T1 L8: Salt and water transport and its control

• Disregulation of water absorption in the GI tract can cause what?

  electrolyte imbalance and life threatening diarrhoea
• An increase in osmotically active particles creates a hypertonic environment.
• Active transport?

  Primary active transport:

  • hydrolysis of ATP provides energy to move ions against their electrochemical gradient
  • Na+/ K+ ATPase pump is responsible in the GI tract for maintaining low intracellular Na+

  Secondary active transport:

  • uses the gradient supplied by Na+/ K+ ATPase for active transport of Na+ out of cell
  • No ATP required
  • via symport or antiport
• Principles of enterocytes?

  enterocytes polarised with apical (gut lumen) and basolateral (submucosa) membrane

  • tight junctions - provide a barrier to free flow of gut lumen contents; more permeable in proximal small intestine
  • tonicity of chyme entering duodenum affets directionality of net fluid flux

  
• Principles of enterocyte transport?

  occurs via two routes:

  • Transcellular absorption: through cell. may be against conc gradient + require ATP
  • Paracellular absorption: around cell. do not require energy

  Solvent drag: water follows Na+ gradient via osmosis, drags other ions (non-specific)

  
• Enterocytes on small intestine villi function?

  absorptive, dominate nutrient transport
• Enterocytes in crypts function?

  secretory, minimal nutrient transport
• Water and electrolyte absorption

  majority of water reabsorption in jejunum (jejunum>ileum>colon)

  net absoprtion and minimal loss of water and electrolytes

  Secretion/absorption depends on:

  • Osmolarity (Gut luminal contents)
  • Enteric and autonomic signal
  • Endocrine hormones
• Small intestine adaptations

  • Vast SI surface area
  • actin filaments driving rhytmic motion
  • dense vasculature + lymphatic system
  • epithelium more permeable than large intestine
  • Rapid response to chyme:
  • if chyme hypertonic, water osmosis into lumen
  • if chyme acidic, rapid HCO3- rich secretions

  
• What are the adaptations of the large intestine?

  • limited absorption of water and salt in crypts
  • no digestive enzyme activity
  • epithelium less permeable (tight junctions)
  • response to chyme: highly hypotonic chyme causes increased absorption of water and NaCl in expense of K+
• What are the 4 mechanisms of intestinal sodium absorption?

  1. Sodium-glucose/Sodium-amino acid Symporters
  2. Na+/ H+ Antiporters
  3. Epithelial Na+ channel absorption
  4. Parallel apical membrane exchangers Na/H+ and Cl-/HCO3-
• Sodium-Glucose / Sodium-Amino acid Symporters

  principle mechanism in jejunum following eating

  SGLT1 (sodium-glucose like transporter 1)

  
• What drives the 4 different mechanisms of intesinal absorption of Na+?

  driven by gradient created by Na+/K+ ATPase pump in basolateral membrane
• Na+-H+ Antiporters

  stimulated by high pH

  HCO3- rich duodenal secretions

  NHE3 (sodium-hydrogen exchanger 3) found in duodenum

  
• Epithelial Na+ channel absorption

  highly efficient Na+ conservation

  stimulated by aldosterone

  found primarily in distal colon

  
• Parallel apical membrane exchangers: Na-H & Cl-HCO3-

  primary interdigestive mechanism in ileum

  influence transport of one another

  
• What are the 2 mechanisms of intestinal absorption of Cl-?

  1. Passive diffusion via Cl- channel
  2. Cl-/HCO3- Antiporter
• Intestial absorption of Cl- via Cl- channel

  passive diffusion

  location: jejunum + distal colon

  small amounts in ileum

  
• Intestinal absorption of Cl- via the Cl- - HCO3- antiporter

  carbonic anhydrase mediated production of HCO3- in cell occurs for Cl- exchange

  location: distal ileum + colon

  
• CFTR mediated Cl- secretion

  1. Na+/K+ ATPase creates Na+ gradient
  2. drives Na+, Cl- and K+ ions through symporter into enterocytes located in intestinal crypts
  3. Cl- leave cell via apical CFTR Cl- channels into intestinal lumen
  4. Cl- electronegativity draws Na+ into lumen
  5. Water moves by osmosis into gut lumen via paracellular routes

  
• Intestinal K+ absorption and secretion in Small intestine

  Passive absorption in jejunum and ileum from diet

  Passive secretion due to negative lumen potential

  
• Intestinal K+ absorption and secretion in Large intestine

  • Active secretion in colon via BK K+ (maxi potassium) channel and NKCC1 (Na-K-Cl cotransporter) activity driven by aldosterone in response to high blood K+
  • Active absorption can also occur in distal colon when blood concentration low

  
• Which endocrine hormones regulate absorption?

  aldosterone, glucocorticoids & somatostatin
• How does aldosterone help regulate absorption?

  released upon dehydration from adrenal cortex

  upregulates Na absorption (via stimulation of Na+/K+ ATPase pump and epithelial channels)

  Increased NaCl and water absorption occurs whilst secreting K+
• How do glucocorticoids and somatostatin regulate absorption?

  increase water and NaCl absorption by upregulation of Na+/K+ ATPase pump
• What factors can cause diarrhoea?

  • Osmotic: disrupt tonicity of gut lumen contents
  • Secretory: increase enterocyte secretion
• How do osmotic laxatives work?

  decreases specific absorption,

  increases tonicity of intestinal lumen,

  draws water out of cells

  examples: lactulose

  commonly prescribed post surgery
• What is the mechanism by which cholera toxin works?

  cholera to crypt cells

  irreversibly upregulate Adenylate cyclase

  generate excess cAMP

  excess Cl- secretion via CFTR channels

  water and Na+ follow into lumen

  profuse, watery, secretory diarrhea

  dehydration

  circulatory shock
• How are the effects of cholera toxin reduced?

  enterocyte replacement
• Oral rehydration therapy

  ORS (oral rehydration solutions) contain glucose and Na+

  promote fluid absorption

  SGLT1 (sodium-glucose transporters) aren't affected in most secretory diarrhea cases

  Potentially life saving therapy replacing ion and water loss in enterotoxin mediated diarrhoea
• How do oral rehydration solutions (ORS) work via SGLT1?

  SGLT-1 binds 2 x Na+ to one glucose

  transport into cell

  Cl- follows electrochemical balance

  decreased tonicity of lumen brings water into enterocytes
• What is the mechanism of Lactose intolerance?

  caused by a deficiency in enzyme lactase

  lactose not digested and remains in lumen

  increases tonicity of lumen

  pulls water from enterocytes

  causes diarrhoea
• How does cystic fibrosis disrupt secretory mechanisms?

  Cl- CFTR channel absent

  defective fluid secretion

  mucus becomes progressively thickened as water is no longer following
• What triggers cystic fibrosis?

  Autosomal recessive inheritance
• What are the symptoms of Cystic Fibrosis?

  recurrent chest infections, weight loss
• What is the treatment of cystic fibrosis?

  No cure; management with antibiotics and anti-inflammatory agents