Download Digestion and Absorption

•7/24/2012
Digestion and Absorption
Jean-Paul Achkar, M.D.
Rainin Endowed Chair for IBD Research
Cleveland Clinic
Overview
•
•
•
•
Carbohydrates
Protein
Fat
Other nutrients:
– Fat soluble vitamins
– Vitamin B12
– Folate
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Digestion- General Concepts
• Most of the food we ingest is in a form that the
intestine cannot readily absorb. Digestion is the
enzymatic conversion of complex dietary
substances to a form that can be absorbed.
• Initiated by the sight/smell/taste of food.
• Most of digestion occurs in small intestine but:
– Carbohydrate digestion begins in mouth
– Some digestion occurs in stomach
Regulation of Exocrine Secretion
Regulation
Endocrine
CCK
Secretin
Secretin
Neurocrine
Ach
GRP
VIP
Substance P
Ach
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Regulation of Pancreatic Secretion
Regulation of Pancreatic Secretion
Vagal afferent
CCK
FFA, peptides,
amino acids,
releasing
peptides
Vagal
efferent
I-cells
Secretin
Acid, FFA,
releasing
peptides
S-cells
Meal-stimulated Plasma
Cholecystokinin Levels
15
meal
10
Immunoreactive
CCK
(pM)
5
0
-10
0
20
40
60
Time (min)
T. Chang & W. Chey, Dig Dis Sci 1983; 28:456
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Five patterns of digestion-absorption
1. Substance does not require digestion and can be directly
absorbed (glucose)
2. A polymer (protein) is digested to its constituent
monomers (amino acids) by pancreatic enzymes prior to
absorption
3. An oligomer (sucrose) is digested into its constituent
monomers by brush border enzymes prior to absorption
4. An oligomer (oligopeptide) is directly absorbed by the
cell and then broken down in to monomers inside the cell
5. A substance (triglycerides) is broken down into
constituent components prior to absorption; the cell then
resynthesizes the original molecule
Carbohydrates
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Different forms of dietary carbohydrates
• Starch (45-60%)- polysaccharide, storage form of
carbs that is primarily found in plants
• Glycogen- storage forms of carbs in animals;
consumed in lesser amounts than starch
• Oligosaccharides (30-40%)- majority are the
disaccharides, sucrose (glucose-fructose) and
lactose (glucose-galactose)
• Monosaccharides (5-10%)- mostly fructose and
glucose which make up 5-10% of dietary carbs
• Fiber- soluble and insoluble forms. Present mostly
in fruits, vegetables, and cereals
Monosaccharides
Glucose
Galactose
Fructose
Disaccharides
Sucrose:
Glucose
Fructose
Lactose:
Glucose
Galactose
Maltose:
Glucose
Glucose
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Starch
Amylose
α1,4 bonds
α1,6 bonds
Amylopectin
Carbohydrate Digestion
•
•
Small intestine can only absorb monosaccharides
Two step process:
1. Intraluminal hydrolysis of starch to
oligosaccharides by salivary and pancreatic
amylase
2. Membrane digestion of oligosaccharides to
monosaccharides by brush-border
disaccharidases
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Carbohydrate Digestion: Step 1
• Starch digestion begins in mouth with salivary
α amylase:
– Similar to pancreatic α amylase
– Relatively limited importance and is inactivated by gastric acid
• Pancreatic α amylase (CCK stimulates release by
acinar cells) completes starch digestion in the SB
lumen.
• α amylase hydrolyzes only internal α-1,4 linkages
between glucose residues. No glucose is
produced.
Digestion of Amylose & Amylopectin
Amylase
Maltose
Maltotriose
α-limit dextrins
Oligomer
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Carbohydrate Digestion: Step 2
• Small bowel brush-border oligosaccharidases:
– Lactase- breaks lactose into glucose & galactose
– Maltase- cleaves terminal α-1,4 linkages and also α-1,4
linkages in straight chain oligosaccharides.
– Sucrase-Isomaltase- 2 enzymes bound together; also
cleave terminal α-1,4 linkages:
• Sucrase- breaks sucrose into glucose and fructose
• Isomaltase- only enzyme that cleaves branching α 1,6 linkages
Disaccharidases
• Distribution in GI tract:
– Most in proximal jejunum
– Less in duodenum and distal ileum
– None in colon
• Rate limiting steps:
– Lactase- enzyme activity is rate limiting step
– Maltase and sucrase-isomaltase- uptake is the
rate limiting step.
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Monosaccharide Absorption
Glucose
Galactose
Fructose
SGLT1
GLUT5
Na+
Na+
K+
Glucose
Galactose
Fructose
GLUT2
Carbohydrate Absorption
• Glucose and galactose absorption:
– Uptake across the apical membrane and into the
epithelial cell is active transport via Na-glucose
transporter, SGLT1
– Exit out basolateral membrane via sugar
transporter, GLUT2- facilitated diffusion
• Fructose absorption:
– Apical step- facilitated diffusion via GLUT5
which is present mainly in the jejunum.
– Exit out basolateral via GLUT2
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Clinical Implications
Which of the following is the preferred fluid
to maintain oral hydration in a patient with
high volume diarrhea?
Component
Sodium (mg/L)
Potassium (mg/L)
Glucose (g/L)
A
155
107
B
847
296
212
C
1030
780
25
D
1725
782
13.5
• Take advantage of Na+/Glucose Co-Transporter
• Avoid glucose osmotic load
Component
Ginger Ale Gatorade
847
Sodium (mg/L)
155
296
Potassium (mg/L)
212
Glucose (g/L)
107
Pedialyte
1030
780
25
ORS-75
1725
782
13.5
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Protein
Sources of Protein
• Dietary- in developed countries, get 70-100 g
per day which far exceeds minimum
requirements
• Endogenous- 50% of protein entering GI
tract:
– Enzymes, hormones, immunonoglobulins and
desquamated intestinal epithelial cells.
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Protein Digestion
• Proteins must be digested to oligopeptides and amino acids
to be absorbed
• Very efficient- < 4% of ingested nitrogen excreted in stool
• 4 general pathways of digestion:
– Breakdown into AA all by luminal enzymes only
– Breakdown into AA by luminal & brush border enzymes
– Breakdown into oligopeptides- absorbed and further
digested by cytosolic enzymes
– Breakdown into oligopeptides- absorbed and move directly
into blood as is
Protein Digestion/Absorption Steps
1. Luminal digestion
2. Brush border and cytosolic digestion
3. Absorption:
– Amino acids
– Oligopeptides
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1. Luminal Digestion
• Involves gastric & pancreatic proteases- secreted as proenzymes
requiring conversion to active forms (unlike amylase)
• Gastric protease- Pepsin:
– Proform is pepsinogen- secreted by gastric chief cells
– Requires low gastric pH for activation and function
– Endopeptidase that digests 10-15% of dietary protein but is
not absolutely necessary (gastrectomy & pernicious anemia)
• Pancreatic proteases:
– 5 pancreatic enzymes
– All secreted as inactive proenzymes
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Zymogen Activation Cascade of Proteases
Enterokinase
Trypsinogens
Trypsin
Chymotrypsinogens
Chymotrypsins
Kallikreinogen
Kallikrein
Procarboxypeptidases
Carboxypeptidases
Procolipases
Colipases
Prophospholipases
Phospholipases
Proelastase
Elastase
Proprotease E
Protease E
Trypsinogens
Trypsins
Protease Actions
Exopeptidases
(e.g. carboxypeptidases)
NH2
Protein
COOH
Endopeptidases
(e.g. chymotrypsin, trypsin)
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Pancreatic Proteases
Enzyme
Trypsin
Action
Endopeptidase; cleaves internal
bonds at lysine or arginine residues;
cleaves other pancreatic
proenzymes
Products
Oligopeptides &
proteolytic
enzymes
Chymotrypsin
Endopeptidase; cleaves bonds at
aromatic or neutral AA residues
Oligopeptides
Elastase
Endopeptidase; cleaves bonds at
aliphatic AA residues
Oligopeptides
Carboxypeptidase A
Exopeptidase; cleaves aromatic AA Aromatic AA &
from C-terminal end of proteins
peptides
and peptides
Carboxypeptidase B
Exopeptidase; cleaves arginine or
lysine from C-terminal end of
proteins and peptides
Arginine, lysine,
and peptides
Adapted from Feldman: Sleisenger & Fordtran’s GI and Liver Disease, 8th ed.
2. Brush Border & Cytosolic Digestion
• Multiple peptidases are present in the brush border
and in cytoplasm of villous epithelial cells.
• Large number of peptidases are required because
each one recognizes only a limited repertoire of
peptide bonds.
• Like pancreatic proteases, the peptidases are
endopeptidases, exopeptidases OR dipeptidases
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3. Absorption: Amino Acids
• Apical:
– At least 7 distinct transport systems
– Predominant transport system is system B- Na+
dependent uptake of neutral AA. Na+ gradient is
maintained by Na-K pump
• Basolateral:
–
–
–
–
At least 5 AA transporters
Bidirectional movement across basolateral membrane
Movement out- mediated by Na-independent process
Movement in- Na-dependent; provides cell nutrition
Amino Acid Transport
AA+
AA0 Na+ AA- 3Na+
AA0
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3. Absorption: Oligopeptides
• Substantial amounts of protein are absorbed as di-,
tri-, or tetrapeptides and then hydrolyzed to AA by
intracellular peptidases.
• Transporter for oligopeptides is distinct from AA
transporters:
– Oligopeptide uptake is active process driven by a
H+/oligopeptide cotransporter, PepT1
– Kinetic advantage- accelerated peptide absorption.
Administering AA as a peptide results in higher blood
levels of the AA compared to administering equivalent
amounts of the AA as a monomer
Oligopeptide Transport
Di/Tripeptides
Na+
Pept-1
H+
H+
Peptides
Peptidases
Peptides
Amino Acids
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Fats
Dietary Sources of Fat
• Triacyl glycerols (TAGs)- 90%
– Triglycerides
– Glycerol backbone + 3 long chain fatty acids
• Phospholipids- 5%
• Cholesterol
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Fats are insoluble in water
• Insolubility in water affects mechanisms to
digest and absorb lipids
• Must overcome:
– Water in the lumen
– Enterocyte surface mucus and water layers
– Water in lymphatics and blood
Digestion & Absorption of Fats
1.
2.
3.
4.
5.
Emulsification
Digestion by lipases
Micelle formation
Movement across enterocyte
Reconstitution into chylomicrons
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1. Emulsification
Transformation of ingested fat and oil into emulsion
of fine oil droplets in water:
• Mechanical processes:
–
–
–
–
Chewing
Gastric churning
Passage through contracted pylorus
Intestinal peristalsis
• Stabilization by preventing dispersed lipid
particles from re-coalescing:
– Biliary phospholipids & cholesterol form surface layer
– TAGs in core of emulsion particles
2. Digestion by Lipases
Enzyme
Optimal pH Site of activity on TAG
Gastric lipase
4.0-6.0
α-1 ester bond
Pancreatic lipase
7.0
α-1 and -3 ester bonds
~15% of fat digestion occurs in the stomach
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Triacyl Glycerols (TAGs)
Gastric lipase
+ 2H2O
Triacyl Glycerols (TAGs)
Pancreatic lipase + colipase
+ 2H2O
Pancreatic lipase + colipase
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Triacyl glycerol Hydrolysis
Triglyceride
Fatty acids
TG lipase
and
Colipases
+ 2H+
+ 2H2O
2-MAG
3. Micelle Formation
• As emulsions droplets become smaller, a vesicle
consisting of several lipid bilayers forms
• Bile salt micelles convert these vesicles to mixed
micelles made up of:
– MAGs
– Fatty acids
– Bile salts
– Phospholipids
– Cholesterol
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4. Movement across enterocyte
• Movement through mucus and water layers:
– Short- and medium-chain FAs are soluble in
water and are able to move through these layers
– Long-chain FAs need to diffuse through via
micelles
• Movement across enterocyte:
– Passive diffusion
– Carrier mediated transport
– Incorporation into enterocyte membrane
5. Reconstitution into chylomicrons
• Enterocyte re-esterifies MAGs and longchain fatty acids into chylomicrons:
– Emulsion-like particles
– Consist primary of TAGs and smaller amounts
of phospholipids, cholesterol, apolipoproteins
• Chylomicrons are exported into lymphatics
via exocytosis at basolateral membrane
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Chylomicrons
FA
MAG
TAG
Apolipoproteins
Fats Release Peptide YY Which
Inhibits GI Functions
PYY
 Gastric acid
secretion
 Gastric
emptying
 Pancreatic
secretion
 Transit rate
FFA
 Colonic
motility
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Clinical Implications
Which of the following is the preferred source of
dietary fat in patients with fat malabsorption?
A. Cholesterol
B. Long-chain fatty acids
C. Medium-chain fatty acids
Medium-Chain Fatty Acids
Handling of TAGs with medium-length fatty
acid chains is different than long-chain FAs:
• Uptake into enterocyte does not depend on
either bile salts or micelles
• Once in enterocyte, medium-chain FAs can
be transported directly into portal
circulation
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Fat Soluble Vitamins
Vitamins A, D, E, K
• After ingestion, released from associated proteins
by gastric acid or proteolysis
• In proximal SB, they incorporate into emulsion
droplets  get to enterocyte surface and move
across by simple diffusion or through transporters
• Absorption efficiency:
– A, D, K 50-80%
– E 20-30%
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Fat Soluble Vitamin Deficiencies
Vitamin
A
D
E
K
Role
Retinal pigment
Ca+ absorption
Antioxidant
Clotting
Deficiency
Night blindness
Rickets
Peripheral neuropathy
Bleeding
Vitamin B12
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Vitamin B12
• Made only by microorganisms, not by mammalian
cells
• Primary source for humans- ingestion of animal
products (meat, fish, eggs). NOT present in fruits
or vegetables
• Main function- coenzyme involved in converting
homocysteine to methionine:
– Essential amino acid
– Serves as methyl donor for several enzymatic reactions
Role of the pancreas in B12 absorption
Cobalamin (Vitamin B12) Absorption & Storage
Intrinsic factor
B12
storage
Salivary haptocorrin
IF
HC
B12
HC
B12
B12
B12
IF
B12 IF
Portal circulation to liver
IF
B12
Terminal ileum
IF
B12
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Causes of Vit B12 Deficiency
• Strict vegetarian diet
• Pernicious anemia:
– Absence of gastric parietal cells  no gastric
acid and IF
• SIBO:
– Bacterial binding of B12
• Terminal ileal disease/resection
• Pancreatic insufficiency
Folate
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Folate
• Present in many foods.
– Folate rich foods- spinach, liver, peanuts, beans
• No large storehouse for folate- deficiency can
develop quickly with poor intake
• The reduced form of folate, tetrahydrofolate, is
essential for synthesis of thymine and purines:
– Folate deficiency compromises DNA synthesis and cell
division  particularly affects bone marrow
Digestion & Absorption
• Most of dietary folate is pteroyl polyglutamate.
Needs to be converted to a monoglutamate for
absorption:
– Brush border exopeptidase- folate conjugase. Present
mainly in proximal jejunum
– Uptake is by a specific folate carrier. Inhibited by certain
drugs (sulfasalazine)
• Once in enterocyte:
– Converted to 5-methyltetrahydrofolate
– Transported out basolateral membrane (carrier not known)
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Summary
•
•
•
•
Carbohydrates
Protein
Fat
Other nutrients:
– Fat soluble vitamins
– Vitamin B12
– Folate
Five patterns of digestion-absorption
1. Substance does not require digestion and can be directly
absorbed (glucose)
2. A polymer (protein) is digested to its constituent
monomers (amino acids) by pancreatic enzymes prior to
absorption
3. An oligomer (sucrose) is digested into its constituent
monomers by brush border enzymes prior to absorption
4. An oligomer (oligopeptide) is directly absorbed by the
cell and then broken down in to monomers inside the cell
5. A substance (triglycerides) is broken down into
constituent components prior to absorption; the cell then
resynthesizes the original molecule
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