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GI Function and Regulation (Intestinal fluid and electrolyte transport…
GI Function and Regulation
Structural considerations
Throughout length, glandular structures deliver secretions into lumen, particularly in stomach and mouth
there are secretions from the pancreas and the biliary system of the liver
Intestinal tract functionally divided into segments by means of muscle rings (sphincters)
4 layers
Mucosa
Submucosa
Muscularis Propria
Adventitia (with mesothelium will be called serosa)
On top of micro-villi in the small intestines is the glycocalyx layer
Protects cells from digestive enzymes, and some digestive enzymes are part of this brush border, performing the final steps of digestion for specific nutrients
Salivary secretion
By 3 glands
Parotid
Serous (proteinaceous)
Sublingual
Mucus
Submandibular
mix of serous and mucus
Initiates digestion (salivary amylase - starch), protect oral activity from bacteria (IgA and lysozyme), lubricate food (into bolus) and facilitate swallowing, keeps mouth and teeth clean, serves as solvent for molecules to stimulate taste buds
Hypotonic compared with plasma and slightly alkaline
While saliva move from acini to ducts, Na+ and Cl- are extracted while K+ and HCO3- are added
as ducts are relatively impermeable to water, loss of NaCl renders saliva hypotonic, particularly at low secretion rates
At higher secretion rates, less time for extraction of NaCl, but still hypotonic relative to plasma
1000-1500ml per day
Control
almost entirely by neural influences
Parasympathetic branch of autonomic nervous system plays most prominent role
Sympathetic input slightly modifies composition (more proteinaceous), has little influence on volume
Triggered by reflexes that are stimulated by the physical act of chewing, and is initiated even before meal reach the mouth as a result of central triggers that are prompted by thinking about, seeing or smelling the food
Can also be prompted by nausea, inhibited by fear or during sleep
Parotid and submandibular glands are innervated by different ganglions (though both triggered by ACh)
Gastric secretion
Food is stored in the stomach, mixed with acid, mucus and pepsin; released at acontrolled, steady rate into duodenum
In cardia and Pyloric, mainly secrete mucus
Pyloric has endocrine cells that secrete gastsrin
cardia has some chief cells, ,but no parietal and endocrine cells
In body of stomach including the fundus, contain parietal (oxyntic) cells that secrete HCL and intrinsic factor (for B12), also contains chief cells (zymogen) which secrete pepsinogens
Secretions mix with mucus secreted by neck cells, opens to gastric pits
Rich in blood and lymphatic supply, parasympathetic from vagi, sympathetic from celiac plexus
Origin and regulation of secretion
Mucus (from mucus neck cells and surface cells) protects the inner lining of the stomach, with trefoil peptides stabilizing the mucus bicarbonate layer.
acid sterilize the meal and begin hydrolysis of dietary macromolecules
Intrinsic factor impt for layer absorption of B12 (or cbalamin)
Pepsinogen is precursor of pepsin, which initiates protein digestion
Gastrin released by G cells in antrum of stomach both in response to specific neurotransmitter released from enteric nerve endings (gastrin-releasing peptide, GRP, due to vagal outflow) and also in response to presence of oligopeptides in gastric lumen.
Gastrin carried through bloodstream to fundic glands, where bind to parietal (and likely chief cells) to activate secretion, and also to enterochromaffin-like cells (ECL) that are located in the gland.
ECL releases histamin, which also trigger parietal cell secretion
Parietal and chief cells both stimulated by ACh released from enteric nerve endings in the fundus
Presence of food and physical distension of the stomach can both provoke vago-vagal and local responses that amplify secretions
presence of meal buffers gastric acidity, that would otherwise serve as negative feedback to shutoff secretion secondary to release of somatostatin (which inhibits both G and ECL cells as well as parietal secretions itself)
About 2.5L/day, dispensable except for cobalamin absorption and antibacterial properties
parietal cells
Packed with mitochondria that supply energy to drive the apical H+/K+ - ATPase or proton pump, moving H+ against gradient.
Pumps are sequestered within cell in a series of membrane compartments known as tubulovesicles
When parietal cells begin to secrete, vesicles fuse with invaginations of apical membrane known as canaliculi, substantially amplufying the apical membrane area and positioning the proton pumps to begin acid secretion
Apical membrane also contains K+ channels (out to supply gradient) and Cl- channels (as counterion for HCl secretion)
Secretion of proton is with release of equivalent no. of bicarb ions into bloodstream, which will later be used to neutralize gastric acidity once function is complete
3 agonists
Gastsrin and ACh
by elevating cystolic free Ca2+ concentrations
Histamine
increase intracellular cAMP
Are synergistic with greater additive effect, inhibition of one can markedly reduce secretion due to this
Pancreatic (juice) secretion
Controlled in part by a reflex mechanism and in part by secretin and cholecystokinin (CCK)
Pancreatic cells contain granules (that contain digestive enzymes, zymogen granules) and are discharged by exocytosis from apexes of cells in to lumens of pancreatic ducts
Small ducts coalesce into a single duct, which joins the bile duct to form the ampulla of Vater, opens through the duodenal papilla which is circles by the sphincter of oddi
Composition
Alkaline, high HCO3- content
About 1500ml/day
Bile and intestinal juices are also neutral or alkaline, all 3 act to neutralize gastric acid by jejunum (nearly neutral)
Digestive enzymes
most are released in inactive forms and only activated when they reach the lumen of the small intestine
Activated following proteolytic cleavage by trypsin (which itself is a pancreatic protease released as trypsinogen and cleaved by enteropeptidase released by intestinal mucosa)
Pancreas also normally secretes a trypsin inhibitor
Phospholipase A2 also activated by trypsin, splits fatty acid of phophatidylcholine (PC), forming lyso-PC, which damges cell membranes
Normally cause acute pancreatitis if activated prematurely
Small amounts leak into circulation, but in acute pancreatitis, it is increased markedly
Regulation
Secretin cause secretion of very alkaline pancreatic juice high in HCO3- and low in enzymes, due to increase intracellular cAMP, and also stimulates bile secretion
CCK acts on acinar cells to cause release of zymogen granules and production of pancreatic juice reach in enzymes but low in volume, effect mediated by phospolipase C
During secretin, level of Cl- falls while HCO3- increases
Like CCK, ACh acts on acinar cells via phospholipase C, cause discharge of zymogen granules and stimulation of vagi cause secretion of a small amount of pancreatic juice rich in enzymes
Biliary secretion
Bile acids important in digestion and absorption of fats
Bile serves as critical excretory fluids by which body disposes of lipid soluble end products of metabolism as well as lipid soluble xenobiotics, only route to dispose of cholesterol (either in native form or conversion to bile acid)
Bile
made up of bile acids, bile pigments and other substances dissolved in an alkaline electrolyte solution that resembles pancreatic juice
About 500ml/day
some components reabsorbed in the intestine and then excreted again by liver (enterohepatic circulation)
Glurinides of bile pigments: bilirubin and biliverdin, gives bile the golden yellow color
Bile acids synthesized from cholesterol and secreted into bile conjugated to glycine or taurin
4 major bile acids
Cholic Acid -> deoxycholic acid
Chenodeoxycholic Acid -> lithocholic acid
Bile acids reduce surface tension, and in conjunction with phospholipids and monoglycerides, responsible for emulsification of fat preparatory to its digestion and absorption
Converted by bacteria in the colon, with some ursadeoxycholic acid fromed from chenodeoxycholic acid
Results of conversion are secondary bile acids
amphiphatic (both hydrophilic and phobic ends), form cylindrical disks of micelles (philic on surface, phobic in core)
90-95% absorbed from small intestine
once deconjugated, can be absorbed by non-ionic diffusion
most absorbed in conjugated forms from terminal ileum through extremely efficient Na+-bile salt contransport system (driven by low Na+ intracellualrlly established by basolateral Na+/K+ ATPase
Remaining 5-10% enter colon and converted
lithocholic acid relatively insoluble, mostly excreted instools and only 1% reabsorbed
deoxycholate is absorbed
Absorbed bile transported back to liver in portal vein and reexcreted in bile, those lost in stool replaced by synthesis in liver, normal rate of bile acid synthesis is 0.2-0.4g/day
Intestinal fluid and electrolyte transport
Intestine supplies a fluid environment in which process of digestion and absorption can occur, once meal is assimilated, fluid is reabsorbed to prevent dehydration.
Water moves passively in and out of GI lumen, driven by electrochemical gradients established by active transport of ions and other solutes.
after a meal, reuptake is driven by coupled transport of nutrients such as glucose (and amino acids) with Na+
between meals, reuptake is driven exclusively by electrolytes
in both, secretory fluxes of fluid are largely driven by active transport of Cl- into lumen, although reabsorption dominates overall
Overall water balance
Input: 9000
Ingested: 2000
Endogenous secretions: 7000
Salivary glands 1500
Stomach: 2500
Bile: 500
Pancreas: 1500
Intestine: 1000
Reabsorbed: 8800
Jejunum:5500
Ileum: 2000
Colon: 1300
Balance in stool 200
In small intestine, between meals when nutrients are not present, Na and Cl both absorbed together from lumen by coupled activity of NHE and Chloride/bicarb exchanged in the apical membrane, water then follows to maintain osmotic balance
In colon, additional electrogenic mechanism for Na absorption is expressed, especially in distal colon
Na cross apical membrance via an ENaC, identical to that expressed in Kidneys
Fluid secretion still occurs to maintain fluidity
Cl- enters enterocytes from interstital fluid via Na+-K+-2Cl- cotransporters in basolateral membranes, and Cl- is secreted via CFTR (cystic fibrosis transmembrane regulator), which is activated by protein kinase A and hence cAMP
Saline cathartics such as magnesium sulfate are poorly absorbed salts that retain their osmotic equivalent of water in the intestine, increasing intestinal vol and consequently exerting a laxative effect
Some K+ secreted into the lumen down gradient, which is offset slightly by active transport through H+-K+-ATPases
Loss of ileal or colonic fluids in chronic diarrhea can lead to hypokalemia
High K+ diet -> more luminal K+
Gastrointestinal regualtion
Endocrine regulation
release of hormones by triggers associated with the meal, targeting distal effectors
Paracrine
Local endocrine regulation
Extensive neural connections -> extrinsic inneravation (CNS) and also large autonomous enteric nervous system
Comprise both sensory and secretomotor neurons
Enteric nervous system integrates central input to gut and regulate gut function independently in response to changes in luminal environment
Hormones/paracrines
Enteroendocrine cells
Many secrete only one hormone, identified by letters
Others manufacture serotonin or histamine, called enterochromag=ffin or ECL cells respectively
Gastrin
Produced by G cells in antrum of stomach, from a large precursor
flask shaped, granules and baso side, narrow apex, receptors respond to changes in gastric contents present on the microvilli
G17 is principal form with respect to gastrin secretion (17 a.a.)
G14 and 17: half life of 2-3 mins
G 34: half life of 15 mins
Principal physiological actions
Stimulation of gatric acid and pepsin secretion, and stimulation of growth of mucosa of the stomach and small and large intestines
affected by
Contents of stomach
Increased by presence of products of protein digestion in the stomach, which act directly on G cells
Acid in antrum inhibits gastrin secretion, partly by direct action on G cells and partly by release of somatostatin (-ve feedback loop)
Rate of discharge of vagus nerves
Not affected by atropine as transmitter secreted by postganglionic vagal fibers that innervate G cells is GRP
bloodborne factors
Can act via a receptor (CCK-B), which is related to CCK-A
Cholecystokinin (CCK)
secreted by endocrine cells : I cells in mucosa of upper small intestine
Stimulates pancreatic enzyme secretion, contraction of gall bladder, and relaxation of the sphincter of Oddi, which allows both bile and pancreatic juice flow into the intestinal lumen
Also produced from a larger precursor
Half life of around 5 min
Also found in nerves in distal ileum and colon, in neurons in the brain (especially cerebral cortex) and in nerves in many parts of the body.
in brain, may be involved in regulation of food intake, related to production of anxiety and analgesia
Also augements action of secretin in producing secretion of an alkaline pancreatic juice
Inhibits gastric emptying, trophic effect on pancrease, increase synthesis of enterokinase and enhance motility of small intesting and colon
along with secretin, augments contraction of pyloric sphincter preventing reflux
Receptors
CCK-A in periphery, CCK-A and B in brain
Secretion increased by contact of intertinal mucosa with products of digestion, particularly peptides and amino acids, and also presence in duodenum of fatty acids containing >10 C.
2 protein releasing factors that activate CCK secretion
CCK releasing peptide (intestinal mucosa) and monitor peptide (pancreas)
bile and pancreatic juice enhance digestion of fats, and digestion product further stimulate CCK secretion --> +ve feedback loop
Terminated when products of digestion move on to lower portions, and also because releasing factors are degraded by proteolytic enzymes
Secretin
By S cells, bloodborne factor, located deep in glands of mucosa of upper portion of the small intestine
Half life of around 5 min
Increases secretion of bicarb by duct cells of pancreas and biliary tract - secretion of watery, alkaline pancreatic juice
Mediated via cAMP
also augments action of CCK in producing pancreatic secretion of digestive enzymes
Decreases gastric acid secretion, may cause contraction of pyloric sphincter
Secretion increased by products of protein digestion and by acid bathing the mucosa of upper small intestine (potential -ve feedback)
GIP
by K cells in duodenum and jejunum
Stimulated by glucose and fats in duodenum
As inhibits gastric secretion and motility in large amounts -> gastric inhibitory peptide
stimulates insulin secretion
although gastrin, CCK, secretin and glucagon also have this effect, GIP is the only one when administered at blood levels
Often called glucose-dependent insulinotropic peptide
VIP
Found in nerves in GI tract
Found in blood with half life of about 2 min
stimulates intestinal secretion of electrolytes and hence wayer
relaxation of sphincters and inhibitoin of gastric acid secretion
Motilin
secreted by enterochromaffin cells and Mo cells in stomach, small intestine and colon
Produce contraction of smooth muscle in period between meals
Somatostatin
Secreted as paracrine by D cells in pancreatic islets and by similar D cells in GI mucosa
2 forms (14 and 28)
Inhibits secretion fo gastrin, VIP, GIP, secretin and motilin
stimulated by acid in the lumen, probably in a paracrine fashion
Enteric nervous system
Myenteric Plexus (auerbach plexus)
outer longitudinal and middle circular muscle
Innervates longitudinal and ciruclar smooth muscle
motor control
Submucous plexus (meissner plexus)
-middle circular layer and mucosa
Innervates glandular epithelium, intestinal endocrine cells and submucosal blood vessels
Control intestinal secretion
Connected to CNS by parasympathetic and sympathetic fibers, can function autonomously without these connections
ACh, norepinerphrine, serotonin, GABA, ATP and gases (NO and CO)
Extrinsic innervation
Parasympathetic cholinergic activty -> increase activity of intestinal smooth muscle
Vagal efferents and other efferents in the sacral nerves, end on cholinergic nerve cells of myenteric and submucos plexuses
Sympathatic noradrenergic activity decreasing it while causing sphincters to contract
end on postganglionic cholinergic neurons, where norepinerphrine inhibit ACh secretion
Innervation of blood vessels, produce vasoconstriction
VIP and NO mediates intrinsic innervation, vasodilates and increases blood flow that accompanies digestion of food
Mucosal immune system
More lumphocytes found here than in circulation
Continuity of lumen with outside world makes it an important portal for infection, but also benefits from a complex community of commensal bacteria that provide beneficial metabolic functions and increasing resistance to pathogens