1. GI Physiology IV: Early Intestinal Phase of Digestion IDP/DPT GI Course, Fall 2011 Jerome W. Breslin, Ph.D. LSUHSC-NO Department of Physiology MEB 7208 (1901 Perdido St.) 568-2669 jbresl@lsuhsc.edu

2. Required Reading Kim Barrett, Gastrointestinal Physiology Chapter 5 - section on cellular basis of transport Chapter 9 Chapter 15 Chapter 16

3. Outline - Lecture 4 Quick review of some things from lecture 3 The Small Intestine & Early Intestinal Phase of Digestion Regulation: Secretin and Cholecystokinin Motility of the Small Intestine Intestinal Digestion and Absorption Proteins, Carbohydrates, Lipids Water Soluble Vitamins Water and Electrolytes

4. Video endoscopy has greatly enhanced our understanding of normal processes in the gut, and reveals complications resulting from disease. Figure 15-34

6. Intestinal Phase Initiated by entry of chyme from the stomach into the duodenum. Reflex response to distention, low pH, osmolarity, and various digestive products. Responses: Modification of osmolarity of chyme. Modification of luminal pH. Secretion of enzymes. Secretion of emulsifying agents. Regulated patterns of motility.

7. Delivery of acid and nutrients into the small intestine initiates signaling that slows gastric motility and secretion which allows adequate time for digestion and absorption in the duodenum. Figure 15-24 (CCK, Secretin)

8. The Small Intestine GI section between pyloric sphincter and ileal-cecal valve. 3 sections – duodenum, jejunum & ileum. Digestion, secretion and absorption all occur here. Final site of digestion. Neuro-hormonal regulation of both secretion and motility.

9. By projecting into the lumen, the villi increases the surface area for absorption of nutrients. Microvilli [aka brush border] fringe the villi to further increase surface area. nutrients Figure 15-7

12. Secretin’s receptors are found in the pancreas, which responds with additional bicarbonate delivery: gastric motility and secretion are inhibited. Figure 15-27 Secretin is secreted by the S Cells in the Crypts of Lieberkühn.

14. Cholecystokinin (CCK) stimulates the gallbladder, which responds by contracting and delivering more bile to the duodenum through the sphincter of Oddi, which relaxes (opens) in response to CCK. Figure 15-31 CCK is secreted by the intestinal mucosa.

16. Cholecystokinin’s receptors are located: in the pancreas, which responds with additional enzyme delivery in the gallbladder, which contracts to deliver more bile in the sphincter of Oddi, which relaxes to facilitate delivery of the enzymes and bile salts Figure 15-28

23. Intestinal Motility Intestinal motility is coordinated by the enteric nervous system and modified by long and short reflexes and hormones. During and shortly after a meal, intestinal contents are mixed by segmenting movements of the intestinal wall. After food is digested and absorbed, segmentation is replaced by peristalsis moving undigested material from small intestine into large intestine.

24. Fig 9-4 Barrett

25. SEGMENTATION/MIXING stationary contraction/relaxation cycles subdivision and mixing of chyme pacemaker cells generate basic electrical rhythm BER decreases along length of intestine duodenum 10-12/min Ileum 7-9/min slow migration toward large intestine Small Intestinal Motility

26. MIGRATING MYOELECTRIC COMPLEX Peristaltic activity that replaces segmentation at completion of absorption Repeated waves traveling about 2 feet Migrates down small intestine taking about 2 hr to reach large intestine Process repeated from beginning candidate hormone: motilin Small Intestinal Motility (continued)

27. Fasting Motor Pattern: “Migrating Myoelectric Complex” (MMC) From Stomach to the Ileum ~100 minute cycle: Phase I (~50 min) = quiescent Phase II (~40 min) = irregular contractions Phase III (5-10 min) = forward contractions

28. Regulation of MMCs is poorly understood: 1. Independent of vagus and splanchnic innervation 2. Phase III of the MMC is related to elevated plasma Motilin (secreted by M cells).

34. Just before vomiting, BER is suspended. Then, rapid burst of electrical activity moving in the oral direction.

35. Laxatives (Cathartics) cause increased spike potentials, and more forward contractions. In the above example, castor oil can act as a laxative vs. a control oil (triolein).

36. Intestinal Digestion Chyme mixed with secretions from pancreas, liver & duodenum. Secretions modify the pH, osmolarity, and continue the digestive process to make the digested material ready for absorption into the intestinal blood or lymphatic system. Type and volume of secretions depend on the constitution of the chyme.

37. Digestion in the Gut LUMINAL Mixing of chyme with enzymes BRUSH BORDER Specific enzymes present on the luminal surface of the enterocytes CYTOSOLIC/INTRACELLULAR Intracellular digestion in the enterocytes 3 SUB-PHASES OF INTESTINAL DIGESTION

39. Digestion in the Gut Proteins: All 3 phases, luminal, brush border and cytosolic digestion may be involved Carbohydrates: Only luminal and brush border digestion – no intracellular digestion by the enterocyte Lipids: All digestion is luminal; triglyceride is re- formed in the enterocyte!

40. Were digestive enzymes synthesized in their active form, they would digest the very cells that make them. Hence, inactive precursors (e.g., trypsinogen) become activated (trypsin). Figure 15-26

42. Absorption in the Gut Proteins: Active transport of amino acids and small peptides (< 5 amino acids). Carbohydrates: Uptake of monomers only Active transport of glucose; facilitated diffusion for other sugars. Lipids: Uptake of free fatty acids and glycerol. Mechanism of uptake by the enterocytes is probably diffusion.

43. Three sites of protein digestion: 1. Lumen 2. Brush Border 3. Cytoplasm PepT1

44. Short peptide uptake coupled to proton transport Barrett Fig. 15-8

45. Activation of Proteases in the Small Intestine Fig. 15-6

46. Protein Digestion Proteases stored in inactive form in pancreas & secreted in response to neurohormonal stimulation. Pancreatic trypsinogen converted to active form by duodenal brush-border enterokinase. Trypsin activates all other luminal peptidases. Digestion of oligopeptides in lumen and small peptides at brush border. Uptake of free amino acids, di- and tri- peptides by active transport mechanisms. Cytosolic degradation of di- and tri-peptides.

47. Amino Acids, Dipeptides, and Tripeptides are Absorbed by Specific Transporters. Barrett, Fig. 15-8 There are also many brush border transporters for individual amino acids. Cytoplasmic Peptidases

49. Carbohydrate Polysaccharides digested in duodenal lumen by pancreatic amylase to produce oligosaccharides and disaccharides. Brush border digestion of polymers by specific amylases and disaccharidases forms monosaccharides. Simple sugars taken up by active transport processes into enterocytes. NO uptake of disaccharides or oligosaccharides!

50. Carbohydrate Digestion & Absorption (continued) Sugars enter blood stream by facilitated diffusion or active transport mechanisms. Glucose in the intestinal lumen stimulates the release of GIP (Glucose dependent insulinotropic peptide or gastrointestinal inhibitory peptide). GIP stimulates the release of insulin from the pancreas in anticipation of glucose in the portal blood. GIP inhibits gastric motility to facilitate digestion and absorption from the GI tract.

51. Digestion of Carbohydrates Occurs in the Intestinal Lumen & at the Brush Border Berne & Levy Fig. 33-2

52. Monosaccharides are absorbed by specific transporters on the brush border membrane. Berne & Levy Fig. 33-2

53. 1. Sodium gradient for SGLT1 driven by Na + /K + ATPase. 2. Basolateral GLUT2 transports monosaccharides to the blood. Berne & Levy Fig. 33-4

56. Lipid Digestion & Absorption Lipid digestion in luminal phase only. Digestion requires bile salts, pancreatic lipase, co-lipase and phospholipids. Lipids emulsified by bile salts and phospholipids. Triglyceride digested to form free fatty acids and a monoglyceride. Digestion productions taken up by diffusion

57. A molecular model of a bile salt, with the cholesterol-derived “core” in yellow. A space-filling model of a bile salt. The non-polar surface helps emulsify fats, and the polar surface promotes water solubility. Figure 15-9

58. Bile salts and phospholipids convert large fat globules into smaller pieces with polar surfaces that inhibit reaggregation. Figure 15-10

59. Big Droplets of Fat Small Droplets of Fat Micelles Fatty Acids and Monoglycerides Chylomicron Assembly Distribution and Processing Figure 15-12

61. Emulsified fat globules are small enough that lipase enzymes gain access to degrade triglycerides to monoglycerides and fatty acids, which enter the absorptive cells by simple diffusion or aggregate to form loosely held micelles, which readily break down. Figure 15-11

62. Lipid Absorption Free fatty acids and monoglycerides reformed into triglycerides inside the enterocytes. Triglycerides packaged together with cholesterol and apo-lipoprotein molecules to form very large lipoproteins – CHYLOMICRONS. Chylomicrons secreted into lacteals – terminal of lymphatic system - enters systemic circulation in neck.

66. Water Soluble Vitamins Each has specific transporters (too many to mention) Vitamin B 12 : Requires Intrinsic Factor secreted by parietal cells in stomach. Pernicious Anemia: Caused by Vitamin B 12 deficiency secondary to Atrophic gastritis (chronic inflammation of stomach mucosa), or more specifically loss of parietal cells.

67. Intrinsic Factor is required for vitamin B 12 (cobalamin) uptake. Absorption is in terminal ileum. Fig. 15-9, Barrett

68. Water and Electrolyte Absorption in the Small Intestine Sodium absorption generally coupled to nutrient absorption (e.g. SGLT1, PEPT1). Electrogenic: forces anions (mainly chloride) to passively follow the sodium transport by paracellular route. Water transported passively, following osmotic gradients (favoring absorption).

69. Water balance in the GI tract. Barrett, Fig. 5-1

70. Chloride secretion in small intestine and colon. Barrett, Fig. 5-8

71. Cholera toxin binds and activates the Gs G- protein, causing elevated cAMP and increased Cl- secretion. Leads to secretory diarrhea. Fig. 5-9: cAMP regulates CFTR Fig. 5-4: Balance between absorption and secretion in health and secretory diarrhea. Immature cells in Crypts of Lieberkuhn

72. Bicarbonate secretion in the duodenum Fig. 5-10 in Barrett Neutralization of HCl from the stomach.

73. CFTR Cl - H2OH2O Na + K+K+ K+K+ 2Cl - ATP Na + GUT LUMEN K+K+ K+K+ BASOLATERAL AREA IMMATURE CELLS IN CRYPTS OF LIEBERKUHN Na + K+K+ ATP Na + H+H+ HCO 3 - Cl - H 2 CO 3 H 2 O + CO 2 CO 2 K+ MATURE ENTEROCYTES