Gastrointestinal Physiology (Part 2)

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Gastrointestinal Physiology (Part 2)

• Xia Qiang, MD PhD
• Department of Physiology
• Zhejiang University School of Medicine
• Email xiaqiang_at_zju.edu.cn

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PANCREATIC SECRETION
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Pancreatic juice

• pH 7.88.4
• 1500 ml/day
• Isosmotic
• Components
• Pancreatic digestive enzymes secreted by
  pancreatic acini
• Sodium bicarbonate secreted by small ductules
  and larger ducts

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At low magnification
At higher magnification
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Secretion of bicarbonate ions

• Secreted by the epithelial cells of the ductules
  and ducts that lead from acini
• Up to 145mmol/L in pancreatic juice (5 times that
  in the plasma)
• Neutralizing acid entering the duodenum from the
  stomach

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Pancreatic acinar cell secretory products
Zymogens Function
Trypsinogens Digestion
Chymotrypsinogen Digestion
Proelastase Digestion
Proprotease E Digestion
Procarboxypeptidase A Digestion
Procarboxypeptidase B Digestion

ACTIVE ENZYMES
a-Amylase Digestion
Carboxyl ester lipase Digestion
Lipase Digestion
RNAase Digestion
DNAase Digestion
Colipase Digestion
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OTHERS
Trypsin inhibitor Blockade of trypsin activity
Lithostathine Possible prevention of stone formation constituent of protein plugs
GP2 Endocytosis? formation of protein plugs
Pancreatitis-associated protein Bacteriostasis?
Na , Cl , H2O Hydration of secretions
Ca ?
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Secretion of pancreatic digestive enzymes

• Carbohydrates -- Pancreatic amylase
• Pancreatic lipase
• Fat Cholesterol esterase
• Phospholipase
• Trypsinogen
• Proteins Chymotrypsinogen
• Procarboxypolypeptidase
• Proelastase

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Starches
Pancreatic amylase
Maltose and 3 to 9 glucose polymers
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• Trypsin Inhibitor
• Inhibits the activity of trypsin and thus guards
  against the possible activation of trypsin and
  the subsequent autodigestion of the pancreas

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Regulation of pancreatic secretion

• Basic stimuli that cause pancreatic secretion
• Ach
• Cholecystokinin
• Secreted by I cells
• Stimulates the acinar cells to secrete large
  amounts of enzymes
• Secretin
• Released by S cells
• Acts primarily on the duct cells to stimulate the
  secretion of a large volume of solution with a
  high HCO3- concentration

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Stimulation of protein secretion from the
pancreatic acinar cell. A, The pancreatic acinar
cell has at least two pathways for stimulating
the insertion of zymogen granules and thus
releasing digestive enzymes. ACh and CCK both
activate Ga , which stimulates PLC, which
ultimately leads to the activation of PKC and the
release of Ca . Elevated Ca also activates
calmodulin (CaM), which can activate protein
kinases (PK) and phosphatases (PP). Finally, VIP
and secretin both activate Ga , which stimulates
adenylyl cyclase (AC), leading to the production
of cAMP and the activation of PKA. B, Applying a
physiological dose of CCK (i.e., 10 pM) triggers
a series of Ca oscillations, as measured by a
fluorescent dye. However, applying a
supraphysiological concentration of CCK (1 nM)
elicits a single large Ca spike and halts the
oscillations. Recall that high levels of CCK also
are less effective in causing amylase secretion.
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In addition to protein, acinar cells in the
pancreas secrete an isotonic, plasma-like
fluid. Stimulation of isotonic NaCl secretion by
the pancreatic acinar cell. Both ACh and CCK
stimulate NaCl secretion, probably through
phosphorylation of basolateral and apical ion
channels. The rise in Cl produced by
basolateral Cl uptake drives the secretion of Cl
down its electrochemical gradient through
channels in the apical membrane. As the
transepithelial voltage becomes more lumen
negative, Na moves through the cation-selective
paracellular pathway (i.e., tight junctions) to
join the Cl secreted into the lumen. Water also
moves through this paracellular pathway, as well
as through aquaporin water channels on the apical
and basolateral membranes. Therefore, the net
effect of these acinar cell transport processes
is the production of an isotonic, NaCl-rich fluid
that accounts for 25 of total pancreatic fluid
secretion.
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Regulation of pancreatic secretion

• Phases of pancreatic secretion A meal triggers
  cephalic, gastric, and intestinal phases of
  pancreatic secretion
• Cephalic Phase
• Gastric Phase
• Intestinal Phase

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The three phases of pancreatic secretion
Phase Stimulant Regulatory Pathway Percentage of Maximum Enzyme Secretion
Cephalic Sight Smell Taste Mastication Vagal pathways 25
Gastric Distention Gastrin? Vagal-cholinergic 10-20
Intestinal Amino acids Fatty acids H Cholecystokinin Secretin Enteropancreatic reflexes 50-80
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Three phases of pancreatic secretion. A, During
the cephalic phase, the sight, taste, or smell of
food stimulates pancreatic acinar cells, through
the vagus nerve and muscarinic cholinergic
receptors, to release digestive enzymes and, to a
lesser extent, stimulates duct cells to secrete
HCO and fluid. The release of gastrin from G
cells is not important during this phase. During
the gastric phase, the presence of food in the
stomach stimulates pancreatic secretions'primarily
from the acinar cells'through two routes. First,
distention of the stomach activates a vagovagal
reflex. Second, protein digestion products
(peptones) stimulate G cells in the antrum of the
stomach to release gastrin, which is a poor
agonist of the CCK receptors on acinar cells. B,
The arrival of gastric acid in the duodenum
stimulates S cells to release secretin, which
stimulates duct cells to secrete HCO and fluid.
Protein and lipid breakdown products have two
effects. First, they stimulate I cells to release
CCK, which causes acinar cells to release
digestive enzymes. Second, they stimulate
afferent pathways that initiate a vagovagal
reflex that primarily stimulates the acinar cells
through M cholinergic receptors.
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Mechanisms that protect the acinar cell from
autodigestion
Protective Factor Mechanism
Packaging of many digestive proteins as zymogens Precursor proteins lack enzymatic activity
Selective sorting of secretory proteins and storage in zymogen granules Restricts the interaction of secretory proteins with other cellular compartments
Protease inhibitors in the zymogen granule Block the action of prematurely activated enzymes
Condensation of secretory proteins at low pH Limits the activity of active enzymes
Nondigestive proteases Degrade active enzymes
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Acute pancreatitis
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Acute pancreatitis

• Acute pancreatitis is sudden swelling and
  inflammation of the pancreas
• The symptomatology and complications of acute
  pancreatitis are caused by autodigestion
  (resulting from the leakage of pancreatic
  enzymes) of the pancreas and surrounding tissue
• It is commonly due to biliary tract disease,
  complications of heavy alcohol use, or idiopathic
  causes
• Mortality rates range from below 10 to more than
  50, depending on severity

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BILE SECRETION
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Bile is stored and concentrated in the gall
bladder during the interdigestive period
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Synthesis of bile acids
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Composition of bile

• HCO3-
• Bile salts
• Phospholipids
• Cholesterol
• Bile pigments (include bilirubin)

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Excretion of bilirubin
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Jaundice

• Jaundice is the most visible manifestation of an
  underlying hepatic and/or biliary tract disease.
• This is a yellow discoloration of the skin,
  sclerae, and mucous membranes that occurs
  secondary to elevated serum bilirubin in adults.
• Jaundice is usually not clinically apparent until
  the serum bilirubin concentration is gt2.5mg/dL.

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Functions of bile

• Emulsifying or detergent function of bile salts
• Bile salts help in the absorption of
• Fatty acid
• Monoglycerides
• Cholesterol
• Other lipids

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Emulsifying large fat particles to facilitate its
digestion
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Bile salts interact with cholesterol to form
micelles to facilitate the absorption of
insoluble fat products
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Increasing bile synthesis secretion
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Enterohepatic circulation of bile acids
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Regulation of bile secretion

• Substances increasing bile production
• Bile salts (Enterohepatic circulation of the
  bile)
• Secretin stimulating H2O and HCO3- secretion
  from the duct cells
• Substance inhibiting bile production
• Somatostatin

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• Contraction of the gall bladder
• Substances causing gall bladder contraction
• ACh
• CCK
• Gastrin

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• Secretin and cholecystokinin are produced and
  secreted by cells in the lining of the alimentary
  tract. Which of the following statements about
  these 2 secretions is true?
• A They are produced by enteroendocrine
  cells in the lining of the stomach
• B They are digestive enzymes present
  within the lumen of the duodenum
• C They are produced by Paneth cells
• D They are hormones whose target cells are
  primarily in the pancreas and biliary tract
• E They are produced by Brunners glands
  and released into the lumina of the crypts of
  Lieberkühn

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• Liver bile flow is increased by
• A Gastrin.
• B Pancreatic secretion.
• C Vagal stimulation.
• D Sympathetic nerve stimulation

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SMALL INTESTINE
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Small intestinal juices

• Secreted by
• Brunners glands
• Crypts of Lieberkuhn
• 13 L/day
• pH 7.6
• Isosmotic
• Components
• H2O
• Electrolytes (Na, K, Ca2, Cl-)
• Mucus
• IgA
• Enterokinase

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Small intestinal juices

• Function Completing the digestion of peptides,
  carbohydrates fat
• Secretion by intestinal glands is mainly due to
  the local effects of chyme in the intestine and
  is regulated by both neural and hormonal factors

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Movement of small intestine during digestion

• Tonic contraction maintaining a basal state of
  intestinal smooth muscle contraction
• Segmentation consisting of the alternate
  contraction and relaxation of adjacent bands of
  circular smooth muscle
• Peristalsis a ring of muscle contraction
  appears on the oral side of a bolus of ingesta
  and moves toward the anus, propelling the
  contents of the lumen in that direction as the
  ring moves, the muscle on the other side of the
  distended area relaxes, facilitating smooth
  passage of the bolus

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Migrating motor complex (MMC)

• Local areas of peristaltic contraction
• Present in the interdigestive period and
  disappear when feeding begins
• Sweeping material (undigested food residues, dead
  mucosal cells, bacteria) into the colon and
  keeping the small intestine clean
• Regulated by autonomic nerves and by the release
  of motilin

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Contractions at three loci in the small bowel.
Note that at each locus, phases of no or
intermittent contractions are followed by a phase
of continuous contractions that ends abruptly.
Also note that the phase of continuous
contractions appears to migrate aborally along
the bowel. Such a pattern is called the migrating
motor complex (MMC). min, minute mm Hg,
millimeters of mercury
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Regulation of intestinal motility

• Autoregulation Regulated by BER
• Neural Reflexes
• mainly by short reflexes in the intrinsic
  plexuses which are responsible for peristalsis
  and segmentation
• also by extrinsic nerves (sympathetic vagal
  nerves) which mediate long reflexes
• Hormonal control
• Gastrin, CCK, motilin, 5-HT ()
• Secretin, VIP, glucagon (-)

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LARGE INTESTINE
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Function of large intestine

• The principle functions of the colon
• Absorption of water and electrolytes from the
  chyme to form solid feces
• Storage of fecal matter until it can be expelled
• Digestion in large intestine very limited
• Bacteria vitamin B, K

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Motility of the colon

• Haustration mixing movement
• Mass movement propulsive movement
• Segmentation

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A normal colon, with the typical haustration
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Two mass movements. A, Appearance of the colon
before the entry of barium sulfate. B, As the
barium enters from the ileum, it is acted on by
haustral contractions. C, As more barium enters,
a portion is swept into and through an area of
the colon that has lost its haustral markings. D,
The barium is acted on by the returning haustral
contractions. E, A second mass movement propels
the barium into and through areas of the
transverse and descending colon. F, Haustrations
again return. This type of contraction
accomplishes most of the movement of feces
through the colon
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ABSORPTION
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General mechanisms of digestion and absorption
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Sites of nutrient absorption
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Major gastrointestinal diseases and nutritional
deficiencies
Disease Organ Site of Predominant Disease Defects in Nutrient Digestion/Absorption
Celiac sprue Duodenum and jejunum Fat absorption, lactose hydrolysis
Chronic pancreatitis Exocrine pancreas Fat digestion
Surgical resection of ileum Crohn disease of ileum Ileum Cobalamin and bile acid absorption
Primary lactase deficiency Small intestine Lactose hydrolysis
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Carbohydrates
The three monosaccharide products of carbohydrate
digestion glucose, galactose, and fructoseare
absorbed by the small intestine in a two-step
process involving their uptake across the apical
membrane into the epithelial cell and their
coordinated exit across the basolateral
membrane. The Na/glucose transporter 1 (SGLT1) is
the membrane protein responsible for glucose and
galactose uptake at the apical membrane. The exit
of all three monosaccharides across the
basolateral membrane uses a facilitated sugar
transporter (GLUT2).
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Proteins
Action of luminal, brush border, and cytosolic
peptidases. Pepsin from the stomach and the five
pancreatic proteases hydrolyze proteinsboth
dietary and endogenousto single amino acids, AA,
or to oligopeptides, (AA) . These reactions occur
in the lumen of the stomach or small intestine.
Various peptidases at the brush borders of
enterocytes then progressively hydrolyze
oligopeptides to amino acids. The amino acids are
directly taken up by any of several transporters.
The enterocyte directly absorbs some of the small
oligopeptides through the action of the H
/oligopeptide cotransporter (PepT1). These small
peptides are digested to amino acids by
peptidases in the cytoplasm of the enterocyte.
Several Na -independent amino acid transporters
move amino acids out of the cell across the
basolateral membrane
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Absorption of whole proteins. Both enterocytes
and specialized M cells can take up intact
proteins. The more abundant enterocytes can
endocytose far more total protein than can the M
cells. However, the lysosomal proteases in the
enterocytes degrade 90 of this endocytosed
protein. The less abundant M cells take up
relatively little intact protein, but
approximately half of this emerges intact at the
basolateral membrane. There, immunocompetent
cells process the target antigens and then
transfer them to lymphocytes, thus initiating an
immune response
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Lipids
The breakdown of emulsion droplets to mixed
micelles
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Micellar transport of lipid breakdown products to
the surface of the enterocyte. Mixed micelles
carry lipids through the acidic unstirred layer
to the surface of the enterocyte. 2-MAG, fatty
acids, lysophospholipids, and cholesterol leave
the mixed micelle and enter an acidic
microenvironment created by an apical Na-H
exchanger. The acidity favors the protonation of
the fatty acids. The lipids enter the enterocyte
by (1) nonionic diffusion, (2) incorporation into
the enterocyte membrane (collision), or (3)
carrier-mediated transport.
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Re-esterification of digested lipids by the
enterocyte and the formation and secretion of
chylomicrons. The enterocyte takes up short- and
medium-chain fatty acids and glycerol and passes
them unchanged into the blood capillaries. The
enterocyte also takes up long-chain fatty acids
and 2-MAG and resynthesizes them into TAG in the
SER. The enterocyte also processes cholesterol
into cholesteryl esters and lysolecithin into
lecithin. The fate of these substances, and the
formation of chylomicrons, is illustrated by
steps 1 to 8.
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Calcium
Active Ca uptake in the duodenum. The small
intestine absorbs Ca by two mechanisms. The
passive, paracellular absorption of Ca occurs
throughout the small intestine. This pathway
predominates, but it is not under the control of
vitamin D. The second mechanismthe active,
transcellular absorption of Ca occurs only in
the duodenum. Ca enters the cell across the
apical membrane through a channel. Inside the
cell, the Ca is buffered by binding proteins,
such as calbindin, and is also taken up into
intracellular organelles, such as the endoplasmic
reticulum
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Iron
Absorption of nonheme and heme iron in the
duodenum. The absorption of nonheme iron occurs
almost exclusively as Fe , which crosses the
duodenal apical membrane through DMT1, driven by
a H gradient, which is maintained by Na-H
exchange. Heme enters the enterocyte by an
unknown mechanism. Inside the cell, heme
oxygenase releases Fe , which is then reduced to
Fe . Cytoplasmic Fe then binds to mobilferrin for
transit across the cell to the basolateral
membrane. Fe probably exits the enterocyte
through basolateral ferroportin. The ferroxidase
activity of hephaestin converts Fe to Fe for
carriage in the blood plasma bound to transferrin.
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Summary

• General properties of GI
• Stomach
• Pancrea
• Small and large intestine
• Absorption

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End.