and undernutrition Laure Bindels, PhD Copenhagen September 7, 2016 - - PowerPoint PPT Presentation

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and undernutrition Laure Bindels, PhD Copenhagen September 7, 2016 - - PowerPoint PPT Presentation

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NuGO week 2016 Role of the gut microbiota in over- and undernutrition Laure Bindels, PhD Copenhagen September 7, 2016 Adapted from Delzenne et al ., Nat Rev Endocrinol 2011 Outline 1. Gut microbiota as a nutritional target 2. Metabolic

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NuGO week 2016

Role of the gut microbiota in over- and undernutrition

Laure Bindels, PhD Copenhagen September 7, 2016

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Adapted from Delzenne et al., Nat Rev Endocrinol 2011

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  • 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

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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

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Gut microbiota-host crosstalk

Delzenne et al., Nat Rev Endocrinol 2011

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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

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Prebiotics Beneficial physiological effects

Gibson & Roberfroid, J Nutr 1995

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Future research on prebiotics

Bindels et al, Nat Rev Gastroenterol Hepatol 2015 Figure 1 Current and proposed definitions for the concept of prebiotics

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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.

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  • 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

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Bindels & Thissen, Clin Nutr Exp 2015

Cancer cachexia

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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

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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

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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

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… independent of the food intake

Bindels et al, The ISME J 2016

2 4 6 8 10 12 14 25 50 75 100 125

CT (BaF) BaF CT (DR) DR

*

# # Days after BAF injection

Daily food intake (% initial food intake)

CT(BaF) BaF CT(DR) DR 7 8 9 10 11

Parabacteroides goldsteinii ASF519 (log10 [AU/g])

CT(BaF) BaF CT(DR) DR 8 9 10

*** *** *** *

Lactobacillus spp. (log10 [cells/g])

CT(BaF) BaF CT(DR) DR 6 7 8 9 10 11

*** ** *** *

Enterobacteriaceae (log10 [cells/g])

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Acetate Propionate Butyrate Acetate Propionate Butyrate Acetate Propionate Butyrate

ITF

CT BaF3 aF3-IT

. . 5 1 .

§ N D

B c r

  • A

b l

m R N A le v e ls (re la tiv e e x p re s s io n )

24 48 72 5.010 6 1.010 7

control propionate 2mM

* *

Number of intact BaF3/w ell

P r

  • p

i

  • n

a t e

CT BaF F3-

2 4 6

§ µ M

Bindels et al, Br J Cancer 2012; Bindels*, Neyrinck* et al, Plos ONE 2015.

BaF

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Selected synbiotic approach

  • L. reuteri 100-23

D0 D1 D13

†

Bcr-Abl-expressing BaF3 cells

ITF

Bindels et al, The ISME J 2016

With Bruno Pot & Corinne Grangette

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Bindels et al, The ISME J 2016 16S rRNA genes from the caecal microbiota analysed by Illumina MiSeq. LEfSe cladogram.

BaF

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Benefits of the synbiotic approach

Bindels et al, The ISME J 2016

BaF

Bcr-Abl

CT BaF BaF-LrI 0.0 0.5 1.0

ND #

mRNA levels (relative expression)

CT BaF BaF-LrI CT BaF BaF-LrI 0.00 0.05 0.10 0.15 0.20 0.35 0.40 0.45 0.50

*

tibialis gastrocnemius

*# * *$

Organ weight (% body weight)

Survival

5 10 15 20 0.0 0.2 0.4 0.6 0.8 1.0 1.2

BaF BaF-LrI p = 0.007 median survival + 2 days Days after BaF injection Fraction survival

Morbidity score

BaF BaF-LrI 1 2 3 4 5

# #

Score

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Hypothetical role of the gut barrier

Bindels & Thissen, Clin Nutr Exp 2015

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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

* * *

# # #

  • ccludin

ZO-1 Muc2 proglucagon

CT BaF BaF-LrI mRNA levels (relative expression)

Paneth cell differentiation and antimicrobials

0.0 0.5 1.0 1.5

* *

# TCF4 Lysozyme -defensins Reg3 Pla2g2

* *# *

#

mRNA levels (relative expression)

0.0 0.5 1.0 1.5 2.0

CD3 Tbet IL-17A Foxp3 #

*

#

*#

#

*

lymphocytes IL-10 Ebi3

*

#

*

$

mRNA levels (relative expression)

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Current working model

Cancer cachexia Prebiotics Probiotics Gut barrier function Propionate New metabolites ? ?

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  • 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

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A role for the gut permeability?

Leclercq et al, Brain Behav Immun 2012; Leclercq et al, Biol Psychiatry 2014.

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A role for the gut permeability ?

Leclercq et al, PNAS 2014

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Dysbiosis

Leclercq et al, PNAS 2014

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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)

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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.

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Hatem Kittana UNL Gnotobiotic Mouse Facility Robert Schmaltz Brandon White Carlos Gomes Neto Rafael Segura Munoz

  • Prof. Jens Walter

Liz Cody

  • Dr. Inés Martínez
  • Prof. Amanda

Ramer-Tait

Maria Isabel Quintero Junyi Yang Maria Ximena Maldonado-Gomez FSR Fellowship

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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. Cani Dr A. Neyrinck Post-doc position in July 2017 : laure.bindels@uclouvain.be