14/11/16 James Yang

BIOM1052 – Gastrointestinal System Physiology 1 Overview of GIT Layers of GIT Gut motility Enteric Nervous System Phases of digestion The digestive tract is a muscular tube extending from the oral cavity to the anus. It passes through the pharynx à oesophagus à stomach à small à large intestines. It allows for digestion/absorption of food, excretion of metabolic waste products, fluid/electrolyte balance and immunity. Components of the digestive tract include: Oral cavity provides mechanical mastication, lubrication/mixing with salivary secretions (digestion of carbs and fats) and sensory analysis of materials. Salivary glands produce saliva containing enzymes that aid digestion (amylase/lipase). Muscular propulsion of materials à pharynx à oesophagus à stomach, which chemically breaks down materials via acid/enzymes + mechanical processing with muscular contraction. The liver secretes bile (lipid digestion) and stores nutrients, the gall bladder stores and concentrates bile to be released into the duodenum of the small intestine. The small intestine digests enzymatically and absorbs water, organic substrates, vitamins and ions. The large intestine dehydrates/compacts indigestible materials (final stage of digestion). The peritoneum is serous membrane that surrounds the abdominal cavity (pancreas is retroperitoneal). Diaphragm separates the abdominal and thoracic cavities. The major layers of the digestive tract from innermost to outermost: Mucosa – gastric mucous surrounding lumen, lubricates GIT and protects stomach epithelium. Submucosa – Dense irregular connective tissue that connects blood vessels, lymphatics and nerves. Contains submucosal plexus that innervates mucosa/muscularis mucosae (located deep of the submucosal plexus). Muscularis externa – inner circular and outer longitudinal smooth muscle layers allowing for peristalsis (rhythmic wave-like contractions) to allow unidirectional movement of food. The two layers of muscle are separated by myenteric plexus which innervates both layers of muscularis externa. Serosa – Outer most layer Digestive epithelium varies based on location, function and stresses. The oral cavity, oesophagus and pharynx undergo much mechanical stress and thus contains stratified squamous epithelium. The stomach, small intestine and large intestine is mostly responsible for absorption and thus has simple columnar epithelium (with goblet cells). Swallowing is the result of pharyngeal contraction and the relaxation of the upper oesophageal sphincter. Food bolus moves through oesophagus via peristaltic action. The lower oesophageal sphincter relaxes soon after the initiation of swallowing and remains relaxed until peristaltic waves arrive. The enteric nervous system is located solely within gastrointestinal tissue (myenteric and submucosal plexa). It contains a complete reflex circuit (afferent sensory neurons, interneurons and efferent secretomotor neurons). It controls the patterns of movement (peristalsis) along the GI tract, secretion of gastric acid, fluid movement through lining epithelium, local blood flow and nutrient handling. It interacts with both immune and endocrine systems of the gut and is organised into ganglionated plexa. Slow waves are sub-threshold changes in resting membrane potential (gut is never stagnant but rather always moving). Slow waves generate muscle tone but are not full contractions (partial) and has different frequencies across the GIT. Acetylcholine causes action potentials and contractions.

14/11/16 James Yang

Frequency and amplitude of contractions is regulated by body temperature, metabolic activity, intrinsic/extrinsic nerves and hormones (CCK - cholecystokinin and motilin). Epithelial cells detect GIT luminal contents via osmoreceptors, chemoreceptors and stretch receptors. Paracrine control (local signalling) directly influences individual gut cells and surrounding cells and is chemical mediated. Endocrine control influencing hormones is also chemical mediated. Enteric/autonomic nervous systems are mediated through neurons (ANS via medulla oblongata). The enteric nervous system is not completely autonomous and still interacts with the central nervous system (vagal, sympathetic and pelvic pathways). Phases of digestion Cephalic phase – prepares stomach for food (short – minutes, neural mechanism, stimulates mucus, enzyme and acid production increasing volume of gastric juice). Gastric phase – stomach acts on food (long – hours, neural, hormonal and local mechanisms, chemical and mechanical digestion). Intestinal phase – maximise absorption (long – hours, neural and hormonal mechanisms, reduce motility and stimulate accessory organs).

14/11/16 James Yang

BIOM1052 – Gastrointestinal System Physiology 2 Gastric secretions Gastric endocrine, exocrine and paracrine functions Functions of the liver Gallbladder function and secretions The stomach aids in mechanical digestion/mixing and chemical digestion. HCl and pepsinogen break down proteins, gastric lipase breaks down fats. No absorption occurs in the stomach (except aspirin and alcohol). The stomach wall consists of mucosa (epithelium, lamina propria and muscularis mucosa), submucosa, muscularis externa (inner oblique – normal GIT doesn’t have this, middle circular and outer longitudinal) and serosa. Gastric pits are indentations in the stomach and the entrance to gastric glands. Visceral smooth muscle tissue present along the digestive tract undergo rhythmic cycles of activity and are controlled by pacesetter cells. Cells undergo spontaneous depolarization triggering waves of contraction through the entire muscle sheet. These pacesetter cells are known as interstitial cells of Cajal (ICC) and are located in the muscularis mucosae and muscularis externa. Figure – Functions of cells in gastric pits

Endocrine – G and D cells Exocrine – Chief, mucous neck and parietal cells Paracrine – Enterochromaffin-like cells Parietal secretion of HCl HCl is not produced in cytoplasm as this would damage the cell. Hydrogen ions and chloride ions produced separately. CO2 + H2O à H2CO3 is formed within parietal cells. H2CO3 à HCO3

- + H+ occurs, H+ actively transported into lumen of gastric gland. HCO3

- exchanged for Cl from interstitial fluid. Gastrin from G cells (endocrine) regulates parietal cell secretion – presence of partially digested proteins à stimulates G-cell secretion of gastrin à stimulates HCl release from parietal cells.

14/11/16 James Yang

Histamine from enterochromaffin-like cells regulates parietal cell secretion – histamine à bind to H2 receptor on parietal cell à stimulates HCl release from parietal cell. Secretion of pepsinogen and activation by HCl – HCl in gastric lumen converts pepsinogen (inactive protease precursor) to pepsin (mentioned in previous lecture). Subsequent conversions are quicker due to pepsin’s protease activity. Neural control of chief cells, parietal cells and enterochromaffin-like cells all require acetylcholine as a neurotransmitter. G cells require gastrin-releasing peptide neuropeptide (GRP). Neurally controlled by vagal efferent pathways and enteric nervous system. Liver functions (gone over previously in past lectures, covering again) Hepatic portal system – network of veins that carries blood from GIT/spleen to the liver. Liver functions to secrete plasma proteins and bile, serves as a blood reservoir, regulates metabolism by extracting nutrients and toxins from blood pre-systemic circulation, processes drugs/hormones, phagocytosis of RBC, WBC and bacteria via Kupffer’s cells and stores vitamins/minerals. Hepatic arterial blood (oxygen rich, nutrient poor) from hepatic artery and portal vein blood (nutrient rich, oxygen poor) collect in hepatic central vein. Discontinuous sinusoidal capillaries are open-pore capillaries (large pores) allowing for bile to be transported into bile ducts. Hepatocytes contain microvilli that take up nutrients, synthesise bile which is then secreted into canaliculi à bile duct. Bile is synthesised from cholesterol, is an amphiphilic molecule (aids in lipid digestion) and is stored/concentrated in the gall bladder – released upon stimulation from enteric nervous system or CCK). RECALL: Gall bladder à cystic duct à common bile duct à duodenum.

14/11/16 James Yang

BIOM1052 – Gastrointestinal System Physiology 3 Overview of small intestine Exocrine pancreas and secretions Nutrient absorption Intestinal water and electrolytes Colon physiology Once again this lecture has some overlap with lectures from the previous week. Small intestine made of duodenum, jejunum and ileum – its function is to digest and absorb, it is the longest part of the GIT beginning at the pyloric sphincter and ending at the ileocecal valve. The duodenum is the mixing bowl for chyme, bile and pancreatic secretions. It is made of longitudinal and circular muscle and has mucous membrane that buffers stomach acid protecting the simple columnar epithelium beneath. Duodenum also releases secretin and cholecystokinin via entero-endocrine cells in response to acidic/fatty chyme – regulating gastric emptying (contractile force and rate – these are also regulated by chemoreceptors and stretch receptors which influence autonomic nervous system). Gastric emptying process: Chyme à duodenum (detects fatty acids in chyme à CCK, detects acidity in chyme à secretin à enters blood à CCK à pancreas à release digestive enzymes Secretin à pancreas à release HCO3

- and mucus CCK à gall bladder à contracts gall bladder/relaxes sphincter à bile enters duodenum Secretin à liver à bile production Jejunum and ileum are the primary sites of absorption via villi and microvilli. Exocrine glands secrete products through ducts onto epithelium. Secretions include bicarbonate solution and enzyme-rich solution. Digestive enzymes include proteolytic enzymes/zymogens (precursor to enzyme) – trypsinogen à trypsin (via enteropeptidase) which then activates other zymogens e.g. procarboxypeptidase à carboxypeptidase). Acini secrete pancreatic juice; zymogen granules store pancreatic juice. The sphincter of Oddi controls the flow of both bile and pancreatic juices into the duodenum. Fats: Bile salts are amphipathic à leads to emulsification (spreading out) of fat molecules à greatly increases SA such that pancreatic lipase can digest fat molecules into monoglycerides and fatty acids à fat-soluble substances form micelles with bile salts and phospholipids. Micelles diffuse into intestinal epithelial cells à fat-soluble substances are packaged into chylomicrons à enter circulation via lacteal. Carbs: Brush border enzymes are integral membrane proteins of intestinal epithelial cells that break down sugars into monosaccharides. These monosaccharides are then transported into the intestinal epithelial cell via active transport or co-transport with sodium ions à transported via facilitated diffusion into capillaries toward the liver. Proteins: Pepsin and pancreatic proteolytic enzymes break down proteins into amino acids à same process as carbs above. 95% of water is absorbed in the small intestine via osmosis (concentration gradient caused by transport of carbs and proteins into intestinal epithelial cell). Fluid movement in GIT: Mouth – Water and saliva Stomach – Gastric juice

14/11/16 James Yang

Small intestine – Bile, pancreatic juice, intestinal secretions and intestinal absorption (95%) Colon – Colonic absorption (4%) and faeces excretion (1%) Sodium is absorbed from lumen into epithelial lining along with nutrients (such as amino acids) à creates osmotic gradient à water is also absorbed Other ions present in lumen may also be absorbed into epithelial lining further increasing concentration gradient à water is also absorbed (water may move back into lumen secreting water alongside). This movement can be controlled by ENS (stretch receptors, osmoreptors and chemoreceptors via acetylcholine neurotransmitter). Colon provides storage, absorption of water and electrolytes, contains goblet cells (secretes mucus and HCO3

-). Colon bacteria ferments undigested carbs to produce acid. Low mixing (colon motility – since slow movement). Mass movements – big contraction wave towards distal colon triggered by upper GIT (gastrin and extrinsic nerves) leads to defecation. Anal canal is composed of internal sphincter (smooth muscle à PNS relaxes, SNS contracts) and external sphincter being skeletal muscle. Defecation reflex: mass movement à faeces toward rectum à distention à internal sphincter relaxes à colon contracts à external sphincter controls defecation.