Gastrointestinal Physiology

Chelsea Dawn Unruh The Basics

Functions of the GI System Ingestion, digestion, absorption, & defecation 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 gastrointestinal tract 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 Stomach Liver Duodenum Small Intestine Large Intestine Rectum 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

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

Enteric Nervous System (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 Peristalsis, 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 reflex 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 reflexes 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 gastrin CGRP (calcitonin gene-related peptide) – stimulates release of somatostatin

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, & swallowing (mucins) Dissolves food – allows for taste Acts as a bonding agent to form bolus Alkaline secretions neutralize regurgitated gastric acid 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 Mucus, HCO 3 neck cells Oxyntic (Parietal) cells HCl, intrinsic factor

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, histamine, 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 pepsin, dissolves food, disinfects, & stimulates duodenum to secrete secretin 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 bile 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

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 diarrhea 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

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 pepsins, continues with pancreatic enzymes Polypeptides cleaved into oligopeptides and amino acids

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 serotonin, 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 (Cholecystokinin)

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 pancreatic juice ↑secretion of enterokinase Potentiates secretin on Stimulates insulin & pancreas glucagon release Inhibits gastric emptying Produces satiety

80 Parietal Cell 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