Organization and control of the gastrointestinal system

1. Organization and control of the gastrointestinal system • Digestive processes – motility, secretion, digestion & absorption • Phases – cephalic, gastric, intestinal & interdigestive period • Contacts external environment • Excretes steroid metabolites • Sphincters - Upper and lower esophageal sphincters, pylorus, ileocecal valve, internal and external anal sphincters • Organs –Teeth, Salivary glands, esophagus, stomach, liver, pancreas, duodenum, ileum, jejunum, colon

2. Mucosa - innermost layer • epithelium- layer of specialized cells that line the lumen • Duodenum, jejunum & ileum have villi and Crypts • Colon has only Crypts • lamina propria - loose connective tissue (collagen, elastin fibrils), glands, lymphatics, lymph nodules, capillaries • muscularis mucosae • innermost layer of contractile tissue Structures

3. Structures • muscularis mucosae • -contractions cause mucosal folding and ridges • - 600-fold increase in surface area • Submucosa • loose connective tissue (collagen, elastin fibrils), glands, nerve trunks, lymphatics, blood vessels • Muscularis externa -2 layers of smooth muscle • inner circular layer • outer longitudinal layer • Interstitial cells of Cajal

4. Structures • Enteric nervous system • submucosal plexus (Meissner’s plexus) • controls secretory and sensory functions • myenteric plexus (Auerbacks’s plexus) • located between the circular and longitudinal muscle layers • coordinates muscle contractions • Serosa • outermost layer of gut • composed of squamous mesothelial cells

5. Autonomic Control • Parasympathetic outflow • Facial VII and glossopharyngeal IX nerves supply salivary glands from ganglia outside of glands. VII sublingual and submaxillary, IX parotid. • Vagus nerve X innervates the GI tract from oropharyngeal cavity to the proximal colon • Pelvic nerve supplies distal colon and rectum • preganglionic parasympathetic fibers are predominantly cholinergic • parasympathetic fibers predominately terminate on intrinsic ganglions within the organs of the GI tract • neurotransmitter - mainly acetylcholine

6. Sympathetic outflow • Paravertebral chain of ganglia receives preganglionic fibers • Hypogastric ganglion • Celiac ganglion • Superior and inferior mesenteric ganglia • effects are typically inhibitory for secretion and motor activity • sympathetic nerves usually terminate on the intrinsic plexuses and not directly on organ structures • norepinephrine inhibit acetylcholine secretion by presynaptic 2 receptors • exceptions include blood vessels and glands which havedirect innervations

7. Enteric Nervous System • myenteric plexus (Auerbach’s) • lies between circular and longitudinal smooth muscle layers • primarily controls contractile functions • submucosal plexus (Meissner’s) • lies in the submucosal space • primarily controls glands, sensory functions, contraction of the muscularis mucosa

8. Enteric Nervous System • numerous connections form between afferent and efferent neurons • local reflex arcs can autonomously control many GI functions locally • GI tract is highly innervated with the same number of neurons as the spinal cord! • sensory nerves include receptors for chemical, physical deformation, pain, temperature stimuli that initiate local reflex responses for secretion and contraction.

9. Peptide control of GI Function • Endocrine hormones circulate in blood to remote sites. • Paracrine peptides act locally on adjacent cells • Neurocrine peptides are secreted at nerve endings

10. Hormones are secreted from Enteroendocrine Cells dispersed along the GI tract • Secreted into the blood; exert actions far from site of release • Gastrin, CCK, secretin, GIP and motilin are major hormones directly controlling the gut. • Many peptides are both neurocrines and hormones. • Gastrin and CCK in brain may inhibit appetite. Gastrointestinal peptides

11. Many different length peptide fragments with same action but different half lives. • Disperse location of cells permits a very accurate quantitative regulation of digestion. Additional hormone secreting cells are recruited as a stimulus (undigested food) penetrates farther down the GI tract. • Enteroendocrine cells (EEC)- open and closed • Enterochromaffin cells also secrete serotonin • Enterochromaffin like cells (ECL) secrete histamine Gastrointestinal peptides

13. Gastrin • discovered by Edkins 1905 • “little” gastrin - 17 amino acids • 90% of gastrin found in gastric mucosa • 7 min half-life • “big” gastrin - 34 amino acids • predominant gastrin in blood after fasting • 38 min half-life • all biological activity depends on 4 C-terminal amino acids Sulfated tyrosine 12 and amidation of carboxyl terminal phenylalanine 17 are equally active.

14. Gastrin released from the G-cells in lateral walls of glands in the gastric antral mucosa endogenous stimulus for release protein digestion products: small peptides and amino acids especially phenylalanine, tryptophan distention of stomach-vagovagal and local reflexes exogenous stimulus for release calcium, caffeinated coffee, wine inhibition of release luminal acidity (pH < 3) by direct inhibition of G cells through somatostatin production

15. Actions of Gastrin stimulation of gastric acid secretion stimulates parietal cells > acid stimulates enterochromaffin-like cells (ECL) > histamine -> parietal cells -> acid gastrin potency is 1500 times greater than histamine trophic activity stimulates growth of the oxyntic glands, mucosa of the stomach, duodenal mucosa, colonic mucosa atrophy of these tissues occur following antral resection hypertrophy occurs with gastrin-producing tumors Zollinger-Ellison syndrome – gastrin producing tumors (gastroma) of pancreas or duodenum that produce ulcers, diarrhea and steatorrhea. High serum gastrin and no acid response to gastrin infusion is diagnostic.

16. Cholecystokinin (CCK) • - discovered in 1928 by Ivy and Goldberg • at least 3 CCK forms: 33, 39, and 8 amino acids • C-terminal 7 amino acids are minimal fragment for activity • 5 C-terminal amino acids are identical to gastrin • Actions • stimulates gall bladder contraction • relaxes sphincter of Oddi • stimulates enzyme secretion from pancreas • potentiates effects of secretin on bicarbonate and liquid secretion • inhibits gastric emptying • Stimuli for released from the I-cells of the duodenum and jejunum • peptides and amino acids (strong) • fatty acids and monoglycerides (strong) • luminal acidity (weak) • Controlled by CCK-releasing peptide (intestine) and monitoring peptide (pancreas)

17. Secretin • - discovered in 1902 by Bayliss and Starling -structurally related to glucagon family of peptides. The first hormone ever described. • Actions • stimulation of bicarbonate and liquid secretion by pancreas and bile ducts (nature’s antacid) • trophic activity- stimulates growth of exocrine pancreas • inhibition of gastric acid secretion • released from the S-cells of the duodenal mucosa • stimulus for release • - duodenal acidity (pH < 4.5)

18. Gastric Inhibitory Peptide - Glucose-dependent Insulino-tropic Peptide (GIP) • structurally similar to secretin and glucagon • Actions • stimulates insulin release in the presence of glucose in the gut (physiologic) • inhibits gastric acid secretion at high concentrations (probably unphysiologic) • released from secretory (K) cells in the duodenum and jejunum Released in response to all three classes of foodstuffs - hydrolyzed fats, amino acids, glucose

19. Motilin - 22 amino acid peptide • Action • associated with migrating motility complexes • released at approximately 90 min intervals during the interdigestive period • release is stimulated by fat and acid in the duodenum • MMC sweep residual food from the GI tract between meals to prepare for the next meal • Peptide YY is released by L cells from the intestine in response to fats, glucose and protein hydrolysates. Peptide YY feeds back to inhibit gastric acid secretion and motility, and also suppresses appetite (antiorexigenic).

20. Other Peptides • Incretins are GI hormones that increase insulin secretion from beta cells after eating before glucose in blood increases. They inhibit glucagon secretion and slow gastric emptying. GIP and GLP-1 (7-36) are incretins. Rapidly inactivated by dipeptidyl peptidase 4 (DPP-4). Long acting GLP-1 analogues and DPP-4 inhibitors are being developed for diabetes. • Ghrelin is a peptide released from the stomach during fasting and stimulates food intake (orexigenic) as well as growth hormone release. Opposite effect of leptin. • Guanylin secreted by mucosal cells binds to guanylyl cyclase to increase cGMP and open CFTR Cl- secretion. E. coli endotoxin mimics effect to cause diarrhea. • GI peptide producing tumors – 50% gastrinomas, 25% glucagonomas, 25% other peptides

21. Paracrines - released by secretory cells near target cells – reach nearby target cells by diffusion through interstitial fluid. • Histamine - important regulator of gastric acid secretion • Somatostatin • - Primary inhibitor of release of all gut hormones • - Inhibits gastrin release when gastric contents are acidified • - Directly inhibits acid secretion from parietal cells • Vagal activation prevents release • Release is inhibited at high pH

22. Neurocrines are released from nerve endings • Vasoactive intestinal peptide (VIP) is a member of secretin-glucagon family • relaxes GI smooth muscle and sphincters, may cause NO release todilate smooth muscle • weak stimulator of bicarbonate and liquid secretion from pancreas and intestinal mucosa • GRP (gastrin releasing peptide) Bombesin • localized to nerves of the gastric mucosa • released by vagal stimulation and causes G-cells to releasegastrin

23. Neurocrines • Enkephalins • Opiate drugs bind the same receptors • Occur in 2 forms - met-enkephalin and leu-enkephalin • Actions • contract smooth muscle • inhibit gastrointestinal liquid secretion • Increase sphincter tone of esophageal, pyloric, and ileocecal sphincters • reduce GI motility and peristalsis • Opiates were formerly used to treat diarrhea, but are very addictive; opiate drug addicts usually have constipation

24. Summary • • The functions of the gastrointestinal tract are regulated by • hormones, which are delivered in the blood; • paracrines, which diffuse through the inter­stitial fluid; and • neurocrines, which are released from neurons. • • Neural regulation of the gastrointestinal (GI) tract is both extrinsic and intrinsic. • • Parasympathetic and sympathetic nerves relay information to and from the GI tract. • • The enteric nervous system within the gut receives and relays information to and from the extrinsic nerves and conducts signals along the gut. • • Two families of related peptides regulate the Gl tract: • gastrin and cholecystokinin and • secretin, vasoactive intestinal peptide (VIP), gastric inhibitory peptide (GIP), and glucagon.

25. Summary •Gastrointestinal hormones are found in endocrine cells scattered over large areas of mucosa. They are released by chemicals found in food, neural activity, or physical distension and may stimulate or inhibit several processes. • The primary gastrointestinal tract hormones: gastrin, cholecystokinin, secretin, GIP, and motilin, but Peptide YY is also a potent inhibitor of gastric function. Proglucagon is processed to fragments in the upper GI tract (glucagon), and lower GI tract to GLP-1 which stimulates insulin release even before blood glucose is increased. • Paracrine agents are: Somatostatin and histamine. • Three peptides function as neurocrines: VIP, bombesin (GRP), and enkephalins.