Gastrointestinal Physiology

1. Gastrointestinal Physiology (5) REGULATION OF GI MOTILITY AND SECRETION • How different regions of GI Tract Respond to the Three Phases of Stimulation: the Cephalic Phase, the Gastric Phase, and the Intestinal Phase • Regulation ofGastric Secretion • Regulation ofPancreatic Secretion

2. Location of stimuli: Location of GI response: Cephalic phase: Sight, smell, thought saliva secretion  Emotion motility and secretion in the stomach Pain, fear Anger, anxiety, hostility motility and secretion in the small intestine motility and secretion in the large intestine motility/constipation motility/diarrhea

3. Location of stimuli: Location of GI response: Gastric phase: Distension of stomach peptides in stomach motility and secretion in the stomach Gastroileal reflex mediated by long neuroreflex and gastrin motility and secretion in the small intestine Gastrocolic reflex mediated by long neuroreflex and gastrin + CCK mass movement in the large intestine

4. Location of stimuli: Location of GI response: Intestinal phase: motility and secretion in the stomach Enterogastric reflexes Inside the lumen of the small intestine: • Distension • Fat digestives, peptides • Acid from the stomach • Hyperosmolarity? motility and secretion in the small intestine Gastrocolic reflex mediated by long neuroreflex and gastrin + CCK mass movement in the large intestine

5. 2. Regulation of Gastric Secretion Phase Stimulus Mechanism Gastric secretion Smell, taste, conditioning Long reflex (Vagus nerve)  30% Long reflex (Vagus nerve) gastrin Distention Peptides, aa  60% CCK Secretin Vagus nerve Small peptides, amino acids, fatty acids, H+  10% Phenylalanine Methionine tryptophan HCl and pepsinogen are actively secreted when the stomach prepares for and contains a meal. Once the meal has started to enter the intestine, feedback adjusts gastric secretion to maximize intestinal digestion and absorption.

6. Figure 64-7 Phases of gastric secretion and their regulation. Guyton p798

7. 3. Regulation of Pancreatic Secretion Phase Stimulus Mechanism Pancreatic secretion Smell, taste, conditioning Vagus nerve Enzymatic secretion Enzymatic secretion Distention Vagus nerve CCK Secretin Vagus nerve Both enzymatic and aqueous secretion Small peptides, amino acids, fatty acids, H+ 80% Phenylalanine Methionine tryptophan

8. Gastrointestinal Physiology (6) DIGESTION AND ABSORPTION • The Concepts of Digestion and Absorption • Digestion and Absorption of Carbohydrates • Digestion and Absorption of Proteins • Digestion and Absorption of Lipids • Digestion and Absorption of Vitamins • Absorption of Minerals

9. The Concepts of Digestion and Absorption • Digestion is the process of breaking down food into components that can be absorbed. Food is broken down mechanically and chemically. • Absorption is the movement of nutrients, salts, and water across the GI epithelium into blood or lymph.

10. Chemical Digestion and Nutrients Nutrients in food: Chemical digestion: Carbohydrates Proteins Lipids Nucleic Acids Vitamins Minerals Water monomers, dimers, trimers etc. hydrolysis polymers (enzymes) non-absorbable absorbable

11. chewing grinding peristalsis segmentation mechanical chemical digestion - Breakdown chemical bonds by enzymes food blood Absorbable nutrients absorption

12. Almost all the carbohydrates of the diet are either • large polysaccharides or disaccharides, which are combinations of monosaccharides bound to one another by condensation. • Almost the entire fat portion of the diet consists of triglycerides (neutral fats), which are combinations of three fatty acid molecules condensed • with a single glycerol molecule. • Proteins are formed from multiple amino acids that are bound together by peptide linkages.

13. 2. Digestion and Absorption of Carbohydrates a. Digestion of carbohydrates Begins in the mouth with salivary amylase. 5% Salivary amylase continues to work in the stomach until food is mixed with gastric juice and acidified (~1hour). Acid denatures amylase. 20-40% Continues in the small intestine with pancreatic amylase. Disaccharides are further digested to monosaccharides by the intestinal brush-border enzymes. 50-80%

14. Three major sources of carbohydrates in the normal human diet: Sucrose (cane sugar or table sugar) Lactose (milk sugar) Starches dissacharides Each hexagon represents a monomer: Green: glucose Blue: fructose Pink: galactose Starch polyssacharide Cellulose (in large amount. Human GI has no enzyme to digest it).

15. Maltoses (trehalase) Maltotrioses Limit dextrins Small branched fragments or oligosaccharides(3-8 glucose residues), salivary amylase pancreatic amylase Starch starch

16. Digestion of Carbohydrates in the Small Intestine Brush border enzymes: Glucose represents more than 80% of the final products of carbohydrate digestion. lactase, sucrase, maltase, α-dextrinase (Intestinal epithelial enzymes)

17. Digestion of carbohydrates.

18. b. Absorption of carbohydrates Driving force Na+-glucose cotransportation (Na+-dependent secondary active transport) facilitate diffuse facilitate diffuse

19. Absorptive Surface of the Small Intestinal Mucosa Villi Folds of kerckring + A villus + microvilli 600~1000-fold, ≥250 square meter, about the surface area of a tennis court

20. Lactose intolerance • Results from the absence of brush border lactase. • Inability to hydrolyze lactose • Lactose remains in the GI tract as a nonabsorbed solute. • H2O remains in the GI tract isosmotically and causes osmotic diarrhea.

21. LACTOSE INTOLERANCE • Failure to produce lactase • Undigested lactose enters the large intestine where it is fermented by the bacteria resulting in gases • Symptoms and signs include diarrhea, gas bloating, and abdominal cramps • Avoiding diary products is helpful • Supplemental lactase can be used

22. 3. Digestion and Absorption of Proteins a. Digestion of proteins 0% Mouth 10-20% Stomach Pepsin (function in acidic pH) 80-90% Upper Small Intestine (duodenum and jejunum)  Pancreatic proteases: Trypsinogen Chymotrypsinogen Procarboxypolypeptidase Proelastase • Brush border peptidases by enterocytes Aminopolipeptidase Dipeptidases  Peptidases inside enterocytes The products of proteins digestion: tripeptides, dipeptides, amino acids (absorbable forms)

23. Protein digestion in the stomach by pepsin: • Digestion of proteins begins in the stomach with pepsin secreted by chief cells. • Pepsin: only major digestive enzyme, maximally active at acidic pH (1-3). • Important feature of pepsin: ability to digest collagen (a protein affected little by other digestive enzymes). This is necessary process for digestive enzymes in the small intestine to penetrate meat.

24. (+)

25. b. Absorption of proteins The products of proteins digestion are: tripeptides, dipeptides, amino acids 140 mEq/L 14 mEq/L

26. Disorder of Proteins Digestion and Absorption Chronic pancreatitis Cystic fibrosis All pancreatic enzymes  Genetic disorder in which the transporter for cystine, lysine, arginine, ornithine absent in both the small intestine and kidney Cystinuria

27. DISORDERS OF PROTEIN DIGESTION AND ABSORPTION Acute/chronic pancreatitis • Results from inflammation or destructive autodigestion of pancreas • Pancreatic duct blockage causes loss of trypsin inhibitor and activation of proteolytic enzymes • Results in deficiency in pancreatic enzymes (including proteases), high serum amylase Cystic fibrosis • One of the most common life-shortening genetic diseases • Mutation of the gene, cystic fibrosis transmembrane conductance regulator, which is responsible for coding of a chloride ion channel important in creating sweat, digestive juices, and mucus. • Formation of a thick mucus substance in the lungs, intestines, pancreas, and liver • In the GIT: failure to secrete bicarbonate and water, decreased Na+ reabsorption,intestinal obstruction by thick mucus, pancreatic insufficiency, hepatic cirrhosis, steatorrhea,

28. 4. Digestion and Absorption of Lipids Triglycerides (neutral fats, abundant) Phospholipids Cholesterols and cholesterol esters Fats of the diet Emulsification In the stomach by the products of protein digestion In the small intestine by bile salts Digestion by enzymes Formation of micelles Absorption

29. oil water Segmentation in the small intestine = shaking the jar above emulsification

30. Fats are first broken up into smaller emulsification droplets bylecithinandbile salts (acids)in the bile. amphipathic

31. 2) When lipase digests fats, the products are twofatty acids(FFAs) and amonoglyceride.

32. 3) Bile salts coat these and other lipids and form droplets calledmicelles.

33. 4) Micelles release their lipids, which diffuse freely across the plasma membrane.

34. 5) Resynthesis of triglycerides. Coating with protein, forming droplets calledchylomicrons. SER Golgi apparatus Intestinal absorptive cell

35. 6) Chylomicrons are too large to enter blood capillaries and must be first transported in thelymphatic lacteal. exocytosis

36. Bile salts lipase & bile salts Fat globule emulsification droplets chylomicrons micelles Intestinal epithelial cells Intestinal lumen lacteal blood

37. Smooth ER Golgi apparatus “ferrying” function of micelle small quantities of short and medium chain fatty acids (more water soluble) are absorbed directly into the portal blood. When bile micelles abundant: 97% of the fat is absorbed. When bile micelles absent: 40-50% of the fat is absorbed. Apoproteins

39. Abnormalities of Lipid Digestion and Absorption Pancreatic insufficiency (chronic pancreatitis, cystic fibrosis) Acidity of duodenal contents Deficiency of bile salts Bacterial overgrowth Decreased intestinal cells for absorption (tropic sprue) Failure to synthesize apoproteins (abetalipoproteinemia) (e.g., Zollinger-Ellison syndrome) (ileal resection) (deconjugating bile salts) Steatorrhea, low plasma chylomicron levels Steatorrhea an excess of fat in the stools, foul smell stool Next

40. Bacteria overgrowth reduces the effectiveness of bile salts by deconjugating them. In other words, bacterial actions remove glycine and taurine from bile salts, converting them to bile acids. At intestinal pH, bile acids are primarily in the nonionized form (since their pKs are higher than intestinal pH); the nonionized form is lipid-soluble and readily absorbed by diffusion across the intestinal epithelial cells. For this reason, the bile acids are absorbed “too early” (before reaching the ileum), before micelle formation and lipid absorption is completed.

41. Enterohepatic Circulation of Bile Salts Cholesterol 7α-hydroxylase (rate-limiting enzyme) 94% diffuse active transport Na+-bile salt cotransporter Back

42. Tropical sprue • a malabsorption syndrome • progressive villi atrophy in the small intestine, profoundly affects intestinal absorptive function • Hypothesized etiology is that the disease is either initiated or sustained by a still-undefined infection. • develops in persons who reside or previously resided in certain regions of the tropics. The disease is endemic in India, Southeast Asia, Africa, the Philippines, and certain Caribbean islands (ie, Haiti, Puerto Rico, and Cuba) Back

43. CELIAC SPRUE (GLUTEN-SENSITIVE ENTEROPATHY) • A common disease, which involves a primary lesion of the intestinal mucosa • Is caused by the sensitivity of the small intestine to gluten – water soluble protein (present in wheat, barley, oats, etc,) • Gluten or products of its digestion interact with intestinal mucosa and cause its lesion (mechanism is not known) • Consequences • ↓ area available for reabsorption • ↓ production of intestinal digestive enzymes • Treatment: gluten-free diet

44. Where does this apoprotein come from? http://www.geocities.com/Heartland/Ridge/4839/triglycerides2.gif Absorptive state postabsorptive state (fasting)

45. A Summary of Digestion of Carbohydrates, Proteins and Lipids Lingual lipase Gastric lipase colipase

46. Exercise: fill in the red box with appropriate enzymes.

47. 5. Digestion and Absorption of Vitamins Fat-soluble vitamins: Vitamin A, D, E, K (via micelles and chylomicrons) B1 B2 B6 C Biotin Folic acid Nicotinic acid Pantothenic acid B12 Na+-dependent cotransport (small intestine) Water-soluble vitamins -intrinsic factor complex

48. 6. Absorption of Minerals - Minerals (electrolytes) are absorbed without digestion. - Iron and calcium are unusual in that they are absorbed in proportion to the body's need. - Other minerals are absorbed at fairly constant rates regardless of need.

49. a. Absorption of calcium 7-dehydrocholesterol diet skin Calcium is absorbed in the small intestine and depends on the presence of the active form of vitamin D, 1,25-dihydroxycholecalciferol. Vitamin D3 (inactive) liver 25-hydroxycholecalciferol (inactive) kidney 1α-hydroxylase 1,25-dihydroxycholecalciferol (active) Intestine Calcium absorption 

50. Actions of Vitamin D Vitamin D induces the synthesis of Ca2+ binding protein: Calbindin D-28K