Unit 6A GI Function

Digestion

break macromolecules (nutrients) into forms that can be transported across epithelium

absorption

transport nutrients, water, ions, vitamins across epithelium

in order to accomplish digestion and absorption:

1. secretion

2. motility

secretion

release of enzymes into gut lumen

motility

keep the gut contents moving

break down of barriers

peptic, duodenal ulcers

function of GI considerations

1. need to digest macromolecules but not itself

2. needs to allow entry of digested nutrients but not pathogens

3. needs to maintain balance between water input/output

GI lining is largest area of contact between internal and external environment

• protection from pathogens mediated by

  1. epithelial barrier

  2. mucus

  3. digestive enzymes

  4. acid

  5. Gut-Associated Lymphoid Tissue (GALT)

     • needs to react to pathogens but not to “foreign” proteins associated with food

needs to maintain balance between water input/output

balance between secretion (exocrine) and (re) absorption

small intestine

duodenum → jejunum → ileum

large intestine

colon → rectum

mucosa (3)

1. epithelium

2. lamina propria

3. musclaris mucosa

generic mucosal surface

1. mucosa

2. submucosa

3. smooth muscle layers

4. serosa

smooth muscle layers (2)

1. circular muscle

2. longitudinal muscle

functions of the GI tract

1. motility

2. secretion

3. digestion

4. absorption

two major patterns of contraction

1. peristalsis

2. segmental contractions

peristalsis

moving food from mouth to anus

segmental contractions

mixing/churning - maximizes exposure to digestive enzymes and epithelium

most gut muscle is single unit smooth muscle connected by

gap junctions

certain regions are tonically contracted (minutes to hours)

smooth muscle sphincters - keeps food from moving backwards

other regions undergo phasic contractions (few seconds)

posterior stomach, small intestine

gut motility between meals

migrating motor complexes sweep slowly down tract (~90 min from stomach to large intestine)

gut motility during/after meal

peristaltic and segmental contractions

single unit smooth muscle

1. autonomic neuron varicosity

2. released neurontransmitter

3. binds to receptors on smooth muscle cell

4. smooth muscle cells connected by gap junctions

5. contracts as single unit

single unit smooth muscle most common

walls of GI and urinary tracts, blood vessels

action potentials fire when

slow wave potentials exceed threshold

the force and duration of muscle contraction are directly related to

the amplitude and frequency of action potentials

slow waves similar to pacemaker potentials in cardiac muscle except much less frequent and do not necessarily reach threshold

• below threshold → no contraction

• above threshold → opening of voltage gated Ca channels → action potentials → contraction

degree of contraction (as in cardiac) is graded, according to amount Ca that enters

longer wave → more time for Ca to enter → larger contraction

amplitude and duration of contraction influenced by

1. neurotransmitters (autonomic input)

2. hormones

3. paracrine factors

slow wave frequency varies in different regions of tract

1. more frequent in duodenum than in stomach

2. set by “pacemaker cells” between smooth muscle layers “interstitial cells of Cajal”

secretion (5)

1. water and ions

2. enzymes

3. mucus

4. saliva

5. bile

secretion of water and ions (Na+, Cl-, K+, HCO3-, H+) (3)

1. mostly via membrane transporters

2. water follows osmotic gradient

3. water and ions in som regions can also pass between cells (paracellular route)

types of transporters involved in secretion of water and ions

1. Na+/K+-ATPase

2. NKCC cotransporter

3. CL’/HCO30 exchanger

4. Na+/H+ exchanger (NHE)

5. H+/K+-ATPase

ion channels involved in secretion of water and ions

1. EnaC

2. K+ channels

3. Cl- (including CFTR channel)

acid secretion by parietal cells

1. lumen can be as low as pH 1, parietal cell is ~7.2, so [H+] a million times higher in lumen!

2. as h+ secreted from apical side, bicarb (from Co2 + OH-) is absorbed into blood

   • “alkaline tide” from stomach can be measured after a meal

NaCl Secretion (Small intestine, Colon, Salivary Glands)

1. Na+, K+ and Cl- enter via NKCC transporter

2. Cl- enters lumen through CFTR channel

3. Na+ is reabsorbed

4. Negative Cl- in lumen attracts Na+ by paracellular pathway, water follows

crypt cells in small intestine and colon secrete “isotonic saline” that

mixes with mucus secreted by goblet cells to lubricate gut contents

similar to pancreatic duct cells

Cl- secretion pulls Na+ and water into lumen

bicarb secretion from pancreas into duodenum

1. bicarb secreted into duodenum neutralizes acid arriving from stomach

2. acinar cells of pancreas secrete enzymes, epithelial cells lining ducts secrete bicarb solution

stomach

fundus → body → antrum → pylorus

pancreatic bicarb secretion cellular level (3)

• requires high expression of carbonic anhydrase (as in kidney and RBCs)

• bicarb secreted via apical Cl/HCO3 exchanger

• Cl- enters via basolateral NKCC transporter and leaves via apical CFTR channel; luminal Cl- then reenters cell via Cl-/HCO3- exchanger

Cystic Fibrosis: pancreatic effects (3)

1. mutation in gene that encodes in CFTR channel

2. leads to defects in Cl- (and water) transport

3. named for changes in the pancreas

   • fluid-filled cysts and fibrosis - scarring

cystic fibrosis; pancreatic effects STEPS

1. cl not transported into ducts

2. various effects, including decreased NA+ and water transport into ducts

3. mucus still produced but greatly thickened due to lack of water

4. blockage of pancreatic ducts

5. exocrine secretions of pancreas not released (bicarb, enzymes)

6. back pressure/inflammation → DAMAGE TO PANCREAS

enzymes secreted by either exocrine glands (pancreas, salivary) or peithelial cells lining stomach and small intestine

synthesized by rough ER, packaged by golgi into vesicles, stored in cell under signal for release by exocytosis

enzymes sometimes remain linked to apical membranes by protein or lipid “stalks”

“brush border” enzymes (carpet of microvilli)

enzymes released are often released as inactive precursors (zymogens) to prevent

autodigestion

secretion of enzymes regulated by

neural, hormonal, paracrine signals, usually stimulated by parasympathetic stimulation (via vagus)

mucus consists of primarily mucins

mixture of glycoproteins

secretion of mucus produced by exocrine cells

1. serous cells in salivary glands

2. mucous cells in stomach

3. goblet cells in intestine

signals for secretion (3)

1. parasympathetic stimulation

2. various neuropeptides (of enteric nervous system)

3. cytokines (form immune cells)

   • infection and inflammation increase mucus secretion

organization of lobule: bile secretion

1. hepatocytes

2. bile canaliculi

3. bile ductules

4. common hepatic duct

5. common bile duct

6. sphincter of Oddi

7. duodenum

most absorbed nutrients move into capillaries in villi, then into hepatic portal vein

fats go into lymphatic system rather than blood

xenobiotics must first

pass through liver before reaching systemic circulation

hepatic portal system

1. aorta

2. hepatic artery

3. GI tract arteries

4. CAPILLARY BED #1 capillaries of GI tract

5. hepatic portal vein

6. CAPILLARY BED # 2 Sinusoids of liver

7. hepatic vein

key components of bile

1. bile salts (facilitate fat digestion)

2. bile pigments (e.g bilirubin, from hb breakdown)

3. cholesterol

Hemoglobin, Iron, and RBC turnover

1. Fe ingested from diet

2. Fe absorbed by active transport

3. transferrin protein transports Fe in plasma

4. bone marrow uses Fe to make Hb as part of RBC synthesis

5. RBCs live about 120 days in the blood

6. spleen destroys old RBCs and converts to bilirubin

7. bilirubin and metabolites are excreted in urine and feces

8. liver metabolizes bilirubin and excretes it in bile

9. liver stores excess Fe as ferritin

bilirubin or its metabolites are responsible for

normal colour of feces and urine

indicators of injury/pathology

yellow pigmentation of jaundice - hb breaking down into bilirubin, too much bilirubin = yellow

digestion - combination of mechanical and enzymatic processes

1. occurs in mouth, stomach, small intestine

2. chewing “churning” - exposes more surface area to enzymes

   • emulsification via bile exposes more surface area for lipid digestion

absorption - crossing the gut epithelium

1. mostly in small intestine (some ions and water absorbed in large intestine)

2. uses many of the same transporters as the kidney!

   • exception: fat enters lymph vessels “lacteals”

digestion and absorption not directly regulated

influenced by motility and secretion, which are regulated by hormones, nervous system, local mechanisms

absorption in small intestine STEPS

1. lumen

2. apical membrane

3. epithelial cell (ENTEROCYTE)

4. basolateral membrane

5. lamina propria

6. capillary / lymph

carbohydrates constitue ~ half caloric intake - mostly starch, sucrose

also: glycogen, cellulose, lactose, maltose, glucose, fructose

carbohydrates can only be absorbed via a membrane transporters

we only have membrane transporters for monosaccharides

how do artificial sweetners work

splenda typically interact in some way, with “sweet” receptors but cannot be digested to a form that can cross into enterocytes

disaccharaides

1. maltose

2. sucrose

3. lactose

breakdown of carbs

1. amylase breaks down starch

2. disaccharaide form

3. maltase, sucrase, lactase breaks down to monosaccharides

carbohydration absorption/digestion steps

1. Glucose or galactose uses SGLT enter epithelium

2. glucose/galactose crosses to basolateral membrane by GLUT 2

3. Na+ crosses to basolateral side by K+/NA+ Atpase

4. fructose enters epithelium on GLUT 5

5. fructose exits to basolateral side by GLUT 2

endpeptidases (aka proteases) + H2O

digests internal peptide bonds

exopeptidases digest terminal peptide bonds to release amino acids

1. aminopeptidase (from brush border)

2. carboxypeptidase (from pancreas)

products of protein digestion

free aas, di-, tripeptides

endopeptidases

pepsin (stomach), trypsin, chymotripsin (pancreas)

protein absorption

1. di and tripeptides cotransport with H+

2. amino acids cotransport with Na+

fats

• triglycerides - most of our fat calories in this form, major lipid in both animals and plants

• cholesterol

• phospholipids

• long chain fatty acids

• fat soluble vitamins

fat digestion complicated by

solubility issues

fat leaves stomach as large droplets mixed with

aqueous chyme 0 low surface area available to interact with enzymes

fat broken down into smaller particles through action of bile salts

bile salts are derivatives of cholesterol (amphipathic)

bile salts (bile acids)

primary bile acids → modified by gut bacteria → secondary bile acids →conjugated in liver → conjugated bile acids

fat digestion 1: action of bile salts

bile salts coat lipids to make emulsions of large droplets

1. hydrophobic side associates with lipids

2. polar side chains (hydrophilic side associates with water)

Pancreatic lipases can act on triglycerides in droplets, aided by colipase from pancreas

Fat Digestion 2: Formation of Micelles

all fats digested in smaller components except cholesterol, micelles can then move close to surface of enterocytes and lipids can diffuse across apical membrane into cells

fat absorption (entire process)

1. bile salts coat fat droplets

2. pancreatic lipase and colipase break down fats into monoglycerides and fatty acids stored in micelles

3. monoglycerides and fatty acids diffuse from micelles and cross cell membranes and recombine into triglycerides in smooth er

4. absorbed fats combine with cholesterol, proteins form chylomicrons which are paced into vesicles and exocytosed (short fatty acids can travel solo, entering capilarries rather than lymph)

5. chylomicrons removed by lymphatic system

nucleic acid digestion and absorption

1. nucleoprotein broken into nucleic acids by gastric, pancreatic proteases, then

2. broken to nucleotides by nucleases

3. phosphate removed, nucleosides absorbed by Na+ coupled transport

4. broken down to purines/pyrimidines and ribose/deoxyribose in tissues

fat soluble vitamins (A, D, E, K)

absorbed in small intestine along with fats

water soluble vitamins (C, most Bs)

typically absorbed in small intestine via membrane transporters

exception: B12 (cobalmin) - participates in metabolic pathways in every single cell, particularly important in RBC synthesis

• absorption (in ileum) requires protein secreted by gastric parietal cells (‘intrinsic factor”)

  • deficiency of intrinsic factor leads to deficiency of B12 that cannot be corrected by oral B12 supplementation

absorptions of ions and water by small (and large) intestine

1. Na+ enters cells by multiple pathways

2. the Na+ and K+ Atpase pumps Na+ into ECF

in general: ions (esp Na+) move across apical side (various transporter); main driver on basolateral side is Na+/k+ ATpase: water follows by osmosis

absorption of iron and calcium

• two of the few substances for which intestinal absorption is regulated

  • decreased levels → detector → signal → increased intestinal uptake