Lactose Intolerance

Question 1

Lactose is not broken down in the ________ so it reaches the _______

Answer 1

Small intestine, colon

Question 2

Is there lactase enzyme expression in the colon?

Answer 2

No

Question 3

What is happens to lactose in the colon

Answer 3

Microbial lactose fermentation,
–> microbiota ferments non-digested lactose in colon

Question 4

What does microbial lactose fermentation lead to

Answer 4

Abdominal pain, gas, diarrhea

Question 5

Where is lactase normally expressed

Answer 5

Jejunum and ileum

Question 6

Enterocytes/epithelial cells

Answer 6

Small intestinal cells that line the brush boarder

Question 7

What 2 boarders must be crossed to enter bloodstream

Answer 7

1. apical
2. basolateral

Question 8

Glucose and galactose cross the apical border via which transporter and what type of transport?

Answer 8

The apical border via SGLT by co-transport with 2NA+

Question 9

Fructose crosses the apical border via which transporter and what type of transport?

Answer 9

Crosses the apical border via GLUT5 by facilitated diffusion

Question 10

What transporter transports all monosaccharides on the basolateral border and by which type of transport?

Answer 10

GLUT2 by facilitated diffusion

Question 11

Normal absorption (transport) of monosaccharides started in s. intestine (jejunum)

Answer 11

1. Active transport of Na+ from enterocyte to blood → removal of Na+ from inside the cell maintains the concentration gradient (low [Na+] inside the cell, high [Na+] outside the cell)
   2.SGLT1 co-transporter needs BOTH Na+ and
   glucose to work (co transport). 2Na+ and 1
   glucose (or galactose) enters the cell.
2. GLUT2 = facilitated diffusion of glucose (or
   galactose) into blood
3. For SGLT1 to keep functioning we need to
   continuously remove Na from inside the cell →
   ongoing activity of the Na+/K+ pump

Question 12

Fructose malabsorption is caused by

Answer 12

Deficient or low expression of GLUT5 in small intestine

Question 13

Hereditary fructose intolerance

Answer 13

liver Aldolase B is NOT expressed leading to accumulation of fructose-1-phosphate (F-1-P) which, over time, results in the death of liver cells

Question 14

Primary lactose deficiency (inherited)

Answer 14

loss of lactase expression after weaning.
IRREVERSIBLE
–> Genetically programmed progressive loss of lactase enzyme expression (mRNA and/or protein) and/or activity in the small intestine

Question 15

Secondary lactase deficiency (acquired)

Answer 15

loss of lactase expression due to GI mucosal injury damaging the brush border of small intestine (REVERSIBLE)
–> causes of mucosal injury include infections, allergies, inflammation due to other
GI diseases (celiac disease, inflammatory bowel disease, etc.).

Question 16

Lactase non-persistance (L.I) WILDTYPE

Answer 16

group of individuals with LOW lactase activity (also called hypolactasia)

Question 17

3 causes of lactase non- persistance

Answer 17

1. Low lactase gene expression –> low lactase protein expression
2. Low lactase protein expression –> SOME protein produced, not all gene expression (mRNA) is translated to proteins
3. Normal expression levels of lactase protein but enzymatic activity is low

Question 18

Lactase enzyme activity through life

Answer 18

Gestation:
-low levels, (dont need)
Birth:
-maximal enzyme activity
Weaning:
-declines in lactase non-persistence, stays the same in lactase persistence
Adulthood:
-same in lactase persistence, very low in lactase non-persistence

Question 19

Lactase persistance

Answer 19

group of individuals who RETAIN their neonatal
level of lactase activity into adulthood

Question 20

Global prevalence of lactose intolerance in adults

Answer 20

70%

Question 21

SNPs are associated with what phenotype

Answer 21

Lactase persistance

Question 22

What gene controls the expression of lactase gene and how does it do this

Answer 22

MCM6 - functions to influence the lactase promoter and control lactase transcription

Question 23

SNPs are located in MCM6 in a _______ region

Answer 23

regulatory

Question 24

Where is MCM6 located in relevance to gene

Answer 24

Upstream

Question 25

Common MCM6 gene SNPs in the European and North American Caucasian population

Answer 25

Intron 13 of MCM6 gene C --> T Intron 9 of MCM6 gene G --> A

Question 26

Are SNPs of MCM6 gene in the European and North American common or rare

Answer 26

Common (SNP=lactase persistence)

Question 27

Are SNPs of the MCM6 gene in the Asian and African populations common or rare

Answer 27

Rare (SNP= lactase persistance) therefore, majority are lactose unpersistant

Question 28

What alleles on MCM6 are lactase non-persistence and what are lactase persistence

Answer 28

LCT13910C-->C = lactase non-persistence LCT13910C-->T = lactase persistence (dominant allele)

Question 29

2 transcription factors that activate LCT transcription

Answer 29

- Cdx2 - HNF-1α

Question 30

PDX-1

Answer 30

Transcriptional Repressor that blocks/inhibits the function of Cdx2 and HNF-1α

Question 31

What happens when someone has SNP causing LOW expression of PDX-1

Answer 31

Have LCT gene expression

Question 32

What happens when someone has SNP causing HIGH expression of PDX-1

Answer 32

Strong repression of LCT gene expression

Question 33

What happens in small intestine in lactose tolerant

Answer 33

Lactase enzyme converts lactose into glucose and galactose

Question 34

What happens in small intestine in lactose intolerant (NO lactase)

Answer 34

-Lactose brought down to colon -Bacterial fermentation produces gases (H2, CO2, CH4) and acids (lactic, and acetic acid) -Flatulence, abdominal pain

Question 35

Some bacteria express the enzyme _____________ which breaks the glycosidic bond in lactose into free glucose + galactose

Answer 35

Beta-galactosidase,

Question 36

Bacteria found in the colon microbiota capable of fermenting intact lactose or the monosaccharide components glucose and galactose

Answer 36

* Enterobacter species (sp.) * Citrobacter sp. * Klebsiella sp. * Escherichia coli * Serratia sp. * Streptococcus sp

Question 37

Non-lactose fermenting bacteria

Answer 37

* Salmonella sp. * Shigella sp

Question 38

Not all patients with lactose maldigestion (lactose intolerance) experience symptoms, because there is high individual variability influenced by

Answer 38

- Genetics & lactase enzyme expression and activity in the small intestine - rate of gastric emptying - GI transit time - large intestine (colon) microbial composition and activity

Question 39

True of false: undigested lactose increases osmotic load in colon

Answer 39

True

Question 40

Putative toxic metabolites generated during lactose fermentation by the colonic bacteria

Answer 40

- Acetaldehyde - Acetoin - Ethanol

Question 40

Ways to diagnose lactose intolerance (not the common way)

Answer 40

* Jejunum biopsies and measure the expression and activity of lactase – invasive and expensive * Genotyping individuals – determine if they carry the lactose persistence associated SNPs in chromosome 2 – expensive simple and non-invasive * Measure blood glucose (or galactose) levels after a lactose load – time consuming and expensive -remember galactose is converted to glucose and used in metabolism (test similar to an oral glucose tolerance test) * Remove lactose containing foods from the diet and see if symptoms improve. Can be followed with re introducing lactose containing foods and should see symptoms reappear. – Not Fun for the patient and can take several weeks

Question 41

Common clinical approach to diagnosing lactose intolerance and how it works

Answer 41

Breath Hydrogen Test (BHT) -cost-effective, non-invasive, reliable -oral ingestion of 50g lactose (∼1L milk) -measurement of breath hydrogen exhaled for 3-6 h after lactose ingestion

Question 42

What H2 values on BHT determine lactose intolerance

Answer 42

H2 > 20 p.p.m. suggests lactose intolerance; < 20 p.p.m. sometimes referred to as “Lactose Maldigesters”

Question 43

Methanobrevibacter smithi

Answer 43

resides in microbiota -converts 4 atoms of hydrogen and 1 atom of carbon into one molecule of CH4

Question 44

What is methane produced by

Answer 44

Produced by class of bacteria in the colon called Methanogens

Question 45

Ideal transit times in both small intestine and colon

Answer 45

-slow transit time through small intestine -faster transit time through the colon

Question 46

Why do we want slow transit time in small intestine

Answer 46

Slower gastric emptying → food bolus/chyme gradually enters the SI →more opportunity for lactase activity (however much is there) to breakdown lactose

Question 47

Why do we want fast transit time in colon

Answer 47

faster transit time through the colon → Minimize symptoms → less time in the colon, less opportunity for lactose fermentation by colonic bacteria (microbiota) → results in less gas production, bloating and diarrhea.

Question 48

Strategies to improve tolerance to dairy

Answer 48

*Adjust the amount of lactose consumed at a time *Drink milk with a meal or snack * Certain dairy foods are better tolerated – choose wisely

Question 49

How does drinking milk with a snack help to improve dairy tolerance

Answer 49

-slows gastric emptying and/or delivery of lactose to the colon, allowing for the remaining lactase enzymes present in small intestine to digest lactose

Question 50

Dairy foods that are better tolerated

Answer 50

* Yogurts with live active bacteria cultures * Whole milk (higher fat content) vs. lower fat milk – fat content slows gastric emptying * Many aged chesses have lower lactose content (cheddar, colby, Swiss, Parmesan).

Question 51

Pasteurization destroys most ___________ activity

Answer 51

beta-galactosidase