the small intestine and mucosal digestion

THE SMALL INTESTINEAND MUCOSAL

DIGESTIONEric Sibley, MD, PhD

Department of Pediatrics

September 25, 2015

Learning Objectives

To understand the physiological processes involved in intestinal digestion of nutrients

To comprehend the mechanisms that allow for mucosal absorption of the products of intestinal nutrient digestion

AmylaseAmylases

Maltase

Chymotrypsin,Carboxypeptidase

Pepsin, trypsin

Monosaccharides(glucose, galactose, fructose)

ProteasesAminopeptidase

Amino AcidsPeptide FragmentsProtein

Lipase Lipases

Fats

Protein

Carbohydrate

Monoglyceride

Free FattyAcids

Nutrient MucosalDigestion

Mucosal Absorption

Triglyceride

DisacccharidePolysacccharide

LuminalDigestion

Tri/Di-peptides

The Small Intestine - Nutrient Digestion

I. Anatomy

II. Carbohydrate Digestion A. Luminal and Mucosal digestion of starch/glycogen B. Mucosal digestion of oligosaccharides – Lactase

– Carbohydrate malabsorption C. Mucosal transport of monosaccharides

– SGLT1, GLUT5

III. Protein Digestion

A. Luminal and Mucosal digestion of proteins

B. Mucosal transport of peptides and AA

C. Intracellular digestion of peptides

Digestive Anatomy

Normal small intestinal mucosa is seen at the left, and mucosa involved by celiac sprue at the right. There is blunting and flattening of villi with celiac disease, and in severe cases a loss of villi with flattening of the mucosa as seen here.

Normal Celiac Sprue

Carbohydrate Digestion

The Small Intestine - Nutrient Digestion

I. Anatomy

II. Carbohydrate Digestion A. Luminal and Mucosal digestion of starch/glycogen B. Mucosal digestion of oligosaccharides – Lactase

– Carbohydrate malabsorption C. Mucosal transport of monosaccharides

– SGLT1, GLUT5

III. Protein Digestion

A. Luminal and Mucosal digestion of proteins

B. Mucosal transport of peptides and AA

C. Intracellular digestion of peptides

AmylaseAmylases

Maltase

Monosaccharides(glucose, galactose, fructose)

Carbohydrate

Nutrient MucosalDigestion

Mucosal Absorption

DisacccharidePolysacccharide

LuminalDigestion

DIGESTION OF CARBOHYDRATE

LUMINAL MUCOSALFOOD SOURCE % OF CHO HYDROLYSIS HYDROLYSIS

STARCH 60(AMYLOPECTIN

AMYLOSE)

LACTOSE 10

SUCROSE 30

Glux

Glux

Amylose

Amylopectin

Maltotriose Maltose

-Limit Dextrins

(1-6) linkage

(1-4) linkages

DIGESTION OF CARBOHYDRATE

LUMINAL MUCOSALFOOD SOURCE % OF CHO HYDROLYSIS HYDROLYSIS

STARCH 60 MALTOSE,(AMYLOPECTIN MALTOTRIOSE,

AMYLOSE) -DEXTRINS

DIGESTION OF CARBOHYDRATE

LUMINAL MUCOSALFOOD SOURCE % OF CHO HYDROLYSIS HYDROLYSIS

STARCH 60 MALTOSE,(AMYLOPECTIN MALTOTRIOSE,

AMYLOSE) -DEXTRINS

LACTOSE 10 NONE

SUCROSE 30 NONE

DIGESTION OF CARBOHYDRATE

LUMINAL MUCOSALFOOD SOURCE % OF CHO HYDROLYSIS HYDROLYSIS

STARCH 60 MALTOSE, GLUCOSE(AMYLOPECTIN MALTOTRIOSE,

AMYLOSE) -DEXTRINS

LACTOSE 10 NONE GLUCOSE + GALACTOSE

SUCROSE 30 NONE GLUCOSE + FRUCTOSE

The Small Intestine - Nutrient Digestion

I. Anatomy

II. Carbohydrate Digestion A. Luminal and Mucosal digestion of starch/glycogen B. Mucosal digestion of oligosaccharides – Lactase

– Carbohydrate malabsorption C. Mucosal transport of monosaccharides

– SGLT1, GLUT5

III. Protein Digestion

A. Luminal and Mucosal digestion of proteins

B. Mucosal transport of peptides and AA

C. Intracellular digestion of peptides

SGLT1 GLUT5

Na+ Glucose Galactose

Fructose

Glucose

Galactose

Fructose

Na+

K+Na+

K+

GLUT2ATPase

Intestinalcell

Blood

Lumen

Starch

Amylase

Maltotriose

Maltose

-Limit DextrinsSucrose Lactose

LactaseSucrase–Isomaltase Maltase-GA

Oligosaccharides

GLUT5 SGLT1

GlucoseFructose Galactose

Facilitated Diffusion Active transport

Inte

stin

al L

umen

Brus

h Bo

rder

Na+

Maturational Decline in Lactase Activity

0

20

40

60

80

100

120

140

160

180

Birth 5 10 15 20 25 30

AGE (days)

Enzyme Activity

(units/gm protein) Lactase

Sucrase

From: Henning SJ, Am. J. Physiol. 235:E451-456, 1978

Prevalence Of Lactase Deficiency In Healthy Populations

Group Lactase Deficient (%)

African Bantu 50 Chinese 87 Danish 3 Eskimo (Greenland) 88 Filipino 95 Indian 55 Mexican 74 Nigerian

Yoruba 99Fulani 58

North American (Black) 70-75 North American (White) 5-20 Thai 97

LactoseBacterial action

Lactic acid + H + CO2 osmotic effect

H2O

Distension ofGut Walls

Watery Diarrhea

Lactase

Fluid Load

IncreasedPeristalsis

Malabsorption

glucose+ galactose

Maturational Decline in Lactase Activity

0

20

40

60

80

100

120

140

160

180

Birth 5 10 15 20 25 30

AGE (days)

Enzyme Activity

(units

/gm pr

otein) Lactase

Sucrase

From: Henning SJ, Am. J. Physiol. 235:E451-456, 1978

Exon 1TATA

Regulatory Protein RNA Polymerase II Complex

Exon 1TATA

Transcription Regulation

Cis Element

Cis Element

EXON 1

5’ Lactase Gene

EXON 2PROMOTER

Lactase Promoter - Luciferase Reporter

Luciferase Gene

EXON 1

5’ Lactase Gene

EXON 2PROMOTER

Age: 7 days (six pups) Age: 4 weeks

In Vivo Detection of Luciferase Activity

gLac2K- F1 Generation: PCR + or –

+– –– –+

–+ +

esophagus

stomach

small intestine

cecum

colon

2Kb Lactase Promoter Directs Spatial Restriction of Expression

Luciferase Activity - gLac2K Transgene (jejunum)

RT-PCR mRNA Abundance

2Kb Promoter Directs Maturational Decline

1 wk 2 wk 4 wkG3PDH

Lactase

Luciferase

1 week 2 week 4 week0

500

1000

1500

2000

2500

AGE

Luc

ifera

se A

ctiv

ity(R

LU

/ug

prot

ein)

Prevalence Of Lactase Deficiency In Healthy Populations

Group Lactase Deficient (%)

African Bantu 50 Chinese 87 Danish 3 Eskimo (Greenland) 88 Filipino 95 Indian 55 Mexican 74 Nigerian

Yoruba 99Fulani 58

North American (Black) 70-75 North American (White) 5-20 Thai 97

LACTASE; LCT

Alternative titles; symbols LACLACTASE-PHLORIZIN HYDROLASE; LPH

CHROMOSOME: 2

Gene map locus 2q21

2q14.1

2q22.1

Chromosome 2

Identification of a variant associated with adult-type hypolactasiaNabil Sabri Enattah et al.

Nature Genetics 30, 233 – 237 (2002)

Identification of a variant associated with adult-type hypolactasia

EXON 1

5’ Lactase Gene

PROMOTEREXON 12

3’ MCM6 Gene

-13,910

C/T

-2,000

LACTASE PERSISTENT

C

LACTASE NON-PERSISTENT

-13910 bp SNP

CGA

T CGA

EXON 1

5’ Lactase Gene

PROMOTEREXON 12

3’ MCM6 Gene

-13,910

C/T

-2,000

Maturational Decline in Lactase Activity

0

20

40

60

80

100

120

140

160

180

Birth 5 10 15 20 25 30

AGE (days)

Enzyme Activity

(units

/gm pr

otein) Lactase

Sucrase

From: Henning SJ, Am. J. Physiol. 235:E451-456, 1978

Protein Digestion

The Small Intestine - Nutrient Digestion

I. Anatomy

II. Carbohydrate Digestion A. Luminal and Mucosal digestion of starch/glycogen B. Mucosal digestion of oligosaccharides – Lactase

– Carbohydrate malabsorption C. Mucosal transport of monosaccharides

– SGLT1, GLUT5

III. Protein Digestion

A. Luminal and Mucosal digestion of proteins

B. Mucosal transport of peptides and AA

C. Intracellular digestion of peptides

AmylaseAmylases

Maltase

Chymotrypsin,Carboxypeptidase

Pepsin, trypsin

Monosaccharides(glucose, galactose, fructose)

ProteasesAminopeptidase

Amino AcidsPeptide FragmentsProtein

Protein

Carbohydrate

Nutrient MucosalDigestion

Mucosal Absorption

DisacccharidePolysacccharide

LuminalDigestion

Tri/Di-peptides

70%

30%

PepT1

PepsinChymotrypsin

Trypsin

PepT1

PepsinChymotrypsin

Trypsin

Adibi, Gastro. 113:332 (1997)

http://www.biochemtech.uni-halle.de/nbiochemie/Pept1.gif

PepT1

PepsinChymotrypsin

Trypsin

Intestinal Amino Acid Transport DisordersDisorder Substrate Cinical Features

Cystinuria Cystine, ornithine,arginine, lysine

Urinary tract calculi, hereditary pancreatitis,cerebral dysfunction, dibasic aminoaciduria. Twotypes of cystinuria exists for which the geneticmutation in Type I has been isolated to theSLC3A1 amino acid transporter gene (1995),whose protein product is involved in cystine,dibasic and neutral amino acid transport

Hartnup disease Neutral amino acids Autosomal recessive. Pellagra-like rash,cerebellar ataxia, psychiatric disorders, neutralaminoaciduria. Consistent with defect in Type Btransporter system

Blue diaper disease Tryptophan Indigo blue discolouration of diapers, notryptophanuria, growth retardation,hypercalcemia

Oasthouse urine disease Methionine Seizures, mental retardation, diarrhea, peculiarurinary odor-increased alpha hydroxybutryic acid.Methionine malabsorption.

Hyperdibasic aminoaciduria Lysine, arginine Familial protein intolerance, diarrhea, failure tothrive, hepatosplenomegaly, dibasicaminoaciduria

PepT1

PepsinChymotrypsin

Trypsin