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1. Biochemistry of Gastrointestinal System

2. GI: Overview: Organ systems
• Gastrointestinal (GI) tract a continuous muscular digestive tube
– Digests:
• breaks food into smaller fragments
– Absorbs:
• digested material is moved through mucosa into the blood
– Eliminates:
• unabsorbed & secreted wastes.

3. Organ systems
Includes:
• Mouth, pharynx & esophagus
• Stomach
• Small intestine
• Large intestine
Accessory digestive organs: teeth,
tongue, gall bladder, salivary
glands, liver & pancreas

4. Processes
• Ingestion: obtaining food
• Propulsion: moves food along the GI tract by peristalsis
• Mechanical digestion : Chewing & mixing with saliva
mixing in stomach
• Chemical digestion : Action of gastric, pancreatic and intestinal enzymes
• Absorption: movement of nutrients across the mucosal membrane into blood/lymph
• Defecation: eliminates unused/indigestible & secreted substances from the body

5. Organs in digestion and absorption

6. Chemical Digestion: Carbohydrates
• Carbohydrates - complex sugars are broken down to simple sugars
• Simple sugars (monosaccharides): glucose, fructose, & galactose can be absorbed
• Disaccharides : sucrose, maltose, & lactose are hydrolyzed by sucrase, maltase, & lactase into
monosaccharides

7. Digestion of carbohydrates
1. Digestion in Mouth
• The digestion of starch and glycogen begins in the mouth.
• α-Amylase is an endoglucosidase.
• The shortened polysaccharide chains that are formed are called α-dextrins.
• Salivary α-amylase is inactivated by the acidity of the stomach contents, which contain HCl.
• Pancreatic α-amylase continues to hydrolyze the starches and glycogen, forming the disaccharide maltose,
the trisaccharide maltotriose, and oligosaccharides.
• These oligosaccharides with branches called limit dextrins.
• The two glucosyl residues that contain the α-1,6 glycosidic bond will eventually become the disaccharide
isomaltose.

8. Contd.,
2. Digestion in stomach
• Practically no action. No carbohydrate splitting enzymes available in gastric juice.
• Some dietary sucrose may be hydrolysed to equimolar amounts of glucose and fructose by HCl.
3. Digestion in Duodenum
• Chyme reaches the duodenum from stomach where it meets the pancreatic juice.
• Pancreatic juice contains a carbohydrate splitting enzyme pancreatic amylase similar to salivary
amylase.

9. • The dietary disaccharides lactose and sucrose, and starch digestion, are converted to monosaccharides
by glycosidases.
• The different glycosidase are glucoamylase, sucrase–maltase complex, trehalase, and lactase-
glucosylceramidase.
• These glycosidases are collectively called the small intestinal disaccharidases, although
glucoamylase is a oligosaccharidase.
1. Glucoamylase
• Glucoamylase is an exoglucosidase that is specific for the α–1,4 bonds
• It begins at the non reducing end of a polysaccharide or limit dextrin, and sequentially hydrolyzes the
bonds into isomaltase, which is subsequently hydrolyzed principally by the isomaltase activity in the
sucrase–isomaltase complex.
Disaccharidases of the Intestine

10. Contd.,
2. Sucrase–isomaltase complex
• Sucrase–maltase site accounts for approximately 100% of the intestine’s ability to hydrolyze
sucrose in addition to maltase activity
• Isomaltase–maltase site accounts for almost all of the intestine’s ability to hydrolyze α-1,6-bonds
3.Trehalase
• It hydrolyzes the glycosidic bond in trehalose, a disaccharide composed of two glucosyl units
linked by an α -bond between their anomeric carbons. Its mainly present in plants, mushroom,
bacteria, fungai and invertebrates.

11. 4. β-Galactosidase complex (lactase)
• The lactase catalytic site hydrolyzes the β-bond connecting glucose and galactose in lactose.
• The major activity of the other catalytic site in humans is the β-bond between glucose or galactose and
ceramide in glycolipids.
5. Location within the intestine
• The production of maltose, maltotriose, and limit dextrins by pancreatic –amylase occurs in the
duodenum.
• Sucrase–isomaltase activity is highest in the jejunum.
• β -Glycosidase activity is also highest in the jejenum.
• Glucoamylase activity progressively increases along the length of the small intestine, and its activity is
highest in the ileum.
Contd.,

12. • Maltase breaks down the disaccharide maltose.
• Maltase catalyzes the hydrolysis of maltose to the simple sugar glucose. This enzyme is found in
plants, bacteria, and yeast.
• Acid maltase deficiency is categorized into three separate types based on the age of onset of
symptoms in the affected individual.
• In most cases, it is equivalent to alpha-glucosidase, but the term "maltase" emphasizes the
disaccharide nature of the substrate from which glucose is cleaved, and "alpha-glucosidase"
emphasizes the bond, whether the substrate is a disaccharide or polysaccharide
Contd.,

13. Wilson and Crane’s Hypothesis of Active Transport
Wilson and Crane have shown that sugars which are ‘actively’ transported have several chemical
features in common.
They suggested that to be actively transported sugar must have the following:
• They must have a six-membered ring,
• Secondly, they must have one or more carbon atoms attached to C5
•Thirdly, they must have a –OH group at C-2 with the same stereoconfiguration as occurs in D-
glucose.
Contd.,

14. Hydrolysis of oligosaccharides is carried out by surface enzymes of the intestinal epithelial cells –
disaccharidases and oligosaccharidases
These enzymes – often exoglycosidases

15. Saccharide absorption
• End products: monosaccharides, mainly D-glucose, D-galactose, D-fructose
• These are transported by a carrier-mediated process into enterocytes and then into the blood of
the portal venous system.
• SGLT are a family of glucose transporter found in the intestinal mucosa of the small intestine

16. Glucose Transporters (GLUT)
• Several glucose transporters GLUT-1 to 7 have been described in various tissues

17. Defects in digestion and
absorption
1. Lactase Deficiency
• Some infants may have deficiency of the enzyme lactase and they show intolerance to lactose, the
sugar of milk.
• Symptoms and signs seen in affected infants include:
• Diarrhoea and flatulence
• Abdominal cramps
• Distension.
• As lactose of milk cannot be hydrolysed due to deficiency of lactase enzyme, there occurs accumulation
of lactose in intestinal tract, which is osmotically active and holds water, producing diarrhea.
Accumulated lactose is also fermented by intestinal bacteria which produce gas and other products,
producing flatulence, distension and abdominal cramps.

18. Types: Lactase deficiency can be of 3 types.
Contd.,

19. • Primary lactose intolerance occurs as the amount of lactase declines as people age.
• Secondary lactose intolerance is due to injury to the small intestine such as from infection, celiac
disease, inflammatory bowel disease, or other diseases.
• Developmental lactose intolerance may occur in premature babies and usually improves over a short
period of time.
• Congenital lactose intolerance is an extremely rare genetic disorder in which little or no lactase is
made from birth.
Contd.,

20. Fructose Intolerance
• Fructose is metabolized by conversion to glyceraldehyde-3-P and dihydroxyacetone phosphate.
• The first step in the metabolism of fructose, Fructokinase, fructose in the 1-position.
• The fructose 1-phosphate formed is not an intermediate of glycolysis but rather is cleaved by aldolase
B to DHAP and glyceraldehyde.
• Glyceraldehyde is then phosphorylated to glyceraldehyde-3-PO4-
• Caused by a low level of defect is a single missense mutation resulting in an amino acid substitution
(Ala to Pro)

21. Galactose Intolerance
• Two different types of galactosemia is present
1. Non-classical galactosemia (Galactokinase)
2. Classical galactosemia (Galactose-1-PO4- uridylyltransferase)

22. 1. Xylose absorption test
• D-Xylose, is rapidly absorbed from the small intestine and excreted in the urine; little is metabolized
in the liver.
• Its concentration in blood or excretion in urine following a standard oral dose of xylose has been used
as tool to investigate the intestine's ability to absorb monosaccharide.
• Impaired absorption and excretion of xylose occurs in patients with disease of the small intestine but
low values may also be observed in patients who have bacterial colonization of the small intestine,
since the bacteria may metabolize xylose.
• Also, low urinary values occur in patients with renal disease, due to impaired excretion of xylose.
Tests of carbohydrate absorption

23. • The patient should be fasted overnight and empty their bladder before the test.
• At t=0: 5 g xylose orally, dissolved in 500ml of water
• Collect all urine for the next 5 hr
• Patient advised to drink 500 ml of water over the next 2 hr
• At t=1 hr: draw blood and determine concentration of xylose
• At t=5 hr: finish urine collection, analyse urine for xylose
Normal results are:
• serum xylose concentration at 1 hr in excess of 1.3 mM
• urinary xylose excretion in excess of 7.0 mmol/5 hr
Contd.,

24. 2. Hydrogen breath test
• The breath hydrogen test may be used to diagnose the malabsorption of specific carbohydrates. Sugars
malabsorbed in the small bowel are metabolised by colonic bacteria with the production of hydrogen. The
hydrogen diffuses rapidly across the colonic mucosa into the blood and can be measured in the breath.
• Following an overnight fast, A basal sample is taken.
• 20-25 grams of lactose in 200 ml of water are then swallowed. End-expiratory breath samples are
recorded at 15 or 30 minute intervals for two hours.
• A positive test is indicated by a rise of 20 ppm of hydrogen above baseline.
False positive – presence of more bacterial colonisation
False negative - absence of the colonic organisms due to antibiotic treatment or acute
gastrointestinal upset.
Contd.,

25. 3. Disaccharidase deficiency
• Disaccharidase deficiency is most commonly presented as intolerance to one or more of the
disaccharides - lactose, maltose or sucrose.
• The defect may be congenital or acquired.
• Disaccharidase activity can be measured in small intestinal mucosa biopsy specimens.
• This is the most reliable way of specifically diagnosing small intestinal disaccharidase deficiency.
Contd.,

26. Digestion of cellulose
• Cellulose contains β (1-4) bonds between glucose molecules.
• In humans, there is no β (1-4) glucosidase that can digest this bonds. So cellulose passes as such in
stool.
• Cellulose helps water retention during the passage of food along the intestine, producing larger and
softer feces, preventing constipation.

27. Lysozyme
• Lysozyme, also known as N-acetylmuramide glycanhydrolase is an antimicrobial enzyme produced
by animals that forms part of the innate immune system.
• Lysozyme is a glycoside hydrolase that catalyzes the hydrolysis of 1,4-beta-linkages between NAM
acid and NAG residues in peptidoglycan, which is the major component of gram-positive bacterial
cell wall causing lysis of the bacteria.
• Lysozyme is abundant in secretions including tears, saliva, human milk, and mucus.

28. Not everything can be digested
• Many plant polymers, including celluloses, hemicelluloses, inulin, pectin, are resistant to human
digestive enzymes
• A small percentage of dietary fibre is hydrolyzed and then anaerobically metabolized by the bacteria
of the lower intestinal tract
• This bacterial fermentation produces H2, CH4, CO2, H2S, acetate, propionate, butyrate, lactate.

29. Chemical Digestion: Proteins
• Proteins: broken down to amino acid monomers.
• Pepsinogen is activated to pepsin by HCL - Thus, the activation of pepsinogen is autocatalytic.
• Pepsin: cleaves peptide bonds associated with tyrosine & phenylalanine forming polypeptides (+ a
few amino acids).
• Pepsin is inactivated by increased pH in the duodenum, optimum 1.6-2.5
• 99% is poured in gastric juice as pepsinogen. Remaining 1 per cent is secreted in the blood stream
from where it is ultimately excreted in the urine. urinary pepsin is known as uropepsin.
• Dietary proteins are denatured by the acid in the stomach.
• However, at the low pH of the stomach, pepsin is not denatured and acts as an endopeptidase, cleaving
peptide bonds at various points within the protein chain.
• Smaller peptides and some free amino acids are produced.

30. Digestive Processes (Stomach)
• Protein digestion: HCl denatures protein
– HCl activates pepsinogen to pepsin
– Pepsin breaks peptide bonds of proteins
– Rennin: an enzyme that breaks down casein (milk protein) secreted in
infants
• Intrinsic factor: required for Vit. B12 absorption (needed to mature
RBC);
• Absence of B12 results in pernicious anemia

31. Digestion in stomach
• Rennin - Rennin is absent in adult humans, and many non-
ruminants.
• Gastriscin - The enzyme is secreted in the gastric juice of
humans as inactive zymogen form, which is activated in
presence of HCl. Optimum pH is 3 to 4. It acts as a Proteinase
and requires an acidic medium for its activity.
• Gelatinase - Gelatin is hydrolysed by the enzyme Gelatinase
present in gastric juice to form polypeptides. It acts in an acidic
medium

32. Digestion by Enzymes from Intestinal Cells
• Exopeptidases produced by
intestinal epithelial cells act
within the brush border and also
within the cell.
• Aminopeptidases, located on the
brush border, cleave one amino
acid at a time from the amino end
of peptides. Intracellular
peptidases act on small peptides
that are absorbed by the cells.

33. Classes of peptidases
Type Active site pH optimum
Serine proteases Ser, His, Asp 7-9
Cysteine proteases Cys, His 3-6
Aspartate proteases 2 x Asp 2-5
Metalloproteases Zn2+ (coordinated to AA) 7-9

34. Peptidases hydrolyze the peptide bond

35. Contd.,

36. Digestion in small intestine
• Enterokinase – Known as enteropeptidase.
• Amino peptidases - Can hydrolyse peptides to tripeptides. Cannot hydrolyse a dipeptide. Requires
presence of Zn++, Mn++ and Mg++.
• Can hydrolyse a terminal peptide bond connected to an end a.a bearing a free-α NH2 group and thus
splits off the end a.a. from the N-terminal end of a peptide, changing the latter gradually stepwise to a
“tripeptide”.
• Prolidase - An exopeptidase and can hydrolyse a proline peptide of collagen molecule, acts on
terminal peptide bond connected to proline as end a.a, liberating a proline molecule.
• Tri and Di-peptidases - Tri-peptidase acts on a tri-peptide and produces a di-peptide and free a.a.
A di-peptidase hydrolyses a di-peptide to produce two molecules of amino acids.
They require the presence of Mn++, Co++ or Zn++ as cofactors for their activity.

37. Contd.,
Luminal surface of intestinal epithelial cells contains endopeptidases, aminopeptidases, and
dipeptidases that cleave oligopeptides released by pancreatic peptidases
Products: AA, di- and tripeptides → absorbed by enterocytes
Di- and tripeptides are hydrolyzed by intestinal cytoplasmic peptidases
AA are absorbed into the portal blood

38. Disorders of Protein digestion & absorption
Hartnup disease (Neutral amino aciduria)
"pellagra-like dermatosis”
• Is an autosomal recessive metabolic disorder affecting the absorption of aromatic amino acid
tryptophan that can be, in turn, converted into serotonin and niacin
• Nicotinamide is necessary for neutral amino acid transporter production in the proximal renal tubules
found in the kidney, and intestinal mucosal cells found in the small intestine.
• Therefore, a symptom stemming from this disorder results in increased amounts of amino acids in
the urine.

39. Cystinuria
• Is an inherited autosomal recessive disease that is
characterized by high concentrations of the amino
acid cysteine in the urine, leading to the formation
of cystine stones in the kidneys, ureter, and
bladder.
• Cystine is the least soluble of all naturally
occurring amino acids thereby precipitates or
crystallizes
• Cystinuria is a cause of persistent kidney stones. It
is a disease involving the defective transepithelial
transport of cystine and dibasic amino acids in
the kidney and intestine, and is one of many
causes of kidney stones
Contd.,

40. Dietary Lipids
• Dietary lipids intake is ~81 g/day
Triacylglycerol is ~ 90%
The remainder includes (10%):
Cholesterol
Cholesterol ester
Phospholipids
Free fatty acids

41. Digestion of lipids
• The digestion of fats and other lipids poses a special problem because of
(a) the insolubility of fats in water,
(b) because lipolytic enzymes, like other enzymes, are soluble in an aqueous medium.
• The above problem is solved in the gut by emulsification of fats, particularly by bile salts, present in
bile and PL.
• The breaking of large fat particles or oil globules, into smaller fine particles by emulsification
increases the surface exposed to interaction with Lipases and thus, the rate of digestion is
proportionally increased.

42. Contd.,
Phases of Digestion and Absorption
• Digestion of dietary lipids and its subsequent absorption may be
arbitrarily divided into three phases:
A. Preparatory phase: Includes the digestion of lipids in the intestine.
The large lipid particles are broken down into smaller particles with the
help of lipolytic enzymes.
B. Transport phase: Includes the transport of digested fats across the
membrane of intestinal villous layer into intestinal epithelial cells.
C. Transportation phase: Includes the events of action that take place
inside intestinal epithelial cells and its passage through lacteals to
lymph/or in portal blood.

43. Preparatory phase
1. Digestion in mouth and stomach
• Lingual lipase is secreted by the dorsal surface of the tongue
Lingual lipase: The pH of activity is 2.0 to 7.5 (optimal pH value is 4.0 to
4.5).
• Lingual lipase is more active on TG having shorter FA chains and is found
to be more specific for ester linkage at 3-position.
• Short chain FAs are relatively more soluble and hydrophilic and can be
absorbed directly from the stomach wall and enter the portal vein.

44. Gastric lipase
There is evidence of presence of small amounts of gastric lipase in gastric
secretion. The overall digestion of fats, brought about by gastric lipase is
negligible because,
• No emulsification of fats takes place in stomach
• The enzyme secreted in small quantity
• pH of gastric juice is not conducive which is highly acidic, whereas gastric
lipase activity is more effective at relatively alkaline pH. Gastric lipase
activity requires presence of Ca++.
Role of fat in stomach: They delay the rate of emptying of stomach,
presumably by way of the hormone enterogastrone, which inhibits gastric
motility and retards the discharge of chyme from the stomach.
Contd.,

45. Digestion in Small Intestine
 Due to the presence of a powerful lipase (steapsin) in the pancreatic juice and
presence of bile salts, which acts as an effective emulsifying agent for fats.
 Secretion of pancreatic juice is stimulated by the:
• Passage of an acid gastric contents (acid chyme) into the duodenum
• By secretion of the GI hormones, secretin and CCK-PZ.
 Secretin: Increases the secretion of electrolytes and fluid components of
pancreatic juice.
 – Pancreozymin of CCK-PZ: Stimulates the secretion of the pancreatic enzymes.
 – Cholecystokinin of CCK-PZ: Causes contraction of the gallbladder and
discharge the bile into the duodenum.
 – Hepatocrinin: Released by the intestinal mucosa stimulates more bile
formation which is relatively poor in the bile salt content.

46. “Micelle” formation
• Higher FA, mono and diglycerides are relatively insoluble in water and
their absorption is largely aided by the hydrotropic action of bile salts.
• Bile salts formed in the intestinal lumen and bicarbonates of pancreatic and
intestinal juices, collect the molecules of higher FA, mono and
diglycerides, lecithins, cholesterol, etc. in the form of “water-soluble
molecular aggregates” called mixed “micelles”, and absorbed mainly from
duodenum and jejunum.
• Studies, indicate that the products of fat digestion, FFA, α- and β-
monoglycerides mainly enter the microvilli
Contd.,

47. Transportation phase
• Within the intestinal epithelial cell, α-monoglycerides are further hydrolysed
by intestinal lipase to produce free FA and glycerol.
• FA absorbed from intestinal lumen and FA formed from hydrolysis of α-
monoglycerides, are activated to “Acyl-CoA”. An ATP-dependant
thiokinase has been shown to be present in the mucosal cells of the intestine.
Contd.,

48. • Glycerol is converted to α-Glycerol-(P) by glycerokinase in presence of
ATP.
• α-glycero (P) thus formed combines with ‘acyl-CoA’ to form TG molecule.
• β-monoglyceride (72%) which is absorbed from intestinal lumen can
combine directly with ‘acyl-CoA’ to reform TG.
Contd.,

49. Re-synthesis of Lipids and Assembly of
Chylomicrons by Intestinal Mucosal Cells

50. • Re-esterification, TG molecule takes place in the cisternae of endoplasmic
reticulum of the mucosal cells.
• Resynthesised TG cannot pass to lymphatics nor to portal blood as it is
insoluble in water (hydrophobic).
• Hence, it is converted to lipoprotein complex called chylomicrons. Each
droplet of hydrophobic and water insoluble TG gets covered with a layer of
hydrophilic PL, cholesterol/cholesterol esters and an apoprotein called apo-
B48.
• Chylomicrons: They are synthesised in the intestinal wall. It is composed
largely of TG, cholesterol, PL and a small per cent less than 2 per cent, of
specific protein, called apo-B48.
• ‘Nascent’, chylomicrons have ‘apo-B48’ only while “circulating”
chylomicrons contain in addition apo-C, which is derived from circulating
HDL.
Contd.,

51. Digestion and absorption of cholesterol
• Pancreatic juice contains an enzyme cholesterol esterase
• cholesterol appears to be absorbed from the intestine almost entirely in “free” form
• Absorption of cholesterol has been reported to be facilitated by presence of unsaturated FA
and bile salts
• Cholesterol cannot be metabolized to CO2 and water and is, therefore, principally
eliminated from the body in the feces as unreabsorbed sterols.
• ABC protein expression increases the amount of sterols present in the gut lumen, with the
potential to increase elimination of the sterols into feces. Patients with a condition known
as phytosterolemia have a defect in the gene in the enterocytes, thereby leading to the
accumulation of cholesterol and phytosterols within these cells.

52. Digestion and absorption of phospholipids
• Dietary phospholipids are absorbed
from intestine without any digestion.
• Pancreatic juice contains
phospholipase A2.
• Some PL is incorporated in
‘chylomicrons’ synthesis and also for
VLDL synthesis in intestinal mucosal
cell and carried in lymphatic vessels

53. Lipid Digestion: Sites and Enzymes
Sites:
1. The stomach
2. The small intestine
Enzymes:
1. Act in stomach:
Mouth: Lingual lipase
Stomach: Gastric lipase
2. Act in small intestine:
Pancreatic enzymes
Lipase and co-lipase
Cholesterol esterase
Phospholipase A2
Lysophospholipase

54. Abnormalities in Lipid Digestion/Absorption
• Liver and gall bladder diseases
• Pancreatic insufficiency
e.g., chronic pancreatitis, cystic fibrosis, surgical removal of the pancreas
• Intestinal diseases:
e.g., Intestinal resection (shortened bowl)
•  incomplete digestion & absorption of fat & protein  abnormal appearance of lipids
(steatorrhea) & undigested protein in the feces (Malabsorption syndrome)

55. Malabsorption of Fats
• Fat malabsorption can result due to both
digestive and absorptive disorders
• Steatorrhoea is one of the primary clinical
features of malabsorption syndromes
such as coeliac disease results in the
production of pale, foul-smelling and oily
stools.
• The steatorrhoea is believed to be due to
inhibition of pancreatic lipase by the high
H+ concentration in the intestinal lumen.
• Coeliac disease, when foods containing
gluten are eaten, auto immune antibodies
are produced against gluten that damages
the lining of the small intestine.
• Chronic pancreatitis
• Obstruction of bile ducts

56. Cystic Fibrosis
• It affects most critically the lungs, and also the pancreas, liver, and intestine. It is characterized by
abnormal transport of chloride and sodium across an epithelium, leading to thick, viscous secretions.
• The name cystic fibrosis refers to the characteristic scaring and cyst formation within the pancreas
• Autosomal recessive disorder due to mutation to the CF Transmembrane conductance Regulator
(CFTR ) gene
• CFTR protein is a chloride channel on epithelium
• Defect leads to decreased secretion of chloride and increased reabsorption of sodium and water
• In the pancreas, decreased hydration results in thickened secretions which cannot reach intestine,
causing pancreatic insufficiency

57. The gut hormones
1- Cholecystokinin
• The presence of partially digested proteins & lipids in the upper small intestine
• Stimulates the release of pancreatic digestive enzymes.
• Stimulates the contraction of the gall bladder & release of bile.
• Decreases gastric motility  slower release of gastric contents into the small intestine.
• Polypeptide hormone in diff. forms CCK-58, 39, 33, 12, 8,4
2- Secretin
• Low pH of the chyme entering the intestine
• Stimulates the pancreas to release a watery solution rich in bicarbonate to neutralize the pH of the
intestinal contents
• Polypeptide hormone with 27 amino acid

58. Intestinal secretions
• Intestinal juice refers to the clear to pale yellow watery secretions from the glands lining the small
intestine walls.
The glands include;
1- Brunners glands
They are located in the first few centimeters of the duodenum , where the pancreatic and bile juices
empty into the duodenum. These glands produce a slightly alkaline highly viscous fluid containing
mucins, the function of the mucus is to protect the duodenal wall from digestion by the gastric juices.
2- The Crypts of Liberkuhn
Located on the entire surface of the small intestine are small pits called crypts of Liberkuhn, they secret
a fluid that is similar to the ECF but has a slightly alkaline pH 7.5 – 8.0 .

59. Composition of the Intestinal secretions
1- mucin whose the function is to protect the duodenal wall from digestion by the gastric juices.
2- Water and electrolytes.
3- Enzymes ; a number of enzymes are present including, peptidase breaks down peptides into amino acids
• sucrase, maltase, lactase – break down disaccharides into monosaccharides
• lipase – breaks down fats into fatty acids and glycerol
• enterokinase – converts trypsinogen to trypsin
• somatostatin – hormone that inhibits acid secretion by stomach
• cholecystokinin – hormone that inhibits gastric glands, stimulates pancreas to release enzymes in
pancreatic juice, stimulates gallbladder to release bile
• secretin – stimulates pancreas to release bicarbonate ions in pancreatic juice
Contd.,

60. Gastrin production
• Gastrin is a polypeptide released by “G” cells gastric antrum and duodenum and is a
potent stimulator of gastric acid production.
• Involved in the stimulation of growth gastric mucosa
• It’s a polypeptide hormone which exists in different forms G14, G17 and G 34. G17 is
the most active.
• Its release is inhibited by low gastric pH, and its circulating levels are increased in
patients with chronic hypochlorhydria.
• So, plasma gastrin may be elevated in cases of decreased HCL production in the
stomach such as due to gastritis, pernicious anemia.
• The most important clinical application for the measurement of gastrin is in the
investigation of patients with gastric acid hyper secretion thought to be caused by a
gastrinoma (Zollinger-Ellison syndrome).
Contd.,

61. Zollinger-Ellison syndrome
• This syndrome is due to a gastrinoma, neoplasia due to either:
a) pancreatic gastrin-producing cells
b) gastric gastrin-producing cells
• About 60% of gastrinomas are malignant and 30% occur as part of the
multiple endocrine neoplasia type 1.
• Increased gastrin production leads to chronic hypersecretion of gastric acid,
which in turn causes peptic ulceration and sometimes diarrhea and fat
malabsorption leading to steatorrhoea.
Contd.,

62. B) Tests for amino acid absorption
• Certain specific disorders of amino acid transport affect both intestinal and
renal epithelial transport.
• In Hartnup disease, there is impaired transport of neutral amino acids, and
deficiency of some essential amino acids (especially tryptophan) may occur.
• In cystinuria , the dibasic amino acids (cystine, ornithine, arginine and lysine)
are affected; however, there is no associated nutritional defect, despite the fact
that lysine is an essential amino acid.
• These disorders are investigated by examining the pattern of amino acids
excreted in the urine by chromatography.
Contd.,

63. C) Tests for fat absorption:
• Efficient digestion and absorption of fat requires both effective
emulsification and solubilization of fats; this function is done mainly
by bile acids.
• Cholic acid and chenodeoxycholic acid are the primary bile acids
formed in the liver from cholesterol, conjugated with glycine and taurin
and then excreted in bile.
• Most are reabsorbed unchanged in the terminal ileum back to the liver
where they are re-excreted in bile.
Contd.,

64. Determination of fat absorption
Triglyceride breath test :
• Following digestion and absorption of an oral dose of [13C]-triolein
(the marker is in the fatty acid component), part of the fatty acid is
metabolized to 13CO2, which is then expelled in expired air.
• A high 13CO2 excretion is associated with normal fat absorption,
whereas 13CO2 excretion is low in patients with fat malabsorption.
• 13CO2 expelled is measured from radio isotope mass spectroscopy
Contd.,

65. Digestion of nucleic acids
• Pancreatic enzymes hydrolyze dietary nucleic acids:
Ø ribonucleases
Ø deoxyribonucleases
• Polynucleotidases of the small intestine complete the hydrolysis to nucleotides which are then
hydrolyzed to nucleosides by phosphatases and nucleotidases
• Nucleosides are used as such or undergo degradation by nucleosidases to free bases and pentose-1-
phosphate
Endo and exonucleases

66. Contd.,

67. • Purine nucleosides are:
A) Catabolized to uric acid
B) Alternatively, purines are released and used for resynthesis of NA
Contd.,

68. • Pyrimidine nucleosides are:
A) Catabolized to NH4
+, CO2, and
β-aminoisobutyrate or β-
alanine, respectively, that are
partially converted to
(methyl)malonyl-CoA
B) Absorbed intact and utilized
for the re-synthesis of nucleic
acids
Contd.,

69. Purine and pyrimidine bases
 Hypoxanthine guanine / adenine phosphoribosyltransferase catalyses the one-step formation of the
nucleotidesfrom either guanine or hypoxanthine, using PRPPas the donor of the ribosyl moiety.
 The enzyme Pyrimidine Phosphoribosyl transferase catalyzes the formation of pyrimidine nucleotide,
using PRPP as the donor of the ribosyl moiety

70. Catabolic Disorders
 Humans convert adenosine and guanosine to uric acid
 When serum urate levels exceed the solubility limit, sodium urate
crystalizes in soft tissues and joints and causes an inflammatory reaction,
gouty arthritis.
 Hyperuricemias may be differentiated based on whether patients excrete
normal or excessive quantities of total urates. Some hyperuricemias reflect
specific enzyme defects. Others are secondary to diseases such as cancer or
psoriasis that enhance tissue turnover
 In von-Gierke’s disease: Deficiency of G-6-phosphatase leads to elevated
rate of pentose formation in HMP. This acts as a good substrate for PRPP
synthetase and enhances the synthesis of purines followed by their
catabolism to uric acid. Increase lactic acid competes with uric acid
excretion resulting to retention of uric acid

71. Lesch-Nyhan syndrome
 Is an overproduction hyperuricemia characterized by frequent uric acid
lithiasis reflects a defect in hypoxanthine-guanine phosphoribosyl
transferase, an enzyme of purine salvage .
 The accompanying rise in intracellular PRPP results in purine
overproduction.
Hypouricemia
 Is increased excretion of hypoxanthine and xanthine are associated with
xanthine oxidase deficiency due to a genetic defect or to severe liver
damage.
 Patients with a severe enzyme deficiency may exhibit xanthinuria and
xanthine lithiasis.
Contd.,

72.  The end products of pyrimidine catabolism are highly water-soluble: CO2, NH3, β-alanine, and β-
aminoisobutyrate.
 Excretion of β-aminoisobutyrate increases in leukemia and severe x-ray radiation exposure due to
increased destruction of DNA.
 Humans probably transaminate β-aminoisobutyrate to methylmalonate semialdehyde, which then
forms succinyl-CoA .
Pyrimidine Catabolism

73. Gastric Atrophy
• In many people who have chronic gastritis, the mucosa gradually becomes
more and more atrophic until little or no gastric gland digestive secretion
remains.
• Some people develop autoimmunity against the gastric mucosa, this
leading eventually to gastric atrophy.
• Loss of the stomach secretions in gastric atrophy leads to achlorhydria and,
occasionally, to pernicious anemia.
• Achlorhydria (and Hypochlorhydria) is a condition in which stomach fails
to secrete hydrochloric acid; it is diagnosed when the pH of the gastric
secretions fails to decrease below 6.5 after maximal stimulation.
• When acid is not secreted, pepsin also usually is not secreted.
Pernicious Anemia in Gastric Atrophy
• Normal gastric secretions contain a glycoprotein called intrinsic factor.
Intrinsic factor must be present for adequate absorption of vitamin B12
from the ileum. That is, IF combines vit B12 and transports to ileum.

74. Vitamin B12 Metabolism (1-2µg/day)

75. Contd.,

76. Contd.,

77. Contd.,

78. Celiac Disease
 Celiac disease is a serious autoimmune disorder that can occur in people
where the ingestion of gluten leads to damage in the small intestine.
 Gluten is a protein found in wheat, barley, rye, and other grains.
 It is the protein that makes dough elastic and gives bread its chewy texture.
 Patients with celiac disease eats something with gluten, their body
overreacts to the protein and damages their villi.
 When the villi are injured, the small intestine can’t properly absorb
nutrients from food. Eventually, this can lead to malnourishment.
 Intestinal problems like diarrhea, gas, constipation are more common
symptoms of celiac disease.
 In children, intestinal problems are much more common than they are for
adults. These symptoms include: Nausea or vomiting, Bloating or a
swelling in the belly, Diarrhea, Constipation and Weight loss

79. • Malabsorption by the Small Intestinal Mucosa—Sprue
“sprue.”Malabsorption also can occur when large portions of the small intestine have been
removed.
Nontropical Sprue.
• One type of sprue, called variously idiopathic sprue, celiac disease (in children), or gluten
enteropathy, results from the toxic effects of gluten present in certain types of grains,
especially wheat and rye.
• Tropical Sprue.
A different type of sprue called tropical sprue frequently occurs in the tropics and can often
be treated with antibacterial agents caused by inflammation of the intestinal mucosa resulting
from unidentified infectious agents.
• Malabsorption in Sprue.
In the early stages of sprue, intestinal absorption of fat is more impaired than absorption of
other digestive products. In very severe cases of sprue, in addition to malabsorption of fats
there is also impaired absorption of proteins, carbohydrates, calcium, vitamin K, folic acid,
and vitamin B12.

80. Contd.,
Peptic Ulcer
Many peptic ulcer patients have been found to have chronic infection by
the bacterium Helicobacter pylori.
Once this infection begins, it can last a lifetime unless it is eradicated by
antibacterial therapy. Furthermore, the bacterium is capable of penetrating
the mucosal barrier by releasing bacterial digestive enzymes that liquefy
the barrier.
As a result, the strong acidic digestive juices of the stomach secretions can
then penetrate into the underlying epithelium and literally digest the
gastrointestinal wall, thus leading to peptic ulceration.

81. Bicarbonate Ion Production
• CO2 diffuses to the interior of the ductule cells from blood and combines
with H2O by carbonic anhydrase to form H2CO3 which will dissociate into
HCO3
- and H+. The HCO3
- is actively transported into the lumen.
• The H+ formed from the dissociated H2CO3 is exchanged for Na+ ions by
active transport through blood, which will diffuse or actively be
transported to the lumen to neutralize the – ve charges of HCO3
- .
• The movement of HCO3
- and Na+ ions to the lumen causes an osmotic
gradient causes water to move from blood to ductule cells of the pancreas
producing eventually the HCO3
- solution.

82. Bicarbonate Ion Production in Pancreas