Gastrointestinal Physiology

Chelsea Dawn Unruh The Basics

Functions of the GI System Ingestion, , absorption, & Principle Processes Motility, secretion, & membrane transport

Stages of Digestion Mechanical & Chemical Mechanical: Increasing surface area Chemical reaction of digestion: hydrolysis Anatomical Tube

2 The Basics

 The is  A tube that propels a substance from one end to the other while attempting to it break down with various digestive juices, absorb as much of its digestive products as possible, & excret what is left  Associated with accessory glands that produce the majority of digestive juices  Controlled by both nervous and hormonal systems

3 Anatomy of GI System

 The Gut Tube  Accessory Glands  Oral cavity  Salivary glands  Esophagus  Pancreas   Liver  Duodenum     Anus Which structures of the GI system are retroperitoneal? • Most of the pancreas (except tail) • Most of the duodenum (except first segment) • Ascending & Descending Colon

4 Despopoulos, Color Atlas of Physiology © 2003 Thieme GI Bloodflow

 Supply  Celiac a.  Superior Mesenteric a.  Inferior Mesenteric a.  Drainage  Portal Vein

 Portal vein carries absorbed substances to liver

5 General GI Wall Structure

6 http://www.enel.ucalgary.ca/People/Mintchev/stomach.htm Nervous System of the GI Tract

 (ENS)  Consists of about 10 −100 million nerve cells located in the ganglia of the intestinal wall.  Consists of sensory neurons, interneurons, and motor neurons  Some sensory signals are transmitted to the CNS  ENS is modulated by the ANS  Two internal nerve plexuses  Auerbach’s & Meissner’s

7 Nervous System of the GI Tract  Myenteric or Auerbach’s plexus  Between the longitudinal and circular smooth muscle layers  Coordinates the movements of muscularis externa  , Segmentation, Propulsion, Grinding, etc.  Excitatory motoneurons contract muscle by ACh to muscarinic receptors;  Inhibitory use VIP and NO  Sensory neurons respond to chemical or mechanical stimuli – receptors in all layers of GI tract  Interneurons are involved in the many arcs through GI

8 Motility

9 Nervous System of the GI Tract  Submucosal or Meissner’s plexus  Located in the submucosa, between the muscularis mucosae and the circular layer of muscularis externa  involved in internal processing – modulates secretion and blood flow  stimulatory secretomotoneurons stimulate glands and epithelium (via Ach, et al.)  sensory neurons respond to chemical or mechanical stimuli to produce secretomotor  submucosal vasodilator neurons dilate blood vessels in the submucosa

10 Nervous System of the GI Tract

 Autonomic Control of GI  Both ANS systems modulate the ENS  Parasympathetic:  Vagus nerve stimulates secretions and motility through distal colon  Pelvic splanchnic nerves innervate distal colon & rectum  Sympathetic:  Innervation through splanchnic & prevertebral ganglia  Reduces motility, increases sphincter tone

11 Nervous System of the GI Tract

 Neurotransmitters  Norepinephrine – adrenergic post-gang neurons  Ach – pre- and postgang enteric fibers & post gang parasymp  VIP – mediates relaxation of circular & vascular muscles  Enkaphalin – intensifies contraction of sphincters  GRP – mediates release of  CGRP (calcitonin gene-related peptide) – stimulates release of

12 Nervous System & GI Wall

13 Segments

14 Segments & Structure

 Mouth  Pharynx  Esophagus  Stomach  Small Intestine  Large Intestine  Rectum  Anus

15 Mouth

 Ingestion & Digestion  Mechanical  Mastication (chewing, cutting & grinding with teeth), mixing with tongue  Chemical  Salivary glands: Parotid, Sublingual, Submandibular  Secretions (1.5L/day)  Mostly salt & water but also includes amylase, lingual lipase, lysozyme, peroxidase, R-binder

(important protein for Vit B12 metabolism), IgA, glycoproteins

16 http://medical-dictionary.thefreedictionary.com/ Functions of Saliva

 Moistens, cleans, & protects enamel  Lubricant aiding in speech, chewing, & (mucins)  Dissolves food – allows for taste  Acts as a bonding agent to form bolus  Alkaline secretions neutralize regurgitated  Enzymes (amylase & lipase) begin digestion  Immunological: Lysozyme, IgA, & lactoferrin

17 Salivary secretion

18 Salivary Reflexes

Conditioned

Unconditioned

19 Pharynx

 Circular muscles  Superior, middle ,and inferior pharyngeal constrictors force food down esophagus while swallowing  Other muscles  Close off oral cavity, nasopharynx, and trachea during swallowing

20 http://www.home-speech-home.com/dysphagia.html Esophagus

 Straight muscular tube  Propels food bolus from pharynx to stomach  1/3 composed of striated muscle, 2/3 smooth muscle  LES – physiological sphincter at cardiac orifice

Clinical: Correlation Achalasia – inability of the LES to relax causing dysphagia, regurgitation, and chest 21 pain. Causes: cancer, Chagas disease Deglutition

 Coordinated by swallowing center in medulla oblongata & pons  ≥ 22 muscles involved  2 stages  Buccal - voluntary  Pharyngeal/esophageal - involuntary

22 Deglutition

23 Stomach

24 Stomach  J-shaped muscular sack for food storage & digestion located in upper abdomen, directly below diaphragm  Empty volume 50 mL, may hold up to 4 L  Structures  4 regions: Cardia, fundus, body, and pylorus/antrum  2 sphincters: Lower esophageal/cardiac, pyloric  Rugae  Innervation  ENS, PNS (vagal), SNS  Circulation  Supplied by celiac artery  Drains to hepatic portal circulation

25 Stomach Wall

Mucus Only

26 Stomach

 Secretory Cells  Secretory Products -  Surface mucous & mucous  , HCO 3 neck cells  Oxyntic (Parietal) cells  HCl,

 Chief (Peptic) cells  Pepsinogen, gastric lipase, rennin/chymosin (infancy?)  Neurendocrine cells  Peptide Hormones  G cells  Gastrin  D cells  Somatostatin

27 Gastric Protection

H. pylori • Gram negative microaerophilic rod • Flagella to bury itself in the protective mucus NSAIDs • • Urease breaks down urea toCO and ammonia COX inhibitors 2 • (neutralizes) ↓ PGs  ↑ acid

•Treatment: Triple Therapy 28 Regulation of Gastric Function

 Cephalic Phase  Stimulated by sight, smell, or thought of food (1/3 of secretion)  Medicated by vagus nerve, secretions begin before food arrives  Gastric Phase  Stimulated by food in the stomach (2/3 of gastric secretion)  Ingested food stretches and raises the pH activating mechanical and chemical receptors  Gastric secretion stimulated by ACh, , and gastrin  Intestinal Phase  Stimulated by chyme entering the duodenum  Enterogastric reflexes reduce gastric motility and secretions

29 Gastric Acid  Basal Acid Output: <10 mmol/hr  Maximum Acid Output: <50 mmol/hr  ↑ c c dda c i-Eis Sy.  ↓ vatmy icis amia

 Gastric HCl has pH ~1.0,  Activates , dissolves food, disinfects, & stimulates duodenum to secrete  Gastric Enzymes  Pepsin – cleaves protein into smaller peptides  Lipase – digests fats, of little importance except with pancreatic insufficiency Gastric juices (pH 1.5 −2, about 2 −3 liters/day) 30 31 Mechanism of HCl secretion by gastric parietal cells.

32 Agents that stimulate and inhibit H + secretion by gastric parietal cells.

33 Gastric Motility  Migrating Motor Complexes (MMC) – 90 min cycle  Pacemaker cells (Interstitial cells of Cajal) create 3 phases  Phase I – no contractions  Phase II – 6 min, irregular contractions  Phase III – 3 min, regular contractions (gastric 3 per min, duodenal 11 per min)  Receptive reflex:  Relaxes stomach to allow entry of food, modulated by swallowing center (vagus)  Enterogastric reflexes: (act on motility & secretion)  Hormonal signaling from intestines slows gastric emptying and reduces motility  Neural reflex: hyperosmolar chyme & mechanical distention

34 Gastric Motility  When receptive reflex is activated, MMC is replaced with peristaltic actions  Mechanical churning for digestion  Emptying time usually ~4hrs  Sympathetic System can prolong emptying  Antrum holds ~30mL of chyme and releases ~3mL into duodenum with each peristaltic wave

35 36 Small & Large Intestines

37 Small Intestine

 In the small intestine (duodenum, jejunum, ileum), contractile activity serves to mix the chyme with the alkaline exocrine secretions of the intestine, pancreas, and liver.  These secretions contain a number of digestive enzymes, including proteases, amylases, and lipases. Protein, lipids, carbohydrate, vitamins, water, and electrolytes are absorbed primarily in the small intestine  3 parts  Duodenum (25cm)  Jejunum (2.5 m)  Ileum (3.5m) and ends at ileocecal junction

38 Small Intestine

39 Small Intestine: Duodenum

 Segment between pylorus of stomach and jejunum  4 segments: only 1 st segment (duodenal cap) is intraperitoneal  Submucosal Brunner’s glands  Produce alkaline mucus to neutralize stomach acid (pepsin is inactivated by the elevated pH and pancreatic enzymes take over the job of chemical digestion)  Receives pancreatic digestive juices and juices from liver  Ampulla of Vater (major duodenal papilla), sphincter of Oddi  Primary site for Fe 2+ absorption

40 Small Intestine: Jejunum & Ileum

 Major site of digestion: brush border contains numerous digestive enzymes  90% absorption – specialized transporters, simple diffusion, facilitated diffusion, active/passive transport  Protection against infection – Peyer’s patches, M cells  Hormone secretion – CCK, Secretin, Somatostatin, etc  Intestinal juice secretion – isotonic fluid (w/ enzymes) secreted by crypts of Lieberkuhn, mucus from goblet cells

41 Small Intestine Motility

42 Large Intestine

 In the large intestine (cecum, colon, rectum, anal canal), colonic contractile activity transports chyme slowly and mixes it thoroughly, exposing it to the absorptive surface where most of the remaining fluid is absorbed.  Anatomy  Colon Parts: Cecum, ascending, transverse, descending, sigmoid  Ileocecal valve, Haustra, teniae coli, epiploic appendages  Retroperitoneal sections:  Ascending & Descending Colon

43 44 Large Intestine

 No further chemical digestion occurs  Most nutrients have already been absorbed  Volume of contents is reduced as liquid is absorbed  Dense population of many species of bacteria = bacterial flora.  Ferment cellulose and other undigested carbohydrates  Synthesize B vitamins and vitamin K

45 Large Intestine Motility

 Basal Electric Rhythm  9 waves /min @ ileocecal valve  Up to16 waves/min @ sigmoid

 Haustral Shuttling – kneading of mass to ↑H2O absorption  Segmental propulsion – from one haustra to next  Mass movements (systolic multi-haustral propulsion) - stronger contractions, moving mass towards rectum 2-5 cm/min. Occur infrequently or as gastrocolic reflex.

46 Large Intestine

 Transit Time  Can take ≥ 12 hours to pass through large intestine  Rectum can hold ≤ 3 days  ↑ fiber = ↓ transit time

 Reflexes  Defecation – spinal reflex  Distention of rectum causes internal sphincter to relax (pressure of 18-55mmHg manifests the urge to deficate)  Gastrocolic –  Mass contraction of colon caused by distention of stomach. Very obvious in infants and children.

47 Major Accessory Glands

Liver & Pancreas

48 Liver

49 50 Liver & Bile Secretion

Clinical: Cholecystitis Cholelithiasis Primary biliary cirrhosis Etc…

51 Bile

 Constituents:  bile salts (taurocholate & glycocholate), bile pigments (bilirubin & biliverdin), lipids (cholesterol, lecithin, fatty acids, and triglycerides), and electrolytes.  Cholesterol usually between 60-170mg/L  High concentrations predispose to gall stones. -  Bile juice has ↑ HCO 3 content, much higher than plasma  Alkaline (pH = 7,0-7,4)  Bile salts are the only important factor for digestion  Amphipathic molecules – steroid nucleus (hydrophobic) + polar (hydrophilic) groups—enhance intestinal absorption of lipids

52 Enterohepatic circulation

 The total bile pool (2–4 g) recirculates about 6–10 times a day  20–30 g of bile salts are required for daily fat absorption

53 Enterohepatic circulation

 85% of bilirubin formed from breakdown of hemoglobin in RBCs  Stercobilin gives stools brown color

Jaundice: Prehepatic – excessive bilirubin formed, i.e. ↑hmysis. Evatd idict biibi. Intrahepatic – liver dysfunction Posthepatic – impairment of flow, i.e. stone or tumor. Elevated direct bilirubin & grey stools. 54 Secretion, Digestion & Absorption

55 Fluid Balance

 Inflow/Secretions:  Saliva 1-2 L/day  Gastric juices 2-3 L/day  Exocrine pancreas 1.2-1.5 L/day  Bile juices 0.5-1 L/day  Small Intestine 1-2 L/day  Total ~ 8.5 L/day secretions  Only 2 L delivered to colon, and only 0.1-0.2 L/day in feces

56 Electrolyte Absorption

57 Absorption

58 Carbohydrates

 Carbohydrates provide ½ - ⅔ of the energy requirement.

 ≥50% of dietary carbohydrates consist of starch (amylose and amylopectin), a polysaccharide  Other important dietary carbohydrates are cane sugar (saccharose = sucrose) and milk sugar (lactose).

 Total of about 350 to 450 grams of carbohydrates per day.

59 Carbohydrate Digestion

 Begins in mouth with salivary amylase.  Resumes in duodenum with pancreatic enzymes  Finishes at brush border with disaccharidases

60 Faller, The Human Body © 2004 Thieme Carbohydrate Digestion & Absorption

61 Carbohydrate Absorption

 α-Amylase breaks α-1,4 bonds of non-terminal sugars (endoenzymes)  Creates maltriose, maltose, and α-limit dextrins  α-Amylase cannot cut:  Terminal α-1,4 link  Adjacent α-1,4 link  α-1,6 link (branching)

62 Carbohydrate Absorption

 Brush border oligosaccharidases continue Lactase deficiency digestion Lactose cannot be broken down and absorbed Lactase = Glc + Gal unless sufficient lactase is available. Lactase deficiencies lead to 1) because water is Both taken up by SGLT1 retained in the intestinal lumen due to osmotic Maltase = Glc + Glc mechanisms, and 2) because intestinal bacteria convert the lactose into toxic substances.  Taken up by SGLT1  Surcase-isomaltase  Actually 2 enzymes capalble of hydrolyzing sucrose, maltose, maltotriose, and and α-limit dextrins

63 Carbohydrate Absorption

 Secondary active transport – SGLT1 uses Na + gradient to drive Glc into cell  SGLT1 & GLUT5 are found on apical membrane  GLUT5 & GLUT2 allow for facilitated diffusion across membranes

64 Fiber

 Fiber = Unavailable carbohydrates,  indigestible oligosaccharides (eg, raffinose)  dietary fiber (cellulose and hemicellulose)

These carbohydrates are not digested in the small intestine. They pass to the colon, where they are fermented by bacterial enzymes.

 Fiber decreases transit time, adds bulk to feces, and allows for easier defecation

65 Lipids

 The average intake of fats (butter, oil, margarine, milk, meat, sausages, eggs, nuts etc.) is roughly 60–100 g/day, but there is a wide range of individual variation (10–250 g/day).  Most fats in the diet (90%) are neutral fats or triacylglycerols (triglycerides). The rest are phospholipids, cholesterol esters, and fatsoluble vitamins (vitamins A, D, E and K). Over 95% of the lipids are normally absorbed in the small intestine. •Deficiency: •Vitamin A - night blindness •Vitamin D – rickets •Vitamin K – clotting factor deficiencies •Excess 66 •Toxicity - hypervitaminosis Lipid Digestion

 Begins in the mouth with lingual lipase  Continues activity in the stomach  Emulsification in duodenum by bile salts, formation of micelles

67 Faller, The Human Body © 2004 Thieme Lipid Absorption

68 69 Cholesterol

 Cholesterol is an important constituent of cell membranes.  Precursor for bile salts, vitamin D, and steroid hormones

Clinical: Familial hypercholesterolemia Atherosclerosis Dyslipidemias

70 Protein Digestion

 Begins in the stomach with , continues with pancreatic enzymes  Polypeptides cleaved into oligopeptides and amino acids

71 Faller, The Human Body © 2004 Thieme Protein Digestion

72 73 Protein Absorption

 Peptidase activity:  brush borders  within the cytoplasm of intestinal mucosa cells.  Aminopeptides must be absorbed by specific amino acid and peptide transport systems. Intracellular peptidases hydrolyze absorbed peptides.  Basolateral transport:  many different AA transporters.

74 Hartnup disease affecting the absorption of nonpolar amino acids, particularly tryptophan that can be, in turn, converted into , melatonin and niacin

75 Absorption of whole proteins

 Normal cells can endocytose proteins and degrade them (90%)  M cells endocytose fewer intact proteins but 50% emerge for presentation to immuno cells

76 Regulation of the GI Tract

Hormonal and neuronal controls

77 Gastrin Family of hormones

78 Gastrin  Secreted by the G cells  Gastric antrum & duodenum Zollinger Ellison Syndrome A non–beta islet cell, gastrin-secreting  Gastrin is released by G cells after:tumor of the pancreas (seen in MEN-1)  vagal stimulation (via GRP) causing over secretion of HCl and resulting  distention of the stomach in peptic ulcers  presence of protein digestion products in the stomach

 Release is inhibited by Somatostatin, PGE 2, or when gastric/duodenal lumen pH <3.5  Stimulates acid secretion and gastric mucosal growth  Gastrin is the only GI hormone known to be released by direct neural stimulation

79 CCK ()

 Produced throughout small intestinal mucosa (I cells)  Release stimulated by presence of long-chain fatty acids, AA, and oligopeptides in lumen Actions:  gall bladder contraction  ↑ motility of SI & LI  Secretion of enzyme-rich  Trophic effect on pancreas  ↑secretion of enterokinase  Potentiates secretin on  Stimulates insulin & pancreas glucagon release  Inhibits gastric emptying  Produces satiety

80 Control

 Neural Control (Vagus)  ACh (+)  Indirect - stimulates ECL to release Histamine which stimulates Parietal cells  Direct - stimulates Parietal cells  GRP (Gastrin Releasing Peptide) (+)  Hormonal Control  Gastrin (+)  Histamine (+)  Somatostatin (-)

 PGE 2(-) Secretin-Glucagon Family

82 Secretin

 Produced in duodenum (S cells)  Release stimulated by acidic chyme & presence of protein digestion products Actions  Stimulates pancreatic  ↑ hepatic secretion of bile bicarbonate secretion  ↓gastric acid  Potentiates CCK effect on  ↑tone of pyloric sphincter pancreas  ↓glucagon secretion

83 GIP (Gastric Inhibitory Peptide)

 Part of Incretin family (with GLP-1)  Produced in duodenum & intestinal mucosa (K cells)  Release stimulated by protein, fat & carbohydrate fragments in lumen

Actions  Inhibits acid secretion & gastric motility  Stimulates insulin release Incretins

Causes an ↑i isi sc. Mchaism is sd by GLP-1 aas t icas isi scti i diabtic atits 84 Others  VIP (Vasoactive Intestinal Peptide)  Dilates blood vessels & relaxes intestinal smooth muscle  ↑ watery secretions VIPoma  Inhibits gastric acid Seen in MEN-1, causes secretory  Peptide YY diarrhea leading to metabolic alkalosis  Inhibitor of gastrin -mediated acid secretion  Release from jejunal mucosa stimulated by fats in lumen  Motilin  Released by neurons in the small intestine and regulates digestive motility  Paracrine transmitters: Histamine, Somatostatin, and prostaglandin are the main paracrine transmitters in the GI tract.

85 86 tmc acesLvrG Gt Brain Gut GB Liver Pancreas Stomach

Despopoulos, Color Atlas of Physiology © 2003 Thieme