Bile acids and Barrett’s
Disease
And the case of the efficient Japanese!
Barrett’sBarrett’s
• 1950 Norman Barrett
• Pre-malignant Condition
– Oesophageal Cancer
• Definition
• Causes
– Age and Ge...
GORD/DGORGORD/DGOR
• What Causes?
Defective Sphincter
Hiatal hernia
Delayed gastric emptying
Over production of acid
Helic...
Acid/Bile RefluxAcid/Bile Reflux
© Altana
What's Known?What's Known?
• Acid alone does not cause Barrett’s
• Mice develop Barretts when their duodenum is connected ...
Cdx2Cdx2
• Cdx2 Amplified in Keratinocytes
• Lane 2 - Deoxycholate Acid
(100 µM )
• Lane 4 – Deoxycholate and
Retinoic Aci...
Muc2Muc2
• Muc2 Amplified in
Keratinocytes
• Lane 12 – Retinoic Acid
(1µM 22hrs)
• Lane 16 – CACO-2 cells
positive control
SummarySummary
• Cdx2
– 48hr treatment of oesophageal keratinocytes with
2µM retinoic acid causes activation of Cdx2
– 12h...
Key ResultKey Result
Bile and Retinoic acid are turning on
genes that are normally only found in
intestinal cells where th...
The JapaneseThe Japanese
• Cell Culture (Rat primary keratinocytes)
– Cholic acid (100µM) turned on Cdx2 after 24hrs
– Deh...
Our PlanOur Plan
• Paper
– DCA and Retinoic acid
– Cdx2 and Muc2
– Human primary keratinocytes
• Lab
– Extract fresh human...
Replacement of lower oesophageal sq
Caffeine Molecule
What’s this molecule?
The Mad Scientist
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Bile acids and Barrett’s Metaplasia

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Original presentation with the finding of bile and retinoic acid amplifying genes in oesophageal stem cells which are normally only found in intestinal cells.

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Bile acids and Barrett’s Metaplasia

  1. 1. Bile acids and Barrett’s Disease And the case of the efficient Japanese!
  2. 2. Barrett’sBarrett’s • 1950 Norman Barrett • Pre-malignant Condition – Oesophageal Cancer • Definition • Causes – Age and Gender – Smoking and Alcohol – Gastro Oesophageal Reflux (GORD) – Duodenogastro Oesophageal Reflux (DGOR)
  3. 3. GORD/DGORGORD/DGOR • What Causes? Defective Sphincter Hiatal hernia Delayed gastric emptying Over production of acid Helicobacter pylori • Backwash Acid Bile • Why? Defence Mechanism Oesophageal (weak) Squamous Stomach (STRONG) Glandular More Resistant to Acid
  4. 4. Acid/Bile RefluxAcid/Bile Reflux © Altana
  5. 5. What's Known?What's Known? • Acid alone does not cause Barrett’s • Mice develop Barretts when their duodenum is connected to their oesophagus • Barrett’s patients exposed to bile and acid for long periods • Bile and retinoic acid are potent gene regulators • Certain genes control cell proliferation and differentiation • CDX2 and MUC2 normally only found in Intestinal cells • Detected in Barretts disease (Immunohistochemistry)
  6. 6. Cdx2Cdx2 • Cdx2 Amplified in Keratinocytes • Lane 2 - Deoxycholate Acid (100 µM ) • Lane 4 – Deoxycholate and Retinoic Acid (100 µM and 1 µM respectively) • Lane 6 – Cheno deoxycholate and Retinoic Acid (100 µM and 1 µM respectively) • Lane 16 – CACO-2 cells positive control
  7. 7. Muc2Muc2 • Muc2 Amplified in Keratinocytes • Lane 12 – Retinoic Acid (1µM 22hrs) • Lane 16 – CACO-2 cells positive control
  8. 8. SummarySummary • Cdx2 – 48hr treatment of oesophageal keratinocytes with 2µM retinoic acid causes activation of Cdx2 – 12hr treatment of oesophageal keratinocytes with DCA/DCA and Retinoic acid/ CDCA and retinoic acid causes activation of Cdx2 • Muc2 – 48hr treatment of oesophageal keratinocytes with 2µM retinoic acid causes activation of Muc 2 – 22hr treatment of oesophageal keratinocytes with 1µM retinoic acid causes activation of Muc2
  9. 9. Key ResultKey Result Bile and Retinoic acid are turning on genes that are normally only found in intestinal cells where their function is to regulate cell proliferation and differentiation.
  10. 10. The JapaneseThe Japanese • Cell Culture (Rat primary keratinocytes) – Cholic acid (100µM) turned on Cdx2 after 24hrs – Dehydrocholic acid (100µM) turned on Cdx2 after 24hrs – Transfection of Cdx2 gene into rat keratinocytes yielded Muc2 expression • Using 7 week old Rats – Attached rats oesophagus to jejunum – Development of columnar epithelium in oesophagus after 6 months (Barrett’s) – Similar concentrations of cholic and dehydrocholic acid were found in rat stomach contents as were used in cell culture experiments
  11. 11. Our PlanOur Plan • Paper – DCA and Retinoic acid – Cdx2 and Muc2 – Human primary keratinocytes • Lab – Extract fresh human keratinocytes – Look at retinoic acid at higher concentrations of 10-100µM – Hepatic circulation of up to 1M – Cdx 1 and 2 expression – RXR/RAR
  12. 12. Replacement of lower oesophageal sq
  13. 13. Caffeine Molecule What’s this molecule? The Mad Scientist

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