Absorption 1: Ions and H2O Flashcards
what are the 5 types of cells in the SI?
It has villi and crypts.
5 cell types
Paneth cells – important in host defence against microbes
Stem cells: At the base of the crypts is where you find stem cells which divide to give rise to trans-amplifying daughter cells which differentiate and migrate up into the villus.
Enteric endocrine cells: S cells and I cells.
Goblet cells produce mucous – involved in Cytoprotection and hydration
Absorptive cells: Enterocytes (What this lectures is based on)
Villous enterocytes are the cells mostly responsible for both nutrient and electrolyte absorption (large SA)
Crypt enterocytes are primarily responsible for secretion.
what is the structure of the large Intestine?
The large intestine only has crypts
The surface epithelial cells are primarily responsible for electrolyte absorption
The colonic gland cells mediate ion secretion.
Each mucosa has a stem cell compartment which controls development
how is the absorption SA designed?
Absorption Surface area (designed to maximise efficiency of absorption)
Small intestine surface area is increased by:
Macroscopic folds of Kerckring (plicae circulares)
Villi – finger like projections
Microvilli on the apical surfaces of the epithelial cells and crypts
This creates a large surface area for absorption
The total SA of human small intestine is approx. 200 m2
what are the daily Volumes of GIT?
The small intestine – majority of water is absorbed in small intestine.
End: 0.1L - defecated
what is transcellular and paracellular movement?
In general, absorptive processes in the small intestine are enhanced in the postprandial state (fed state)
The “transepithelial” movement of a solute across the entire epithelium can be either absorptive or secretory.
In each case, the movement can be either transcellular or paracellular.
Transcellular: the solute must cross the two cell membranes in series (both apical and basolateral). Active transport implicated
Paracellular: the solute moves passively between adjacent epithelial cells via the tight junctions. Does not require energy.
describe absorption of water
The absorption of water depends on the absorption of ions, principally Na+ and Cl-:
Transport of Na, Cl - and HCO3- into the lateral intercellular spaces
The resulting high NaCl concentration near the apical end of the intercellular space causes this region to be hypertonic.
This causes an osmotic flow of water from the lumen into the intercellular space via the tight junctions.
Where in the gut ions are absorbed?
what are the 4 routes of entry for sodium transport?
Na+ is absorbed along the entire length of the intestine
4 different routes of entry:
1. Na/Glucose transport or Na/Amino acid transport
2. Na-H exchanger
3. Parallel Na-H and Cl-HCO3 Exchange
4. Epithelial Na+ Channels
describe Na/Glucose transport (SGLT 1) or Na/amino acid transport
Na+ crosses the membrane down an electrochemical gradient.
This is set up by the active export of Na+ from epithelial cells by the Na+, K+ ATPase in the basal and lateral plasma membrane.
This electrochemical gradient in-turn provides the energy for moving the sugars (glucose and galactose) and neutral amino acids into the epithelial cells against their concentration gradients.
Transporters e.g. SGLT1 couple the transport of Na into the cell with the transport of sugars and neutral amino acids from the lumen into the cell as well.
The net rate of absorption of Na+ is highest in the jejunum where Na+ absorption is enhanced by the presence of glucose, galactose, and neutral amino acids in the lumen.
Important postprandial (fed state)
describe the mechanism of an Na-H exchanger
Mostly occurs in jejenum and to a lesser extent in duodenum
Na+ crosses the membrane down an electrochemical gradient.
This is set up by the active export of Na+ from epithelial cells by the Na+, K+ ATPase in the basal and lateral plasma membrane.
This electrochemical gradient in-turn provides the energy for moving H+ into the intestinal lumen.
The Na-H exchanger couples Na+ uptake across the apical membrane to proton extrusion into the intestinal lumen.
This process is enhanced by both decreases in intracellular pH and increases in luminal pH.
The increase in luminal pH occurs due to luminal HCO3- secretion by pancreatic, biliary, and duodenal tissues.
The energy for Na-H exchange comes from the Na+ gradient:
Active export of Na+ from epithelial cells by the Na+, K+ ATPase in the basal and lateral plasma membrane lowers intracellular Na+ concentration, creating and electrochemical gradient.
describe the mechanism of Electroneutral NaCl absorption Parallel Na-H and Cl-HCO3 exchange
This is the primary method of Na+ absorption between meals (fasted state).
Occurs in the ileum and throughout the large intestine. It is not affected by either luminal glucose or luminal pH, or nutrient linked (glucose or AA)
Electroneutral NaCl absorption is due to two apical membrane Na-H and Cl-HCO3 exchangers closely linked
Na+ crosses membrane down an electrochemical gradient set up by the active export from epithelial cells by the Na+, K+ ATPase in the basal and lateral plasma membrane.
The Na-H exchanger couples Na+ uptake across the apical membrane to proton extrusion into the intestinal lumen.
H+ comes from reaction of carbonic anhydrase.
You also have a chloride bicarbonate HCO3- exchanger.
(Where chloride ions come in and bicarbonate ions leave)
Bicarbonate comes from carbonic anhydrase reactions
This process is electroneutral (1+ charge entering and leaving the cell)
The process is regulated by cAMP and cGMP as well as intracellular Ca2+.
Increases in each of these three intracellular messengers reduce NaCl absorption.
Enterotoxins induce secretory diarrhoeas by elevating cAMP and inhibiting NaCl absorption.
By inhibiting sodium transport the luminal sodium and chloride concentrations are high which allows osmosis of water into the lumen causing secretory diarrhoeas.
describe the mechanism of Epithelial Na+ channels
Na+ entry occurs across the apical membrane via ENaC channels (found predominantly in colon) that are highly specific for Na+
Na+ absorption in the distal colon is highly efficient as it is capable of absorbing Na+ against large concentration gradients
Mineralocorticoids (e.g., aldosterone and angiotensin) increase Na+ absorption by
Increase in the opening of apical Na+ channels
Insertion of preformed Na+ channels from sub-apical epithelial vesicle pools into the apical membrane
Increased synthesis of apical Na+ channels and Na-K pumps.
what are the names of the types of chemical mediators that regulate intestinal electrolyte transport?
Absorptagogues promote absorption
Secretagogues promote secretion-diarrhoea
what are Absorptagogues?
(mineral corticoids)
Angiotensin and aldosterone
Released due to dehydration
Dehydration and a drop in the effective circulating volume leads to stimulation of the renin-angiotensin-aldosterone axis. Both angiotensin and aldosterone are released, and these regulate total body Na+ homeostasis by stimulating Na+ absorption.
Angiotensin in the small intestine enhances electroneutral NaCl absorption by upregulating apical membrane Na-H exchange
Aldosterone in the colon stimulates Na+ absorption through ENaC.
These create hyperosmotic environment in intercellular space to draw water in to combat dehydration.
Other absorptogogues include somatostatin, enkephalins and noradrenaline
what are Secretagogues?
4 categories:
Bacterial enterotoxins
laxatives
hormones and neurotransmitters
immune mediated
describe the process by which the secretory diarrhoea is caused by bacterial enterotoxins
Bacterial enterotoxins (cholera toxin, e-coli toxins, yersinia toxin, Clostr. diff toxin) induce secretory diarrhoeas
They induce various secondary messengers (cAMP, Ca2+)
These secondary messengers inhibit NaCl absorption via electroneutral sodium transport
They also increase anion secretion – actively pump chloride ions and potassium ions into lumen
So you are not absorbing sodium ions and chloride ions and are pumping anions into the lumen so there is a high chloride and sodium ion concentration in the lumen which will mediate diarrhoea as a consequence.
what do laxatives do?
Laxatives treat constipation
Stimulant Laxatives, Prokinetic agents
Increase peristalsis – less time for water to be extracted from digesta – resolves constipation.
Osmotic laxatives
Increase the osmotic potential in the lumen of the gut.
E.g. Lactulose – is not absorbed in small intestine, it is fermented by microbio.
This creates osmotic particles which in the lumen of the gut act (through the process of osmosis) to draw water from interstitial spaces into lumen of gut and relieve constipation.
Bile Acid induce diarrhoea through Ca2+
what are the 3 steps that active Ca2+ absorption involves?
The uptake of Ca2+ across the apical membrane via Ca2+ channels
Cytosolic Ca2+ binds to calbindin which acts as a buffer – keeps intracellular free calcium low
A Ca2+-H+ pump and a Na-Ca exchanger on the basolateral membrane extrude the Ca2+ from the cell into the interstitial fluid ( fluid between blood vessels and cells)
The active form of vitamin D-1,25-dihydroxy-vitamin D stimulates all three steps of this pathway.
The Vitamin D you consume via diet is in form of vitamin D3.
Then via kidneys and liver action you hydroxylate vitamin D3 to 1,25D3 which then binds to VDR (nuclear transcription factor) which then regulates the proteins involved in calcium metabolism.
Rickets: Vitamin D deficiency which leads to hypocalcaemia.
Treatment involves increasing dietary intake of calcium, phosphates and vitamin D. Exposure to ultraviolet (sunshine), fish oils are good sources of vitamin D.
describe the physiological processing of iron
Plasma iron pool: The Iron that circulates in blood
Large amount of iron in the plasma moves to bone marrow for RBC production (erythropoiesis)
When RBCs become senescent, they are engulfed by splenic macrophages
Iron is liberated from haemoglobin and enters back into plasma iron pool
The liver is a major storage region for iron:
When there is excess iron in the plasma pool, the iron is stored in the liver.
When plasma iron pool diminishes the iron stored in the liver can be released to top it up.
Iron out: We lose very small amounts of iron per day (1-2mg)
This is in the form of shedding of skin cells and enterocytes.
women lose iron via blood during menstruation
Iron in: 1-2mg of iron per day enters our body from our diet to top up the iron we lose.
what are the 2 forms of Dietary iron?
Inorganic iron
Source: green vegetables e.g. broccoli
Majority of the iron from these sources is non-absorbable as:
A lot of the iron is bound anti-oxidants –> makes iron inert and inaccessible.
Inorganic iron is in an Fe3+ state - needs to be reduced to Fe2+ before it can be absorbed
Haem iron
Source: red meats
Haem iron is far more bioavailable (greater absorption)
We have equal absorption of haem iron and inorganic iron
We eat less meat and more vegetables it balances out
There is a gradient of iron absorption from small to large bowel - most absorbed in small, less absorbed in large bowel
how does luminal enterocyte uptake of Inorganic iron occur?
Inorganic ferric Fe3+ iron is reduced to ferrous Fe2+ form
This is done partly by stomach acid
This means iron uptake may be affected for patients who have had gastrectomies
PPIs could potentially be used to treat hereditary haemochromatosis
The iron is mosty reduced by binding to Dcytb (duodenal cytochrome B) (a ferric reductase)
Ferrous (Fe2+) iron can now be absorbed by the enterocyte
The iron is taken up by DMT1 (divalent metal transporter 1)
The absorbed iron now has 3 possible fates:
- Iron used by cell in metabolic processes
- Iron stored in cell by being bound to ferritin
This storage protein makes iron inert
Prevents damage to cells (e.g. DNA damage), as iron drives free radical production
- Iron is effluxed out of enterocytes and into the blood through Ferroportin
Iron will then be oxidised in the blood and it binds to transferrin (Iron on its own is toxic)
How do cells which are NOT enterocytes (which can get ferrous iron from lumen) get iron?
Transferrin receptor mediated endocytosis
Cells express transferrin receptor on their cell surface
Involves both transferrin receptor, DMT-1 + ferric reductase STEAP-3
This allows them to capture of transferrin-bound iron
Iron is liberated from complex
Occurs in cells that need iron, e.g. erythroid precursor
what happens during Infection & inflammation?
When you have an infection or inflammation the body triggers Interlukin-6
Interlukin-6 them stimulates hepcidin transcription and translation
Hepcidin prevents iron from being effluxed by enterocyte into the plasma pool
Hepcidin also binds to Ferroportin on cell surface of macrophages
Macrophages would usually efflux iron after engulfing senescent RBCs
Due to the binding of hepcidin, the macrophage becomes iron loaded, as iron is trapped so cannot be effluxed into plasma iron pool
Lowering plasma iron is useful:
Bacteria/pathogens they need iron to survive. Low iron therefore limits bacterial damage and proliferation
Also, a depleted plasma iron pool is good because lots of iron makes inflammation worse through driving reactive oxygen species.
what is coeliac disease?
Coeliac Disease: An inappropriate autoimmune response to gluten that effects the SI
More specifically it results in a reaction to gliadin, a gluten protein found in wheat, barley and rye.
Upon exposure to gliadin, the enzyme tissue transglutaminase modifies the protein + immune system cross-reacts with the bowel tissue causing an inflammatory reaction
This Causes villous atrophy and crypt hyperplasia (gives flattened surface epithelium in place of villi)
This results in damage to the absorptive surface of intestine meaning you are unable to take nutrients from your food as effectively.
