Digestive Physiology

Oesophageal physiology and function:

 Swallowing: rapid events taking less than 1 second coordinated by the swallowing center in the brainstem. Skeletal muscles provide pressure of up to 200 mmHg. There are two phases to swallowing
- oral phase: voluntary action to push the bolus to the back of the mouth along with the elevation of soft palate (block entry to nose) and posterior tongue to prevent nasal and oral regurgitation
- pharyngeal phase: reflex action where the bolus is pushed toward the UES. Main events are the elevation of larynx and closure of epiglottis to protect the airway.
 Relaxation of UES: occurs for only 0.5 to 1.0 sec with swallowing and also belching and vomiting.
 Peristalsis: coordinated contraction of the muscular wall of the GI to propel bolus along the gut tube. This is stimulated by the distention of esophagus by the bolus and through the mechanism of descending inhibition, i.e. contraction above and relaxation below the bolus. Longitudinal muscle shortens during peristalsis.
- primary peristalsis: induced by swallowing and is a continuation of the pharyngeal contraction producing pressure from 30 – 80 mmHg and speed 3-5 cm/sec and coordinated with relaxation of the UES
- secondary peristalsis: propagated involuntary contractions caused by distension in esophagus from bolus or acid (not from swallowing). It is used to clear residual matter in the esophagus through stripping waves.
 Lower esophageal sphincter: special segment of smooth muscle at the cardia of the stomach. The sphincter maintain tonic contract at 20-35 mmHg through spontaneous depolarization.
- Relaxation of the LES: occurs 1-2 secs after swallowing and lasts for 5–10 sec, followed by hypercontraction to prevent reflux of food and acid. Transient relaxation unrelated to swallowing also occur at regular intervals only with upright position. These are vagally mediated and used to get rid of air in stomach.
- Basal tone of LES is critical to protect esophageal squamous against gastric reflux.
 Oesophageal sphincter problems:
- Zenker’s diverculum: failure of the UES to relax prevents entry of bolus. The high pressure of swallowing pushes the bolus against the wall forming a posterior pouch where the food can be trapped.
 Pathophysiology of gastro-oesophageal reflux: reflux episodes occur mostly during transient relaxation of the LOS. Esophagus, normally having a pH of 6-7, is unable to handle the acid and the esophageal nerve fibres give a burning sensation, i.e. heart burn. Chronic acid reflex can cause ulceration and reflux oesophagitis.
- disordered gastric motility: more acid accumulates in the fundic region
- hiatus hernia: strangulation of part of the stomach through the diaphragm due to abnormal lengthening of the esophagus, to produce a reservoir effect of gastric acid. Hence during the transient relaxations, increase amount of acid is refluxed into the esophagus.
- Impaired esophageal peristalsis: inability of esophagus to clear acid with secondary peristalsis.
- Other causes: drug tetracycline, radiation, alkali ingestion and infection
 Long term gastro-esophageal reflux:
- oesophageal stricture: scarring from repeated acid exposure and ulceration creates a fiber stricture of the lumen and causes dysphagia (difficulty in swallowing). Normal esophageal diameter is 2.0 – 2.5 but is reduced to 1.5 cm with this.
- Oesophageal cancer: carcinoma of squamous cells block food
- Barrett’s esophagus: a change from squamous lined to columnar lined epithelium in the esophagus due to chronic acid exposure, i.e. metaplasia of cells to for adaptation. This causes an elevation of the squamo-columnar junction which is a risk factor for oesophageal cancer.
- Schatsksi’s ring: a fibrous ring at the gastro-oesophageal junction and cause blockage of food bolus (meat) along the entire length of the oesophagus. Commonly known as steak house syndrome.
 Motility disorder: abnormalities of the esophagus involved with motor functions and dysphagia caused by damage to nerve or smooth muscle. Symptoms are intermittent and liquid and solid are affected equally unlike that of esophageal stricture where problems progress from solid to liquid. Gastro-oesophageal reflux is also considered as part of motility disorder as the absence of peristalsis impaired acid clearance.
- oesophageal spasm: corkscrew shaped esophagus that is non-peristaltic or the walls simultaneously contract. There is chest pain and dysphagia by bolus obstruction.
- Achalasia: degeneration of neural element in the esophagus particularly ganglionic cells in the myenteric plexus result in a loss of peristalsis. The LES also fails to relax due to loss of inhibitory neurons that turn off tonic contraction (uses CCK and/or NO as neurotransmitter). Disease characterized by a progressive dysphagia development for both liquid and solid.
- Scleroderma: fibrosis of the submucosa and muscle layers of the oesophagus leading to malfunctioning smooth muscle and damaged vagal nerve and complete loss of peristalsis and LOS tone. Results are severe gastric reflex.

Oral and gastric secretion:

 Saliva: watery mucus secretion of the mouth containing the following elements:
- electrolytes: for example high HCO3- levels to maintain pH neutrality in mouth and increase pH in esophagus. Also dilute/buffer harmful substances
- mucin: lubrication of bolus and enhance chewing action. It is slowly degraded by proteinases
- salivary amylase: enzyme that intinate digestion of complex carbohydrates to smaller starch molecules. Effect is lost when pH is below 4 (in stomach) but can last for up to one hour due to buffering effect and unstirred layer of food
- lactoferrin and lysozyme: antibacterial action and lingual lipase provided limited digestion of fat in stomach.
 Control of saliva:
- stimulated by light
- smell of food
- inhibited during sleep
- stimulated by acid in esophagus
 Xerostomia: Loss of saliva that can lead to drying of mouth, oral infections, dental decay and loss of taste as saliva irrigate the taste buds.
- Sjogren’s disease: keratoconjuctivitis sicca; chronic inflammation of salivary glands causing xerostomia
- Anti-cholinergic drug can inhibit vagal stimulation of salivation
 Function of stomach:
- reservoir of food during initial digestion and changing them to chyme
- adjust osmolarity of content before they are delivered into the small intestine
- antrum functions as a grinding mill for churning and mixing of food while pylorus regulate size of particles that pass through to the duodenum
- secretion of gastric acid to sterilize stomach
- secrete other substances such as intrinsic factor for B12 absorption, mucus, pepsinogen for protein hydrolysis and prostaglandin which stimulate contraction.
 Gastric motility:
- fundus: relaxation of wall by vagovagal reflex to accommodate increased amount of food
- body and antrum: contraction and mixing of food by retropulsion
- pylorus: contraction to limit exit of chyme
 Control of gastric motility:
- feedback mechanism from acid in duodenum, fat, amino acid and osmolarity
- requires intact antrum, pylorus and duodenum
- require normal vagal activity
- require normal hormonal function
 Rapid gastric emptying: caused usually by post gastric surgery and will lead to dumping symptoms
- dumping symptom: presence of concentrated hyperosmolar chyme in the small intestine due to uncontrolled rapid gastric emptying, hence increased absorption overstimulates production of insulin and result in hypoglycemia
 Delayed gastric emptying: the lack of motility of stomach wall causing food to leave the stomach at a much slower rate.
- diabetic gastroparesis: neuropathy of autonomic nerves that innervate stomach muscles and pyloric sphincter due to diabetes will impair relaxation of the sphincter, hence delaying gastric emptying. Symptom includes upper abdominal discomfort.
 Drugs that affect gastric emptying:
- prokinetics: drugs that speed up gastric emptying, e.g. metoclopramide that release Ach at myenteric plexus
- anti- cholinergic drugs: drugs that delay gastric emptying
 Role of gastric acid:
- main role of sterilization of stomach as acidic environment is hostile to bacteria except H. Pylori
- limited role in digestion but aids denaturation of tertiary proteins (break ionic bond)
- helps absorption of Fe and B12
 Achlorhydria: condition of absence of HCl in stomach. This is associated with atrophy of the lining of the stomach and loss of parietal cells hence unable to secrete intrinsic factor (pernicious anaemia). Bacterial overgrowth and risk of gastric cancer is increased. Enteric infection is also possible.
 Mechanism of parietal cells:
- When stimulated, cytoplasmic tubulovesicles fuse with canaliculus in the parietal cells, H+K+ATPase becomes transmembrane in activated position and secretory surface is increased drastically. Acid secretion is against a 3 million fold concentration gradient
- HCO3- is produced intracellularly by carbonic anhydrase and exits into the bloodstream in exchange for Cl- producing an alkaline tide, i.e. transient increase in pH of blood during gastric digestion.
- H+ is actively pumped out across the apical membrane with K+ (supplied from plasma) and Cl- follows to maintain charge neutrality.
 pH profiles: during the day pH increases to around 5-6 due to buffering of meals in stomach while during night, the pH gradually falls to 1.5.
 Activation of gastric secretion:
- autonomic vagus nerve activated directly stimulate the parietal cell through acetylcholine to secrete acid (neurocrine control) while also stimulating G-cells by GRP (neurotransmitter gastrin-releasing polypeptide) to secrete gastrin
- G-cells are also be activated by the presence of amino acid and peptide (metabolites of protein) to release gastrin into the blood (endocrine control).
- The neighbouring ECL (enterochromaffin-like) cells situated near parietal cells are stimulated by gastrin and acetylcholine to produce histamine (paracrine control).
- Gastrin, acetylcholine and histamine act synergistically to stimulate maximum acid secretion. These three agonists bind to independent receptors on the parietal cells – gastrin on to CCK2 receptor, acetylcholine on to M3 receptor and histamine on to histamine H2 receptor. While histamine transduce the activation signal through a G-protein link cAMP dependent pathway, the other two does this through a Ca2+ dependent pathway.
 Inhibition of gastric secretion:
- acid in the duodenum will stimulate S-cells located deep in the intestinal glands produce secretin that will inhibit G-cells from releasing gastrin, inhibit gastric emptying and stimulates pancreatic alkaline secretion.
- Decreasing pH in the stomach activates D-cells and release somatostatin which is a potent mediator for reducing acid secretion. Somatostatin travels paracrine to inhibit G-cells
- Fatty acids in duodenum stimulate K cells to produce GIP (gastric inhibitory polypeptide) and inhibit gastrin and parietal cells, even though the main function of GIP is to stimulate pancreatic release of insulin.
- CCK inhibit gastric emptying
 Phases of gastric secretions:
- cephalic phase: vagus nerve activation by thought, sight and smell of food accompanied by some gastrin release due to GRP
- gastric phase: vagal activation by distension of the body and antrum of stomach in addition to release of histamine and gastrin
 Other gastric secretions:
- pepsinogen: secreted by chief cells and is cleaved in acid to form pepsin, an active protease that hydrolyzes proteins at aspartic amino acid (stimulant of G-cells). Also important in early digestion of collagen. Pepsin is not active above pH of 4 thus acid inhibition is useful to aid healing of ulcers as clots will not be dissolved.
- Intrinsic factor: absorption of B12
- Prostaglandin: protection and repair of gastric mucosa
- Mucus and HCO3-: forms protective surface against acid
- Gastric lipase: secreted by chief cells to remove fatty acid from triglyceride but weaker than pancreatic lipase.
 Abnormal gastric acid secretion:
- H. pylori gastritis and tumours of gastrin both increase acid secretion
- Loss of parietal cells through atrophy and inflammation, vagotomy (used to reduce acid and treat ulceration) and drugs such as proton pump inhibitors or histamine 2 antagonists all act to decrease acid production.

Pancreatic and biliary secretion

 Regulatory role of duodenum: carried out by endocrine cells and vagal afferents that respond to luminal contents and nutrients
- inhibit gastric emptying
- inhibit acid secretion
- stimulate pancreatic and biliary secretions
 Pancreatic secretions:
- alkaline secretion: required to neutralize gastric acid and maintain pH neutrality for optimal function of enzymes (1.5L per day)
- pancreatic enzymes: used to digest food particles to be absorbed
- majority mediated by direct vagal stimulation from afferents of duodenum and limited stimulation by vagus of cephalic and gastric phase. Truncal vagotomy can decrease secretion by 60%)
 Mechanism of alkaline secretion:
- secretin produced in response to acid in the duodenum (pH<4) binds to pancreatic cells and transduce a signal through cAMP amplification to activate CFTR channels.
- Increased activity of CFTR pumps more Cl- ions into luminal spaces as a mean to enhance HCO3- secretion by the HCO3-/Cl- exchangers on the apical membrane.
- Na+, K+ and water travel paracellularly to maintain charge neutrality and isotonicity
- Within the cells HCO3- is produced by carbonic anhydrase from CO2 that diffused in through capillaries.
- Duodenum also secretes bicarbonate
 Mutation of CFTR: impaired pancreatic secretion of thick mucus leading to blockage and secondary damage from pancreatitis.
 Mechanism of enzyme release:
- Cholecystokinin secreted into blood in response to I cells sensing the presence of fatty and amino acids in the small intestine on the apical membrane or vagal stimulation. Neurotransmitter involves is mainly Ach but also GIP and VIP
- CCK acts by stimulating vagal afferent next to I-cells to brainstem and then vagal efferent down to the pancreas or directly through endocrine control.
- Proteases and phospholipases are secreted in their inactive proenzyme form, e.g. trypsinogen, procarboxypeptidase and activated in the lumen because these enzyme would digest away pancreatic gland if activated in pancreas
- Other enzyme such as lipase and amylase are stored and secreted in their active form as pancreas does not contain starch or triglyceride.
 VIP: vasoactive intestinal peptide is a peptide hormone whose function is mainly stimulate intestinal secretion such as water and electrolyte
 Inhibition of pancreatic secretion:
- Glucagon, somatostatin and pancreatic polypeptide inhibit pancreatic secretion, for example pancreatic polypeptide acts on brainstem and inhibit vagal efferent
- Peptide YY, released from ileum and colon, in response to increased levels of FFA
- Possible feedback mechanism from intraluminal action of proteases
 Homology of hormones:
- N-terminal homology: secretin, VIP, GIP, and glucagons
- C-terminal homology: gastrin and CCK – more important for binding receptors
 Acute pancreatitis: rapid onset of pancreatic inflammation. Causes include:
- pancreatic duct obstruction e.g. from gallstone impacted in common bile duct close to the ampulla of Vater
- direct acinar cell toxicity (mainly alcohol; some prescribed drugs)
- involves auto-digestion by activated proteases, particularly trypsin
 Chronic pancreatitis
- Result of repeated episodes of inflammation
- Chronic and severe pain is main problem because of involvement of peri-pancreatic neural tissue
- Eventually exocrine function is impaired enough to cause weight loss, fat malabsorption (steatorrhoea), loss of lipase most critical
- Pancreatic enzymes can be taken by mouth but problems with gastric degradation of acid (denaturation)
- calcification of proteinaceous material in pancreas can form protein plugs and needs to be removed to relieve pain
 Mechanism of bile secretion:
- bile-acid dependent flow: secretion of bile salt into canaliculus of the liver creates an hyperosmolar condition that promote water secretion by osmosis, allowing bile flow
- Secretory pressure causes uni-directional flow of bile and as the ducts enlarges in size, more water and Na+ is removed
- Active secretion of cholesterol and phospholipid occurs and coupled with bile salt secretion. Organic anions (bilirubin) are also carried along the flow.
- Bile-acid independent flow also exists but mechanism of it is unknown.
 Source of bile acid:
- synthesized from cholesterol forming primary bile acids (around 600mg per day)
- enterohepatic circulation
 Enterohepatic circulation:
- Bile salt released into the small intestine is reabsorbed in terminal ileum by the Na+ dependent reuptake system. Passive absorption in jejunum and ileum also occur.
- 99% of bile salt now circulating in blood is then taken up by the bile acid/Na+ transporter from the portal vein and back into liver hepatocytes
- Bile lost in faeces is roughly the same as the amount synthesized per day. Failure of reuptake will lead to diarrhea.
- There is a pool of around 2.5g of bile salt at anytime but total secretion is between 15-30g.
 Gallbladder function: responsible for storage of bile between interdigestive period
- In the absence of digestion, the sphincter of Oddi and bile duct is closed and bile released from the liver simply flow into the gallbladder where the bile is concentrated up to 20 times.
- When stimulated by CCK, the sphincter will relax and the gallbladder is stimulated to contract hence squeezing out the bile into the duodenum.
 Cholestasis: obstruction to bile flow within either the liver or the hepatic and common bile duct. This will lead to
- increased pressure in the biliary tract that can cause rupture of tight junction of cells and leakage of bile back into circulation
- maldigestion of fat
- Reflux of bile content back into the liver and blood leading to jaundice and itching.
 Effect of long term bile duct obstruction:
- jaundice: yellow discoloration of skin/sclera from bilirubin, palpable gallbladder, bruising etc
- itching: most likely due to bile salt accumulation under skin
- nausea: from bile salt
- renal perfusion: probable to cause renal failure
- malabsorption of fat and fat-soluble vitamin

Intestinal Motility and Secretions

 Swallowing: voluntary action in which the tongue is raised against the roof and bolus is pushed to the back of the mouth
- co-ordinated by the swallowing center
 Activities of the oesophagus:
- 10 sec peristalsis pushes the food down the oesophagus
- Vagal reflex of the oesophagus causes the fundus to relax
- Liquid travels faster than solids
 Neural control: gut is provided with enteric plexus. Sympathetic inhibits motility and secretion of the gut while parasympathetic stimulates.
 Gastric motility: Stomach contents forms layers so contents needed to be mixed. Gastric contraction is controlled by pace maker so tone of the gut is dependent on membrane potential of muscle fibres.
- contraction begins at cardia and passes through the stomach
- the pylorus sphincter suddenly contract to push the stomach content back in a movement called retropulsion
- motility of stomach is controlled by feedback signals from duodenum, i.e. acid, fat and peptide inhibit gastric emptying so duodenum is not overwhelmed.
 Electrical activity: measurement of electrical activity of the muscle will reveal a migrating myoelectric complex from the oral to aboral end of the gut tube. This is associated with the tone of smooth muscles and the bases of peristalsis.
- Occurs once every 75-90 minutes in the fasting state
- It begins in the cardia through pace maker depolarization
 Vomitting: mediated by the vomiting center. Stimulus involves vertigo, pain in genicourinary system, food poisoning.
- events: pressure in the stomach increase and relaxation of the esophagus to straighten the channel. Perfuse salivation to help protect esophagus from acid and finally relaxation of diaphragm and abdominal muscles provide tension to expel the stomach content
 Mechanism of food poisoning:
- bacterial in food ingested released toxin into the stomach
- the stomach destroys the bacteria but the toxin is retained and is absorbed into the portal vein
- blood borne toxin damage cells in the blood vessel to trigger neurotransmitter release and also detected by an area in the brain stem
- toxin acts on vagal receptors in the gut cell to release serotonin and signal is send up the afferent nerve to the great visceral nerve center (nucleus of tract soltaris)
- nerve impulse is carried to the vomiting center and vomiting is promoted.
 Motility of small intestine: waves of contraction clear any residue in the gut to prevent obstruction. Segmentation (separate and independent contraction) of the small intestine mixes chyme with enzymatic and bile in small intestine
- law of intestine: contraction at oral end and relax at aboral end (peristalsis)
- distention of stomach relax to incorporate food
- ileogastric reflex: distention of small intestine inhibition contraction above, i.e. in the stomach to decrease delivery of food
- gastroileal reflex: distention of stomach cause small intestine to contract to clear material
 Colonic motility: predominating movement toward ileum and segmental contraction of haustra maximize absorption. Mass movement of material (faeces) once to three times a day to transverse and descending colon
- coloncolonic reflex: colon distention causes relaxation
- gastrocolic reflex: stomach distended causes mass movement of the colon and hence cause defecation
 Defecation: mechanoreceptors sends signal via sacral spinal cord to medulla to co-ordinate defecation.
- material in the rectum cause reflex relaxation of internal anal sphincter while voluntary relaxation of external sphincter expel the faeces

Fluid and electrolyte balance:

 Fluid balance: balance of fluid influx and fluid efflux
- Ingestion is dependent on social factors
 Diarrhea is loss of 200mL of liquid in faeces
 Liquid absorption: small intestine is the major source of fluid intake while colon does 400mL of liquid
 Regulation of stomach secretion:
- secretion of saliva is entirely under parasympathetic neural control, stimulated by food smell. Usage of atrophin blocks nerve ending and produce dry mouth
- Cephalic phase: conditioned reflex for small taste and hypoglycemia etc to stimulate vagus nucleus and nerve, causing stomach to produced enzyme and digest proteins. Parasympathetic release acetylcholine on parental cells to produce H+. Intermediate neurons activate G-cells and gastrin is released by action of neurotransmission GRP. Gastrin attach to parietal cell receptors producing a stimulating effect.
- Gastric phase: stretch receptors stimulated by food distention in stomach and action potential of the afferent nerve are fired. Both extraneural reflex (signal to brain center) and intraneural reflex (signal to G-cells and parietal cells) triggered to maintain secretion during food digestions
- Intestinal phase: more significant for pancreas
 Pancreatic Secretion:
- Cephalic phase: prepare the content of duodenum to receive stomach. G-cell stimulated, gastrin acts on acinar cells leading to production of enzyme and alkaline solution. But this pathway is much less significant compared to direct stimulation by vagal to acinar and duct cells.
- Gastric phase: exist
- Intestinal phase: vagus nerve efferent is maintained and watery secretion continues. Fat and proteins are digested into their metabolites and act on two type of cells – I cells and S cells. S cells makes secretin in response to acid to promote bicarbonate secretion of duct cells while I cells (stimulated by the peptides) produce cholecystekinin to stimulate production of enzyme of acinar cells and water secretion of ducts
 Liver and gallbladder:
- Bile produced is stored in gallbladder where water is absorbed to concentrate it and released in the duodenum. Bile is an emulsifier used to aid digestion of fat and make molecules small so water soluble enzyme can act
- CCK cause gallbladder to contract and squirt bile into duodenum
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