Gut microbiome-derived metabolites

1. Pizza Club
-
GUT MICROBIOME–DERIVED METABOLITES
MODULATE INTESTINAL EPITHELIAL CELL
DAMAGE AND MITIGATE GRAFT-VERSUS-
HOST DISEASE
Mathewson et al.
2016
Nature Immunology 17(5):505-513.
25.05.2016 Anne Kaysen

2. 2
Background - Microbiome
… a whole microbial ecosystem
Bacteria
Archaea
Eukaryotes
Viruses
• Development and
maintenance of
the immune
system
• Induction of IgA
production
Immune functions
• Ferment non-digestible
oligosaccharides ( SCFA)
• Ion absorption
• Metabolism of xenobiotics
• Synthesis of several vitamins
Metabolic functions
• Prevention of overgrowth by
potential pathogens
• Pathogen displacement
• Nutrient competition
• Production of anti-microbial factors
Protective functions
Modified from: O’Hara & Shanahan. EMBO Rep (2006), 7(7):688-693.
 Important role in human health and disease
2
Modified from: O’Hara &
Shanahan. EMBO Rep
(2006), 7(7):688-693.

3. Allogeneic stem cell transplantation
Graft-versus host disease:
Donor-derived immune cells target the patient’s tissues

4. Background – what is known?
4
 Intestinal microbiota composition is altered
after allogeneic stem cell transplantation in
patients with graft-versus-host disease
 Alterations correlate with graft-versus-host
disease severity

5. Background – Open questions?
5
 Direct causality between changes in host
microbiota and GvHD severity is unclear.
 Microbiota community structure changes –
microbial-derived metabolites?
 Changes in microbial metabolites – effect on
outcome after allogeneic stem cell
transplantation

6. Experimental setup
6
 3 groups of mice
 naïve mice – no BMT
 syngeneic BMT (same strain of mice)
 BALB/c→BALB/c or C57BL/6J→C57BL/6J
 in humans: donor – identical twin
 GvHD rare and usually not severe
 allogeneic BMT (different strains of mice)
 C57BL/6J→BALB/c
 in humans: ideally a matched donor
Donor Recipient

7. Experimental setup
7
 3 groups of mice
 naïve mice – no BMT
 syngeneic BMT (same strain of mice)
 BALB/c→BALB/c or C57BL/6J→C57BL/6J
 in humans: donor – identical twin
 GvHD rare and usually not severe
 allogeneic BMT (different strains of mice)
 C57BL/6J→BALB/c
 in humans: ideally a matched donor
Donor Recipient

8. Do changes in microbiota result in alterations in
levels of microbial metabolites?
8
Does the decrease in butyrate in intestinal
epithelial cells have a functional impact?

9. Histone deacetylases Histone acetyltransferase
What functional impact does the
decrease in butyrate in IECs have?
9
 Butyrate is an important histone deacetylase
inhibitor
Reduction of histone acetylation in IECs is a
result of decreased amounts of butyrate.
Lower level of butyrate in IECs due to impaired
uptake?

10. Why is the level of butyrate in IECs
decreased? Imparied uptake?
10
Intense inflammatory mileu after allo-BMT
causes decreased expression of butyrate
transporters.
Can the level and functional effect of butyrate be
restored?
Butyrate transporter Butyrate receptor

11. Restoration of butyrate in IECs and
functional effect on histone acetylation
11
 Intragastric gavage
Positive feedback mechanism.

12. Butyrate - effect on GvHD and survival
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Body weight GvHD Survival
Butyrate induces GvHD protective effects.
How?

13. Effect of butyrate – improved epithelial
integrity?
13
 Transmission electron microscopy
 Leakage of the electron-dense stain ruthenium
red
Change the gastrointestinal microbiome?

14. Change of GI microbiota – higher
butyrate – effect?14
16S sequencing Stool IECs
17 strains of Clostridia
day -14 – day 21

15. Conclusion
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 Butyrate is the only SCFA to decrease
significantly in amount after allo-BMT
 Significant decrease only in the intestinal
tissue
 High levels of butyrate (and possibly of
specific bacteria) seem to protect from GvHD
 Butyrate increases junctional integrity
 Other effects of butyrate?

16. THANK YOU16