4-Digestion and Absorption of Fluids and Electrolytes

Secretion v. Absorption

Secretion = Adding to the lumen

Absorption = Removing from the lumen (happens in the SI for fluids/electrolytes)

Small Intestine characteristics & epithelium

Villi (absorptive cells)

Crypts (secretory cells)

Columnar epithelium

Large Intestine characteristics & epithelium

Surface epithelium (absorptive cells)

Colonic crypts (gland cells)

Columnar epithelium

Progenitor Cells

Found in base of crypts in SI and LI

Large cell turnover!

When does progenitor cell turnover decrease?

During starvation

Fluid Movement within intestines?

8-9 L/day (1.5-2.5 from diet)

Absorptive capacity for LI?

Up to 5 L/day

Types of heterogeneity?

• Segmental

• Surface

• Cellular

Segmental Heterogeneity

• Differences in transport along the length of the intestines

Surface Heterogeneity

• Differences in transport from the top of a villus to bottom of a crypt

Cellular Heterogeneity

• Differences in transport mechanisms in different cells within the same villus/crypt

Net absorption and secretion of ions in SI?

• Net absorption of Na⁺, Cl^-, and K⁺

• Net secretion of HCO^-₃

Net absorption and secretion of ions in LI?

• Net absorption of Na⁺ and Cl^-

• Net secretion of K⁺ and HCO^-₃

Transcellular v. Paracellular Movement

• Transcellular movement

  • solute crosses two membranes in series

• Paracellular movement

  • solute moves passively between epithelial cells through tight junctions

What is mucosal resistance dependent upon?

Dependent on paracellular resistance which is a function of tight junction permeability which depends on tight junction structure.

• Resistance increases as you move away from the mouth and down the crypt!

Secretagogues

• Induce secretion

• Second messengers

• Toxins

• Hormones & NT’s

• Laxatives

  • Bile salts

Absorptagogues

• Induce absorption

  • Neural, endocrine, & paracrine

• Mineral and gluco- corticoids

• Somatostatin

• NE

Osmotic Diarrhea

• Dietary component that is not absorbed

  • Ex. lactose intolerance

Secretory Diarrhea

• Secretion of fluid and electrolytes from the intestine

• Induced by secretagogues

  • Enterotoxins from bacteria

Oral Rehydration Solution

• Used to treat secretory diarrhea

  • Secretory Diarrhea doesn’t affect Na+ absorption so Na+ and Glucose help reverse it!

Where is Na+ most absorbed?

Villous epithelium SI

Surface epithelium LI

Na-K Pump

• Used for all transcellular Na+ movement at basolateral membrane

• Gradient drives Na+ entry and other molecules running with it

4 types of Na+ Apical Transport

• Nutrient-Coupled Na+ Transport

• Na-H Exchanger

• Electroneutral NaCl Absorption

• Electrogenic Na+ Absorption

Nutrient-coupled Na+ Transport (transport type, fun facts, inhibition, and 2 main types to know)

• Secondary active transport

• Downhill Na+, uphill glucose/AA’s

• Only type of Na+ transport NOT inhibited by cAMP or cAMP agonists!

• Inhibited by E.coli or cholera

• Na-Glucose Cotransporter SGLT1: Apical Membrane

• Na-AA Cotransporters: Apical Membrane

Na-H Exchanger (function, stimulated by, location)

• Couples Na uptake (out) with H+ extrusion (into lumen) to increase pH

• Stimulated by: Bicarb secretion in duodenum/pancreas/bile

• Location: throughout intestine!

  • Proximal SI : Apical, no Cl-Bicarb exchanger here though

Electroneutral NaCal Absorption (function, fun fact, location, inhibitors)

• Exchanges Na-H and Cl-Bicarb

• Main method of Na absorption between meals!

• Location: Apical

  • Ileum

  • LI

• Inhibitors:

  • cAMP

  • cGMP

  • Increased intracellular Ca

What inhibits Electroneutral NaCl absorption?

• Decreasing NaCl absorption important in pathogenesis of diarrhea

• E. coli induced traveler’s diarrhea activates cAMP

Electrogenic Na+ Absorption (location, function, enhanced by, depends on)

• Location: Apical

  • Distal colon! Conserves Na+ concentration

• Na+ channels

• Enhanced by:

  • Aldosterone (increases opening and expression of channels)

• Depends on:

  • Na-K Pump Gradient on basolateral membrane

Amiloride

Diuretic which inhibits Na-H exchanger and electrogenic Na+ absorption.

Water follows the Na out!

Methods of Cl absorption in intestines

• Passive

  • Voltage dependent

• Active

  • Cl-Bicarb Exchanger

  • Electroneutral NaCl Absorption

Voltage dependent Cl- absorption (type of transport, driven by?)

• Passive transport

• Driven by either:

  • Nutrient coupled Na absorption in SI

  • Electrogenic Na absorption in distal colon

• Both make a negative potential in the lumen, both depends on Na-K pumps on the basolateral memb.

Cl-Bicarb Exchanger (function, location, can lead to?)

• Take a Cl from lumen (absorbed), secrete one bicarb into lumen

• Location: Apical

  • Villous Ileum

  • Surface LI

• Can lead to Congenital Cl Diarrhea

Congenital Cl Diarrhea (cause and findings)

• Cause:

  • No Cl-Bicarb Exchanger

• Findings:

  • High Cl in stool

  • High plasma Bicarb (alkalosis)

Cl Secretion Methods (location, function, pathogenesis, activated by?)

• Location: Crypts & Apical/Basolateral Membranes

• Promotes Na+ secretion, NaCl secretion

• Pathogenesis: Diarrhea

• Activated by: Secretagogues

Cl Secretion Basolateral Membrane Methods

• Na-K pump

  • lowers intracellular [Na+]

  • driving force for Cl- entering through Na/K/Cl cotransporter

• Na/K/Cl cotransporter

  • Increases intracellular [Cl-]

• K+ channels

Cl Secretion Apical Membrane Methods

• Cystic fibrosis transmembrane regulator (CFTR)

  • Cl- channel to get Cl out

Aldosterone (functions/MOA’s)

Increases passive secretion of K

• Activates Na-K pump (increases absorption of Na)

Increases active secretion of K

• Activates Na-K pump

• Activates apical K channels

cAMP and Ca2+ on K

Activates apical/basolateral K channels

Kicks off Cl secretion (K+ loss from diarrhea)

K Absorption (location, passive, active)

• Location: SI

• Passive:

  • Solvent Drag

    • Paracellular via tight junctions

• Active

  • ONLY IN DISTAL COLON!

  • Transcellular

  • Apical: H-K Pump (brings H into lumen, K absorbed)

  • Basolateral: Na-K pump (Na into lumen, K absorbed)

K Secretion (location, passive & location & CC, active & location & activation & pump-leak based on memb.)

• Location: LI

• Passive

  • Main route

  • Paracellular

  • DISTAL COLON

  • Dehydration (causes aldosterone secretion)

• Active

  • WHOLE COLON

  • Activated by aldosterone and cAMP

  • Pump Leak:

    • Apical: K Channel

    • Basolateral: Na-K Pump, Na-K-Cl Cotrasnporter, K Channel

Ca Active Transcellular Absorption (location, controlled by?)

• Location: ONLY DUODENUM

• Under control of Vitamin D in Villous Epithelial Cells

  • Kicks off synthesis of Calbindin!

Ca Active Transcellular Absorption Steps

1. Uptake via Ca channels at apical membrane via gradient

2. Binds to Calbindin

3. Move Ca through Ca pumps and Na-Ca Exchanger at basolateral membrane into interstitial fluid

Ca Passive Paracellular Absorption (location, compare to passive fun fact, enhanced by)

• Location: SI (jejunum & ileum)

• NOT influenced by Vitamin D

• Higher concentration than active absorption!

• Enhanced by: low plasma Ca concentration

Ferric Iron Fe3+

• Soluble only pH 3+

• Forms salt complexes with anions

• Not readily absorbed

Ferrous Iron Fe2+, what complexes with it?

• Soluble until pH 8

• Ascorbic Acid (Vitamin C)

  • Complexes with Iron

  • Reduces Iron from ferric (3) to ferrous (2)

  • Increases absorption

Anemia

Iron Depletion

Hemochromatosis

• Iron overload

• Can be hereditary (HH)

Hereditary Hemochromatosis (HH) (what is it? what causes it? who is at risk?)

• Body absorbs excess iron

• Autosomal recessive via HFE gene

  • Affects MHC, hepcidin

  • Affects males in mid 30s, females safe due to menstruation!

Excess what can be toxic to the liver?

Iron (Fe)

That’s why hemochromatosis is dangerous!

What does hereditary hemochromatosis cause?

• Cirrhosis

• Bronze pigmentation

How to detect hereditary hemochromatosis?

• Elevated iron and transferrin saturation

• Elevated ferritin

• Liver biopsy

How to treat hereditary hemochromatosis?

Remove blood from patient (phlebotomize) every few months to normalize iron and ferritin.

What are the 2 forms of dietary iron?

Heme Irone

Non-Heme Iron

Heme Iron (absorption fact, type of transport, location, steps (2))

• Absorbed more efficiently

• Active Transcellular Transport ONLY

• Location: Duodenum (enterocytes)

• Transports to cytoplasm, heme oxygenase releases free Fe3+ & biliverdin (which goes to liver & is excreted as bile)

• Enterocyte reduces Fe3+ to Fe2+

Non-Heme Iron (absorption fun fact, transport type, location, steps (6))

• Absorbed less efficiently

• Active Transcellular Transport ONLY

• Location: Duodenum (enterocytes)

1. DMT1 (divalent metal transporter)

   • Transports Fe2+ and H into cytoplasm

   • Downregulated by hepcidin from Kupffer’s Cells

2. Ferric Reductase Dcytb

   • Reduces Fe3+ to Fe2+ on Apical membrane!

3. Mobilferrin

   • Binds Fe2+ in cytoplasm

   • Takes it to Basolateral membrane

4. FP1 (ferroportin transporter)

   • Moves Fe2+ across Basolateral membrane

5. Ferroxidase Hephaestin

   • Fe2+ reaches interstitial fluid, then oxidized to Fe3+

   • Binds to Transferrin (carrier in plasma)

6. Fe3+ reaches blood and is stored in liver

   • Binds Apoferritin to form Ferritin