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GLM Biochemistry of Gastroenterology
GLM Biochemistry of Gastroenterology
Digestion is the degradation of nutrient molecules into components simple enough to be subsequently
absorbed in intestine.
Absorption is the process of transport of nutrients and electrolytes from the intestinal lumen across the
intestinal epithelial cells into blood or lymph.
Mechanical changes – by motility of GIT
Enzymatic (chemical changes) - by enzymes of GIT, Most of digestive enzymes are secreted as zymogens
All digestive enzymes are hydrolases (IUBMB Class 3)
Maintenance of appropriate pH is different parts of GIT is crucial.
• Lactase (galactosidase) splits lactose into galactose and glucose. Its specificity is β Gala 1, 4 Glc bond.
• Sucrase hydrolyzes sucrose into glucose and fructose. Its specificity is α – Glc 1, 2 β Fru bond.
• Trehalase hydrolyzes trehalose into 2 glucose breaking α – 1, 1- glycosidic bond.
End products of digestion of carbohydrate are monosaccharides; the hexoses - glucose, mannose, galactose
and fructose and as pentoses like ribose.
Absorption of carbohydrate
• Carbohydrates are absorbed as monosaccharides in the jejunum and passes into the portal venous system.
• There are 2 mechanisms (a) Na+ dependent glucose/galactose transport (SGLUT) (b) Na+ independent
transporters (GLUT or carrier mediated diffusion). All the monosaccharides can cross the intestinal
epithelium by simple diffusion process but it is extremely low.
SGLUT -1 is located on the brush border of enterocytes. It is the secondary active transport. Low
intracellular Na+ concentration is maintained by Na+-K+ ATPase on the serosal side of the cell that utilizes
ATP. Thus, glucose is transported with cotransport of Na+. SGLUT also transports galactose.
Facilitated glucose transporters are located on both luminal (GLUT 5) and serosal (GLUT 2) side of
the absorptive cells.
Maximum glucose absorption is 120g/hr. Galactose is absorbed via the same mechanism as glucose.
Fructose both enters and leaves absorptive epithelial cells via facilitated diffusion.
• Pentoses are absorbed by simple diffusion.
Biomedical importance
• Non-digestible carbohydrate, fibres are beneficial for prevention of constipation, colon cancer and
lowering blood cholesterol level.
• Food with low glycemic index are more beneficial since they cause less fluctuation in insulin secretion.
• Flatulence after ingestion of leguminous seeds is due to presence of raffinose which cannot be hydrolyzed
by human intestinal enzymes.
• Congenital deficiency of sucrase-isomaltase occurs among the Inuit, leading to sucrose intolerance, with
persistent diarrhoea and failure to thrive when the diet contains sucrose.
HCl
Lactose intolerance
Milk sugar lactose is normally digested to glucose and galactose by the brush border enzyme lactase prior
to absorption. Deficiency or lack of lactase is the most common disaccharidase deficiency in human and leads
to intolerance to lactose. It causes osmotic diarrhoea, abdominal cramps, diarrhoea and flatulence. These are
due to accumulation of lactose which is osmotically active and holds water. Bacterial fermentation on lactose
produces short-chain fatty acids, (acetic acid, lactic acids) hydrogen (that can be measured in the breath) and
carbon dioxide. Dietary exclusion of lactose is recommended and addition of commercial lactase preparation
to milk has been effective but is costy.
There are 3 types of lactase deficiency.
1. Inherited deficiency – it is rare and symptoms of intolerance develop very soon after birth. Lactose free
milk results in disappearance of symptoms
2. Primary low-lactase activity – the enzyme is deficient in up to 90% of adult Africans, Asians and South
Americans but only 5% of Northern Europeans. It is represented by gradual decline in lactase activity
throughout the childhood.
3. Secondary low – lactase activity – it is due to a consequence of intestinal disorders which damage the
jejunal mucosa e.g., viral gastroenteritis.
Glycemic index
• The increase in blood glucose after a test dose of a carbohydrate compared with that after equivalent
amount of glucose is known as the glycemic index.
• The Glycemic Index (GI) is a relative ranking of carbohydrate in foods according to how they affect blood
glucose levels. Carbohydrates with a low GI value (55 or less) are more slowly digested, absorbed and
metabolised and cause a lower and slower rise in blood glucose and, therefore usually, insulin levels.
• For pure glucose = 100
• There are three classifications for GI: Individual food portion:
• Low: 55 or less
• Mid: 56 – 69
• High: 70+
➢ Native proteins are resistant to digestion because few peptide bonds are accessible to proteolytic enzyme.
➢ Prior denaturation by heat in cooking and by HCl in stomach is required.
➢ The protein load received by the gut is derived from two primary sources.
o Dietary protein (75-100g) animal or plant origin e.g., meat, egg, fish, beans and peas
o Endogenous protein (35-200g)
▪ Secreted proteins (mostly digestive enzymes)
▪ Proteins shed from epithelium as a result of cell turnover
➢ Protein digestion and absorption is very efficient as only 1-2 g nitrogen (= 6-12 g protein) is lost in the
faeces daily.
Enteropeptidase
Trypsinogen Trypsin + polypeptide
• Trypsin will activate additional trypsinogen and other zymogens.
Chymotrypsinogen Trypsin Chymotrypsin
Proelastase Elastase
Procarboxypeptidase Carboxypeptidase
Pancreatic proteases act on proteoses & peptones released from stomach to form oligopeptides,
dipeptides and amino acids. Trypsin is specific for attacking peptide bonds formed by carboxyl group of basic
amino acids; Arg, Lys. Chymotrypsin acts on peptide bonds made by carboxyl group of uncharged amino
acids; leucine and aromatic amino acids; Phr, Tyr. Elastase attacks peptide bonds next to small amino acids;
glycine, alanine and serine. Carboxypeptidase attack the carboxyl terminal peptide bond of oligopeptide
liberating single amino acid and dipeptide.
(b) Digestion by intestinal enzyme
Aminopeptidase is an exopeptidase that attacks N-terminal peptide bond of oligopeptides to release
free amino acids and dipeptide. Dipeptidase completes the digestion of dipeptides to free amino acids.
Intracellular peptidases act on small peptides producing free amino acids. End products of digestion of dietary
proteins are amino acids.
Absorption of dietary protein
It occurs in jejunum into the portal blood. Amino acids are absorbed via (a) Na + dependent transport
(b) facilitated diffusion (c) Transport linked to the γ- glutamyl cycle.
At the luminal membrane, amino acids are absorbed by semi-specific Na+ dependent transporters. It is
secondary active transport. Some are also transported by facilitated transport. Most amino acids are
transported by more than one transport system.
There are at least six Na+ dependent transport systems in the apical brush border of intestinal cells.
1. Neutral amino acid symporter for short and polar side chain,; Ala,Ser, Thr
2. Neutral amino acid symporter for aromatic or hydrophobic side chain; Phe, Tyr, Met
3. Imino acids transporter; Pro, Hyp
4. Acidic amino acids transporter; Asp, Glu
5. Basic amino acids transporter; Lys, Arg, Cys
6. β- amino acids transporter; β- Ala, taurine
In the serosal membrane, amino acids are principally absorbed into blood by facilitated transporters.
During starvation, intestinal epithelial cells take up amino acids from blood. Thus, transport across the
serosal membrane is bidirectional.
The γ- glutamyl cycle is involved in the transport of amino acids into the cells of the intestine and
kidney. It is aided by glutathione and γ – glutamyl transpeptidase. A γ glutamyl amino acid is formed and
travels across the cell membrane and releases the amino acid into the cell. Glutathione is then reformed.
GLM Y-1 (1/23) Biochemistry of Gastroenterology 8
Biomedical importance
• Congenital defect in the transport mechanism of neutral amino acids in the intestine and renal tubules
cause Hartnup disease. Reduced tryptophan absorption results in reduced synthesis of nicotinamide and
serotonin. Pellagra-like dermatitis and neurological involvement may occur.
• Basic amino acid absorption defect in intestinal and renal tubules causes cystinuria.
• In infants, Ig in the colostrums is absorbed intact providing passive immunity to the infant.
• Relatively large peptides may be absorbed intact and these often stimulate antibody formation causing
allergic reactions to food.
r glutamyl cycle
Amino acid
r glutamyl transpeptidase
Glutathione Glu
Cys
Cys
Gly Gly Amino acid
Glu
Dr.MPK 36
Adult consumes about 60-150g of lipids per day. Dietary lipids are triacylglycerol (> 90%),
cholesterol, cholesterol ester, phospholipids, free fatty acids and fat soluble vitamins.
Digestion in the oral cavity
Lingual glands secrete lipase for digestion of TAG. This does not take place here.
Digestion in the stomach
Gastric lipase is secreted by Chief cells and the secretion is stimulated by gastrin. Lingual lipase and
gastric lipase has optimal pH of 2.5-5.0 and about 5.4 respectively, thus are active in the stomach. Both lipase
attack sn -3 ester bond of TAG to produce 1,2 – diacyl glycerol and free fatty acids. Gastric lipase hydrolyzes
TAG with short and medium chain fatty acids and its action in stomach is not important. Lingual lipase
hydrolyses TAG with shorter chain fatty acids (SCT – short chain triglycerides). SCTs are present in milk,
nutter and ghee. Up to 30% of TAG digestion occurs in the stomach.
Digestion in the small intestine
Lipids are emulsified into small droplets and surface area of droplets is increased. This process is favoured by
(1) detergent action of bile salts
(2) Surfactant action of degraded lipids
(3) Mechanical mixing due to peristalsis.
The emulsified fat is attacked by digestive enzymes from pancreas.
Action of bile salts
• Dietary lipid and partially digested protein stimulate secretion of cholecystokinin (CCK) from mucosal
cells of upper small intestine. It causes contraction of the gall bladder and secretion of pancreatic
enzymes.
• The alkaline content of pancreatic and bile secretion neutralizes the acid of the chyme for action of all
digestive enzymes of the intestine.
• Bile salts are amphipathic lipids and essential for solubilizing lipids during the digestive process.
• Bile salts act as detergent and causes emulsification of lipid. Thus they increase the surface area of
droplets for enhanced action of enzymes.
• The bile (pH 7.7) entering the duodenum serves to neutralize the acid chyme form the stomach and
provides favorable environment for the action of pancreatic enzymes.
(a) Digestion by pancreatic enzymes
Pancreas secretes pancreatic lipase, procolipase and prophospholipase A2. Prophospholipase A2 and
procolipase are activated by trypsin.
GLM Y-1 (1/23) Biochemistry of Gastroenterology 10
Digestion of triacylglycerol
Pancreatic lipase is the major enzyme for digestion of TAG. Pancreatic lipase is inhibited in the
presence of bile salts and its inhibition is overcome by colipase. It is specific for the primary ester linkage (sn1
& 3) of TAG producing free fatty acids and 2- MAG. Removal of secondary ester linkage requires
isomerization to a primary ester linkage. Pancreatic esterase further digests 2MAG to glycerol and FFA. Less
than ¼ of the digested TAG is completely broken down to glycerol and fatty acids. Major end products of
dietary TAG are 2MAG and FFA.
Digestion of phopsholipid
Phospholipase A2 hydrolyzes sn 2 position of phospholipids of both dietary and biliary origin into free
fatty acid and lysophospholipid.
Digestion of dietary cholesterol ester
Cholesterol esterase catalyzes the hydrolysis of cholesterol esters into free fatty acid and cholesterol.
(b) Digestion by intestinal enzymes: Phospholipases attack phospholipids to give glycerol, fatty acids,
phosphoric acid and base- choline and ethanolamine.
The end products of digestion of lipids are cholesterol, free fatty acid, monoacyl glycerol, bases, phosphoric
acid, and glycerol.
Absorption of lipids
Fat absorption is greatest in the upper part of the small intestine, but appreciable amount are also absorbed
in the ileum. On moderate fat intake, 95% or more of ingested fat is absorbed. In infant, 10 -15% of ingested
fat is failed to absorb. Almost 100% of fatty acids and monoacylglycerols are absorbed whereas only 30-40%
of cholesterol is absorbed.
The digested products of lipids (2MAG, FFA, cholesterol, Pl and lysophospholipids) interact with
amphipathic bile salts to form micelles for solubility and transport. The micelles are spherical particles with a
hydrophilic exterior and hydrophobic interior core. The Micelles move down their concentration gradient
through the unstirred water layer to brush border of the mucosal cells. The lipids diffuse out of the micelles
and enter the cells by passive diffusion. The bile salts are left behind and are mostly reabsorbed from the
ileum and then to the liver (enterohepatic circulation).
In the intestinal epithelium, 1-MAG are hydrolysed to fatty acids and glycerol. Glycerol released in the
epithelium is reutilized for TAG synthesis by normal phosphatidic pathway. Glycerol released in the intestinal
lumen is not reutilized but passed into portal vein. Fatty acids containing < 10-12 carbon atoms are absorbed
directly into the portal blood. The fatty acids containing > 10-12 carbon atoms are re-esterified to TAG and
cholesterol ester in the mucosal cells. Some of the lysophospholipids are also esterified into phospholipids.
In the mucosal cell, the product of glucose metabolism, glycerophosphate can be converted to
triacylglycerol and glycerophospholipids. The triacylglycerols and cholesterol ester are then coated with a
layer of apoprotein (Apo B48), cholesterol and phospholipids to form chylomicron. They are extruded by
exocytosis into systemic circulation through lymphatics and thoracic duct.
Lipid soluble vitamins are absorbed together with digested lipids and transported into circulation.
GLM Y-1 (1/23) Biochemistry of Gastroenterology 11
Biomedical importance
• Defect in fat digestion and absorption due to pancreatic and biliary diseases leads to steatorrhoea (fatty,
bulky stool) and deficiency of fat-soluble vitamins especially vitamin K. Vitamin K deficiency leads to
prolonged prothrombin time.
• Plant sterols and stanol inhibit cholesterol absorption helping to lower serum cholesterol.
• Orlistat is a non-hydrolyzable analog of a triacylglycerol and a powerful, reversible inhibitor of pancreatic
lipase. It is used as pharmacological interventions to prevent fat absorption and obesity.
Absorption of water
Ingested fluid 2L + GI secretion 7L → 98 % reabsorbed + 200ml in faeces
Only a small amount of water moves across the gastric mucosa but water moves in both directions across the
mucosa of the small intestine and large intestine in response to osmotic gradient. Water absorption is
absolutely dependent on absorption of solutes, particularly sodium. Osmolarity of the duodenal contents may
be hypotonic or hypertonic depending on ingested meals, but by the time when the meal enters the jejunum,
the osmolarity is equal to that of plasma. In the colon, sodium is actively pump out and water moves passively
with it, along the osmotic gradient.
Iron – duodenum by active transport, ascorbic acid enhances its absorption. Inorganic iron is absorbed in
reduced state and transported into mucosal cell by proton linked divalent metal transporter. Heme iron is
absorbed separately.
Zinc absorption requires zinc binding ligand secreted by pancreas.
Na+ is absorbed in the intestine by several mechanisms. Na+-K+ ATPase pump present on the basolateral
membrane creates the sodium concentration gradient and increases the passive transport of sodium from
lumen to the enterocytes, mainly by cotransport with glucose and amino acids. In the colon, sodium
absorption occurs by sodium/hydrogen exchanger accompanied by chloride absorption by
chloride/bicarbonate exchanger (anion exchanger).
Cl- is normally secreted in the lumen of the small intestine by the Cl- channels that are activated by
cAMP. Na+, K+ and Cl- are also taken up by enterocytes by a 1Na+ -1K+-2Cl- cotransporters in the basolateral
membranes. In the ileum and colon, Cl- is actively absorbed in exchange for HCO-3 resulting in the alkalinity
of the intestinal contents.
High dietary intake of potassium for prolonged periods can cause an increased aldosterone secretion
with resulting increase secretion of K+ into the colon due to increased synthesis of Na+ -K+ ATPase pump. As
a result, intracellular K+ concentration increased and then K+ diffuses out of the cell into the colon. However,
Potassium absorption is mediated by H+/K+ ATPase in the luminal membrane of cells in the distal colon. On
the basolateral membrane, potassium enters the enterocytes together with chloride through KCC1 (potassium
chloride cotransporter). Nevertheless, excessive loss of ileal and colonic fluids in chronic diarrhoea can lead to
severe hypokalaemia.
GLM Y-1 (1/23) Biochemistry of Gastroenterology 13
Biomedical importance
• Excessive loss of Na+ and water loss in diarrhea (e.g, in cholera), ORS (oral rehydration salts) or
solutions containing NaCl and glucose is given orally as a treatment because the presence of glucose in
the intestinal lumen facilitates the reabsorption of Na+.
• Saline cathertics such as Magnesium Sulfate are poorly absorbed salts that retain their osmotic
equivalence to water in the intestine, increasing intestinal volume and consequently exerting a laxative
effect.
Cholera diarrhoea
• Cholera vibrio toxin causes ADP-ribosylation of active Gs at the membrane of intestinal mucosal cell,
inhibiting GTPase activity of alpha subunit. It causes continuous stimulation of adenylate cycles and
↑cAMP. Increased cAMP causes ↑Cl- secretion and inhibits Na+ reabsorption leading to profuse diarrhea.
It can be life threatening and decreased blood volume and circulatory shock. Metabolic acidosis and K+
depletion can occur. However, Na+ -K+ ATPase and Na+ – glucose cotransporter are not affected in
cholera diarrhea. In this case, the presence of glucose and NaCl in ORS (oral rehydration salt) allows
absorption of Na+ and water by SGLUT to replenish body NaCl and water loss.
GLM Y-1 (1/23) Biochemistry of Gastroenterology 14
Biomedical importance
• In liver disease, impaired liver function results in ammonia in toxic levels in blood (hyperammonemia)
and this must be treated promptly. Neomycin used in advanced liver disease, cirrhosis has antibacterial
action and reduces ammonia formation.