Digestive and Absorptive Functions of GI PDF

Dr. Kelly Roballo 1. Identify major cells and structures in the GI tract that are responsible for carbohydrates, fats or proteins digestion. 2. Differentiate the mechanisms by which enzymes of the salivary gland, pancreas and intestinal membrane contribute to sequential digestion of carbohydrat...

Dr. Kelly Roballo 1. Identify major cells and structures in the GI tract that are responsible for carbohydrates, fats or proteins digestion. 2. Differentiate the mechanisms by which enzymes of the salivary gland, pancreas and intestinal membrane contribute to sequential digestion of carbohydrates. 3. Differentiate the mechanisms by which enzymes of the stomach, pancreas and intestinal membrane contribute to sequential digestion of protein. 4. Identify the enzymes and molecules responsible for the digestion and solubilization of lipids in the small intestine. 5. Identify the mechanisms involved in the absorption, processing, and release of lipids by the small intestinal epithelium. 6. Identify the mechanisms of absorption in the large intestine. 7. Describe the mechanisms involved in the absorption of water-soluble vitamins. 8. Describe the mechanism for feces formation. Absorption and Digestion Basics • Most nutrients need to be digested before absorption • Digestion processes is mechanical and chemical • Digestion begins in the mouth and continues to the small intestine • Most usable nutrients are absorbed by the time chyme reaches the terminal ileum • The colon ferments some unabsorbed nutrients, absorbs fluids and electrolytes and processes waste • There are multiple mechanisms for absorption: ‒ Facilitated diffusion ‒ Cotransport ‒ Micelle formation and diffusion ‒ Binding proteins • The basolateral Na/K exchange pump is VERY important and drives many absorptive functions • Timing of delivery of chyme to sites of absorption is critical for proper digestion and absorption • The GI is remarkably efficient, >95% of the carbohydrates, fat and protein that we eat are absorbed • There are also dietary requirements for other substances, such as Vitamins and minerals • Fluid absorption is intimately related to nutrient electrolyte absorption 3 4 Lumen § Carbohydrates are ingested as: § § § Starch Disaccharides (mostly lactose and sucrose) Monosaccharides (glucose and fructose) § Only monosaccharides can be absorbed § Two Phases of Digestion: § § Brush Border Luminal Brush border (brush border enzymes) Lumen Note: Salivary amylase: does some digestion in the stomach before being inactivated by H+ 5 Brush border and apical membrane: Apical border: § Sodium-coupled nutrient transport via SGLT-1 (sodium/glucose transporter-1): § Glucose § Galactose § Facilitated diffusion via GLUT 5: § Fructose Basolateral border: § All monosaccharides use GLUT2 Brush border and apical membrane Clinical correlation: High fructose load. Consuming large quantities of fructose can overwhelm fructose absorption 6 and lead to bloating and diarrhea. To Colon Chug or Uhg? “Osmotic diarrhea” 7 § Two sources of protein: § Dietary <50% § Endogenous 50-80% § Proteins need to be digested by proteases before absorption in the intestines. § Proteases are secreted in inactive form and need to be activated § The ultimate products of protein digestion that are absorbable are amino acids, dipeptides and tripeptides. § Activation (see diagram) § Pepsinogen – activated by H+ and pepsin § Trypsinogen activated by enterokinase and trypsin § Trypsin activates all other pancreatic proteases =essential aa’s 8 § 3 Phases of protein digestion: § Gastric § Proteins digested to peptides and oligopeptides § Lumen of intestines § Peptides digested to oligopeptides § Brush Border § Oligopeptides digested to aa’s, di-and tripeptides 9 Ultimate products of protein digestion: Amino Acids § Di- and tripeptides § At the Luminal Membrane: § Amino acids § Cotransport with Na+ § Depends on gradient created by Na+/K+ ATPase H+ NHE § Di-and Tripeptides § Cotransport with H+ (PEPT1) § H+ source is Na/H exchanger (NHE) Na+ In the Cell: § Most Di- and Tripeptides cleaved to aa’s by peptidase At the Basolateral Membrane: § Amino acids § Facilitated Diffusion Clinical correlation: Hartnup disease Autosomal recessive. Difficulty absorbing non-polar aa’s (tryptophan). Tryptophan is necessary to synthesize serotonin, melanin and niacin. Presents as pellagra. PEPT1 11 Source of lipids: § Dietary Lipids: § Triglycerides § Phospholipids § Cholesterol § Endogenous lipids: § Phospholipid and cholesterol § Basic principles: § Digestion of lipid is mechanical and enzymatic § Because lipid is hydrophobic, fat needs to be emulsified Digestion of lipids: § Gastric phase § Intestinal phase Lipids, like this poor fish, are HYDROPHOBIC This makes fat digestion a bit more complicated 12 § Mechanical digestion: § Mixing and grinding action of stomach churns fat into small globules § Globules get coated with dietary proteins to keep them from reforming large globules (emulsification) § Enzymatic digestion: § Minimal digestion occurs with gastric and lingual lipase (10%) § No absorption of lipid takes place in the stomach § Controlled gastric emptying is important for effective digestion and absorption of lipid in the small intestine § Review: Fatty acids in duodenum lead to CCK release which slows gastric emptying 13 § Mechanical digestion: § Segmentation contractions of intestine continue to mechanical break down lipid and mix it with secretions Bile salts inhibit pancreatic lipase § Fat droplets become coated with bile salts to allow suspension in aqueous solution = emulsification § Enzymatic digestion: § Enzymes from the pancreas digest lipid (see diagram below) on the surface of emulsified lipid droplets § Products of digestion are fatty acids, monoglycerides, cholesterol, Colipase to the Rescue! lysolecithin (water insoluble). § Products of digestion form mixed micelles with bile acids The challenge of oil and water: • Pancreatic lipase is not lipid soluble. • Lipid is not water soluble • Bile salts emulsify fat droplets so they can be suspended in aqueous environment • Bile salts inhibit pancreatic lipase from reaching triglyceride • Colipase functions as a cofactor to allow for enzyme function 14 § Enzymatic digestion takes place on the surface of emulsion droplet § Products of digestion form mixed micelles with bile salts § Function of mixed micelles § Keep products in suspension § Prevent them from re-esterifying § Transport them to the epithelial surface § Micelles contain cholesterol, fat-soluble vitamin, monoglycerides and phospholipids with bile acids allowing for suspension (1) § Micelles travel to the apical membrane of the enterocytes and products of fat digestion enter cell by simple diffusion (2) § Without micelle formation, some free fatty acids can be absorbed but not cholesterol and other lipid products. 15 § Products of fat digestion enter the cell by simple diffusion or carried molecules (2) § Lipid digestion products are re-esterified with free fatty acid (FFA) within the cell cytoplasm (3) § Chylomicrons are formed in the cell (packed on the Golgi complex). They contain a lipid core surrounded by phospholipids and Apolipoprotein B (4) § Fat soluble vitamins are also incorporated into chylomicrons § Chylomicrons exit the cell via exocytosis and enter the lymphatic system (lacteals) and then are returned to vascular system by thoracic duct.(5) Ch = chylomicrons Vit ADEK Clinical Correlation: Abetalipoproteinemia. Patients with abetalipoproteinemia cannot form chylomicrons. Fat can enter the cell but cannot be absorbed into the system. Epithelial cells appear swollen with fat on histologic section. Lacteal 16 § Vitamins can be classified into fat-soluble and water soluble. § They are organic compounds that cannot be synthesized by humans Clinical correlation: Pellagra Pellagra is due to vitamin B3 (niacin) deficiency. This has multiple etiologies including Hartnup disease (see previous disease). It presents with the 3 D’s: dermatitis, diarrhea and psychiatric manifestations (Dementia, Delirium or Depression) 17 Water soluble vitamins (except B12) • Include B1, B2, B3, B5, B6, B9, C • Absorbed by Na+-dependent cotransport • Most absorbed in duodenum and jejunum Fat soluble vitamins (A,D,E and K) § Absorbed by the same mechanism as lipids: § Micelles -> Diffusion into Cell -> Chylomicrons -> Lymphatics § Vitamin K can be from diet or synthesized by intestinal bacteria § Clinical note: Causes of lipid malabsorption can cause fat soluble vitamin deficiencies Vitamin B12 • From diet bound to protein • Cleaved by pepsins, binds with another molecule • Intrinsic factor (IF)secreted by parietal cells • Bound B12 and Intrinsic factor enter duodenum • Proteases free B12 and B12-IF form complex. • Complex binds IF receptor in the terminal ileum • B12 travels in bloodstream bound to Transcobalamin II Clinical correlation: Schilling’s Test Schilling’s test is a test for pernicious anemia (inability to absorb B12 due to IF deficiency) Two phases of test: ‒ Phase 1: Replete patient’s B12 then give radiolabeled B12. If no renal excretion then B12 malabsorption. Go to phase 2 – Phase 2: Give radiolabeled B12 and intrinsic factor. If renal excretion then pernicious anemia (IF deficiency). If no excretion then look for other causes of malabsorption. 18 Calcium § Only about 40% of calcium is absorbed from the GI tract § Calcium mostly absorbed in the duodenum and jejunum § Regulated by circulating plasma concentration and parathyroid hormone (PTH). § Relies on Vitamin D to enhance absorption § Mechanism: § At the apical surface calcium diffuses into the cell down a concentration gradient (why is there a gradient? Don’t cells have a lot of calcium?) § In the cell Ca2+ binds to Calbindin D (CaBP). It can be stored in the cell (sequestered) or transported out of the cell. § At the basolateral membrane calcium is actively transported by Ca-ATPase. § Vitamin D has three roles with respect to calcium absorption: § Increases luminal absorption § Upregulates Calbindin D synthesis § Increases Ca-ATPase activity Several dietary factors can affect calcium absorption in the intestines and excretion in the kidneys. Clinical correlation: Rickets and osteomalacia. Rickets: Seen in children, Vitamin D deficiency or impaired activation can lead to severe calcium deficiency and bone mineralization problems. Lower extremities have a characteristic bowing on x-ray. Osteomalacia: is demineralization of bone due to inadequate intake, Vitamin D deficiency and several other causes. X-ray shows 19 Rickets Osteomalacia Iron § Iron is important in heme synthesis and also participates in many enzymatic reactions § Most iron absorption occurs in duodenum and proximal jejunum § Two forms of dietary iron: § Heme § Non-heme § There are three components to iron absorption: § Apical border transport § Inside the cell (Apoferritin + Fe) § Basolateral membrane transport § At the apical border: § Heme form: Absorbed by the intestinal epithelium intact by facilitated transport Rhoades and Bell Apical Border § Non-Heme form: Fe3+ is insoluble at duodenal pH so it is reduced to Fe2+ and absorbed by active transport (Divalent metal transporter or DMT-1). § Note: Tannic acid in tea can form insoluble complexes with iron and prevent absorption. 20 Iron § Inside the cell: § Heme Fe2+ is released by heme oxygenase § Fe2+ complexes with a protein called apoferritin. This complex is called Ferritin and it is a storage form of iron. Some iron stays stored in the enterocytes. § At (Apoferritin + Fe) the basolateral membrane: § Iron is transported to bloodstream where it is bound to transferrin and travels to the liver. The liver is a major storage site for iron. § Note: the liver synthesizes transferrin Inside Cell 21 Iron 4 1 • The balance of iron stores is important in normal physiologic functioning. 5 • Note on diagram at left: 1. Some does not get absorbed 2. Some is stored in the cell 3. 4. 5. 3 Some is transferred into the blood Note that some iron is lost to intestinal epithelial cell sloughing Some iron travels from blood to cell for cell homeostasis 2 3 Rhoades and Bell 22 Summary of Mechanisms of Digestion and Absorption of Nutrients Thank you