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NuGO week 2016
Role of the gut microbiota in overand undernutrition
Laure Bindels, PhD
Copenhagen
September 7, 2016
Adapted from Delzenne et al., Nat Rev Endocrinol 2011
Outline
1.
2.
3.
4.
Gut microbiota as a nutritional target
Metabolic disorders associated with obesity
Metabolic disorders associated with cancer
Gut microbiota in alcohol-dependent
patients
The gut microbiota
40 000 000 000 000 microbes
30 000 000 000 000 human cells
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
Gut microbiota-host crosstalk
Delzenne et al., Nat Rev Endocrinol 2011
Prebiotics
i.e. inulin-type fructans
Probiotics
i.e. lactobacilli
Bacteriocins
Antibiotics
FMT
Gut microbiota
Experimental tools to
study our microbial
partners
Adapted from Bindels & Delzenne, Int J Biochem Cell Biol 2013
Prebiotics
Beneficial
physiological effects
Gibson & Roberfroid, J Nutr 1995
Future research on prebiotics
Figure 1 Current and proposed definitions for the concept of prebiotics
Bindels et al, Nat Rev Gastroenterol Hepatol 2015
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.
Outline
1.
2.
3.
4.
Gut microbiota as a nutritional target
Metabolic disorders associated with obesity
Metabolic disorders associated with cancer
Gut microbiota in alcohol-dependent
patients
Cancer cachexia
Bindels & Thissen, Clin Nutr Exp 2015
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
Giacometti, Walking man
Fearon et al., Cell Metab 2012; Fearon et al., Nat Rev Oncol 2013; Argiles et al, Nat Rev Cancer 2014.
A microbial signature in cancer cachexia
Community-wide approach to characterize the gut
microbiota in two mouse models of cancer cachexia
C26
BaF
BaF3 cells
with Bcr-Abl
Bindels et al, The ISME J 2016
A microbial signature in cancer cachexia
BaF
16S rRNA genes from the caecal microbiota analysed by Illumina MiSeq.
Logarythmic LDA score.
↑ Enterobacteriaceae
↑ Parabacteroides goldsteinii
↓ Lactobacilli
With Inès Martinez and Jens Walter
Bindels et al, The ISME J 2016
C26
… independent of the food intake
Enterobacteriaceae
(log10 [cells/g])
Daily food intake
(% initial food intake)
*
11
125
100
75
#
CT (BaF)
BaF
CT (DR)
DR
50
25
#
*
0
10
***
***
**
9
8
7
6
0
2
4
6
8
10
12
14
CT(BaF)
BaF
CT(DR)
DR
CT(BaF)
BaF
CT(DR)
DR
Days after BAF injection
Lactobacillus spp.
(log10 [cells/g])
***
***
***
Parabacteroides goldsteinii
ASF519 (log10 [AU/g])
*
10
9
8
CT(BaF)
BaF
CT(DR)
Bindels et al, The ISME J 2016
DR
11
10
9
8
7
1
.0
5.0 10 6
§
*
*
0
0
24
48
Acetate
72
mRNAlevels
(relativeexpression)
Number of
intact BaF3/w ell
BaF
B
c
r-A
b
l
control
propionate 2mM
1.0 10 7
Propionate
Butyrate
0
.5
0
.0
N
D
CT
BBaF3-ITF
aF3
ITF
Acetate
P
r
o
p
i
o
n
a
t
e Propionate
§Butyrate
6
0
µM
4
0
2
0
Acetate
Propionate
Butyrate
0
BaF3-ITF
BaF3
CT
Bindels et al, Br J Cancer 2012; Bindels*, Neyrinck* et al, Plos ONE 2015.
Selected synbiotic approach
D0
D1
D13
L. reuteri 100-23
Bcr-Abl-expressing BaF3
cells
Bindels et al, The ISME J 2016
†
ITF
With Bruno Pot & Corinne Grangette
BaF
16S rRNA genes from the caecal microbiota analysed by Illumina MiSeq.
LEfSe cladogram.
Bindels et al, The ISME J 2016
Benefits of the synbiotic approach
Bcr-Abl
BaF
0.45
1.0
#
0.5
Organ weight
(% body weight)
mRNA levels
(relative expression)
0.50
*
0.40
0.35
0.20
*
0.15
*$
0.10
0.05
ND
0.0
0.00
CT
CT
BaF BaF-LrI
BaF BaF-LrI CT
tibialis
Morbidity score
5
1.2
4
1.0
3
##
2
1
0
BaF BaF-LrI
gastrocnemius
Survival
Fraction survival
Score
*#
BaF
BaF-LrI
p = 0.007
median survival + 2 days
0.8
0.6
0.4
0.2
0.0
BaF
BaF-LrI
0
5
10
15
Days after BaF injection
Bindels et al, The ISME J 2016
20
Hypothetical role of the gut barrier
Bindels & Thissen, Clin Nutr Exp 2015
Hypothetical role of the gut barrier
Gut permeability
BaF
mRNA levels
(relative expression)
↘ Gut permeability ↗
1.5
#
#
1.0
*
*
CT
BaF
BaF-LrI
#
*
0.5
0.0
occludin
ZO-1
Muc2
proglucagon
Paneth cell differentiation and antimicrobials
↘ Antimicrobial peptides ↗
↘ Immune system ↗
mRNA levels
(relative expression)
1.5
#
#
1.0
*
*#
*
*
0.5
*
0.0
Lysozyme -defensins Reg3
TCF4
Pla2g2
↘ Decreased in leukemic mice
↗ Increased by synbiotics
mRNA levels
(relative expression)
2.0
*#
#
1.5
0.5
*
$
*
*
*
0.0
CD3
Bindels et al, The ISME J 2016
#
#
#
1.0
Tbet
IL-17A
Foxp3
lymphocytes
IL-10
Ebi3
Current working model
Gut barrier
function
Cancer
cachexia
Probiotics
?
Propionate
Prebiotics
New metabolites ?
Outline
1.
2.
3.
4.
Gut microbiota as a nutritional target
Metabolic disorders associated with obesity
Metabolic disorders associated with cancer
Gut microbiota in alcohol-dependent
patients
A role for the gut permeability?
Leclercq et al, Brain Behav Immun 2012; Leclercq et al, Biol Psychiatry 2014.
A role for the gut permeability ?
Leclercq et al, PNAS 2014
Dysbiosis
Leclercq et al, PNAS 2014
Altered fecal metabolite profil
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)
Leclercq et al, PNAS 2014
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.
Carlos
Gomes Neto
Hatem
Kittana
Rafael
Segura Munoz
UNL Gnotobiotic
Mouse Facility
Robert Schmaltz
Brandon White
Prof. Amanda
Ramer-Tait
Liz Cody
Prof. Jens Walter
Dr. Inés Martínez
FSR Fellowship
Maria Isabel Quintero
Junyi Yang
Maria Ximena Maldonado-Gomez
Post-doc position in July 2017 : [email protected]
Prof N. Delzenne
Dr A. Neyrinck
Prof P. Cani
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
UCL (BE)
Prof E. Hermans
Dr B. Koener
Dr O. Schakman
Prof J. Mahillon
Prof J.B. Demoulin
Dr V. Havelange
Dr Fl. Bindels
ULG (BE)
Dr B. Taminiau
Prof G. Daube
E. François
Prof C. Blecker
Prof A. Richel
Katholieke Universiteit
Leuven (BE)
Dr H. Schoemans
Prof J. Maertens
University of Alberta
(CA)
Prof J. Walter
Dr I. Martinez
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