Gastrointestinal Physiology 2

Identify the major sites of Ca2+ absorption from the intestine. Summarize the process of calcium absorption and the role of vitamin D in this process:

1. Calcium is absorbed in the small intestine through either active transport (duodenum at low intake concentration) or passive transport (ileum and jejunum at high intake concentration) 2. From Costanzo : " [1,25 -dihydroxycholecalciferol]'s most important action is to promote Ca 2+ absorption from the small intestine by inducing the synthesis of Vitamin D- dependent Ca 2+ binding protein (calbindin) in intestinal cells."

Define chylomicron. List some component molecules of the chylomicron particle:

1. Chylomicron= lipoprotein particle 2. Consists of triglycerides (re-esterified), cholesterol, cholesterol esters, phospholipids and apoproteins. Mature Chylomicrons have Apo B48, Apo C2, and ApoE

Describe the reassembly of large lipid molecules in the intestinal cells:

1. Digested lipids are re-esterified on the smooth ER of the enterocyte with free fatty acids to form the original ingested lipids

Explain briefly how commonly prescribed drugs (such as atropine, cimetidine, omeprazole) inhibit stomach acid secretion:

Atropine: Acetylcholinergic neurons of the parasympathetic autonomic nervous system activate muscarinic receptors on parietal cells, which then secrete H+. ACh also activates ECL cells to release histamine, which will act on parietal cells to secrete H+. As a competitive antagonist of muscarinic receptors, atropine blocks both these actions. Cimetidine: Histamine will typically bind H2 receptors on parietal cells and increase H+ secretion. Cimetidine blocks H2 receptors on parietal cells. Omeprazole: H+ is pumped out of parietal cells via a H+/K+ ATPase. Cl- will diffuse out of Cl- channels in the parietal cell membrane, following the H+. Omeprazole inhibits the ATPase.

Describe the role of the proteases associated with the brush border that are produced by intestinal epithelial cells:

Brush border proteases break down oligopeptides into smaller units (amino acids etc...) in order to be absorbed by the intestinal epithelial cells. E.g. Aminopeptidase and Dipeptidase are two examples of brush border enzymes

List and describe the transport processes used by intestinal cells to absorb glucose, fructose, and galactose:

From lumen to cell: • Glucose and galactose: secondary active transport using Na-glucose cotransporter (SGLT1) ○ Uses ATP indirectly through Na+/K+ ATPase that uses ATP to create Na+ gradient • Fructose: facilitated diffusion via GLUT 5 From cell to blood: • Glucose, galactose, and fructose: facilitated diffusion via GLUT2

Describe the role of pancreatic digestive enzymes in the chemical digestion of carbohydrates and list the resulting end products: IE What do pancreatic digestive enzymes digest?

Pancreatic amylase is responsible for digestion of starch. The three disaccharide end products are 1) a-limit dextrins, 2) maltose, and 3) maltotriose.

List the major intestinal cell brush border enzymes, describe the role of each enzyme in the chemical digestion of carbohydrates, and list the resulting end products:

a-dextrinase, maltase, sucrase, trehalase, and lactase are all intestinal cell brush border enzymes Maltase: maltose → glucose a-dextrinase: a-dextrins → glucose Sucrase: maltotriose → glucose; sucrose → glucose + fructose Lactase: lactose → glucose + galactose Trehalase: trehalose → glucose The three end products of carb digestion are glucose, galactose, and fructose which are all monosaccharides.

List the classes/types of carbohydrates entering the small intestine from the stomach:

○ Soluble starches that have BEGUN DIGESTION BY SALIVARY AMYLASE ○ Trehalose- disaccharide (two α-glucose with α,α-1,1-glucoside bond) ○ Lactose- disaccharide ○ Sucrose- disaccharide ○ Free glucose molecules ○ Maltose ○ Maltotriose ○ oligosaccharides (if branched then called limit dextrins)

Describe how the macroscopic and microscopic architecture of the gut epithelium contributes to creating a large and specialized absorptive surface:

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 small intestine is lined with plicae circularis and projecting from these structures are the villi. The surfaces of these villi are lined with epithelial cells and goblet cells. On the apical surface of the epithelial cells are small enfoldings called microvilli. The microvillar surface is termed the brush-border due to its "brush-like" appearance under a light microscope. SI: plicae circularis > villi > microvilli

Contrast the secondary active transport (absorption) of amino acids with the absorption of dipeptides and tripeptides:

1. Amino acids are transported from the intestinal lumen into enterocytes via secondary active transport as Na+ goes down its concentration gradient 2. Dipeptides and tripeptides are transported from the intestinal lumen into enterocytes via secondary active transport as H+ goes down its concentration gradient. 1. Cytosolic peptidases hydrolyze most of these oligopeptides into single amino acids

Describe the process of vitamin B12 absorption. List common causes of B12 malabsorption and consequences:

1. B12 absorption 1. Dietary vitamin B 12 is released from foods by the digestive action of pepsin in the stomach 2. Free vitamin B 12 binds to R proteins, which are secreted in salivary juices 3. In the duodenum, pancreatic proteases degrade the R proteins, causing vitamin B 12 to be transferred to intrinsic factor 4. The vitamin B 12 -intrinsic factor complex travels to the ileum, where there is a specific transport mechanism for its absorption. 2. Common Causes of B12 malabsorption 1. Gastrectomy- removal of parts of stomach containing parietal cells which secrete intrinsic factor. 2. Chronic atrophic gastritis 3. Celiac disease (in some cases) 4. Crohn's disease (in some cases) 5. Bacterial overgrowth 3. Clinical Effects of B12 malabsorption 1. Pernicious anemia- B12 is key in folate cycle. 1. Macrocytic/megaloblastic anemia + Neurological symptoms

Describe the role of bile salts in the digestion of dietary lipids:

1. Bile salts are produced in the liver and secreted into the small intestine via the gall bladder 1. Bile salts are amphipathic 1. Hydrophobic steroid portion interacts with the products of lipid digestion 2. Hydrophilic portion is soluble in the aqueous environment of the intestine 2. Bile salts surround and emulsify lipids to form micelles 1. Emulsification produces small lipid droplets with a large surface area to be hydrolyzed by lipases

Define micelle and explain the role the micelles play in lipid absorption and the uptake of fat-soluble vitamins:

1. Bile salts surround the products of lipid digestion to form micelles in the intestinal lumen 2. Micelles diffuse towards the brush border of enterocytes 3. Digested lipids are released from the micelle and they diffuse into enterocytes 4. The fat-soluble vitamins, A D E & K, are incorporated into the micelles to facilitate their absorption.

Describe the process of HCl production and secretion by stomach parietal cells. Describe the ion transport mechanisms and cellular enzymes needed to allow parietal cell homeostasis during gastric acid secretion:

1. In intracellular fluid, CO2 produced from aerobic metabolism combines with H2O to form H2CO3, catalyzed by carbonic anhydrase. H2CO3 dissociates into H+ and HCO3-. The H+ is secreted with Cl- into the lumen of the stomach (H+ pumped by H+/K+ ATPase; Cl- diffuses through ion channel), and the HCO3- is absorbed into the blood (HCO3-/Cl- exchange on basolateral side). 2. At the apical membrane of gastric parietal cells, H+ is secreted into the lumen of the stomach via the H+ - K+ ATPase. Cl- follows H+ into the lumen by diffusing through Cl- channels in the apical membrane. 3. At the basolateral membrane of gastric parietal cells, HCO3- is absorbed from the cell into the blood via a Cl-/HCO3- exchanger. 4. Net effect of events at apical and basolateral membranes: secretion of HCl and absorption of HCO3-

Explain how Olestra functions as a non-digestible artificial fat used in commercial foods:

1. Olestra is synthesized from sucrose and oils. It's molecular shape is MUCH LARGER than typical triglycerides. The difference in shape prevents lipases from functioning; thus, it is excreted undigested. The problem is that it excretes fat-soluble nutrients with it, including vitamins and carotenoids. 2. Since it cannot be digested, the food was able to maintain its texture and taste, but without increasing fat absorption.

Explain the mechanism of Orlistat, why it might be prescribed and what side effects might be expected with its use.:

1. Orlistat is a lipase inhibitor. 2. Mechanism of action: A REVERSIBLE of gastric and pancreatic lipases, thus inhibiting absorption of dietary fats by 30%. 3. For obesity management, including weight loss and weight maintenance, when used in conjunction with a reduced-calorie diet; to reduce the risk for weight regain after prior weight loss. 1. Given to patients with BMI > 30 + other risk factors including hypertension, diabetes, dyslipidemia 4. Side effects: 1. increase risk of cholelithiasis (gall bladder stones) 2. hepatotoxicity 3. increased urinary oxalate → renal malfunction 4. Decrease absorption of fat-soluble vitamins 5. Steatorrhea 5. the following side effects are reported to get better with time 1. headache, upper respiratory infections, influenza, neuromuscular pain, GI symptoms (diarrhea, pain, leakage)

Describe the steps involved in the activation and role of enteropeptidase, trypsin, phospholipase, pancreatic lipase and colipase in the digestion of lipids. List the resulting end-products:

1. Trypsinogen is secreted by the pancreas into the small intestine. 1. Trypsinogen → Trypsin 1. Initially catalyzed by Enteropeptidase ("Brush border" enzyme secreted by enterocytes) 2. Reaction can also be autocatalyzed by Trypsin 2. Trypsin hydrolyzes peptide bonds within proteins to produce small peptide chains (oligopeptides) 2. Phospholipase A2 and Colipase are secreted by the pancreas in the inactive forms and activated by Trypsin 1. Phospholipase A2 hydrolyzes phospholipids into Lysolecithin and FA's 2. Colipase binds to pancreatic lipase-displacing bile salts (which are inhibitory) to allow Pancreatic Lipase to hydrolyze TAG's 3. Pancreatic Lipase is secreted in its active form Pancreatic Lipase hydrolyzes TAG's into monoglyceride and 2 FA's

Describe the process of iron absorption and explain how vitamin C enhances iron absorption. Contrast absorption of iron in a person whose diet is deficient in iron with iron absorption in an individual whose diet contains more iron than he/she needs:

1. absorbed across apical membrane as free iron or as heme bound iron. 1. Heme iron is then digested by lysozymes, releasing free iron 2. apoferritin binds to iron to facilitate transport across basolateral membrane into the blood. 1. apoferritin + Iron = ferritin 3. In the circulation, iron is bound to a beta-globulin called transferrin, which transports it from the small intestine to storage sites in the liver. 4. From the liver, iron is transported to the bone marrow, where it is released and utilized in the synthesis of hemoglobin. • Iron tends to form insoluble salts. Vitamin C complexes iron and keeps it soluble and in the Fe2+ state, which is more soluble and better absorbed. ○ Decreased dietary iron: § Increase in DMT1 (a Fe2+ transporter) on apical surface of enterocytes → allowing a greater influx of Fe2+ into enterocytes § Basolateral side of enterocytes sees an increase in expression of Hephastatin and Ferroportin 1 (both important in the efflux of iron out of enterocytes and into circulation) ○ Increase in dietary iron: § You would get the opposite ○ These changes are driven by the release of Hepcidin in the liver § Increased Hepcidin in iron overload § Decrease Hepcidin in iron deficiency

Define steatorrhea and predict the effects of steatorrhea on the absorption of fat-soluble vitamins. Describe common causes of steatorrhea:

1. steatorrhea: fat excreted in the feces 1. can occur due to any problem in the digestion and absorption sequence, including 1. pancreatic enzyme secretion and function, bile acid secretion, emulsification, micelle formation, diffusion of lipids into intestinal epithelial cells, chylomicron formation, and transfer of chylomicrons into lymph 2. specific conditions that cause steatorrhea are: 1. PANCREATIC INSUFFICIENCY: failure to secrete adequate amounts of pancreatic enzymes 2. acidity of duodenal contents: need to increase pH to activate enzymes 1. causes: parietal cells secreting too much H+, pancreas isn't secreting enough HCO3- 3. deficiency of bile salts: can't form micelles 1. ex. due to ileal resection (more than 100 cm resected) 4. bacterial overgrowth: causes the bile salts to become deconjugated (form bile acids, which are too readily absorbed across the epithelial membrane) 5. decreased intestinal cells → decreased surface area 1. ex. tropical sprue 6. failure to synthesize apoproteins: chylomicrons aren't formed or are unable to be transported out of the intestinal cells 2. effect on fat soluble vitamins: decreased absorption, because they are processed in the same manner as dietary lipids 1. these vitamins are K, A, D, E

Explain briefly the mechanism and stimuli for emesis. Explain how emesis can cause metabolic alkalosis:

Emesis= the process of vomiting A vomiting center in the medulla coordinates the vomiting reflex. Afferent information comes to the vomiting center from the back of the throat, the GI tract, and the chemoreceptor trigger zone in the fourth ventricle (found in the brain). Vomiting Reflex: 1. Reverse peristalsis begins in the small intestine 2. relaxation of the stomach and pylorus 3. Forced inspiration to increase abdominal pressure 4. Movement of larynx upward and relaxation of lower esophageal sphincter 5. Closure of the glottis 6. Forceful expulsion of gastric and sometimes duodenal contents Emesis causes metabolic alkalosis because you are expelling the gastric contents which contain acid. This results in an accumulation of HCO3- and a subsequent increase in tissue pH.

Describe in a sentence the pathophysiology of a lactase enzyme deficiency and list the resulting signs and symptoms of this deficiency. Understand how the major symptoms listed arise and predict what symptoms other brush border enzymes deficiencies (sucrase, trehalase, etc.) may cause. Identify ethnic/age groups who commonly exhibit a lactase enzyme deficiency:

Pathophysiology: Decreased synthesis of lactase leads to a deficiency of lactase, allowing lactose accumulation in the lumen that results in an increased amount of water retention in order to keep the intestinal contents isosmotic. Signs/Symptoms: lactose intolerance, (osmotic) diarrhea, bloating, gas, nausea, and cramps • Most common cause of selective carbohydrate malabsorption • No concomitant weight loss How symptoms arise: • Lactose is not broken down into glucose and galactose (soluble monosaccharides) • Unabsorbed lactose = osmotically active ○ WATER AND IONS are DRAWN into lumen ○ Dilation of the intestine caused by osmosis = accelerated small intestine transit • In the LARGE INTESTINE, lactose is FERMENTED by colonic bacteria into short-chain fatty acids, CO2, and H2 gas ○ Once colonic capacity for short-chain FA absorption is exceeded, osmotic diarrhea results. ○ CO2 and H2 gas → flatulence and abdominal pressure • Summary: Increase in water retention, increased small intestinal transit speed, and H2 gas = GI symptoms Other brush border enzyme def. would probably cause the same symptoms (undigested carbs → increase osmotic pressure→ diarrhea and malabsorption) Prevalence: Lactase deficiency is very common in adults • Most individuals (except northern European descent) begin to lose lactase activity by age 5 yrs. • 25% of Caucasians have lactase deficiency • Greater in Asians, Africans, Native and South Americans (85-100%) • Increasing age = greater prevalence

List the chemical classes of proteins (e.g. dipeptides, etc.) that enter small intestine from the stomach:

The stomach only has one protease - the endopeptidase pepsin Not actually an essential process The pancreatic and brush-border proteases can take care of normal protein digestion on their own Pepsinogen is the inactive precursor (zymogen) form of pepsin Secreted by gastric chief cells Activated by the low pH of the stomach (pH of 1-3) Deactivated again when it hits pH above 5 (i.e. in the duodenum) Pepsin has 3 isozymes that all do basically the same function, and they all have an optimal pH of 1-3

Explain the underlying pathophysiology of gastric and duodenal ulcers:

Tl;dr: peptic ulcers are caused by an imbalance in factors that protect the gastroduodenal mucosa and those that damage it • Protective factors: mucus, HCO3-, prostaglandins, mucosal blood flow, growth factors • Damaging factors: H+, pepsin, H. pylori, NSAIDs, stress, smoking, alcohol consumption Gastric ulcers form primarily because the mucosal barrier is defective. H. pylori is a major causative factor because it releases cytotoxins that destroy mucus and underlying cells. H. pylori can survive in the stomach because it produces urease and alkalinizes its local environment. Duodenal ulcers are more common and form primarily as a result of excess H+ secretion in the stomach, which can't be effectively buffered. H. pylori has a causative but indirect role • H. pylori colonization can inhibit D cells in the gastric antrum. D cells unable to release somatostatin → somatostatin doesn't inhibit gastrin release as it typically would → increased gastrin → increased H+ • H. pylori colonization spreads to the duodenum and inhibits HCO3- secretion

In a patient with Zollinger Ellison syndrome, describe the physiologic impact of uncontrolled secretion of gastrin on the GI tract:

Zollinger Ellison syndrome is caused by a gastrin-secreting tumor in the non-beta-pancreatic cells. This uncontrolled secretion of gastrin leads to: 1. Increased H+ secretion by parietal cells 2. HYPERTROPHY OF GASTRIC MUCOUSA (trophic effect of gastrin) 3. DUODENAL ULCERS caused by the increased H+ secretion 4. The increased H+ secretion causes acidification of intestinal lumen: 1. This causes inactivation of pancreatic lipase 2. As a result, dietary fats are not properly digested or absorbed leading to fat in the stool (steatorrhea)

Describe the process of protein chemical digestion that occurs in the small intestine. Define zymogen and describe the steps (endocrine and catalytic) involved in pancreatic zymogen activation that occurs in the small intestine:

Zymogen - Inactive form of an enzyme 5 Major Proteases - all secreted in inactive forms (zymogens) Trypsin, chymotrypsin, elastase, carboxypeptidase A, and carboxypeptidase B Trypsin - Starts digestion in small intestine Converted from trypsinogen to its active form trypsin by enteropeptidase (brush border enzyme, also called enterokinase) Trypsin autocatalyzes its inactive to active form Trypsin then catalyzes the formation of the rest of the proteases: chymotrypsin, elastase, carboxypeptidase A, and carboxypeptidase B The 5 major enzymes convert proteins to amino acids, dipeptides, tripeptides etc... These forms can be absorbed by intestinal epithelial cells (Note: does not have to be an amino acid to be absorbed)

List the stomach cell types and secreted substances that contribute to regulation of gastric acid secretion via paracrine, hormonal, and neuroendocrine pathways. Understand the integrated feedback regulation of acid secretion via these pathways during a meal. Describe the role of duodenal contents in regulating gastric secretion

• Three substances stimulate H+ secretion by gastric parietal cells: 1. Histamine (a paracrine) TL;DR: ECL in gastric mucosa: histamine (paracrine) → ** H2R on parietal cells → ** Gs → ** adenylyl cyclase → ↑ cAMP → ** PK A → ** parietal cells: H+ 1. Released from enterochromaffin-like (ECL) cells in the gastric mucosa and diffuses via a paracrine mechanism to nearby parietal cells, where it binds to H2 receptors 2. H2 receptors are coupled to adenylyl cyclase by a Gs protein 3. When adenylyl cyclase is activated, there is increased production of cAMP 4. cAMP activates protein kinase A, leading to secretion of H+ by the parietal cells 1. ACh (a neurocrine) TL;DR: Vagus nerves: ACh → ** M3 on parietal cell → ** Gq → ** IP3/Ca2+ second messenger system → ** parietal cells: H+ 1. Released from vagus nerves innervating the gastric mucosa 2. Binds directly to muscarinic (M3) receptors on the parietal cells 3. Gq protein is activated 4. Phospholipase C is activated and liberates diacylglycerol and IP3 from membrane phospholipids 5. IP3 releases Ca2+ from intracellular stores 6. Ca2+ and diacylglycerol activate protein kinases that produce the final physiologic action: H+ secretion by parietal cells 7. Also increases H+ secretion indirectly by causing release of histamine from ECL cells 1. Gastrin (a hormone) TL;DR: G cells (stomach antrum): gastrin (hormone) → CCKBR on parietal cells → ** Gq → ** IP3/Ca2+ second messenger system → parietal cells: H+ (direct) → ** ECL (on parietal cells): histamine → ** parietal cells: H+ (indirect) 1. Secreted into the circulation by G cells in the stomach antrum. 2. Gastrin reaches the parietal cells by an endocrine mechanism, so it is secreted from the stomach antrum into systemic circulation and then delivered back to the stomach via the circulation 3. Gastrin binds to cholecystokinin B (CCK B) receptors on the parietal cells 4. Gastrin stimulates H+ secretion through the IP3/Ca2+ second messenger system 5. Also stimulates H+ secretion indirectly by causing release of histamine from ECL cells • The rate of H+ secretion is regulated by both the independent actions of histamine, ACh, and gastrin, and the interactions among the three agents ○ Called potentiation: ability of two stimuli to produce a combined response that is greater than the sum of the individual responses. • Inhibition of HCl secretion ○ Direct pathway: somatostatin binds to receptors on parietal cells that are coupled to adenylyl cyclase via a Gi protein → Gi activated --| adenylyl cyclase → ↓cAMP → somatostatin antagonizes the stimulatory effect of histamine on H+ secretion § Prostaglandins also antagonize histamine's stimulatory action on H+ secretion by activating a Gi protein and inhibiting adenylyl cyclase ○ Indirect pathway: somatostatin inhibits both histamine release from ECL cells and gastrin release from G cells • Three phases of gastric HCl secretion: ○ Cephalic § Stimuli: smelling and tasting, chewing, swallowing, and conditioned reflexes § Direct stimulation of the parietal cell by vagus nerves, which release ACh § Indirect stimulation of the parietal cells (via ECL activation → histamine) by gastrin (stomach hormone) ○ Gastric § Stimuli: distention of the stomach and the presence of breakdown products of protein, amino acids, and small peptides § Distention causes direct vagal stimulation of the parietal cells and indirect stimulation of the parietal cells via gastrin release § Distention of the stomach antrum → local reflexes that stimulate gastrin release § Direct effect of amino acids and small peptides on the G cells ○ Intestinal § Mediated by products of protein digestion • Role of duodenal contents in regulating gastric secretion ○ Stimulation: § AAs/peptides in duodenum → gastrin from G cells in the duodenum and jejunum § AAs/peptides in blood → gastrin from G cells in the stomach § Distension → releases entero-oxyntin & stimulates enteric and vagovagal reflexes to ECL, G, and parietal cells ○ Inhibition: § Acid □ Release of secretin and bulbogastrone --| parietal cell secretion (negative feedback loop) □ In duodenum → activates inhibitory pathways of the enteric and vagovagal reflexes § Fat content → release CCK and GIP --| HCl secretion § Hyperosmotic chyme → releases an enterogastrone --| forward motion of the chyme