Download FMT - American Gastroenterological Association

FMT: Can we cure obesity and
insulin resistance?
Max Nieuwdorp MD PhD
Internist-endocrinologist
Dept of Vascular Medicine Amsterdam
Wallenberg Laboratory, Gothenberg, Sweden
session Panacea or Pandora’s Box 17th
august 2014: 0840-0905am
Disclosure slide
• Scientific advisory board Seres Health
• Founder Caelus pharmaceuticals
Take home message
• Decreased butyrate producing bacteria in obesity
associated with malign obesity and insulin resistance
• FMT incudes changes in (small) iIntestinal microbiota and
affects insulin resistance (but it is not a panancea)
• Using FMT as a working model can derive novel probiotics on
top of current treatment for insulin resistance
Intestinal microbiota
in obesity and MetSyn
Benign vs malign obesity
• 66% metabolically
healthy obese
• 34% insulin
resitance and DM2
• Low grade
inflammation
involved
Samocha-bonet et al, obesity Reviwws 2014.
Gut microbiota and obesity/type 2
diabetes mellitus
Qin, Nature 2012
Le Chatelier, Nature 2013
Karlsson, Nature 2013
Ridaura, Science 2013
Diagnostic and clinical value of gut
microbiota composition in Dm2
• Reduced short-chain fatty acid butyrate producers
(Roseburia species and Faecalibacterium prausnitzii)
in DM2
• Enrichment of Lactobacillus gasseri and
Streptococcus mutans in fecal sample has
predictive value for developing insulin resistance
Karlsson, Nature 2013
Results of these cohort based
studies using fecal samples
F prausznitzii lower
Ruminococcus lower
Smits/Nieuwdorp, Gastroenterology 2013 [in press]
Major disadvantages of current fecal
sample centered approach
• 1. Small intestine is more involved
in metabolism than the colon
• 2. Association is not causality!
• 3. Sequencing vs culturing bacteria
pH dictates bacterial survival and gutmicrobiota composition
Hartstra/nieuwdorp, Diabetes Care 2014.
Koch’s postulates
for causality
• The microorganism must be
identified/isolated from a diseased
organ(ism).
• The microorganism should be associated with
disease (association/intervention).
• The cultured microorganism should induce
beneficial or adverse effects when introduced
into an organism (inoculation).
Manipulating gut microbiota by
fecal transplant
Effects of fecal transplantations in
clostridium difficile diarroea
Van Nood, NEJM 2013
Gutmicrobiota Diversity in Cdiff After FMT
Correction of Low Diversity of Patients by Transplantation
Diverse Community Stably Maintained for Over 2 Months
FMT Randomized controlled
trials performed at AMC
•
Since 1958 casereport by Eiseman,
at least 4500 patients treated
worldwide with donor feces (since
2007 at AMC),
•
RCT superiority of fecal Tx in
clostridium difficile diarrhea and
MetSyn
•
At AMC ongoing/finished RCT’s for:
-IBD (Colitis ulcerosa, TURN trial)
- insulin resistance
-NAFLD/NASH
•
Long term side effects not seen yet
Smits/Nieuwdorp, Gastroenterology 2013 [in press]; van Nood/Nieuwdorp, NEJM 2013
• No adverse effects!
• No effect on weight 6 weeks after lean
donor FMT
A.Vrieze, Gastroenterology 2012
Effect donor faeces on
periferal insulin sensitivity
A.Vrieze, Gastroenterology 2012
Fecal gut microbiota composition
Gutmicrobiota diversity increased
F prausznitzii higher
Ruminococcus higher
A.Vrieze, Gastroenterology 2012
Small intestinal gut microbiota
composition
A.Vrieze, Gastroenterology 2012
Koch’s postulates
Eiseman (Surgery 1958)
•
Fecal transplant doesn’t induce a definate cure!
•
The cultured microorganism should induce beneficial or adverse effects
when introduced into a healthy organism (3rd postulate)
•
Concentrations of Eubacterium hallii in small intestinal biopsies
correlated significantly with improved insulin sensitivity upon lean donor
Fecal Tx
Manipulating gutmicrobiota by
Eubacterium hallii : effect on
insulin resistance
Eubacterium hallii
• belongs to Firmicutes phylum (spore
former)
• Anaerobic gram positive lactate-utilizing
SCFA butyrate- producing bacterial
strain
• Can produce butyrate at pH 5-6 (small
intestine) as well as at pH 6-7 (colon)
• Sensitive to vancomycine
Studyprotocol I
• Db/db male mice (8 weeks old), n=8 per
group
• Daily gavage (100ul/mouse) with E. Hallii
(stored in 10% glycerol at -80C), gavage
within 1 hour after thawing for 4 weeks
with: -10^6 CFU/ml
- 10^8 CFU/ml
- 10^10 CFU/ml
- placebo (dissolvens = 10% glycerol)
Insulin tolerance test (insulin
sensitivity)
E. Hallii normalises insulin sensitivity (ITT) compared to placebo
Udayappan/Manneras, submitted
Gutmicrobiota analyses:
Ehallii treatment significantly increases
Ehallii in cecum
Mean ±SEM
Studyprotocol II
• Db/db male mice (8 weeks old), n=7-9 per group
(Gothenborg university, Sweden)
• Daily gavage (100ul/mouse) with alive or heat
inactivated E. Hallii 10x6CFU/ (stored in 10%
glycerol at -80C), gavage within 1 hour after
thawing for 4 weeks followed by:
• -48h in Metabolic cages (Somedic cages)
- hyperinsulinemic normoglycemic clamp
Effect E. Halli on food intake
and bodyweight
Udayappan/Manneras, submitted
10^8 E.hallii treatment significantly
increases E.halli in cecum
Eubacterium hallii et rel.
Relative abundance (%)
0.012
P<0.05
0.01
0.008
0.006
0.004
0.002
0
10^8
Placebo
Udayappan/Manneras, submitted
Active E. Hallii treatment significantly increases verruco bacteria,
cyanobacteria, deferribacteres and fusobacteria
100
80
70
60
50
40
30
20
10
0
Bacteroidetes
0.04
Relative abundance (%)
Relative abundance (%)
90
Firmicutes
*
0.035
0.03
Cyanobacteria: p=0.015(2-tailed),
.007 (1-tailed)
0.025
Deferribacteres: p=0.028 (2tailed), .0014 (1-tailed)
*
0.02
Fusobacteria: p=0.028 (2-tailed),
.0014 (1-tailed)
0.015
0.01
0.005
Verrucomicrobia: p=0.028 (2tailed), .0014 (1-tailed)
*
Red: E hallii 10x8CUF
0
Cyanobacteria Deferribacteres Fibrobacteres
Fusobacteria
TM7
Green: plaecbo
* Significant p<0.05
Mann Whitney U
Resting energy increased upon E. hallii
Udayappan/Manneras, submitted
Mean ±SEM
Peripheral insulin sensitivity
Insulin sensitivity (clamp) increased upon E. hallii
*
Udayappan/Manneras, submitted
E. hallii increases fecal secondary bile
acids
Mean ±SEM
Ehallii treatment: effect on fecal SCFA
P<0.05
Mean ±SEM
E.Halli as novel therapeutic in
in insulin resistance?
• Has beneficial effects on insulin
sensitivity
•
• Potential mechanism via
bileacids and brown fat
(Increased Energy Expenditure)
• Human intervention phase 1
dosefinding trial with E.hallii
curently ongoing at AMC
Eubacterium hallii
De Vos WM and Nieuwdorp M. Nature 2013; 498(7452):48-9
Take home message
• Decreased butyrate producing bacteria in obesity
associated with malign obesity and insulin resistance
• FMT incudes changes in (small) iIntestinal microbiota and
affects insulin resistance (but it is not a panancea)
• Using FMT as a working model can derive novel probiotics on
top of current treatment for insulin resistance
Acknowledgments
Willem de Vos
WUR/Helsinki
Fredrik backhed
Gothenborg
Ruud Kootte MD
Fleur van der Valk, MD
Pim Gilijamse, MD
Loek Smits, MD
Sophie Bernelot Moens, MD
Mara Sandberg, MD
Kristien Bouter, MSc
Pieter de Groot, MD
Annick Hartstra MD
Shanti Udayappan
Anne Vrieze
MD PhD
AMC
Han Levels PhD
Geesje Dallinga, PhD
Alinda Schimmel, Bsc
Hans Romijn
AMC
Louise Manneras
Erik Stroes
AMC
Mireille Serlie MD PhD
AMC