Gastrointestinal Tract Structure

Structure of the Gastrointestinal Tract

• The gastrointestinal tract is arranged linearly, including the mouth, esophagus, stomach, small intestine (duodenum, jejunum, ileum), large intestine, and anus.
• Other structures include the salivary glands, pancreas, liver, and gallbladder, which all have secretory functions.
• The gastrointestinal tract wall has two surfaces, the mucosal and serosal.
• The mucosal surface faces the lumen, and the serosal surface faces the blood.
• Layers of the gastrointestinal wall, starting from the lumen: mucosal layer, lamina propria, muscularis mucosae, submucosal layer, circularmuscle, longitudinal muscle, serosa.
• The mucosal layer consists of epithelial cells, the lamina propria, and the muscularis mucosae.
• Epithelial cells are specialized for absorptive and secretory functions.
• The lamina propria is primarily connective tissue with blood and lymph vessels.
• The muscularis mucosae consists of smooth muscle cells, changing the shape/surface area of the epithelial cell layer upon contraction.
• The submucosal layer is beneath the mucosal layer and consists of collagen, elastin, glands, and blood vessels.
• Motility is provided by circular and longitudinal muscle layers between the submucosa and serosa.
• The longitudinal muscle layer is thin with few nerve fibers, while the circular muscle layer is thick and more densely innervated.
• Neurons release transmitters from varicosities instead of forming true synapses on smooth muscle fibers.
• The submucosal and myenteric plexuses contain the nervous system of the gastrointestinal tract.
• Submucosal plexus (Meissner plexus) lies between the submucosa and circular muscle.
• The myenteric plexus lies between the circular and longitudinal muscle.

Innervation of the Gastrointestinal Tract

• Regulation is partly through the autonomic nervous system, with extrinsic and intrinsic components.
• The extrinsic component involves sympathetic and parasympathetic innervation.
• The intrinsic component is the enteric nervous system within the submucosal and myenteric plexuses.
• The enteric nervous system communicates with the parasympathetic and sympathetic nervous systems.

Parasympathetic Innervation

• The vagus nerve (cranial nerve X) and pelvic nerve supply parasympathetic innervation.
• The vagus nerve innervates the upper gastrointestinal tract, including the striated muscle of the upper third of the esophagus, stomach wall, small intestine, ascending colon, and part of the transverse colon.
• The pelvic nerve innervates the lower gastrointestinal tract, including walls of the transverse, descending, and sigmoid colons.
• Parasympathetic nervous system ganglia are located in the myenteric and submucosal plexuses within organ walls.
• Information from the parasympathetic nervous system is coordinated in these plexuses and relayed to smooth muscle, endocrine, and secretory cells.
• Postganglionic neurons of the parasympathetic nervous system are either cholinergic, releasing acetylcholine (ACh), or peptidergic, releasing peptides like substance P or vasoactive intestinal peptide (VIP).

Vagus Nerve Composition

• The vagus nerve is a mixed nerve, having 75% afferent and 25% efferent fibers.
• Afferent fibers carry sensory information (mechanoreceptors/chemoreceptors) to the central nervous system (CNS).
• Efferent fibers deliver motor information (smooth muscle, secretory, and endocrine cells) from the CNS to target tissues.
• Sensory information relays to the CNS via the vagus nerve, triggering a vagovagal reflex, where both afferent and efferent limbs are within the vagus nerve.

Sympathetic Innervation

• Preganglionic fibers of the sympathetic nervous system are short, synapsing in ganglia outside the gastrointestinal tract.
• Four sympathetic ganglia – celiac, superior mesenteric, inferior mesenteric, hypogastric – serve the gastrointestinal tract.
• Postganglionic nerve fibers are adrenergic, releasing norepinephrine and synapsing on ganglia in the myenteric and submucosal plexuses.
• They directly innervate smooth muscle, endocrine, and secretory cells.
• Approximately 50% of sympathetic nerve fibers are afferent and 50% are efferent for sensory and motor relay between the gastrointestinal tract and CNS and coordinated by the submucosal and myenteric plexuses.

Intrinsic Innervation

• The intrinsic or enteric nervous system directs gastrointestinal tract functions even without extrinsic innervation.
• It is located in ganglia within the myenteric and submucosal plexuses, controlling contractile, secretory, and endocrine functions.
• These ganglia receive input from the parasympathetic and sympathetic nervous systems, which modulate their activity.
• Ganglia receive sensory information from mechanoreceptors/chemoreceptors in the mucosa.
• Ganglia send motor information to smooth muscle, secretory, and endocrine cells, with relay through interneurons.

Neurochemicals in the Enteric Nervous System

• Neurons in the enteric nervous system have numerous neurochemicals, or neurocrines.
• Some are neurotransmitters, and some are neuromodulators, which modulate neurotransmitter activity.
• Neurons typically contain more than one neurochemical and may co-secrete two or more neurocrines when stimulated.

Gastrointestinal Regulatory Substances

• Gastrointestinal peptides, including hormones, neurocrines, and paracrines, regulate the functions of the gastrointestinal tract.
• Functions include contraction/relaxation of smooth muscle and sphincters, secretion of digestive enzymes, secretion of fluid/electrolytes, and trophic (growth) effects.
• Some peptides regulate the secretion of other gastrointestinal peptides, such as somatostatin inhibiting all gastrointestinal hormone secretion.

Gastrointestinal Peptide Classification

• Classified as hormones, paracrines, or neurocrines based on release from endocrine cells or neurons and the route taken to reach the target cell.

Hormones

• Hormones are peptides released from endocrine cells that enter the portal circulation, pass through the liver, and enter the systemic circulation.
• The systemic circulation delivers the hormone to target cells that have receptors for it.
• Target cells can be located in the gastrointestinal tract like gastrin.
• Four gastrointestinal peptides categorized as hormones which include gastrin, cholecystokinin (CCK), secretin, and glucose-dependent insulinotropic peptide (GIP).
• Endocrine cells are not concentrated in glands but exist as single or grouped cells scattered across large areas of the gastrointestinal mucosa.

Paracrines

• Peptides secreted by endocrine cells that act locally within the same tissue.
• Paracrine substances reach target cells by diffusing short distances through interstitial fluid or are carried short distances in capillaries.
• Major gastrointestinal peptide is somatostatin.

Neurocrines

• Substances synthesized in neurons and released after an action potential, diffusing across the synapse to act on a target cell.
• Neurocrine substances include ACh, norepinephrine, vasoactive intestinal peptide (VIP), nitric oxide (NO), gastrin-releasing peptide (GRP) or bombesin, enkephalins, neuropeptide Y, and substance P.

Gastrointestinal Hormones

• Enteroendocrine cells are specialized hormone-secreting cells within the gastrointestinal tract.
• A substance must be secreted in response to a physiologic stimulus.
• It must be carried in the bloodstream to a distant site, where it produces a physiologic hormone. Its function must be independent of any neural activity. It must be isolated, purified, chemically identified, and synthesized.
• The "official" hormones include gastrin, CCK, secretin, and GIP.
• Motilin, pancreatic polypeptide, somatostatin, serotonin, ghrelin, leptin, glucagon-like peptides 1 and 2, enteroglucagon, peptide YY (PYY), and neurotensin meet some but not all of the criteria.

Gastrin

• Gastrin is crucial for digestive processes and exists in two forms: G 17 (little gastrin) and G 34 (big gastrin).
• Primarily released post-meal to promote digestion, while G 34 is secreted at lower levels between meals.
• Both originate from progastrin and proceed through separate biosynthetic pathways. Biologically active component of gastrin is the C-terminal tetrapeptide.
• Food intake, particularly amino acids (phenylalanine and tryptophan) and stomach distension primarily stimulates gastrin secretion.
• Vagal stimulation triggers gastrin through gastrin-releasing peptide (GRP) or bombesin.
• Secretion is inhibited by low gastric pH and somatostatin.
• Actions of gastrin are to stimulate hydrogen ion (H+) secretion by gastric parietal cells and promote gastric mucosa growth.
• Gastrin excess in Zollinger-Ellison syndrome leads to increased H+ secretion, duodenal ulcers, gastric mucosa hypertrophy, and fat digestion complications.
• Treatments include H2 receptor-blocking drugs, H+ pump inhibitors, tumor removal, or gastric resection.

Cholecystokinin (CCK)

• Cholecystokinin is a 33–amino acid peptide related to gastrin and a member of the gastrin-CCK family.
• C-terminal five amino acids (CCK-5) are identical to gastrin, the tetrapeptide necessary for gastrin activity, thus, CCK has some gastrin activity.
• CCK 1 receptors are selective for CCK, while CCK 2 receptors are equally sensitive to CCK and gastrin.
• The minimum fragment necessary for its biologic activity is the C-terminal heptapeptide (CCK-7).
• CCK is secreted by I cells in the duodenal and jejunal mucosa in response to monoglycerides/fatty acids and small peptides/amino acids, signaling that a meal has fat and protein that must be digested and absorbed.
• CCK helps aid by ensuring that pancreatic enzymes and bile salts are secreted.
• Functions of CCK include contraction of the gallbladder with simultaneous relaxation of the sphincter of Oddi for bile release, secretion of pancreatic enzymes to help digest lipids, carbohydrates and protein. Secretion of bicarbonate (HCO3−) from the pancreas, growth of the exocrine pancreas and gallbladder, and inhibition of gastric emptying to allow for fat digestion and absorption.

Secretin

• Secretin is a 27–amino acid peptide homologous to glucagon, belonging to the secretin-glucagon family.
• Fourteen amino acids are identical to glucagon.
• All 27 secretin amino acids are required for biologic activity, requiring the entire molecule to fold into its tertiary structure, an α-helix.
• It is secreted by S cells (secretin cells) of the duodenum in response to H+ and fatty acids in the small intestine lumen. The secretion begins when acidic gastric contents which is pH < 4.5 arrives in the small intestine.
• Secretin secretes pancreatic and biliary HCO3−, which neutralizes H+ in the small intestine lumen critical for fat digestion as pancreatic lipases digest between pH 6 to 8. It is inactivated when the pH is less than 3. Also inhibits gastrin effects on parietal cells.

Glucose-Dependent Insulinotropic Peptide (GIP)

• A 42-amino acid peptide, similar to the secretin-glucagon family.
• GIP shares nine amino acids with secretin and 16 with glucagon.
• Pharmacologic levels create most secretin actions.
• Secreted by K cells of the duodenal and jejunal mucosa. It is the only gastrointestinal hormone responding to all three nutrients: glucose, amino acids, and fatty acids.