Digestion And Absorption Notes PDF

Digestion and Absorption: Dr. Komnenov Page 1 of 18 Digestion and Absorption Learning Objectives: 1. Describe the mechanism of carbohydrate digestion and absorption. a. Describe the digestion of carbohydrates. b....

Digestion and Absorption: Dr. Komnenov Page 1 of 18 Digestion and Absorption Learning Objectives: 1. Describe the mechanism of carbohydrate digestion and absorption. a. Describe the digestion of carbohydrates. b. Describe the absorption of carbohydrates by enterocytes. c. Describe the following clinical disorders of carbohydrate absorption: osmotic diarrhea and lactose intolerance. 2. Describe the mechanism of protein digestion and absorption. a. Describe the digestion of proteins. b. Describe the absorption of proteins by enterocytes. c. Describe the following clinical disorders of protein absorption: chronic pancreatitis, cystic fibrosis, and cystinuria. 3. Describe the mechanism of fat digestion and absorption. a. Describe the digestion of lipids. b. Describe the absorption of lipids. c. Describe the following clinical disorders associated with malabsorption of lipids (steatorrhea): pancreatic insufficiency, deficiency of bile salts, bacterial overgrowth, and abetalipoproteinemia. 4. Describe the absorption of other substances within the alimentary canal. a. Describe the absorption of vitamins. b. Describe the absorption of calcium. c. Describe the absorption of iron. 5. Describe the mechanism responsible for intestinal fluid balance and electrolyte transport. a. Describe intestinal absorption of fluid and electrolytes. b. Describe intestinal secretion of fluid and electrolytes. c. Describe mechanisms responsible for diarrhea. Digestion and Absorption: Dr. Komnenov Page 2 of 18 Outline: (1) Carbohydrates (a) Digestion of carbohydrates (b) Absorption of carbohydrates (c) Clinical disorders of carbohydrate absorption (2) Proteins (a) Digestion of proteins (b) Absorption of proteins (3) Lipids (a) Digestion of lipids (b) Absorption of lipids (c) Malabsorption of lipids-steatorrhea (4) Absorption of other substances (a) Vitamins (b) Calcium (c) Iron (5) Intestinal Fluid and Electrolyte Transport (a) Intestinal absorptions (b) Intestinal secretion (c) Diarrhea Digestion and Absorption: Dr. Komnenov Page 3 of 18 Digestion and Absorption Digestion and absorption are the ultimate functions of the GI tract. o Digestion: the chemical breakdown of ingested foods into absorbable molecules. The digestive enzymes are secreted in salivary, gastric, and pancreatic juices and also are present on the apical membrane of intestinal epithelial cells. o Absorption: the movement of nutrients, water, and electrolytes from the lumen of the intestine into the blood, and this can be achieved via two paths: a cellular path and a paracellular path. In the cellular path, the substance must cross the apical (luminal) membrane, enter the intestinal epithelial cell, and then be extruded from the cell across the basolateral membrane into blood. Absorptive processes are aided by transporters in the apical and basolateral membranes. In the paracellular path, substances move across the tight junctions between intestinal epithelial cells, through the lateral intercellular spaces, and into the blood. Structural features of the intestinal mucosa called villi and microvilli increase the surface area of the small intestine, maximizing the exposure of nutrients to digestive enzymes and creating a large absorptive surface. The surface of the small intestine is arranged in longitudinal folds, called folds of Kerckring. Fingerlike villi project from these folds. The length of the villi decreases from the duodenum (where most digestion and absorption occurs), to the terminal ileum. The surfaces of the villi are lined with epithelial cells (enterocytes) interspersed with mucus-secreting cells (goblet cells). The apical surface of the epithelial cells is further expanded by tiny enfoldings called microvilli, which is collectively called the brush border because of its “brushlike” appearance under light microscopy. Together, the folds of Kerckring, the villi, and the microvilli increase total surface area by 600-fold. (1) Carbohydrates Ingested carbohydrates are polysaccharides, disaccharides (sucrose, lactose, maltose, and trehalose), and small amounts of monosaccharides (glucose and fructose). (a) Digestion of carbohydrates Only monosaccharides are absorbed by the intestinal epithelial cells, so all ingested carbohydrates must be digested to monosaccharides: glucose, galactose, or fructose. Digestion of starch begins with salivary α-amylase in the mouth; it is however inactivated by the low pH of the gastric contents. Digestion n and Absorption: Dr. Komnenov v Page 4 of 18 Pancrreatic amyla ase digests innterior 1,4-gglycosidic boonds in starcch, yielding tthree disacccharides, α-liimit dextrinss, maltose, aand maltotrioose. These diisaccharidess are furtheer digested to o monosacch harides by thhe intestinal brush-bordeer enzymes, α α- dextrinase, malta ase, and sucrase. The prroduct of eacch of these ffinal digestivve steps is i glucose. The thhree disaccharides in foood are trehaloose, lactose,, and sucrosee. Each moleecule of disaaccharide is digested to two moleculles of monossaccharide bby the enzym mes trehalase, lactase and sucra se (Fig. 1). T Thus, the thrree possible end productts of carbohhydrate digeestion are: gllucose, galacctose, and fruuctose. Fig. 1- Carbohydra C ate digestion in the smalll intestine (b b) Absorptio on of carbohy ydrates Gluco ose and galacctose are abssorbed acrosss the apical membrane m by y secondary active transport t mechaanisms. Gluco ose and galacctose are exttruded from thet cell into the blood, across a the baasolateral meembrane, by facilittated diffusio on (GLUT 2) (Fig. 2). Fructo ose is handleed differently y from glucosse and galacctose. Fructose is transpported acrosss both the appical and baasolateral membranes by y facilittated diffusio on: in the apical F Fig. 2- Absoorption of Caarbohydratess memb brane, via thee fructose-sppecific transpporter is calleed GLUT 5, and in the bbasolateral m membrane, viia GLUT 2 ((Fig. 2). Digestion n and Absorption: Dr. Komnenov v Page 5 of 18 (cc) Clinical disorders d off carbohydrrate absorpttion - Osmootic diarrheaa The most m common n culprit for disorders off carbohydraate absorptioon is the inabbility to break down inggested carboh hydrates to aan absorbablle form (i.e.,, to monosaccharides)). When non n-absorbable carbohydrattes remain inn the GI lum men, they associate a witth an equivallent amount of water to kkeep the inteestinal conteents isosm motic. Retentiion of this soolute and waater in the inttestine causees osmotic diarrh hea. Lactoose intoleran nce, which iss caused by lactase defiiciency in thhe brush-bordder and laactose is not digested to glucose g and galactose. L Lactose holdds water in thhe lumen n, and causess osmotic diaarrhea. (2) Proteins Dietary prroteins are digested d to ab bsorbable foorms, which include amino acids, dipeptidess, and tripep ptides, by prooteases in thee stomach annd small inteestine and thhen absorbed into the bloo od. The proteins containned in GI seccretions (e.g.., pancreatic enzymes) are similarlly digested and a absorbedd. (aa) Digestion n of proteins The digestion d of protein p beginss in the stom mach with the acction of pepsin and is complleted in the small s intestiine with pan ncreatic and brrush-border proteases (Fig. 3). 3 The two classes of proteaases are endop peptidases and a exopeeptidases. Endop peptidases hyydrolyze the intterior peptid de bonds of prooteins. The endop peptidases off the GI tract are a pepsin, trypsin, t chymmotrypsin, an nd elastaase. Exopepttidases hydrolyze one am mino acid Fig. 3- Diggestion of prroteins in thee (A) stomacch and me from the C-terminus (B) small iintestine at a tim of proteiins and peptiides. The exopeeptidases of the t gastrointtestinal tract are carboxyypeptidasess A and B. Digestion n and Absorption: Dr. Komnenov v Page 6 of 18 The beginning of protein digeestion occurss in the stom mach (Fig. 4, A), via pepssin. There are three iso ozymes of pepsin, each oof which hass a pH optimmum rangingg betweeen pH 1 andd 3; above pH H 5, pepsin iis denaturedd and inactivaated. Proteiin digestion continues in n the small in ntestine (Figg. 4, B) withh the combinned action ns of pancreaatic and brussh-border prooteases. Fivee major panccreatic proteeases are secreted as inaactive precurrsors: trypsinnogen, chymmotrypsinogeen, proelastaase, procarrboxypeptidase A, and procarboxype p eptidase B. First, trypsinogen is activated to trypsin bby the brushh-border enzymme enterokin nase (Fig. 4,, B). Initiallyy, a small am mount of tryppsin is produuced, whichh then catalyzes the conv version of alll of the otherr inactive prrecursors to ttheir activee enzymes (in ncluding its own). The aactivation steeps yield fivve active enzyymes for prootein digestiion: trypsin, chymotrypssin, elastase, carboxypepptidase A, annd carbox xypeptidase B that digesst all proteinns to the absoorbable unitss. Finally, thhe pancreeatic proteasses digest theemselves annd each otherr. Fig g. 4- Activatiion of GI pro oteases in th he (A) stomacch and (B) ssmall intestinne Digestion n and Absorption: Dr. Komnenov v Page 7 of 18 (b b) Absorptio on of protein ns The products of protein digesttion are amin no acids, dipepttides, and tripeptides. Each form f can be abssorbed by in ntestinal epitheelial cells. The L-amino L acidds are absorbbed by mech hanisms analoggous to thosee for monosaccharide absorpption. The am mino acids are transportted from the lummen into thee cell by Na+−aamino acid Fig. 5- Abssorption of aamino acids,, dipeptides and cotran nsporters in the t apical tripeptidess in the smalll intestine memb brane, energiized by the NaN + gradientt (Fig. 5). Thhere are fourr separate cotrannsporters: oneo each for neutral, aciddic, basic, annd imino am mino acids. T The aminoo acids then are a transportted across thhe basolateraal membranee into the bloood by faccilitated diffu usion, again by separate mechanism ms for neutrall, acidic, bassic, and im mino amino acids. a Most ingested pro otein is absorrbed by intesstinal epitheelial cells in tthe dipeptid de and trripeptide forrms rather th han as free aamino acids. Inside the cell, most of the dipepttides and trip peptides are hydrolyzed to amino accids by cytossolic peptidaases, produ ucing amino acids that ex xit the cell byy facilitated diffusion; thhe remainingg dipepttides and trip peptides are absorbed unnchanged (Fig. 5). (cc) Disorders of protein n digestion and a absorptiion Disord ders of proteein digestionn or absorptioon occur whhen there is a deficiency of pancreeatic enzymees or when theret is a deffect in the trransporters oof the intestinnal epitheelial cells. In n disorders of the exocrinne pancreas such as chroonic pancrreatitis and cystic c fibrossis, there is a deficiency of all pancrreatic enzym mes includ ding the protteases. Dietaary protein caannot be abssorbed if it iss not digesteed by proteaases to amino o acids, dipeeptides, and tripeptides. The absencee of trypsinn alone mak kes it appearr as if all of tthe pancreattic enzymes aare missing becauuse trypsin iss necessary for f the activaation of all pprecursor enzzymes (incluuding trypsinn itself) to th heir active fo orms. Several diseases are a caused by y a defect inn or absence of a Na+−am mino acid nsporter. Cysstinuria is a genetic disoorder in whiich the transpporter for the cotran dibasiic amino acid ds cystine, lyysine, arginiine, and orniithine is abseent in both thhe small intestine and d the kidneyy. Consequenntly, none off these aminoo acids is absorbbed by the in ntestine or reeabsorbed byy the kidneyy. The intestiinal defect reesults Digestion n and Absorption: Dr. Komnenov v Page 8 of 18 in faillure to absorrb the amino acids, whichh are excreteed in feces. T The renal deefect resultss in increaseed excretion of these spe cific amino acids and giives the disease its namme, cystinurria or excess cystine excrretion. (3) Lipids L The dietarry lipids incllude triglyceerides, choleesterol, and pphospholipidds. A factor tthat greatly co omplicates liipid digestion n and absorpption is theirr insolubilityy in water (thheir hydrophobicity). Becaause the GI tract t is filledd with aquueous fluid, the lipids mmust somehow w be solubilizzed to be dig gested and abbsorbed. (aa) Digestion n of lipids The digestion d of dietary d lipidss begins in thhe stomach w with the actiion of linguaal and gastricc lipases and d is completeed in the small intestine with the acttions of the pancreeatic enzymees pancreaticc lipase, choolesterol esteer hydrolase,, and phosppholipase A2 (Fig. 6). Fig. 6- Dig gestion of lip pids in the sm mall intestinee Stoma ach Chhurns and mixes m dietary lipids and innitiates enzyymatic digesttion. The ch hurning actioon breaks thee lipids into small dropleets, increasinng the surfacce area for digesttive enzymes. In the stom mach, the lippid droplets are emulsified by y dietary proteins. Liingual and gastric g lipasses initiate liipid digestioon by hydrolyyzing ap pproximately y 10% of ing gested triglyccerides to glyycerol and ffree fatty acids (F Fig. 6). Onne of the mo ost importantt contributioons of the stoomach to oveerall lipid digestion (and d absorption)) is that it em mpties chymee slowly intoo the small inttestine, allow wing adequaate time for ppancreatic ennzymes to diigest lipids. The ratte of gastricc emptying, which is so critical for ssubsequent iintestinal digestive and absorptive steps, is slow wed by CCK K. CCK is secreted whenn dietary lipids first f appear in i the small intestine. Digestion and Absorption: Dr. Komnenov Page 9 of 18 Small Intestine Bile salts are secreted into the lumen of small intestine, where together with lysolecithin and products of lipid digestion, they surround and emulsify dietary lipids. The pancreatic enzymes (pancreatic lipase, cholesterol ester hydrolase, and phospholipase A2) and one special protein (colipase) are secreted into the small intestine to accomplish the digestive work (Fig. 6). Pancreatic lipase is secreted as an active enzyme. It hydrolyzes triglyceride molecules to one molecule of monoglyceride and two molecules of fatty acid. A potential problem in the action of pancreatic lipase is that it is inactivated by bile salts. This is why colipase is secreted in pancreatic juices in an inactive form, procolipase, which is activated in the intestinal lumen by trypsin. Colipase then displaces bile salts at the lipid-water interface and binds to pancreatic lipase. With the inhibitory bile salts displaced, pancreatic lipase can proceed with its digestive functions. Cholesterol ester hydrolase is secreted as an active enzyme and hydrolyzes cholesterol ester to free cholesterol and fatty acids. It also hydrolyzes ester linkages of triglycerides, yielding glycerol. Phospholipase A2 is secreted as a proenzyme and, like many other pancreatic enzymes, is activated by trypsin. Phospholipase A2 hydrolyzes phospholipids to lysolecithin and fatty acids. The final products of lipid digestion are monoglycerides, fatty acids, cholesterol, lysolecithin, and glycerol (from hydrolysis of ester bonds of triglycerides). With the exception of glycerol, each end product is hydrophobic and therefore is not soluble in water. Now the hydrophobic digestive products must be solubilized in micelles and transported to the apical membrane of the intestinal cells for absorption. b) Absorption of lipids Absorption of lipids occurs in a series of steps illustrated in Figure 7 and is described as follows: 1. The products of lipid digestion (cholesterol, monoglycerides, lysolecithin, and free fatty acids) are solubilized in the intestinal lumen in mixed micelles, except glycerol, which is water soluble. The hydrophilic portion of the bile salt molecules dissolves in the aqueous solution of the intestinal lumen, thus solubilizing the lipids in the micellar core. Digestion n and Absorption: Dr. Komnenov v Page 10 of 18 Fig g. 7- Mechan nism of abso orption of lip pids in the sm mall intestinee 2. Thhe micelles diffuse d to thee apical memmbrane of thhe intestinal eepithelial cells. Thhe lipids are released fro om the micellle and diffusse down theiir concentrattion grradients into the cell. Thee micelles peer se do not enter the celll, however, and the bile salts are a left behin nd in the inteestinal lumenn to be absorrbed downsttream in the ileum. nside the inteestinal epitheelial cells, thhe products oof lipid digesstion are re- 3. In esterified withh free fatty acids on the ssmooth endooplasmic retiiculum to form the original in ngested lipidss, triglyceriddes, cholesteerol ester, annd phospholippids. nside the cellls, the re-esteerified lipidss are packaged with apopproteins in liipid- 4. In caarrying particcles called chhylomicron ns which are composed oof triglyceriddes an nd cholestero ol at the coree and phosphholipids and apoproteinss on the outsiide. Phhospholipidss cover 80% of the outsidde of the chyylomicron suurface, and tthe remmaining 20% % of the surfface is coverred with apooproteins. Appoproteins, w which are synthesizeed by the inteestinal epitheelial cells, arre essential ffor the ab bsorption of chylomicron ns. 5. Thhe chylomicrrons are packaged in seccretory vesiccles on the G Golgi apparattus. Thhe secretory vesicles mig grate to the bbasolateral m membranes, and there is ex xocytosis of the t chylomiccrons. The cchylomicrons are too largge to enter hey can enterr the lymphaatic capillaries (lacteals) by vaascular capilllaries, but th moving betweeen the endotthelial cells that line the lacteals. Thhe lymphaticc cirrculation carrries the chy ylomicrons too the thoraciic duct, whicch empties innto the bloodstreaam. Digestion and Absorption: Dr. Komnenov Page 11 of 18 c) Malabsorption of lipids-steatorrhea Pancreatic insufficiency. Diseases of the exocrine pancreas (e.g., chronic pancreatitis and cystic fibrosis) result in failure to secrete adequate amounts of pancreatic enzymes including those involved in lipid digestion, pancreatic lipase and colipase, cholesterol ester hydrolase, and phospholipase A2. Deficiency of bile salts - interferes with the ability to form micelles, which are necessary for solubilization of the products of lipid digestion. Ileal resection (removal of the ileum) interrupts the enterohepatic circulation of bile salts, which then are excreted in feces rather than being returned to the liver. Because the synthesis of new bile salts cannot keep pace with the fecal loss, the total bile salt pool is reduced. Bacterial overgrowth - reduces the effectiveness of bile salts by de-conjugating them. At intestinal pH, bile acids are primarily in the non-ionized form, which 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. Similarly, decreased pH in the intestinal lumen promotes “early” absorption of bile acids by converting them to their non-ionized form. Abetalipoproteinemia - failure to synthesize Apo B (β-lipoprotein). In this disease, chylomicrons either do not form or are unable to be transported out of intestinal cells into lymph. In either case, there is decreased absorption of lipids into blood and a buildup of lipid within the intestinal cells. (4) Absorption of other substances (a) Vitamins Vitamins are required in small amounts to act as coenzymes or cofactors for various metabolic reactions. Because vitamins are not synthesized in the body, they must be acquired from the diet and absorbed by the GI tract. Categorized as either fat soluble or water soluble (Fig. 8). (i) Fat Soluble Vitamins Vitamins A, D, E, and K. The mechanism of absorption of fat-soluble vitamins is the same as that for the dietary lipids: fat-soluble vitamins are incorporated into micelles and transported to the apical membrane of the intestinal cells, diffuse across the apical membrane into the cells, are incorporated into chylomicrons, and then are extruded into lymph, which delivers them to the general circulation.  n and Absorption: Dr. Komnenov Digestion v Page 12 of 18 Fig. 8-- Water solub ble and fat ssoluble vitam mins (ii) Water W Solublee Vitamins Vitamins B1, B B2, B6, B12, C, biottin, folic acid, nicotinic acid, and pantotheniic acid. In most m cases, abbsorption off the water-sooluble vitam mins occurs viaa a Na+-depenndent cotrannsport mechaanism in the small intesttine. The excep ption is the ab bsorption off vitamin B12 (cobalam min) (Fig. 9). Absorption n of vitamin n B12 requirees intrinsic faactor and occcurs in the following steps: (1) Diietary vitam min B12 is released d from foods by the digesstive action of pepsin p in thee stomach. (22) Free vitamin B12 binds to R proteins, w which are secreteed in salivary y juices. (3) In the duodenum m, pancreatic proteases deegrade the R proteeins, causing g vitamin B112 to be transferrred to intrin nsic factor, a glycoproteein secreted by b the gastriic F Fig. 9- Absorp rption of B122 parietal ceells. (4) The vitamin v B122-intrinsic faactor compleex is resistannt to the degraddative actions of pancreaatic proteasess and travelss to the ileum m, where therre is a speciffic transport mechanism for its absorrption. A consequ uence of gasttrectomy is lloss of the soource of intrrinsic factor, the parietal ceells. Thereforre, after a gaastrectomy, ppatients fail to absorb vitamin B12 from the ileum, eventtually becom me vitamin B B12 deficiennt, and may develop d pernnicious anem mia. To prevvent pernicioous anemia, vitamin B12 must be administered a d by injectionn; orally suppplemented vitamin B12 cannot bee absorbed inn the absencce of intrinsicc factor. Digestion and Absorption: Dr. Komnenov Page 13 of 18 b) Calcium Ca2+ is absorbed in the small intestine and depends on the presence of the active form of vitamin D, 1,25-dihydroxycholecalciferol. Its most important action is to promote Ca2+ absorption from the small intestine by inducing the synthesis of vitamin D–dependent Ca2+-binding protein (calbindin D-28 K) in intestinal epithelial cells. In vitamin D deficiency or when there is failure to convert vitamin D to 1,25- dihydroxycholecalciferol (as occurs in chronic renal failure), there is inadequate Ca2+ absorption from the GI tract. In children, inadequate Ca2+ absorption causes rickets, and in adults, it causes osteomalacia. c) Iron Iron is absorbed across the apical membrane of intestinal epithelial cells as free iron (Fe2+) or as heme iron (i.e., iron bound to hemoglobin or myoglobin). Free iron binds to apoferritin and is transported across the basolateral membrane into the blood. In the circulation, iron is bound to a β-globulin called transferrin, which transports it from the small intestine to storage sites in the liver. From the liver, iron is transported to the bone marrow, where it is released and utilized in the synthesis of hemoglobin. (5) Intestinal fluid and electrolyte transport Together, the small and large intestines absorb approximately 8.5 L of fluid daily, an amount almost equal to the entire extracellular fluid volume (Fig. 10) Of this 8.5 L, most is absorbed by the epithelial cells of the small intestine ( ~ 6.5L) and colon (~ 1.9L). The small remaining volume that is not absorbed (~ 100 mL) is excreted in feces. Fig. 10- Fluid balance in the GI tract Digestion and Absorption: Dr. Komnenov Page 14 of 18 The small intestine and colon not only absorb large quantities of electrolytes (Na+, Cl−, HCO3−, and K+) and water, but the epithelial cells lining the crypts of the small intestine also secrete fluid and electrolytes. This additional secretion contributes to the volume already in the intestinal lumen, which then must be absorbed. The mechanisms for fluid and electrolyte absorption and secretion in the intestine involve cellular and paracellular routes. The permeability of tight junctions between the epithelial cells determines whether fluid and electrolytes will move via the paracellular route or whether they will move via the cellular route. The tight junctions in the small intestine are “leaky” (have low resistance) and permit significant paracellular movement, whereas the tight junctions in the colon are “tight” (have a high resistance) and do not permit paracellular movement. (a) Intestinal absorption Intestinal epithelial cells lining the villi absorb large volumes of fluid. The first step in this process is the absorption of solute, followed by the absorption of water. The solute absorptive mechanisms vary among the jejunum, the ileum, and the colon. 1. Jejunum The jejunum is the major site for Na+ absorption in the small intestine (Fig. 11, A). Na+ enters the epithelial cells via several different Na+-dependent coupled transporters (electro-neutral transport). The apical membrane contains Na+-monosaccharide cotransporters (Na+-glucose and Na+-galactose), Na+−amino acid cotransporters, and Na+-H+ exchanger. After Na+ enters the cell on the coupled transporters, it is extruded across the basolateral membrane via the Fig. 11 A- Mechanism of electrolyte + + Na -K ATPase. Note that the transport in jejunum source of H+ for Na+-H+ exchange is intracellular CO2 and H2O, which are converted to H+ and HCO3−. H2O moves in response to Na+ gradient built up across the epithelium.  n and Absorption: Dr. Komnenov Digestion v Page 15 of 18 2. Ileum Th he ileum con ntains the sam me traansport mech hanisms as the t jejjunum plus a Cl−- HC CO3− exchan nge mechaniism in the apical mem mbrane and a Cll− transporter, instead off an HC CO3− transpo orter, in the baasolateral meembrane (Fig g. 11 B)). Thus, wheen H+ and HC CO3− are gen nerated insidde the ep pithelial cellss in the ileum m, the H+ is secreted into the lum men via FFig. 11 B- M Mechanism of electrolytee the Na+-H+ ex xchanger, and d the ttransport in ileum HC CO3− also iss secreted intto the lummen via the Cl−-HCO3− exchanger ((rather than bbeing absorbbed into bloood, as in the jejunum mbined Na+-H m). The result of the com H+ exchangee and Cl−- HC CO3− exchan nge in the ap pical membraane is net m movement of NaCl into thhe ceell, which theen is absorbeed. Thus, T in the illeum, there is i net absorpption of NaC Cl, whereas iin the jejunuum there is net absorption of NaHCO N 3. 3. Colon n Th he apical meembrane con ntains Na+ annd + K channels, which w are ressponsible for Na+ absorrption and K+ K secretion n. Sy he Na+ chann ynthesis of th nels is induced by ald dosterone, which w leads to N + absorptio increases in Na on and, secondarily, too increases inn K+ secretion (FFig. 12). In ncreased num mber of Na+ channel c leadds + to increased Na N entry acrross the apicaal membrane and N + pumpedd d increased Na ouut across the basolateral membrane bby the Na+-K+ AT TPase, which h leads to Fig. 122- Electrolytte transport in + increased K pumped p o the cell, andd, the collon into + fin nally, increased K secreetion across tthe apical mmembrane. Inn diarrhea, tthe high flow ratee of intestinal fluid causees increased colonic K+ ssecretion, resulting in increased K+ loss l in feces and hypokaalemia. Digestion n and Absorption: Dr. Komnenov v Page 16 of 18 (b b) Intestinal secretion The eppithelial cellls lining the intestinal crrypts secretee fluid and ellectrolytes. T The + + − basolaateral membrane also haas an Na -K -2Cl cotrannsporter. Thiis three-ion cotran nsporter brinngs Na+, Cl−, and K+ intoo the cells froom the blood (Fig.13). Cl− moves m into thee cells on the Na+-K+-2C Cl− cotranspoorter, and thhen diffuses iinto the lum men through h Cl channeels in the apiical membranne. Na+ folloows Cl− secrretion − passiv vely, moving g between th he cells. Finallly, water is secreted s into the lumen, ffollowing thhe secretion oof NaCl. C − channelss of the apicaal membranee usually aree closed, but they may oppen The Cl in resp ponse to binnding of vario ous hormonees and neurootransmitterss (i.e. ACh, V VIP) to receeptors on thee basolaterall membrane.. The neurotransmitter or horm mone binds too the basolateeral receptorr, activating adenyylyl cyclase and a generatin ng cAMP inn the crypt ceells. cAMP oopens the Cl− ch hannels in th he apical memmbrane, initiiating Cl− seecretion; Na+ and water w Cl− into thee lumen (Fig follow g. 13). Normmally, the elecctrolytes and d water secreeted by intesstinal crypt ccells are absoorbed by inttestinal villarr cells. Howeever, in diseeases in whicch adenylyl ccyclase is maximmally stimulaated (e.g., ch holera), fluiid secretion bby the crypt cells overw whelms the ab bsorptive caapacity of thee villar cells and causes severe, life- threatening diarrh hea. Fig. F 13- Mecchanism of Cl- C and fluidd secretion inn epithelial ccells in i intestinal crypts Digestion and Absorption: Dr. Komnenov Page 17 of 18 (c) Diarrhea Diarrhea is a major cause of death worldwide. Serious illness or death may be caused by the rapid loss of large volumes of extracellular-type fluid from the GI tract. The previous discussion emphasizes the enormous potential for fluid loss from the gastrointestinal tract, as much as 9 L or more per day. In diarrhea, the loss of extracellular-type fluid results in decreased extracellular fluid volume, decreased intravascular volume, and decreased arterial pressure. The baroreceptor mechanisms and the renin–angiotensin II–aldosterone system will attempt to restore blood pressure (pressure natriuresis mechanism), but these attempts will be futile if the volume of fluid lost from the GI tract is too great or if the loss is too rapid. In addition to circulatory collapse, other disturbances caused by diarrhea are related to the specific electrolytes lost from the body in the diarrheal fluid, particularly HCO3− and K+. Diarrheal fluid has a relatively high concentration of HCO3− because the fluids secreted into the GI tract have a high HCO3− content including salivary, pancreatic, and intestinal juices. Loss of HCO3− (relative to Cl−) causes hyperchloremic metabolic acidosis with normal anion gap. Diarrheal fluid also has a high concentration of K+ because of flow-rate–dependent K+ secretion by the colon. Excessive loss of K+ from the GI tract results in hypokalemia. The causes of diarrhea include decreased absorptive surface area, osmotic or secretory disturbances. Decreased Surface Area for Absorption Disease processes that result in a decreased absorptive surface area including infection and inflammation of the small intestine cause decreased absorption of fluid by the GI tract. Osmotic Diarrhea Fig. 14- Mechanism of osmotic and Osmotic diarrhea is caused by the secretory diarrhea presence of non-absorbable solutes in the lumen of the intestine. For example, in lactase deficiency, lactose is not digested to glucose and galactose, the absorbable forms of this carbohydrate. Undigested lactose is not absorbed and remains in the lumen of the intestine, where it retains water and causes osmotic diarrhea (Fig. 14). Bacteria in the intestine may degrade lactose to more osmotically active solute particles, further compounding the problem. Digestion and Absorption: Dr. Komnenov Page 18 of 18 Secretory Diarrhea Caused by excessive secretion of fluid by crypt cells (Fig. 14). The major cause of secretory diarrhea is overgrowth of enteropathic bacteria (pathogenic bacteria of the intestine) such as Vibrio cholerae or Escherichia coli. For example, the bacterial cholera toxin (Fig. 13) enters intestinal crypt cells by crossing the apical membrane (Step 1). Inside the cells, the A subunit of the toxin detaches and moves across the cell to the basolateral membrane. There, it catalyzes adenosine diphosphate (ADP) ribosylation of the αs subunit of the Gs protein that is coupled to adenylyl cyclase (Step 2). ADP-ribosylation of the αs subunit inhibits its GTPase activity, and as a result, GTP cannot be converted back to GDP. With GTP permanently bound to the αs subunit, adenylyl cyclase is permanently activated (Step 3), cAMP levels remain high, and the Cl− channels in the apical membrane are kept open (Step 4). The resulting Cl− secretion is accompanied by secretion of Na+ and H2O. The volume of fluid secreted into the intestinal lumen overwhelms the absorptive mechanisms of the small intestine and colon, leading to massive diarrhea.