GI Fundamentals 2024_ Lectures 8 and 9.pdf

3/5/2024 Gastrointestinal Physiology Ronaldo P. Ferraris Professor of Pharm, Physiol, Neuro Renal = kidney; respiratory = lungs Gastrointestinal Physiology integrates the function of the different organs of the GI tract: salivary glands, esophagus, stomach, pancreas, liver, gallbladder, small & larg...

3/5/2024 Gastrointestinal Physiology Ronaldo P. Ferraris Professor of Pharm, Physiol, Neuro Renal = kidney; respiratory = lungs Gastrointestinal Physiology integrates the function of the different organs of the GI tract: salivary glands, esophagus, stomach, pancreas, liver, gallbladder, small & large intestines 1 Introduction: major organ systems of GI https://www.docsity.com/en/news/ education-2/systems-humanbody-interactive-gifs/ 2 1 3/5/2024 Understanding GI Physiology ~ Nutrition Two general process involved: secretion and absorption secreted Food + water + ions + enzymes yield nutrients + ions + water + byproducts absorbed Enzymes & nutrients transported with water + ions Enzymes: R1-R2 + H2O ======> R1OH + R2H (hydrolytic) Carbohydrates & proteins => hydrophilic Lipids => hydrophobic, special handling required by GI System ~ analogous to a mining operation: Extract precious nutrients from chunks of raw material 3 General Objectives understand the contribution of each organ system in the gastrointestinal (GI) tract to human nutrition explain how food is processed so macronutrients and micronutrients can be digested and absorbed explain the role of epithelial, nervous and smooth muscle cells in secretion and absorption 4 4 2 3/5/2024 ENGINEERING: 1. Pulverizer ~ teeth & stomach 2. Autoclave ~ stomach acid 3. Chemical factory ~ salivary, gastric, pancreatic, liver and intestinal secretions 4. Extraction plant ~ absorptive processes in the small intestine 5. Conveyor belt ~ smooth muscle contractions 6. On-off controls ~ nerves & hormones Raff & Levitsky 2011 7. Waste processing ~ large intestine 8. Quality control ~ (mouth - spit; esophagus, stomach, small intestine - vomit; small and large intestines - diarrhea) 5 GI tract = 4 anatomical layers from lower esophagus to colon for secretion & absorption Serosa; blood side Lumen; food side Fig. 32-1, Berne and Levy, Principles of Physiology 6 3 3/5/2024 Functional description Of Each Layer: (1) Mucosal Epithelia responsible for SECRETION ABSORPTION Secretory products involved in digestion & protection Have receptors for mainly endocrine signals (secretagouges) that initiate secretion. Absorbed compounds: ions, water; carbohydrates, proteins, fats; minerals, vitamins No hormonal signal but “nutrient sensing” initiates absorption. Absorption is regulated INTERACTIONS WITH GUT MICROBIOTA Receptors that sense microbes & initiate response 7 7 Description of each anatomical layer (continued): (2) Submucosa =connective tissue (support & connect mucosa to muscle layer); capillaries (O2 in, nutrients to liver); immune cells (protect) (3a) Smooth muscle cells = contractile tissues of GI tract (exceptions: pharynx, upper 3rd of esophagus & external anal sphincter = has skeletal muscle) www.siumed.edu/ ~dking2/erg/GI001b.htm functions: move food from one region to another; mix gut contents; reduce food particle size 8 4 3/5/2024 (3b. nerve mainly in muscularis) - ANS in GI tract Parasympathetic NS (PNS) : vagus transmitter acetylcholine or a peptide (e.g.VIP). GI innervated by PNS via vagus & pelvic nerves function - usually stimulates motor & secretory activity of GI tract. Fig. 25-7 Rhoades 9 Sympathetic NS (SNS): transmitter - norepinephrine. function – usually inhibits motor & secretory activities. Fig. 25-9, Rhoades 10 5 3/5/2024 Description of each anatomical layer (continued): (4) Connective tissue: keeps organs in appropriate space minimizes friction. www.siumed.edu/ ~dking2/erg/GI001b.htm 11 Secretion Introduction Secretions of - Oral Cavity - Stomach - Pancreas - Liver 9 L in = 9 L out Secretions required for enzymatic digestion of nutrients aqueous environment for digestion 12 6 3/5/2024 Physiology of Salivary Secretion Human: volume of saliva secreted ~ one liter per day. 1/3 of plasma volume, or 7% of extracellular fluid. secretions are reabsorbed in distal GI regions. (vegetarians secrete more saliva) 13 functions of saliva lubricates food for ease of swallowing dissolves solid substances in food. Only dissolved compounds stimulates taste receptors. starts the process of digestion. kills bacteria maintains pH in oral cavity ~ 7 (chemical buffer). functions as a temperature buffer & protects oral cavity from temperature extremes. lubricates oral cavity, and aids in speaking. 14 7 3/5/2024 Composition of saliva Aqueous component Sodium, potassium, calcium, magnesium, chloride, bicarbonate, phosphate Organic component Urea, ammonia, uric acid, glucose, lipids, free amino acids, proteins 15 Effect of flow rate on aqueous composition HCO3 regulates pH of saliva. Since HCO3 concentration in saliva varies with flow rate, then pH of saliva also varies with flow rate. (low flow = low pH) 16 8 3/5/2024 Ion composition of saliva relative to that of plasma Fig. 32-3, Berne et al 17 Organic Composition of Saliva a. Proline-rich proteins: antimicrobial properties, lubrication & enamel maintenance e.g. lactoferrin, lactoperoxidase = part of innate immune system, kills bacteria & fungus b. Mucus: lubrication c. Kallikrein: vasodilator 18 9 3/5/2024 d. Enzymes: -amylase - digests starch by breaking down 1-4 linkages. Active ~ pH 4 – 11; pH optimum ~ 6.7. Activity is reduced in stomach lumen. (Function: digestion vs. taste???) lingual lipase - hydrolyzes triglycerides. Stable (lipolytic activity continues to stomach & proximal intestine), pH optimum 4.5 - 5.4, can catalyze reactions with lipids without bile salts. Is not important except in cases of pancreatic insufficiency & cystic fibrosis. 19 Autonomic control of secretion by salivary glands Chewing Taste Smell Conditioned reflex Nausea } + Group of neurons called salivatory nucleus (medulla) _ { Parasympathetics Cranial Nerve (CN)IX CNVII MAIN REGULATOR ACh Sympathetics Superior cervical ganglion NE Sleep Fatigue Dehydration Fear Drugs M3 IP3  cAMP Ca2+ Salivary Gland + Secretion Myoepithelial cell contraction Vasodilation Metabolism Growth 20 10 3/5/2024 Stomach & Pancreas functions of stomach 1. the autoclave of the GI tract because of high luminal acidity. 2. mechanical digestion. The strong muscles in the stomach are appropriate for this function 3. protein hydrolysis. Pepsin works in an acidic environment to break down dietary protein 4. food storage. The stomach is unique because it relaxes when food is present (receptive relaxation). 5. secretion of the intrinsic factor (required for intestinal vitamin B-12 absorption). 6. quality control: provides a second panic button: vomiting 21 Cardiac/fundic 3 regions of stomach Antral Gland have gastric “pits” (glands); cell population depends on gland location Mucus Surface mucus cell fundus cardiac corpus (body) antrum Fig 50.1 Raff Mucus neck cell D cell somatostatin G cell gastrin PG-II PG = prostaglandin; from submucosa but exact cell type not known 22 11 3/5/2024 Composition, luminal gastric secretions Aqueous component Organic components (e.g. HCl) 1. Pepsinogen secreted by chief (peptic) cells. At pH < 5, pepsinogen converted to active enzyme, pepsin that then catalyzes its own conversion. Pepsin activity highest between pH 1 - 3. Pepsin hydrolyzes dietary protein. 2. Intrinsic factor by parietal cells - only secretion essential for life. Protects vit B12 (cobalamin) from digestion & facilitate its absorption in small intestine. 3. Mucus – from neck & surface cells, protection.23 23 Composition of aqueous gastric secretions changes as a function of secretion rate Basal. Secretion consists mostly of Na & Cl. Na levels < plasma Cl levels > plasma K concentrations > plasma. ~hypotonic to plasma Stimulated. Production of gastric juice increases ~ 5 - 8X volume increases luminal fluid composition changes from NaCl to HCl. H levels >> plasma Fig. 26-7, Rhoades 24 12 3/5/2024 At high HCl secretion rates, gastric juice ~ isotonic with plasma. Aqueous component = little HCO3 to buffer HCl, so luminal pH ~1. Lethal acid concentrations. Lumen of stomach H+H+ H+ H+ + H H+ + H+HH+ H+H+ H+ H+ pH = > sum of individual effects Suggest final rate of secretion depends on interactions of these secretagogues Interactions called potentiation. 28 28 14 3/5/2024 Interactions: Ach stimulates parietal, G (by GRP (gastrin releasing peptide)) & ECL cells; inhibits D cells from making somatostatin, an inhibitor of acid secretion, of G cells & of ECL cells. Gastrin stimulates ECL (++) > parietal (+) cell. Histamine is main stimulator of acid production. H2 blockers (e.g. Zantac, Tagamet) are potent anti-ulcer drugs). D cells secrete SS, inhibits parietal, G, ECL. + GRP Fig. 32-15, Berne et al, 5th 29 In general, factors that release HCl from parietal also release pepsinogen from chief cells, linking their secretion. Increases efficiency of protein digestion. Baseline mucus secretion is high, and secretion still stimulated by these secretagouges, especially by Ach and by mechanoreceptors (via Ach). 30 30 15 3/5/2024 Protection from HCl (A) by Gastric Mucosal Barrier B. Mucus produced by the cells forms a gel overlying the stomach mucosa, creating a protective lubricating coat. Note pH change. B, C. HCO3 produced by surface epithelial cell makes the mucus alkaline. Mucous layer traps the HCO3 made by surface epithelial cells, so that solution nearest the stomach cell surface has a pH near 7 C, D. Tight junctions & phospholipid bilayer have low H permeability; monolayer of peptic cells can survive pH = 2. E = interstitial fluid; F = capillary, separated by one cell layer from H lumen mucosa M.Komorniczak 2011, Wikipedia.org 31 Pathophysiology (1) Damaging forces overwhelm protective defenses (2) >90% of duodenal & >70% of gastric ulcers are caused by Helicobacter pylori Fig 16-16, Cotran 32 16 3/5/2024 ~ 5% of duodenal & 25% of gastric ulcers caused by drugs used to control inflammation & pain (aspirin). ~ Aspirin irreversibly inhibits COX-1 (required for PG synthesis) in mucosa & reduces levels of prostaglandins, PGE2 & PGI2, & of thromboxanes (blood clot). https://tmedweb.tulane.edu/pharmwiki/dok u.php/non-selective_cox_1_2_inhibitors 33 Pancreas endocrine function Insulin & glucagon (& somatostatin) exocrine function Bicarbonate neutralizes stomach acid Enzymes required for digestion of fats, proteins and carbohydrates 2424 Exocrine & Endocrine Pancreas, OpenStax College – Anatomy & Physiology, Wikipedia 34 34 17 3/5/2024 Composition of pancreatic secretions Aqueous component most important: bicarbonate Organic component amylases - breaks up starch into smaller units. Synthesized & secreted in active form. lipases - break down fats. Synthesized & secreted in inactive & active forms. proteases - digest proteins. Secreted in inactive form called zymogens, to prevent autodigestion of the pancreas. Trypsin inhibitors in pancreas prevent premature activation. ribonucleases digest DNA and RNA from food 35 http://m.photoviewer.naver.com 36 18 3/5/2024 Composition of aqueous changes with secretion. Basal rates: consists mostly of Na, Cl & HCO3. [HCO3] > & [Cl] < plasma. Na & K similar to plasma. Stimulated. Secreted volume increases ~10 X. Cl decreases but HCO3 increases with increasing secretion. Na & K independent of secretion rate. Sum (Cl + HCO3) always = sum (Na + K). Osmolality not change w/ flow rate: always similar to plasma. Fig. 51-4, Raff & Levitsky 37 Molecular mechanisms, HCO3 secretion by pancreatic duct Cytosol: 1. H2O+CO2 (diffused from blood) = H2CO3 = HCO3+H. Apical: 2. HCO3/Cl exchanger 3. Cl channel (CFTR) recyles Cl Fig. 51-7; Raff & Levitsky Basolateral: 4. Na/H exchange at BL 5. Na/K exchange at BL 38 19 3/5/2024 HCO3 in cell increases rapidly & secreted into lumen (~140 mM) in exchange for Cl which enters cell against an electrochemical gradient. Lumen is negative, so Na & K diffuse to lumen through paracellular pathway. Water via aquaporins (channels) osmotically follows the transport of HCO3, Na & K to lumen. Na+, K+ 39 Hormone that controls secretion of aqueous component is secretin. Stimulus for secretin release is HCl & also fatty acids in duodenal lumen. Because secretin is releaser of the body’s own natural antacid, HCO3, it is adaptive that luminal HCl releases secretin. Note: amylase concentration decreases (gets diluted). Amylase is released by Ach, CCK. Ganong, Fig. 26-19 40 20 3/5/2024 Organic component (enzyme) secretion mainly via vagus releasing Ach on M3 receptor in BLM of acinar cells. CCK: 2ndary control of enzyme secretion. Receptor is CCKA. 2nd mssngr of Ach & CCK: Ca. acinar cell main minor Secretin & CCK are made & released from duodenum (S and I cells, respectively). 41 Liver & Gallbladder: not make hormones or enzymes. Main digestive function: synthesize bile for fat digestion. http://www.veomed.com/files/powerpoints _images/node308467/Slide3.JPG Bile made in hepatocytes, then secreted into canaliculi to bile ductules. Other hepatocyte functions: metabolism of drugs, bilirubin, nutrients storage of lipid soluble vitamins. 42 21 3/5/2024 Bile from liver stored in gallbladder, then released to intestinal lumen during meals. http://www.veomed.com/files/powerpoint s_images/node308467/Slide3.JPG Has aqueous & organic components. Aqueous: isotonic secretion by liver modified by bile duct cells when stimulated by secretin - increases volume & HCO3. High HCO3 concentrations = bile slightly alkaline. 43 Organic components, bile 1. 2. 3. 4. 5. Bile acids (65% of dry wt) Cholesterol (4%) Phospholipids (20%) Bile pigments (1%) Proteins (5%) Secreted bile acid is a polar or amphipathic molecule. Bile acid made of cholesterol, OH groups, amino acids Cholesterol backbone = hydrophobic (grey) OH & COO = hydrophilic (red) Hydrophobic groups of bile acids associate with each other or with lipids, while hydrophilic groups associate with water. Fig. 32-27, Berne et al 44 22 3/5/2024 (1) Bile acids important for: (a) digestion, via emulsification of lipids, thereby allowing efficient hydrolysis by lipolytic enzymes. Mechanism ~ geometry: (greater surface to volume ratio, more area for enzymes to work on) (b) absorption, via micelle formation (described in lipid absorption section). https://www.drawittoknowit.com/course/bioc hemistry/glossary/physiological-process 45 Organic components, bile (continued) 2. Cholesterol secreted by hepatocytes; bile is its only route of excretion. Dissolves in hydrophobic areas of micelles. (cholesterol gallstones form when bile contains too much cholesterol & bilirubin, or not enough bile salts, or when gallbladder does not empty normally) Micelle 3. Phospholipids have hydrophobic & hydrophilic components. Lecithins = most common type. Phospholipids act like bile acids & help solubilize cholesterol. 4. Bile pigments from degradation products of hemoglobin (bilirubin). Hepatocytes remove bilirubin from blood & conjugate it w/ glucuronic acid then secreted into bile. Fig. 38-27, Berne and Levy 46 23 3/5/2024 4. Bile pigments from degraded hemoglobin. bilirubin (B) uptake from blood into hepatocytes linked to glucoronic acid by UDP GT, secreted with bile bacteria convert conjugated bilirubin to more hydrophilic urobilinogen in GI lumen then further converted to brown stercobilin & defecated. 47 47 HOW BILE IS SECRETED FROM LIVER Bile does not go straight from liver to duodenum. Prevented from entering by Sphincter of Oddi. Between meals, sphincter is constricted, gallbladder relaxed. Bile goes from liver to gallbladder - accumulates bile. 48 24 3/5/2024 HOW BILE MOVES FROM GALLBLADDER TO GUT LUMEN Between meals, VIP nerves (vasoactive intestinal peptide) inhibit gallbladder contractions During meal, CCK released in response to fats & essential amino acids. CCK ~ strongest stimulus for contraction: via (1) blood as endocrine & (2) vagus releasing Ach on gallbladder (contract) and VIP + nitric oxide on sphincter (relax) Dietary fat, via CCK (& Ach) “tells” gallbladder to release bile for fat digestion. Raff & Levitsky VIP: relax between meals relax contract during meals Figure 28-8, Ganong 25th ed 49 HOW BILE IS RECYCLED: ENTEROHEPATIC CIRCULATION Gallbladder concentrates bile. Inspite of high levels of bile acids in gallbladder, bile pool may be too small to emulsify all fats in a single meal. Thus, bile acids used in early fat digestion are absorbed in ileum, recycled by the liver, and reused by the intestine in processing later fat components of same meal. Process called enterophepatic circulation; gallbladder not involved. Fig. 33-14, Berne and Levy Principles 50 25 3/5/2024 COORDINATION OF SECRETION involves CNS, intrinsic plexuses of gut & hormones. (1) regulation with CNS = long or vagovagal reflexes (2) regulation involving the enteric nervous system:short Fig. 32.2, Berne & Levy, Principles or local reflexes. 51 Control of secretion three phases named after site of receptors initiating secretory process A. Cephalic phase occurs before food enters stomach (e.g. sham feeding is used to study cephalic phase). when you seriously think of food, or when senses are stimulated by food. B. Gastric phase occurs when food enters stomach, stimulating its chemo- & mechanoreceptors. C. Intestinal phase when contents of stomach are emptied into duodenum activate chemo- & mechanoreceptors in mucosa 52 26 3/5/2024 A. CEPHALIC PHASE A1. Salivary glands in all three phases, under neural or ANS control: Stimulation of olfactory (nasal) or taste (tongue) or mechano (oral) receptors -- followed by central processing in CNS then by efferent signals to salivary glands cephalic phase mediated by PNS transmitter is Ach; blocked by atropine inhibition of salivation (by sleep, fatigue, fear) also by PNS because control involves CNS -- is a long reflex. Fig. 51-8, Raff & Levitsky 53 A.2. Gastric secretion during cephalic phase affects, via vagus nerve, 4 cell types simultaneously: mucus neck cells, chief cells, parietal cells and G cells release Ach on plexuses, Ach on target cells except G (GRP) cephalic phase accounts for 30% of response of these cells to a single meal. Ach Ach Ch 37, Fig. 12, Essential Med Physiol Johnson, 2nd ed 54 27 3/5/2024 A.3. Pancreatic secretion, cephalic phase Vagovagal (long) pathway: weak stimulant of pancreatic secretion -low volume & high protein content. Ch 37, Fig. 22, Essential Med Physiol Johnson, 2nd ed No secretin released, no HCO3 secreted, no increase in volume Gastrin (related to CCK, receptor = CCKb): only hormone released. Low affinity binding to CCKa(or 1) receptors in duodenal sensory nerves & via blood to CCKa in acinar cells. low affinity 55 55 B. Gastric phase: 1. Salivary secretion (regulated by ANS (long) pathway). 2. Gastric secretion Food distends stomach & stimulates mechano or stretch receptors. Impulses relayed to intrinsic plexus, nerve network operating independently within stomach wall. Gastric network interconnects gut receptor-intrinsic plexus-secretory response of cells, mediates local reflexes. Releases Ach in plexus Efferent fibers of intrinsic plexus release Ach to stimulate parietal, chief & G-cells, which then release their secretory products. Ch 37, Fig. 13, Essential Med Physiol Johnson, 2nd ed Stretch receptors also send afferent signals via vagus (long pathway) Long reflex releases Ach on interneurons, GRP on G, Ach on parietal 56 28 3/5/2024 B. 2. Gastric secretion during the gastric phase Chemoreceptors on Gcells detect dietary protein & small peptides from pepsin digests, then release gastrin. Chemoreceptors on parietal cells may respond to dietary Ca, alcohol & caffeine then release acid. https://quizlet.com/21738914/digestive-system-flash-cards/ 57 B. 3. Pancreatic secretion in the gastric phase Hormones regulating pancreatic secretion not released, stimulation of secretion minimal. modest secretion is due to: no secretin released gastrin (structurally similar to CCK), bind by low affinity to CCK1 in duodenal afferents, release Ach in acinar cell in pancreas via long reflex; also bind to CCK1 in acinar Ch 37, Fig. 13, Essential Med Physiol Johnson, 2nd ed 58 29 3/5/2024 C. Intestinal phase: C. 1. salivary secretion still regulated solely by ANS C. 2. gastric secretion At pH > 2-3, acid production by parietal cells stimulated, at < 2-3, acid production inhibited. C. 2a. Stimulatory by mechano & chemo continue secreting digestive juices until stomach empties completely distention of duodenum stimulates mechanoreceptors releasing gastrin & enterooxyntin, a gut hormone enhancing acid secretion by parietal cells digested proteins stimulate chemoreceptors releasing enteroxyntin from unknown cells & gastrin from G-cells in duodenum) From duodenal cells: enterooxyntin and gastrin 59 C. 2b. Inhibitory Effects. When food is almost gone from stomach, intestinal phase “inhibits” gastric secretions. Three factors mediate: i. less food to buffer H+ in stomach, so chyme entering duodenum highly acidic, stimulate release of secretin that inhibits G cells from secreting gastrin. Secretin stops acid twice: secretion of HCO3 from pancreas, & inhibition of gastrin release by G-cells. ii. less distention of duodenum = less stimulation of mechano-receptors which release enterooxyntin. 60 30 3/5/2024 Inhibitory Effects (continued) (iii) Excess gastric acid (no food remaining in stomach) stimulates D cells to release somastostatin (SS). SS inhibits gastrin release by G cells in gastric glands and H release by parietal (P) cells. SS is a potent paracrine inhibitor of gastric secretions. Ch 37, Fig. 15, Essential Med Physiol Johnson, 2nd ed + + BLOOD SIDE SS D + P acid 61 FOOD SIDE 61 Interactions: * Ach stimulates parietal, G (by GRP via interneuron) & ECL cells, and inhibits D cells from making somatostatin (SS). * SS an inhibitor (---) of acid secretion, of G cells and of ECL cells. * HCl stimulates D but inhibits via secretin G cells. + GRP - + -- 62 31 3/5/2024 C. Intestinal phase C. 3. pancreas - arrival of acid, fat & protein digestion products in duodenal lumen stimulates pancreas. - intestinal phase accounts for ~ 80% of human pancreatic response. http://en.wikibooks.org AQUEOUS RESPONSE: acid induces release of secretin from S cells of the duodenum. ORGANIC: Dietary fats & amino acids stimulate secretion of CCK from I cells. CCK causes Ach release via vagus to acinar cells (main response). CCK enters systemic circulation and binds to CCKa in acinar cells. 63 Digestion & Absorption Total volume secretions & fluid intake: ~ 10 L. Absorbed by small intestine but 2 to 3 L enter large intestine. Most nutrients absorbed in duodenum & jejunum (mid intestine). Most water & ions absorbed by jejunum. Ileum (most distal region) absorbs vitamin B-12, bile acids, water, ions. Colon absorbs remaining water & ions. Raff & Levitsky http://www.hyogoajet.net SECRETION: digest food to absorbable units (nutrients) ABSORPTION of hydrophilic nutrients across membranes requires transporters 64 32 3/5/2024 Carbohydrate digestion Fig. 58-1, Raff & Levitsky 65 Disaccharide digestion & monosaccharide absorption: 66 33 3/5/2024 muzarp.poznan.pl http://flickrhivemind.net/Use r/Justin%20Jackson/ Lactase present in children of all human ethnic groups (congenital LD is rare), but is often lost in adults Loss rare in adult Caucasians, Africans w/ history of pasture ~ 25% of U.S. (~ 40 million) lactose intolerant. Distribution: 90% of Asian Americans, 80% of African, 62-100% of Native, 53% of Mexican Americans, 15% of Caucasians lactase “persistence” is increasing in all populations. Excellent example of human gene:culture coevolution 67 Protein digestion in small intestine luminal protein from: diet, GI secretions & exfoliated intestinal cells require min ~ 50 g (1.5 oz) of protein/d to maintain weight because ~ 50 g of protein/d lost via secretions, sloughed cells, other losses. Protein hydrolysis begins in stomach by pepsin active at low pH, inactive in duodenum with high pH. Pepsin digests ~15% of dietary protein Fig. 58-4, Raff & Levitsky Pancreatic proteases (zymogens) activated in lumen enterokinase in brush border of duodenum activates trypsinogen, autocatalytic activation follows. enterokinase – resistant to digestion; deficiency malnutrition 68 34 3/5/2024 Fig. 33-7, Berne et al 69 small peptides of 2 - 3 AA absorbed by peptide carrier PEPT1 in apical membrane. Energy provided by H gradient, ultimately by Na/K ATPase. Unique as no analogous di or trisaccharide transporter. Net absorption of AA is faster via PEPT1 From: Raff & Levitsky 70 35 3/5/2024 Fat Digestion & Absorption (>> complicated than carbo, protein; hydrophobic substrate in aqueous) Stomach fats separate out into oily phase small surface area of these large fatty globules means little digestion by salivary or gastric lipases. Small intestine. bile in small intestine produces an emulsion of fat droplets (diameters ~ 1 µm). Surface area now greatly increased & becomes target of pancreatic lipase. 71 Enzymes for lipid digestion: (1) glycerol ester hydrolase (pancreatic lipase, secreted in active form). Needs colipase for hydrolysis of lipids in presence of bile. (2) Colipase (secreted as inactive procolipase) required by pancreatic lipase to bind to surface of emulsion droplets & displace bile acids. Lipase + colipase digestion products = 2 free fatty acids & 1 monoglyceride emulsion emulsion globule (3) cholesterol esterase hydrolyzes cholesterol esters, fat soluble vitamins and other esters. Yields fatty acids & cholesterol. (4) phospholipase A-2: produce fatty acids & lyosphosphatides. Also released in inactive form, activated by trypsin 72 36 3/5/2024 LIPID ABSORPTION products of lipid digestion (FFAs, cholesterol, phospholipids) initially form micelles with bile acids micelles ~ 5 nm diameter, contain ~25 molecules 73 micelles diffuse across apical membrane thru unstirred layers (UL< ~ 500 um thick). It is rate-limiting step of fat absorption digested lipids leave micelle to diffuse across lipid matrix. Micelles bring products of fat digestion to apical membrane for diffusive absorption, some by FATP (fatty acid transport protein) Without micelles, absorption is possible but inefficient. Bile acids remain in jejunal lumen Fig. 39-20, Berne and Levy 74 37 3/5/2024 Cytosolic reprocessing In cytosol, FAs bind to fatty-acid binding proteins (FABP) which bring them to SER. mainly diffusion, others via FATP Lipids re-esterified, accumulate in SER, where they form lipid droplets. Droplets transferred to RER, coated with apolipoproteins Surface of lipid droplets: mainly phospholipids & apolipoproteins. Now called chylomicrons. 75 Basolateral exit Chylomicrons cross BL membrane by exocytosis. Chylomicrons “large” (> 100 nm); cannot fit through basement membrane Leave intestine via lymph circulation then enter blood in thoracic duct & brought to liver for processing. Fig. 33-20, Berne and Levy 76 38 3/5/2024 big picture: dietary fat = + bile = EMULSION + bile + enzymes = digestion into absorbable lipids + bile = MICELLES cross unstirred layer = lipids in cytosol for reprocessing in SER = fats + apolipoproteins in RER = CHYLOMICRONS = exocytosis = lymph https://rockedu.rockefeller.edu/com ponent/parenteral-nutrition/ 77 ELECTROLYTE & WATER ABSORPTION Permeability to fluids & electrolytes: paracellular: junctions between cells transcellular permeability of cell membranes. small intestine, paracellular >> transcellular. Fig. 1 - 16, Berne et al Intestinal regions differ in paracellular permeability: duodenum (most permeable) > jejunum > ileum > large intestine (least permeable, para approaches transcellular). Transporters for various ions more abundant in distal regions. 78 39 3/5/2024 Duodenum = permeable because of low resistance tight junctions. Direction of water flow mainly depends on whether contents are hypertonic or hypotonic to the blood. Contents: usually hypertonic; net flow of fluids from blood to lumen. Jejunum & ileum: paracellular much less permeable than in duodenum. Contents isotonic, not much gradient for passive ion & water transport. Ion transport more dependent on carriers 79 Cl Na & Cl transport in duodenum, jejunum & ileum. 1. Absorption of Na: via co-transport w/ nutrients apical NHE-3. basolateral Na/K ATPase 2. Absorption of Cl: paracellular as lumen (–) transcellular: via Cl/HCO3 exchanger basolateral KCCl cotransporter CO2 Fig. 52-6, Raff & Levitsky Secreted H combines with HCO3, forming H2CO3 then CO2 & water. CO2 is lipid soluble, diffuses from lumen into cell & blood. HINT: Na & Cl normally absorbed 80 40 3/5/2024 Jejunum: site of water absorption by standing gradient isotonic conditions yet water absorption occurs w/o osmotic difference between lumen & blood. “standing gradient hypothesis” explains jejunal absorption of H2O. obeys principles: no active transport of water, & driving force of water flow is ion absorption NaCl absorbed across apical relies on numerous Na pumps in lateral surface. Cl follows, creating transient “hypertonic” environment. water thru aquaporins (H2O channels) flow into hypertonic lateral spaces McGill Faculty of Medicine e-curriculum hydrostatic pressure builds up then water & ions flow through basement membrane. similar in ileum, colon, gallbladder 81 Colon is much less permeable than ileum: has no mechanisms for sugar & amino acid absorption has similar Na/H, Cl/HCO3 & paracellular Cl transporters Has 2 more mxnsms not found in small intestine: transport of Na through ENaC channels into cell. Process is electrogenic, regulated by aldosterone => increases number of ENaC when plasma Na is low. Fig. 33-10 Berne et al secretion of K thru high conductance channels into lumen. Can lead to hypokalemia in chronic diarrhea. 82 41 3/5/2024 Infectious diarrhea Reports of E. coli Outbreak Investigations from 2018 Romaine Lettuce – E. coli O157:H7 Ground Beef – E. coli O26 Romaine Lettuce – E. coli O157:H7 83 Role of cAMP in secretory diarrheas Cholera & E. coli toxins bind to GM1, stimulate Gs, increase cAMP by activating adenylyl cyclase. cAMP locks open CFTR channels, cause Cl secretion. Water & Na follow. Normal conditions: absorption >> secretion Diarrhea: secretion >> absorption If untreated, 50 -75% of cholera patients die from dehydration & loss of salts within hours after onset of symptoms. Treatment: rapidly replace water & salts. A comatose patient can be alert within minutes after rehydration. http://www.bmb.leeds.ac.uk/teaching/icu3/mdcases/ws4/index.htm 84 42 3/5/2024 Most effective oral method of rehydration takes advantage of SGLT1 (not affected by toxin). Oral rehydration therapy (ORT): give solutions with Na & glucose. K & HCO3 also added to replace salts lost by diarrhea. GLUT2 SGLT1 Mechanism underlying oral rehydration therapy: SGLT1mediated glucose absorption https://www.pinterest.co.uk/pin/426645764677084487 85 Minerals: required for normal metabolism. Focus on Ca and Iron as many Americans are deficient… Table below = % US population below required daily allowance Absorption: more Ca absorbed than other divalent ions. Gastric acid solubilizes Ca salts, liberates Ca ions Absorption by transcellular route in duodenum (proximal SI) By paracellular route in jejunum & ileum (mid and distal SI). 86 43 3/5/2024 Transcellular transport cross apical membrane by Ca channels (CaT1 or TRPV6) transport down electrochemical gradient (cytosol: has less Ca, is electrically negative). Ca binds to Ca binding protein (calbindin or CaBP), for transport across cytosol). Some dietary Ca enter vesicles which move to BL membrane. CaT1 Fig. 39-14, Berne, Physiology Dietary Ca must not change intracellular concentration of Ca: Ca is 2nd msngr; Ca can form salts with cytosolic anions. 87 Basolateral active transport against electrochem gradient via: i. Ca-ATPase (predominant) ii. Na/Ca exchanger iii. exocytosis of vesicles Regulation: less Ca content of diet = greater number of TRPV6 & CaBP. Vit D stimulates absorption of Ca at all levels: paracellular, apical, cytosol, basolateral. Fig. 39-15, Berne, Physiology Pathology, deficiency: poorly developed bones & teeth. rickets – bone growth abnormal. elderly - osteoporosis (loss of organic matrix & demineralization) 88 44 3/5/2024 Iron deficiency: most prevalent nutrient deficiency in world. necessary for proper red cell function. adults require ~ 10 mg/d women of reproductive age ~ 20 mg/d. pregnancy ~ 30 mg/d. absorbed in the small intestine, absorption efficiency tends to be low vitamin C will improve the absorption of nonheme iron phytates in legumes & grains and some proteins found in soybeans inhibit nonheme iron absorption (poses risk for vegetarians) 89 Dietary iron: two forms absorbed in different ways. Nonheme. DCT1 (DMT1) specific for divalent Fe++, so iron reductase in brushborder (BB) reduces Fe+++ (food). DCT1 moves Fe++ into cytosol. Heme (from red meat) released from other proteins by proteolysis heme uptake facilitated. In cytosol, heme iron separated by oxidase HO2 Iron is then processed as for non-heme iron. Fe++ reversibly bound to iron binding proteins like mobilferrin but irreversibly to ferritin reductase mobilferrin? Fig. 26-8, Ganong 90 90 45 3/5/2024 Ferroportin (FPN)/hephaestin (HEPH) takes Fe++ from cytosol, converts it to Fe+++, releases to blood bound to transferrin (Tf). mobilferrin? X Regulation of absorption by irreversible binding of Fe to ferritin If iron status is high, more bind irreversibly to ferritin. Less iron transport out of BL membrane. When cell dies & is extruded into lumen, excess iron bound to ferritin defecated. If body has little iron (e.g. after menstruation), less iron bind to ferritin, more iron is sent to FPN & absorption for iron increases. 91 Absorption of water-soluble vitamins Table 33-6, Berne Hydrophilic & large, cannot diffuse through lipid membrane Vitamin Site of absorption Transport mechanism Ascorbic acid (C) Entire small intestine SVCT Biotin (B7) Small & large intestine SMVT Choline Small intestine CHT (choline transporter), OCT folates (B9) Small & large intestine PCFT (proton-coupled folate trans) Inositol Small intestine SMIT Nicotinamide/Niacin (B3) Small intestine Carrier-mediated Pantothenic acid (B5) Small & large intestine SMVT Pyridoxine (B6) Small & large intestine Diffusion Riboflavin (B2) Small & large intestine RFVT Thiamin (B1) Small & large intestine THTR Cobalamin (B12 Distal ileum Receptor-mediated endocytosis Deficiencies: primary (dietary in origin) or secondary (reduced transport) Defects/deficiencies in transporters (e.g. intrinsic factor from surgery) Reduction (e.g. via intestinal resection) in gut surface area: affects mainly 92 pyridoxine absorbed by diffusion 92 46 3/5/2024 Motility of the GI tract Muscle cells in the GI tract act as the conveyor belt. move contents in proper direction & appropriate speed (slow motility increases bacterial populations in lumen) mix food with GI secretions for optimal digestion & absorption General properties of GI smooth muscles: in other excitable tissues, resting membrane potential (MP) constant over time until tissue is depolarized. In GI smooth muscle, resting MP changes with time. oscillations in MP called basic electrical rhythm (slow waves) initiated by interstitial cells of Cajal (ICC) in muscle layer. Fig. 31-6 Berne et al 93 If peak of slow wave exceeds electrical threshold for action potentials (APs), APs occur. APs enhance the contractile force of GI smooth muscle. Upper red line shows change in MP, lower red line shows contraction of the muscle. Usually, the more APs, the greater the contraction force. 1 = slow wave but no contraction; 2 = slow wave with contraction; 3 = slow wave with few APs; 4 = slow wave with many APs 3 2 4 1 94 47 3/5/2024 Between APs, muscle tension drops but not back to zero. Smooth muscle tension when no action potential is called tone. tone 95 Each part of GI tract has its characteristic slow wave: stomach ~ 3 waves/min duodenum, 11 - 13 waves/min; ileum, 8 – 9 colon ~ 6 slow waves/min Frequency of contractions in each organ determined by basic electrical rhythm, because contractions occur at top of slow wave. Frequency of muscle contraction can be modulated. Fig. 25.3 Rhoads & Bell, 3rd ed, 2009 This specific pattern of slow waves occurs during and shortly after meals. Contractile behavior of stomach & small intestine different between meals. 96 48 3/5/2024 Frequency of muscle contraction can be modulated. Slow waves by themselves do not cause contraction, but determine pattern of APs produced. ACh depolarizes MP (e.g -50 to -40 mV below), so APs are easier to generate. Ach then increases frequency of APs – followed by increase in frequency of contraction & in muscle tone. Others: substance P Fig. 62-3, Guyton 97 Sympathetic stimulation or norepinephrine (VIP, NO): hyperpolarizes cell & decreases or abolishes APs because cells more difficult to depolarize. frequency of contraction of smooth cells diminishes. decreases muscular tension or tone. Basis of why “urge to go to restroom” disappears when one is scared or is exercising. Fig. 62-3, Guyton 98 49 3/5/2024 OTC antidiarrheal drug loperamide: opiod receptor agonist metabolized in intestinal wall & does not affect CNS molecular mechanism: opioid receptors inhibit release of Ach (morphine also inhibits Ach release but …). □ = lopermd  = vehicle functional mechanism (activates inhibitor of Ach release): inhibits activity of myenteric nerves & decreases motility of circular & longitudinal muscle layers increases amount of time substances stay in intestine, allowing for more fluids to be absorbed out of the chyme. many anti-diarrheal drugs inhibit peristalsis Tan-No et al 2003, Eur J Pharm Sci, 20:357 99 Sphincters divide gut into functional segments under varying CNS control; prevent reflux between segments 100 50 3/5/2024 Mouth and esophagus movements. Chewing lubricates & breaks up food mechanically so digestion can proceed faster. Muscles involved controlled by the brain stem. Swallowing. At rest, the pharyngeal muscle exhibits a low level of tone. The cricopharyngeous muscle contracts to close the esophageal inlet by compressing inlet against the cricoid cartilage. The esophageal body is flaccid, w/o appreciable tone. Fig. 37-8, Berne and Levy 101 Swallowing is under reflex control by a group of nerves called the swallowing center. It has 3 phases: 1. An oral, voluntary phase: Initiation of a swallow involves the clenching of the jaws followed by elevation of the tongue against the hard palate. Soft palate is pushed back – can swallow upside down bolus of food is then forced into pharynx food stimulates tactile receptors in pharynx this initiates second stage of swallowing. Fig. 37-8, Berne and Levy 102 51 3/5/2024 2. A pharyngeal, involuntary phase. Upper esophageal sphincter or UES relaxes for 1 sec to let food through next, it contracts forcefully for ~1 sec before going back to contracted baseline during this phase, respiration is inhibited, trachea is covered by epiglottis, & food goes into esophagus. 103 After food passes UES, the sphincter constricts. an initial wave of peristalsis (primary peristalsis or PP), pushes food down. PP controlled by CNS – “swallowing center”. Wave of contraction, UES to LES takes 6-9 s LES relaxes when UES contracts & waits for PP to arrive. As front of moving wave of contractions hits LES, it contracts for 1 sec, then returns to its regular contracted tone. pharyngeal area Luminal pressure (mm Hg) 3. An esophageal, involuntary phase. Fig. 31-9, Berne and Levy 104 52 3/5/2024 If primary peristalsis fails to push all of food down, esophagus initiates secondary peristalsis. secondary peristalsis is controlled locally persists so long as food in esophagus. http://www.answers.com/topic/peristalsis 105 Motor Functions of the Stomach Cardia LES Proximal Stomach highly distensible main function = reservoir no basal electrical activity Pylorus regulates emptying Pacemaker region fundus Corpus Antrum main function = grinding chamber basal electrical activity phasic peristaltic contractions 106 53 3/5/2024 Gastric Slow Waves cycle continuously through the distal stomach doudenum 107 Gastric Peristalsis Reduces Size of Digestible Solids and Promotes Emptying http://teachmeanatomy.info/wp-content/uploads/Peristaltic-Contractions-of-the-Stomach.gif 108 54 3/5/2024 What determines the rate of gastric emptying? hypertonicity and acidity impair emptying of liquids solid particles must be small (≤1 mm3) meals rich in fat and protein empty slowly Isotonic saline % Emptied 100 5 mm plastic beads 0 0 1 2 Hours 3 4 Why? Prevents overloading the duodenum’s capacity to digest and absorb How? Enterogastric reflexes! 109 from stomach to small intestine small intestine: muscularis externae mainly responsible for two general types of contractions : (1) Peristalsis is produced by coordinated contraction & relaxation of smooth muscle involves short lengths of intestine. inhibiting peristalsis (codeine, opiates, loperamide) = longer transit time; stimulating peristalsis (castor oil, laxatives) = short transit time; diarrhea. http://en.wikipedia.org/wi ki/File:Peristalsis.gif 110 55 3/5/2024 (2) Segmentation: back & forth movement of contents of digestive tract, characterized by closely-spaced, rhythmic contractions, so one segment contracts then relaxes while an adjacent segment relaxes then contracts occurs throughout small intestine during fed state. has little propulsive power, presents new chyme closest to the mucosal surface for further digestion and absorption. http://www.vivo.colostate.edu/hbooks/pa thphys/digestion/basics/gi_motility.html 111 from small to large intestine The large intestine has very low motility. The frequency of the slow waves is only 4 6/ min. Slow motility maximizes time for optimal absorption of water and remaining electrolytes. ~18 to 40 h to traverse large intestine; ~ 3 to 10 h to traverse small intestine Fig. 25-37 Rhoads 112 56 3/5/2024 Fig. 25-38, Rhoads There are two types of movements in the colon: 1. Segmentation - very similar to the small intestine, mixes contents, & divides colon into sac-like structures (haustra). 113 2. mass movement this type of contraction occurs 1-3 times a day. accomplished by a strong peristaltic wave (colonic segments remain contracted for some time). is a form of peristalsis. push contents distally. mediated by Ach Fig. 31-24, Berne et al - Colon also has peristalsis sim ilarto thatofsm allintestine butis notthe prim ary propulsion. - m ass m ovem entis m ain propulsive m echanism ,propelling the chym e (now feces)tow ard the rectum. 114 57 3/5/2024 from large intestine to rectum defecation reflex - modulated by sacral region of spinal cord via pelvic nerves, under voluntary control (thank goodness). filling of rectum stimulates: reflex relaxation of internal anal sphincter (circular smooth muscle), and reflex contraction of external anal sphincter (entirely striated & innervated by somatic nerves) initiates urge to defecate. Fig. 31-25, Berne et al 115 GUT MICROBIOTA https://mpkb.org/ Over 95% of microbes in the gastrointestinal tract. Weight ~ 2 kg (4.5 lbs) 116 116 58 3/5/2024 “We are not alone.” in small intestine, 5 trillion bacteria/teaspoon immense impact on human metabolism, nutrition and immunity gut bacteria come from human contact & foods, colonizes gut dead bacteria constitute much of normal stool http://www.probionov.com/humanmicrobiome/the-intestinal-microbiota/ 117 COMPOSITION OF GUT MICROBIOTA CHANGES WITH AGE, NUTRITIONAL STATUS & HEALTH. Ottman 2012 Front Cell Infect Microbiol 118 59 3/5/2024 In SE Asia time (day) David et al 2014, BMC Genome Biology food poisoning time (day) Gut microbiota is specific for each individual, generally stable over time, but can be perturbed by environment and illness. Subject A on travel (d 71 to 122), had diarrhea (d 80 to 85, 104 to 113) Subject B had food poisoning: Enterobacteriaceae (Salmonella’s parent family) Proteobacteria) accounted for 10% of daily reads during the diarrheal illness and peaked at 29.3% on day 159. Otherwise, 0.004% on other days. No antibiotics 119 used. 119 abnormal microbiota composition Aw & Fukuda 15, Diseases; Also Penn State U Extension Prebiotics (1995): food for growth of good bacteria Probiotics (1980): microbes claimed to provide health benefits when consumed Fecal microbiota transplantation (FMT): infusion of stool from healthy donor to recipient’s gut by colonoscopy, enema, orogastric tube, mouth. FDA-regulated since 2013 when FMT conceived to combat an 120 epidemic of C. difficile infection in US & Europe 120 60