Small Intestinal Anatomy & Physiology PDF

Small intestinal Anatomy & Physiology  Small Intestine: Anatomy Divided into 3 regions: Duodenum Shortest and widest portion of the small intestine starts at pyloric sphincter, about 25 cm long C-shaped, mostly retroperitoneal Closely associate...

Small intestinal Anatomy & Physiology  Small Intestine: Anatomy Divided into 3 regions: Duodenum Shortest and widest portion of the small intestine starts at pyloric sphincter, about 25 cm long C-shaped, mostly retroperitoneal Closely associated with the head of the pancreas Jejunum About 1 meter and extends to ileum Ileum Longest: about 2 meters Joins the large intestine at ileocecal sphincter  Duodenal Anatomy Note the relationships with: The major ducts and vessels associated with the liver and gall bladder The stomach The pancreas The vast majority of the duodenum is retroperitoneal Intra-peritoneal structures removed in this dissection Jejunal and Ileal Anatomy The jejunum has larger plicae circulares The ileum has many large lymphoid nodules (Peyer patches) Arterial supply to the small intestine First 2/3 of the duodenum from the hepatic artery off the celiac trunk Hepatic art. → gastroduodenal art. → superior pancreaticoduodenal art. Pancreaticoduodenal artery supplies… the pancreas and the duodenum The inferior pancreaticoduodenal artery is supplied by the superior mesenteric artery (SMA) The pancreas and duodenum receive arterial blood from both the SMA and hepatic artery  Arterial supply to the small intestine The rest of the small intestine (last part of duodenum → ileum) as well as the first part of the large intestine (up to the transverse/descending colon) receives arterial blood from the superior mesenteric artery Jejunal and ileal arteries Basic venous drainage of the intestines Superior mesenteric vein – receives venous blood from small intestine and portions of the large intestine, stomach, and pancreas Splenic vein receives blood from: Stomach, spleen, pancreas Distal large intestine via the inferior mesenteric vein The splenic vein and superior mesenteric vein join to form the hepatic portal vein, which drains almost all sub-diaphragmatic fore-, mid-, and hindgut structures The hepatic portal vein drains into the liver – more about liver vasculature on liver physiology day Overview of abdominal visceral venous drainage  GI: Small Intestine Histology Mucosa Epithelium Simple columnar, villi Lamina propria Loose CT, blood vessels, lymph vessels, nerves, smooth muscle Duodenum Crypts of Lieberkuhn Jejunum Crypts of Lieberkuhn Ileum Crypts of Lieberkuhn, Peyer’s patches Muscularis Inner circular, outer longitudinal mucosae Submucosa Plica circulares – more notable in the jejunum and ileum Duodenum Brunner’s glands Jejunum No glands Ileum No glands Muscularis externa Inner circular, outer longitudinal Serosa / adventitia Serosa and adventitia  Small Intestinal Histology Plica circulares Folds of mucosa and submucosa Permanent ridges about 10 mm “tall” (projecting into the lumen) Enhance absorption by increasing surface area Plicae circulares cause chyme to Encourages mixing → “spiral” and “slosh” through the intestine  GI Small Intestine Histology Villi Finger-like projections of mucosa that are 0.5 – 1 mm long Vastly increase the SA of epithelium Each villus: Covered by epithelium with core of lamina propria In connective tissue: arteriole, venule, capillary network, lacteal  Microvilli Projections of apical membrane of absorptive cell 1 um long cylindrical, contains bundle of 20-30 actin filaments Too small to be seen individually (smaller than a cell) = brush border Greatly increase surface area  GI Small Intestine: Histology Cell types: Surface absorptive cell / enterocytes Simple columnar epithelium with microvilli Life span is short: a few days Goblet cell: Scattered among the absorptive cells Specialized for secretion of mucus Facilitates passage of material through bowel Paneth cells: Typical serous-secretory appearance, with basophilic basal cytoplasm and apical secretory vesicles basal portion of the intestinal crypts, below the stem cells, release lysozyme, phospholipase A2, and defensins regulate the microenvironment of the intestinal crypts and innate immune responses (more during e-learning)  GI Small Intestine: Histology Cell types that secrete hormones: Enteroendocrine cells I cells: Cholecystokinin S cells: Secretin D cells: Somatostatin K cells: GIP L cells: Peptide YY, incretins Mo cells: Motilin Mucosal cells: Secrete incretins, similar to L-cells Incretins will be discussed in more depth next week  Important Enteroendocrine Cells Cell Location Hormone (Stimulus) Main Hormonal Functions Stomach, Somatostatin Generally “turns down” the release of hormones D duodenum, (many different stimuli cause from nearby cells pancreas release) ECL – stomach ECL – histamine (stimulated by ECL – stimulates acid production EC – stomach, vagus) EC – increased motility EC, ECL small and large EC – serotonin, substance P intestines (mechanical, neural, endocrine) Gastrin (amino acids in the Increases secretion of stomach acid G* Stomach stomach, vagal stimulation, gastrin-releasing peptide) Small Intestine CCK (fats and proteins in the Pancreatic enzyme secretion, gallbladder I* (especially duodenum) contraction, satiety duodenum) Inhibits gastric acid secretion Glucagon-like peptide (amino GLP - Insulin secretion, satiety acids & carbs) Inhibits gastric acid secretion L Small intestine Peptide YY (distal small Peptide YY – inhibits gastric secretion & intestine) motility – slows gastric emptying Motilin (fasting) Migrating motor complex Mo* Small intestine Secretin (acid in small intestine, Bicarbonate and water secretion from pancreas S* Small intestine especially duodenum) Inhibits gastric acid secretion and gastric emptying Small Intestine: Regulation and Motility Mixing / Segmentation Contractions Stretch from chyme against intestinal wall elicits concentric contractions (local reflex) Spaced 1 to 5 cm = causes segmentation and “chain of sausage” appearance Contraction band does not progress Chyme from one contracting Mixes chyme with segment forced into relaxed areas digestive enzymes creates motion that chops and mixes luminal content → Circulates chyme for optimal exposure  Small Intestine: Regulation and Motility Propulsive Movements (Peristalsis) Chyme propelled through small intestine by peristaltic waves (weak) Occur in any part of small intestine and move towards anus Velocity: 0.5 to 2.0cm/sec Peristaltic rush a powerful wave of contractile activity that travels long distances down the small intestine caused by intense irritation or unusual distension  GI Small Intestine: Movements Control of peristalsis Nervous Peristaltic reflex: “law of the gut” mediated by ENS “law of the gut” – distention in the alimentary canal causes distal parts of the canal to relax and proximal parts to contract (circular muscle) Major mechanic of peristalsis Chyme entering duodenum Gastroenteric reflex initiated by distension of the stomach and conducted via the myenteric plexus Hormonal Enhanced by: Gastrin, CCK, serotonin Inhibited by: Secretin, Peptide YY, epinephrine Control of gastric emptying Requirements for chyme entering the duodenum: Food particles must be very small (< 2 mm) Small volumes of low pH fluid Large volumes of acidic fluid will damage the duodenum and denature pancreatic enzymes Gradual release Time is needed for pancreatic enzymes to perform chemical digestion Large volumes “released right away” will limit the absorptive time at the microvilli Therefore the duodenum is the major organ that regulates the rate of gastric emptying Other segments of the small intestine also contribute in a similar fashion Small intestinal control of gastric emptying Nervous control: Both sympathetic nervous system reflexes (at the level of the spinal cord) and enteric nervous system reflexes (submucosal and myenteric plexuses) will inhibit gastric emptying in response to: Increased or decreased osmolarity in the duodenum Decreased pH in the duodenum Distention or any chemical irritation of the duodenum Breakdown products of proteins and fats (mostly proteins) in the duodenum Other areas of the small intestine may participate, but the duodenum seems to be the major nervous regulator Small intestinal control of gastric emptying Hormonal Control: Duodenal hormones: CCK – secreted by I cells throughout the small intestine, but mostly in the duodenum Substances that elicit CCK release: Fats > peptides > carbohydrates (carbohydrates quite ineffective) CCK is likely the major paracrine regulator or gastric emptying – increased CCK release → slowed gastric emptying Secretin – secreted by S cells throughout the duodenum and jejunum Substances that elicit secretin release: low pH > fats, capsaicin, bile acids Mild impact on gastric emptying – slows gastric emptying Small intestinal control of gastric emptying Hormonal Control: Distal small intestine Peptide YY - major hormone that performs the role of the “ileal brake”, secreted by L-cells in the ileum Substances that elicit peptide YY release: Fats > carbohydrates, amino acids If undigested foods are reaching the distal small intestine, then peptide YY “slows everything down” – not just gastric motility, but motility of the proximal intestines as well Other hormones were hypothesized to limit gastric emptying, but were later shown to be unimportant in physiologic conditions Glucagon-like peptide, gastrin-inhibitory peptide – many Type of meal and gastric emptying Explain the variability in the rate of gastric emptying based on its hormonal and neural regulation discussed in the last 3 slides  GI Small Intestine: Movements Emptying at the Ileocecal Valve Protrudes into lumen of cecum Forcefully closed when excess pressure builds up in cecum Wall of ileum has thickened circular muscle called ileocecal sphincter which remains mildy constricted GI Small Intestine Secretions Intestinal Digestive juices by enterocytes Secrete large quantities of water and electrolytes Rate of about 1800mL/day Very similar to extracellular fluid, pH 7.5 to 8.0 A little more alkaline, so a bit more HCO3- Rapidly reabsorbed by villi Supplies a watery vehicle for absorption of substances from the chyme as it comes in contact with villi  GI Small Intestine Secretions Brunner’s Glands Found proximal to the sphincter of Oddi Secrete alkaline mucous in response to: Tactile stimuli or irritating stimuli of the overlying mucosa Vagal stimulation GI hormones: especially secretin Functions Protect duodenal wall from digestion by gastric juice Inhibited by sympathetic stimulation Pancreatic and Hepatic Involvement in Digestion – the Basics 1. Chyme arrives in the duodenum through the pyloric spincter 2. Nutrients and low pH stimulate enteroendocrine cells as well as receptors in the mucosa 3. The enteric nervous system and enteroendocrine cells respond by: CCK secretion → gall bladder contraction, pancreatic enzyme secretion, relaxation of the sphincter of Oddi Secretin release → bicarbonate-rich secretions from the pancreas and the small intestine enterocytes 4. Bile and pancreatic enzymes chemically digest macromolecules in the chyme Bile – emulsification of lipids Pancreatic enzymes – hydrolysis of fats, proteins, carbohydrates into smaller molecules Ducts of the biliary apparatus Bile is secreted by the liver by the right and left hepatic ducts → Join to form the common hepatic duct → The common bile duct is formed at the junction of the cystic duct and common hepatic duct → The sphincter of Oddi regulates release of bile into the duodenum from the ampulla of Vater Sphincter of Oddi = major duodenal papilla Ampulla of Vater = hepato-pancreatic ampulla Ducts of the biliary apparatus and pancreas If the sphincter of Oddi is closed, then bile is stored in the gall bladder The main pancreatic duct meets the common bile duct at the ampulla of Vater The sphincter of Oddi regulates both biliary and pancreatic secretions into the duodenum Sphincter of Oddi = major duodenal papilla Ampulla of Vater = hepato-pancreatic ampulla  Digestive enzymes of the pancreas Protein digestion Enzyme Name Inactive Form Activator Basic Function (FYI*) Trypsin Trypsinogen Enterokinase Cleaves peptide bonds next to arginine or lysine* Chymotrypsin Chymotrypsinogen Trypsin Cleaves peptide bonds next to a wide range of a.a.s Elastase Proelastase Trypsin Cleaves elastin Carboxypeptidase Procarboxypeptidase Trypsin Cleaves the carboxy-terminal ends of peptides Carbohydrate digestion Enzyme Name Inactive Form Activator Basic Function Pancreatic amylase N/A N/A Digests starch Lipid digestion Enzyme name Inactive Form Activator Basic Function Pancreatic N/A Co-lipase activates Cleaves triglycerides to FAs and 2-monoacyl lipase/co-lipase lipase at the micelle glycerol Phospholipase A2 Pro-phospholipase Trypsin Cleaves phospholipids Chemical Digestion – Review Chemical digestion = breaking down macromolecules into smaller molecules to increase absorption Enzymatic digestion – enzymes break macronutrients down into smaller and smaller particles through the process of hydrolysis All pancreatic, gastric, and brush-border enzymes use hydrolysis as a means of breaking a macromolecule into smaller molecules Digestion of Carbohydrates in the Mouth & Stomach Food is first mixed with saliva which contains the enzyme ptyalin (α-amylase or salivary amylase) secreted mainly by the parotid glands Ptyalin hydrolyzes starch into the disaccharide maltose and other small polymers of glucose (3-9 glucose molecules) Activity of ptyalin is blocked by the acid of gastric secretions (pH < 4)  Digestion of Carbohydrates in the Small Intestine Digestion by pancreatic amylase almost identical in its function with salivary amylase ptyalin, but several times as powerful Pancreatic amylase is the most important enzyme for digestion of starches Starches are almost totally converted into maltose and other very small glucose polymers (mostly disaccharides) before they have passed beyond the duodenum or upper jejunum  Hydrolysis of Disaccharides into Monosaccharides The brush border formed by the microvilli contain 3 major enzymes that digest the major disaccharide sugars in our diet Lactase Maltase (Isomaltase) Sucrase Carbohydrate Absorption - Review Monosaccharides are then able to be absorbed via facilitated diffusion or via co-transport via the sodium gradient SGLT-1 GLUT5 GLUT2 When monosaccharides build up in the cytosol of the enterocyte, they are then transported to the capillary network across the basolateral surface Digestion of Proteins Mouth Mechanical only, no enzymatic digestion Stomach HCL Denatures protein, not involved in hydrolysis Denaturation improves the “exposure” of peptide bonds to digestive enzymes Pepsin Most active between pH 1.5 to 3.5 Only begins the process of digestion (10 to 20%) Ability to digest collagen FYI - Most efficient in cleaving peptide bonds between hydrophobic and aromatic amino acids However, there are multiple different types of pepsins with somewhat different activities Digestion of Proteins by Pancreatic Secretions Most protein digestion occurs in duodenum and upper jejunum from proteolytic enzymes of pancreatic secretion Protein that is digested by pepsin are still mostly in the form of large polypeptides Upon entering the small intestine, they are attacked by enzymes: trypsin, chymotrypsin, carboxypolypeptidase, proelastase  Targets peptide bonds next Trypsin to lysine or arginine Split protein molecules into small polypeptides Chymotrypsin Targets peptide bonds next to phenylalanine, tyrosine, tryptophan Also methionine, asparagine, histidine Carboxypeptidase Cleaves individual amino acids from carboxyl ends of polypeptides A Aromatic neutral or aliphatic FYI neutral amino acids Don’t need to B know the Basic amino acids: lysine, peptide bonds arginine, ornithine cleaved Protein digestion in the duodenum The brush Trypsinogen is activated by enterokinase in the border lumen of the duodenum Enterokinase = a brush border enzyme After trypsinogen is activated to trypsin, it activates a wide variety of other inactive enzymes (zymogens) Chymotrypsin, pro-elastase, procarboxypeptidases Pro-phospholipaseA2 Trypsin ALSO digests pancreatic hormones after the nutritional substrate (food) has “run out” Carboxypeptidase digests proteins at their carboxy-terminal ends The rest are known as “endopeptidases” – they are not limited to the ends of polypeptides Protein Digestion - Brush Border Peptidases The brush border Membrane-bound peptidases aid in digestion of large peptides to di- and tri-peptides FYI – brush-border peptidases: Aminopeptidases Attack N-terminal end of oligopeptides Dipeptidases Hydrolyze N terminal side of dipeptides Tripeptidases Cleave tripeptide into amino acids and dipeptide Absorption of Amino Acids & Peptides 33% of protein absorption as free amino acids, 67% of protein absorption as peptides Multiple ATP dependent systems with overlapping specificity, many are Na+ co-transporters Amino acids Active transport or secondary transport with Na+ Dipeptides and tripeptides Some are Na+ dependent Some are via secondary active transport with H+ Within cytoplasm of the enterocyte most peptides are hydrolyzed to free amino acids Fat digestion - Intro Digestion of fat presents a challenge: Not very water soluble, so tends to accumulate in large droplets Reduces surface area Reduced SA, poor water solubility impairs the process of chemical digestion as well as absorption Answer: emulsify the fat droplets into very small droplets that have an amphipathic molecule on the outside of the droplet Structure = micelle Improved interaction of water, much larger SA:volume ratio Fat emulsification and bile Bile contains a variety of amphipathic molecules that help the formation of micelles Lecithins (i.e. phosphatidylcholine) Bile salts Cholesterol Mixing movements in the duodenum and bile secretion help sequester dietary lipids into micelles “outside” of the micelle – hydrophilic portions of bile components Inside of the micelle Hydrophobic portions of bile components Dietary lipids Fat digestion Once micelles have been formed in the duodenum and the jejunum, pancreatic lipase can act on the triglycerides in “interior” of the micelle Vast majority of dietary lipids are triglycerides Less cholesterol and phospholipids Pancreatic lipase is not very effective alone Needs colipase to help it insert into the micelle and activate it Pancreatic lipase breaks triglycerides into 2 free fatty acids and 2- monoacyl glycerol These lipids can then diffuse from the micelle into the enterocyte, across the brush border 1 Pancreatic 2 + Lipase 3 Triglyceride 2-Monoglyceride Free Fatty Acid  Digestion of Fats Phospholipase works similarly Phospholipids broken down into fatty acids and other components After lipids have been chemically digested and absorbed into the enterocyte, they’re reassembled into triglycerides and other lipids and inserted into chylomicrons Chylomicrons are built within the enterocyte and secreted into the lymphatic vessels at the base of the villi transported to a variety of cells via the thoracic duct → venous blood Chylomicrons are necessary for transporting triglycerides (longer fatty acids), cholesterol esters into the circulation Chylomicron = a lipoprotein Spherical structure with a phospholipid bilayer and proteins on the outside, absorbed triglycerides, cholesterol on the inside Proteins on the outside can have enzymatic and receptor functions that help the chylomicron be “delivered” to and used by cells throughout the body Assimilation of Lipids lecithin Emulsified lipase-colipase 2-MG FOOD FFA bile salts fat micelles (enterocyte) bile salts apoprotein + TG 2-MG 2-MG TG FFA FFA (micelles) chylomicrons lymph vessel A chylomicron  Absorption at the villus Carbohydrates and amino acids are transported across the basement membrane of the enterocyte, and diffuse into the capillary loops within the villus Small free fatty acids can diffuse into the blood and be carried by serum proteins (i.e. albumin) Larger lipids need to be carried by chylomicrons Chylomicrons are secreted via exocytosis into the lamina propria Enter the openings of the lacteals (lymphatic capillaries within the villi) Malabsorption – an intro When absorption at the small intestine fails, nutrients remain in the lumen of the intestine. This can result in: Diarrhea much of the contents of chyme are osmotically active → they draw water into the lumen of the intestine and/or prevent the overall absorption of fluid Bacteria can also metabolize undigested/unabsorbed nutrients → gas, abdominal distention, abdominal pain Micronutrient deficiency (aka vitamin, mineral deficiencies) Macronutrient deficiencies Inadequate caloric and protein intake for basic metabolic requirements Malabsorption – an intro Types of malabsorption can be pathophysiologically organized into four major problems: Disturbances in intraluminal digestion Enzymes/bile that are secreted into the lumen by the stomach, pancreas or gall bladder/liver are inadequate for the near- complete breakdown of proteins, carbohydrates, or fats Disturbances in terminal digestion The brush border enzymes cannot break down small peptides or disaccharides Disturbances in transepithelial transport nutrient, fluid, and/or electrolyte transport are disordered Disturbances in lymphatic transport – lipid transport is impaired  Malabsorption – common illnesses Disease Intraluminal Terminal Trans- Basic pathogenesis Digestion Digestion Epithelial Transport Celiac disease No Yes Yes Damage to the villi and microvilli results in loss of surface area and overall absorptive enterocyte function Chronic Yes No No Lack of major digestive enzymes from the pancreas pancreatitis leads to major impairment of absorption, diarrhea, and nutrient deficiencies Disaccharidase No Yes No Lack of disaccharide results in unabsorbed sugar in the deficiencies lumen → bacterial gas (lactose production and osmotic intolerance) diarrhea Gastroenteritis No Yes Yes Damage to the brush border or dysregulation of electrolyte (bacterial, viral, transport results in impaired parasitic) ability to absorb nutrients