role of the gut microbiota in over- and undernutrition - nugo · · 2016-09-19role of the gut...
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NuGO week 2016
Role of the gut microbiota in over-and undernutrition
Laure Bindels, PhDCopenhagenSeptember 7, 2016
1. Gut microbiota as a nutritional target
2. Metabolic disorders associated with obesity
3. Metabolic disorders associated with cancer
4. Gut microbiota in alcohol-dependent patients
Outline
40 000 000 000 000 microbes
30 000 000 000 000 human cells
The gut microbiota
for a 'reference man' (70 kilograms, 20–30 years old and 1.7 meters tall)Numbers from Sender et al, preprint on bioRxiv, 2016. Neish, Gastroenterology 2009
Adapted from Bindels & Delzenne, Int J Biochem Cell Biol 2013
Experimental tools to
study our microbial
partners
Bacteriocins
Antibiotics
Probiotics
i.e. lactobacilli
Prebiotics
i.e. inulin-type fructans
Gut microbiota
FMT
Future research on prebiotics
Bindels et al, Nat Rev Gastroenterol Hepatol 2015
Figure 1 Current and proposed definitions for the concept of prebiotics
Resistant starches
Resistant starches (RS) include all starch and starch degradation products not absorbed in the small intestine of healthy individuals.
Asp, Trends Food Sci Technol, 1992; Birt et al., Adv Nutr 2013; Martinez et al, Plos ONE 2010.
1. Gut microbiota as a nutritional target
2. Metabolic disorders associated with obesity
3. Metabolic disorders associated with cancer
4. Gut microbiota in alcohol-dependent patients
Outline
Cancer cachexia
• Up to 80% of cancer patients, depending of the tumor site
• Reduces quality and length of life
• May be a cause of cancer therapy discontinuation
• No valid treatment
Fearon et al., Cell Metab 2012; Fearon et al., Nat Rev Oncol 2013; Argiles et al, Nat Rev Cancer 2014.
Giacometti, Walking man
Community-wide approach to characterize the gut microbiota in two mouse models of cancer cachexia
BaF3 cells
with Bcr-Abl
A microbial signature in cancer cachexia
Bindels et al, The ISME J 2016
C26 BaF
A microbial signature in cancer cachexia
Bindels et al, The ISME J 2016
BaF C26
↑ Enterobacteriaceae↑ Parabacteroides goldsteinii
↓ Lactobacilli
16S rRNA genes from the caecal microbiota analysed by Illumina MiSeq.Logarythmic LDA score.
With Inès Martinez and Jens Walter
… independent of the food intake
Bindels et al, The ISME J 2016
0 2 4 6 8 10 12 140
25
50
75
100
125
CT (BaF)
BaF
CT (DR)
DR
*
#
#
Days after BAF injection
Daily f
oo
d in
take
(% in
itia
l fo
od
in
take)
CT(BaF) BaF CT(DR) DR7
8
9
10
11
Para
bacte
roid
es g
old
ste
inii
AS
F519 (
log
10 [
AU
/g])
CT(BaF) BaF CT(DR) DR
8
9
10
******
***
*
Lacto
bacillu
ssp
p.
(lo
g10
[cell
s/g
])
CT(BaF) BaF CT(DR) DR6
7
8
9
10
11
*****
***
*
En
tero
bacte
riaceae
(lo
g10 [
cell
s/g
])
Acetate
Propionate
Butyrate
Acetate
Propionate
Butyrate
Acetate
Propionate
Butyrate
ITF
CTBaF3BaF3-ITF0.0
0.5
1.0
§
ND
Bcr-Abl
mRNA levels
(relative exp
ression)
0 24 48 720
5.010 6
1.010 7 control
propionate 2mM
**N
um
be
r o
f
inta
ct
Ba
F3
/we
ll
Propionate
CTBaF3BaF3-ITF0
20
40
60§
µM
Bindels et al, Br J Cancer 2012; Bindels*, Neyrinck* et al, Plos ONE 2015.
BaF
Selected synbiotic approach
L. reuteri 100-23
D0 D1 D13
†Bcr-Abl-expressing BaF3
cellsITF
Bindels et al, The ISME J 2016 With Bruno Pot & Corinne Grangette
Bindels et al, The ISME J 2016
16S rRNA genes from the caecal microbiota analysed by Illumina MiSeq. LEfSe cladogram.
BaF
Benefits of the synbiotic approach
Bindels et al, The ISME J 2016
BaF Bcr-Abl
CT BaF BaF-LrI0.0
0.5
1.0
ND
#
mR
NA
levels
(rela
tive e
xp
ressio
n)
CT BaF BaF-LrI CT BaF BaF-LrI0.00
0.05
0.10
0.15
0.20
0.35
0.40
0.45
0.50
*
tibialis gastrocnemius
*#*
*$
Org
an
weig
ht
(% b
od
y w
eig
ht)
Survival
0 5 10 15 200.0
0.2
0.4
0.6
0.8
1.0
1.2 BaF
BaF-LrI
p = 0.007median survival + 2 days
Days after BaF injection
Fra
cti
on
su
rviv
al
Morbidity score
BaF BaF-LrI0
1
2
3
4
5
# #
Sco
re
Hypothetical role of the gut barrier
Bindels et al, The ISME J 2016
↘ Gut permeability ↗
↘ Immune system ↗
↘ Antimicrobial peptides ↗
BaF
↘ Decreased in leukemic mice↗ Increased by synbiotics
Gut permeability
0.0
0.5
1.0
1.5
**
*
# ##
occludin ZO-1 Muc2 proglucagon
CT
BaF
BaF-LrI
mR
NA
levels
(rela
tive e
xp
ressio
n)
Paneth cell differentiation and antimicrobials
0.0
0.5
1.0
1.5
* *
#
TCF4 Lysozyme -defensins Reg3 Pla2g2
**#
*
#
mR
NA
levels
(rela
tive e
xp
ressio
n)
0.0
0.5
1.0
1.5
2.0
CD3 Tbet IL-17A Foxp3
#
*
#*#
#
*
lymphocytes
IL-10 Ebi3
*
#
*
$mR
NA
levels
(rela
tive e
xp
ressio
n)
Current working model
Cancer cachexia
Prebiotics
Probiotics
Gut barrierfunction
Propionate
New metabolites ?
?
1. Gut microbiota as a nutritional target
2. Metabolic disorders associated with obesity
3. Metabolic disorders associated with cancer
4. Gut microbiota in alcohol-dependent patients
Outline
A role for the gut permeability?
Leclercq et al, Brain Behav Immun 2012; Leclercq et al, Biol Psychiatry 2014.
Altered fecal metabolite profil
Leclercq et al, PNAS 2014
Analysis of Volatile organic compounds by gas-chromatography-mass spectrometry (K. Verbeke, Kuleuven B)
Bi-plot analysis reveals ADT1 HP- versus LP are differentiated (14 metabolites)
Conclusions
• Importance of the prebiotic concept.
• Microbiota-dependent and independent effects of functional foods: strategies to demonstrate causality exist.
• Underexplored areas could benefit from targeted prebiotic or synbiotic approaches.
HatemKittana
UNL GnotobioticMouse Facility
Robert Schmaltz Brandon White
Carlos Gomes Neto
Rafael Segura Munoz
Prof. Jens Walter
Liz CodyDr. Inés Martínez
Prof. Amanda Ramer-Tait
Maria Isabel QuinteroJunyi YangMaria Ximena Maldonado-Gomez
FSR Fellowship
UCL (BE)
Prof G. Muccioli
Prof P. Buc Calderon
Prof J.P. Thissen
Prof O. Feron
Prof P. Sonveaux
Dr P. Porporato
Dr J. Verrax
Dr R. Beck
Katholieke Universiteit
Leuven (BE)
Dr H. Schoemans
Prof J. Maertens
University of Alberta
(CA)
Prof J. Walter
Dr I. Martinez
UCL (BE)
Prof E. Hermans
Dr B. Koener
Dr O. Schakman
Prof J. Mahillon
Prof J.B. Demoulin
Dr V. Havelange
Dr Fl. Bindels
Rowett Institute, Aberdeen (UK)
Dr K.P. Scott and J.C. Martin
University of Reading (UK)
Prof S. P. Claus and C. Leroy
Institut Pasteur, Lille (FR)
Prof B. Pot and Dr C. Grangette
Prof N. Delzenne
ULG (BE)
Dr B. Taminiau
Prof G. Daube
E. François
Prof C. Blecker
Prof A. Richel
Prof P. CaniDr A. Neyrinck
Post-doc position in July 2017 : [email protected]