NuGO week 2016

Role of the gut microbiota in over-and undernutrition

Laure Bindels, PhDCopenhagenSeptember 7, 2016

Adapted from Delzenne et al., Nat Rev Endocrinol 2011

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

Gut microbiota-host crosstalk

Delzenne et al., Nat Rev Endocrinol 2011

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

Prebiotics

Beneficial physiological effects

Gibson & Roberfroid, J Nutr 1995

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

Bindels & Thissen, Clin Nutr Exp 2015

Cancer cachexia

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 & Thissen, Clin Nutr Exp 2015

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.

A role for the gut permeability ?

Leclercq et al, PNAS 2014

Dysbiosis

Leclercq et al, PNAS 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 : laure.bindels@uclouvain.be