and Tri- peptides - - different carrier system than amino acids - absorbed faster than amino acids - hydrolyzed to amino acids in cytoplasm

24. Protein Digestion and Absorption Protein Pepsin Pancreatic proteases Di- and Tri- peptides Large peptides Free amino acids Carriers Peptidases Carriers Small amounts Dipeptides and tripeptides Amino acids Cytoplasmic peptidases Amino acids

25. Abnormalities of ProteinAssimilation • Pancreatic insufficiency - • pancreatitis or cystic fibrosis • decreased absorption - nitrogen in stool • Congenital absence of trypsin • no trypsin - no other proteolytic enzymes • protein malabsorption • Hartnup’s disease • cannot absorb neutral amino acids • neutral amino acids can still be absorbed as di- and tri- peptides

26. Assimilation of Lipids –Overall Scheme Triglyceride Duodenum Fatty acid 2-monoglyceride Enterocyte Triglyceride

27. Basic Steps of Lipid Assimilation • Most dietary lipid is neutral fat or triglyceride. Three main processes must occur for triglyceride to be absorbed into blood: • Emulsification - large aggregates of dietary triglyceride are broken down. • Enzymatic digestion - to yield monoglyceride and fatty acids. Both can diffuse into enterocyte. • Reconstitution of triglyceride and chylomicron formation

28. Assimilation of Lipids lipase-colipase Emulsified fat lecithin 2-MG FFA FOOD bile salts bile salts micelles (enterocyte) apoprotein + TG 2-MG FFA (micelles) 2-MG FFA TG chylomicrons lymph vessel

29. Summary of Lipid DigestionProducts 1 cholesterol-ester 1- cholesterol 1- FFA 1 phospholipid 1- lysolecithin 1- FFA 1- Triglyceride 1- 2-MG 2- FFA or 1- glycerol 3- FFA Chylomicron 90% triglyceride 7% phospholipid 2% cholesterol 1% protein

30. “Malabsorption” • Malabsorption as a general phenomenon is defined clinically in terms of fat malabsorption because fat can be measured easily in stool, unlike carbohydrates and proteins. • Motility disorders - moving through too rapidly • Digestion disorder - pancreatitis / cystic fibrosis - (not enough lipase) • Absorption disorder - tropical and nontropical sprue - resection of small intestine

31. Sprue • Diseases that result in decreased absorption even when food is well digested are often classified as “sprue” - - Nontropical sprue - also called celiac disease - allergic to gluten (wheat, rye) - destroys microvilli and sometimes villi - Tropical sprue - bacterium (?) - treated with antibacterial agents • Steatorrhea - if stool fat is in the form of FFA - digestion has occurred

32. Fluid and Electrolyte Absorptionand Secretion

33. Fluid Entering and Exiting the Gut Volume entering Volume absorbed 10 Diet (2) Duodenum and Jejunum (4) 8 Saliva (1) 6 Volume (L/day) Stomach (2) Ileum (3.5) 4 Bile (1) Volume Excreted 100-200 ml Pancreas (1) 2 S.I. (2) Colon (1.4) 0

34. Water Movement in Small Intestine • Water moves into or out of gut lumen by diffusion in accordance with osmotic forces - • Hypotonic chyme - water is absorbed • Hypertonic chyme - water enters intestine • Chyme is isosmotic with plasma except in colon. Stool water is hypertonic.

35. Sodium Absorption CausesWater Absorption • Sodium is absorbed by epithelial cells (enterocytes) of small intestine. • Sodium uptake creates negative electrical potential in gut lumen, that provides gradient for chloride uptake. • Water follows sodium and chloride in accordance with osmotic forces.

36. Salt Absorption in Small Intestine • Sodium is absorbed across apical cell membrane by 4 mechanisms - 1. Diffusion - through water-filled channels 2. Co-transport - with AA and glucose 3. Co-transport - with chloride 4. Counter-transport - in exchange for H+ • Chloride follows electrical gradient created by absorption of sodium

37. 3 4 2 1 Na+ Na+ Na+ S S Na+ Na+ Na+ P K+ K+ Na+ Cl- Cl- Na+ Na+ H+ Na+ H+ Cl- Cl- Sodium Absorption in Small Intestine Aldosterone increases Na+ reabsorption and K+ secretion in S.I. and colon.

38. Intestinal Sodium Balance • 15% of total body sodium is absorbed each day by intestine. • Diet - 5-8 g/day • S.I. secretion - 20-30 g/day • Intestinal absorption - 25-35 g/day • Excretion in feces - 0.1 g/day • Decreased absorption of sodium can lead to rapid sodium depletion and death.

39. Water Secretion by Small Intestine • Large quantities of water are secreted into lumen of small intestine during digestive process. • Two processes establish an osmotic gradient that pulls water into lumen of intestine: • Increased osmotic pressure resulting from digestion of foodstuffs • Crypt cells actively secrete electrolytes, leading to water secretion

40. Water Secretion by Crypt Cells • Water secretion by crypt cells is driven by chloride secretion: • The apical (lumenal) membrane contains a cyclic AMP-dependent chloride channel - “cystic fibrosis transmembrane conductance regulator” or CFTR. • When chloride exits cells through chloride channel, sodium and water follow • Mutations in gene for ion channel (CFTR) result in cystic fibrosis.

41. Na+ Na+ P K+ K+ Na+ Cl - Na+ Cl - Cl - cAMP Na+ H2 0 Na+ H2 0 Crypt Cell Secretion  cAMP activates Cl- channels  Na+ follows electrical gradient  H2O moves along osmotic gradient

42. Diarrhea • Diarrhea is the third leading cause of death by disease worldwide • 5-8 million children per year worldwide • 250,000 hospital visits in US • 8 million office visits in US

43. Common Causes of Diarrhea • Increased secretion and/or increased motility of large or small intestine. • Infectious diarrhea - viruses, bacteria, protozoa • Ulcerative colitis - • Drug related - • Psychogenic diarrhea -

44. Cholera (Vibrio cholerae) • Cause - cholera toxin stimulates secretion of water and electrolytes from crypt cells - lose 10 L or more fluid per day • Prognosis - untreated, 50% will die - treated, <1% will die • Treatment - oral rehydration solutions (glucose and electrolytes) - glucose facilitated absorption of sodium and water remains intact

45. Na+ Na+ P K+ K+ Na+ Cl - Na+ Cl - Cl - cAMP  Cholera toxin Na+ H2 0 Na+ H2 0 Crypt Cell Secretion cAMP activates Cl- channels  Na+ follows electrical gradient  H2O moves along osmotic gradient  Cholera toxin increases cAMP levels irreversibly