The Effect of Different Nutrients On Gut Microbiota - Judith Aron Wisnewsky

«The effect of different nutrients on gut
microbiota»
Dr Judith Aron-Wisnewsky
MD-PHD Nutrition
ICAN Institute Cardiométabolisme et Nutrition

Inserm U872 NutriOmique
University Pierre & Marie Curie/Paris 6
Pitié-Salpêtrière, hospital Paris
3rd october 2017

Presentation flow-chart
• I- Microbiota: introduction
• Physiological functions
• Food habits and microbiota composition
• II- microbiota obesity, cardiometabolism and nutrients

• Mice data : changes in food intake
changes in outcomes…
• Human data: diet intervention
changes microbiota composition
• III- modulation of gut microbiota with different nutrient

• Acute changes
• Fat
• Protein
• IV- modulation using prebiotcs

I-1 initial Composition
Birth Diversification
Vaginal vs. C section: Breast feeding Antibiotics (17-26 S)
↗ E.Coli, ↘ des E.Coli (1st month) (1st month)
↗Bifidobactéries ↗ Bifidobactéries ↘ Bifidobactéries ↗ Bacteroidetes
and firmicutes
↗ Bacteroides fragilis
Rautava et al Nature gastro reviews 2012 Ajslev et al; IJO 2011; Penders et al; Pediatrics 2006;
Yatsunenko et al; Nature 2012; Fouhy Gut microbes 2012
I-1 Gut microbiota
- 300–500 different
species inhabits the
digestive tract
- >1014 microorganismes,
mostly unknown
10M de
genes
Q-PCR
Specific known bacteria
Pyrosequencing
< 30 % culture Quantitative and large
identification
Metagenonomic Aron-wisnewsky et al; Nature reviews gastro 2012;
Fraher et al; Nature reviews gastro 2012Qin et al;
Other Quantitative, large Nature 2010; Qin et al Nature 2012, Nielsen et al
technologies identification and Nature techno 2014; Sender et al plos 2016
fonctionnality
I-1 Gut microbiota physiologic functions
Vitamin synthesis
Biliary acid
production
…..
Immunity
Drug metabolism
Fouhy Gut microbes 2012; Prakash et al; Journal of Biomedicine and BiotechnologyNature 2011
I-1 Gut microbiota physiologic functions
Digestion Vitamin synthesis
Biliary acid
production
…..
Immunity
Metabolites
Host Metabolites
Drug metabolism
Fouhy Gut microbes 2012; Prakash et al; Journal of Biomedicine and BiotechnologyNature 2011
I-1 Gut microbiota: characteristics
7 phylum
Firmicutes
Bacteroidetes
Proteobacteria
Fusobacteria
Verrucomicrobia
Cyanobacteria
Actinobacteria
Decreased bacteroidetes in obesity

and increased Firmicutes
Ley et al Nature 2006, ley et al PNAS 2005

I-1 Gut microbiota: characteristics
LGC
↗ Pro-inflammatory
• totalDiversity
adiposity matters=
• insulin resistance
Gene richness is
• Dyslipidemia
•
decreased with
inflammation (systemic and WAT)
↘ Anti-inflammatory
obesity and
metabolic diseases
METAHIT Micro-Obese
292 subjects 49 subjects
LGC (23%) HGC (77%) LGC (40%) HGC (60%)
Qin et al; Nature 2010; Qin et al Nature 2012, Nielsen et al Nature techno 2014; Le chatelier et al Nature 2013; Cotillard et al
Nature 2013
I-1 Relations between “Poor” Microbiota and Diet
7 days report “unweighed food diaries” Micro-Obese
49 subjects
Overweight and obese
« Healthy »
3 Clusters
A baseline healthier dietary
26 food groups
35 nutriments pattern was associated with
higher bacterial gene richness,
which might partly account for the
better phenotype observed in
HGC subjects.
« Healthy »
Kong et al, Plos One 2014



• Acute changes
• Fat
• Protein

I-2 food intake, microbiota ecosystem
Digestion
Composition difference
according to age
Function Difference
according to age
Metabolites
(indirect marker of food intake)
Baby: increase in functions

associated with de novo folates synthesis
Adults: Increase in functions liked
to diet related folate metabolisation
Baby: in gene involved in simple sugar

dégradation (lactose galactose)
Children : in genes involved in polysaccharides
Degradations and vitamin production
De Fillipo et al PNAS 2010; Yatsunenko et al; Nature 2012;

I-2 food intake, microbiota ecosystem
Population study
3948 individuals séquenced with
metagénomic
Animal fat carboHydrates
African children: European children :

Fiber content 10.0 g/d Fiber content 5.6 g/d (0.67%) à
(2.26%) à 14.2 g/d (3.19%) 8.4 g/d (0.9%)
↘ SCFA
Wu et al science 2011; Arunmangan et al; Nature 2011 Qin et al Nature 2012; Falony et al science 2016; De
Fillipo et al PNAS 2010


• Acute changes
• Fat
• Protein

II-1 Microbiota obesity metabolism
Conventionalized
Germ Free
Microbiota induce
increased energy storage
Backhed F. et al., PNAS 2004; Backhed F. et al. PNAS 2007; Turnbaugh P.J. et al. Nature 2006;
Aron-wisnewsky, Clement Nature review nephrology 2016
II-1 Microbiota obesity metabolism
Conventionalized
Germ Free
Microbiota induce
increased energy storage
Microbiota transfer
replicate weight gain
and metabolic
comorbidities in germ
free mice
Backhed F. et al., PNAS 2004; Backhed F. et al. PNAS 2007; Turnbaugh P.J. et al. Nature 2006;
Aron-wisnewsky, Clement Nature review nephrology 2016
II-2 Microbiota, weight gain
Yet the effects depend

on food intake
Walker et al, Science 2013; Ridaura et al, Science 2013

II-2 Microbiota, weight gain, food intake
Coprophagie
After cohousing,
microbiota
ressemble that
of lean twins
Pauvre en graisses saturées et riche en fibres
Walker et al, Science 2013; Ridaura et al, Science 2013

Coprophagie
After cohousing,
microbiota
ressemble that
of the obese
twins
High fiber low saturated fat High saturated fat low fiber
Coprophagie
Change in food
composition modulates
outcomes and
microbiota
composition


• Acute changes
• Fat
• Protein

II-3 modulation of Gut microbiota
Increase in
Bacteroidetes
correlates with body
weight loss
inependantly of calorie
intake reduction Decreased bacteroidetes in obesity
and increased Firmicutes
Low carb
Low fat
Increased bacteroidetes and decreased in

Firmicutes with weight loss
Ley et al Nature 2006, ley et al PNAS 2005
II. 3 Gene richness after a diet intervention
LGC subjects HGC subjects
Physical
activity
Kong et al AJCN 2013; Cotillard et al, Nature 2013

Physical
activity
HGC subjects
LGC subjects
Kong et al AJCN 2013; Cotillard et al, Nature 2013

Same modulation in
food intake does not
induce the same Physical
activity
metabolic effects:
importance of gut
microbiota
Cotillard et al nature medicine 2013



• Acute changes
• Fat
• Protein

III-1 Acute changes in food intake, microbiota
Fiber
Fat
Protein
David et al, nature 2014

Acute changes
Changes in gut Animal based diet
in food intake
microbiota is able to increase
(24h)
β-diversity shortly
after introduction
Fiber
Fat
Protein

Acute changes
Changes in gut Change in food
in food intake
microbiota composition
(24h)
modulates microbiota,
its gene expression, its
metabolites as well as
Fiber host metabolites
Fat
Protein

Wash out
Acute changes
Changes in gut period: come
in food intake
microbiota back at steady
(24h)
state (72h)
Fiber
Fat
Protein



• Acute changes
• Fat
• Protein

III-2 Fat intake, microbiota, outcomes
Isocaloric diet
Differential
weight gain and
metabolism
outcomes (IR)
Severe
modifications in
gut microbiota
composition and
diversity
cesar et al cell metab 2015

Isocaloric diet
WT mice
compared to
Myd88 KO
(TLR)
These differential
outcomes orginate
from TLR
activation in the
WAT
KO mice for TLR activation are protected against weight gain and
metabolic alterations

Isocaloric diet
Differential
weight gain
Ceacal microbiota
transfert to ATB
treated mice
Protection against
Altough fed the adipose tissue
same diet, infammation
microbiota
composition
remain
significantly
different
Singh et al, J transl med 2017; cesar et al cell metab 2015



• Acute changes
• Fat
• Protein

III-3 protein intake, microbiota, outcomes
Protein intake
positevly
correlates with gut
microbiota
diversity
Reduced protein
intake is asociated
with reduced fecal
SCFA
African children: European children:

Fiber content: 10.0 g/d Fiber content: 5.6 g/d (0.67%) à
(2.26%) à 14.2 g/d (3.19%) 8.4 g/d (0.9%)
↘ SCFA
Philippo et al PNAS 2010; clarke et al gut 2014

III-3 phosphatidyl choline, microbiota
Omnivores vs
veggies have
increased level of
circulating TMAO
as well as urinary
Wilson Tan et al NEJM 2013; Wang et al, Nature 2011; Aron-wisnewsky Nature review nephrol 2016; de philippis
et al gut 2016
III-3 phosphatidyl choline, microbiota
Wilson Tan et al NEJM 2013; Wang et al, Nature 2011; Aron-wisnewsky Nature review nephrol 2016; de philippis
et al gut 2016
III-3 changes in food intake modifies microbiota
Singh et al, J transl med 2017



• Acute changes
• Fat
• Protein

IV-1 prebiotics microbiota metabolic
outcomes
WT
Obese + placebo Prebiotics imrove metabolic phenotype
(↘ weight , ↘ insulin resistance, ↘ inflammation,
Obese + prebiotic ↘ intestinal permeability)
Akkermanisia muciniphila
CT
CT + Akker
HF
HF + Akker
Oral gavage with Akkermanisia muciniphila

Replicates beneficial outcomes observed with prebiotics
(↘ weight , ↘ insulin resistance, ↘ inflammation,
↘ intestinal permeability)
Cani et al, Gut 2009; Everard Diabetes 2011; Everard ISME 2011
IV-1 Akkermansia
I Introduction sur le: probiotic;
microbioteAmuc metabiotic
CT Improves intestinal barier
HFD + akker Pasterized akk protect

HFD + amuc (prot) from weight gain and IR
Amuc protein that binds to TLR2
reproduces the same effects
Currently tested in humans

Good tolerance
no secondary effects
No results yet on
metabolic outcomes
Plovier et al Nature medicine 2016

III-1prebiotics:
IV-1 acute changes
non in
digestible
food intake,
fermentable
microbiota
carbohydrates
Delzenne et al Microbial cells factory 2011

IV-1 prebiotics:
I Introduction surnon digestible fermentable carbohydrates
le microbiote
Induce microbiota modifications
Controls
* Decrease in post-OGTT glycemia
Controls + 16g
prebiotics
Modifications correlates with
3 months improvement in
inflammation and fat masse
Dewulf et al Gut 2012

IV.2- polyphenols,
I Introduction sur leAkkermansia,
microbiote metabolic alterations
Db/Db (DM) Insulin-resistance ↘ inflammation

Db/Db + phlorizin Protect against
(DMT)
Insulin-resistance
Control (CC)
Protect from
weight gain
Mei et al; J Agric Food Chem. 2016

IV.2- polyphenols, Akkermansia, metabolic alterations
Db/Db (DM) Insulin-resistance ↘ inflammation

Db/Db + phlorizin Protect against Increase
(DMT)
Insulin-resistance Akkermansia
Control (CC)
Protect from
weight gain
T0 T cinétique T cinétique
Mei et al; J Agric Food Chem. 2016

Conclusions
Annimal data demonstrate Interventions impacts on

links between microbiota gut microbiota
and weight gain composition and
metabolic outcomes
- Diet
Human data underlign the - Differential nutrients
importance of diversity in - Prebiotics
links with favourable
metabolic outcomes
Interventions modify gut

microbiota signatures. But
for how long ?
Metabolic outcomes depend

on food intake New therapeutic area ?
INRA - MICALIS
Sean KENNEDY
Nicolas PONS
Jean-Pierre FURET
Emmanuelle LE CHATELIER
Mathieu ALMEIDA
Benoit QUINQUIS
Florence LEVENEZ
Nathalie GALLERON
Jean-Michel BATTO
Salwa Pierre RENAULT
Christine Joel DORE
Poitou Rizkalla
Stanislav Dusko EHRLICH
Pr Karine Clement
Contributors :Oluf Pedersen ‘s team
Coll. Patrice Cani (Belgium)
Metacardis community www.metacardis.eu

Jean- Aurelie Carlota
Daniel Cotillard Dao
Zucker
Edi Prifti
IV-1 prebiotics:
le microbiote
Induce mild microbiota modifications
Decrease in bacteroidetes
placebo
↗ fat oxydation in polyphenols patients
epigallocatechin-3- ↗ skeletal muscle mitochondrial oxidative capacity
gallate and resveratrol
Baseline bacteroidetes levels
12 weeks impacts on
post prandial fat oxydation in men
Small effects on gut microbiota

Differential effects regarding gender
Not consistent with previous mice
studies
No increase in Akkermansia
Most et al European Journal of Clinical Nutrition 2017

IV-1 prebiotics:
le microbiote
Induce microbiota modifications
Controls
No change in IR (clamps)
Controls + 15g GOS
No changes in BMI,
12 weeks Convincing
SCFA (syst data in mice
and fecal) , FFA
but smaller or even none
effects in humans
Canfora et al Gastroenterology 2017

III-1prebiotics:
IV-1 acute changes
non in
digestible
food intake,
fermentable
microbiota
carbohydrates
IV- Microbiota and cardiometabolic diseases
Hazen team; Aron-wisnewsky, clement Nature review nephrology 2016

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«The effect of different nutrients on gut

ICAN Institute Cardiométabolisme et Nutrition

3rd october 2017

• II- microbiota obesity, cardiometabolism and nutrients

• III- modulation of gut microbiota with different nutrient

• IV- modulation using prebiotcs

Digestion Vitamin synthesis

Decreased bacteroidetes in obesity

Ley et al Nature 2006, ley et al PNAS 2005

LGC (23%) HGC (77%) LGC (40%) HGC (60%)

Kong et al, Plos One 2014

• II- microbiota obesity, cardiometabolism and nutrients

• III- modulation of gut microbiota with different nutrient

• IV- modulation using prebiotcs

Baby: increase in functions

Baby: in gene involved in simple sugar

De Fillipo et al PNAS 2010; Yatsunenko et al; Nature 2012;

Animal fat carboHydrates

African children: European children :

• II- microbiota obesity, cardiometabolism and nutrients

• III- modulation of gut microbiota with different nutrient

• IV- modulation using prebiotcs

Yet the effects depend

Walker et al, Science 2013; Ridaura et al, Science 2013

Pauvre en graisses saturées et riche en fibres

Walker et al, Science 2013; Ridaura et al, Science 2013

• II- microbiota obesity, cardiometabolism and nutrients

• III- modulation of gut microbiota with different nutrient

• IV- modulation using prebiotcs

Increased bacteroidetes and decreased in

LGC subjects HGC subjects

Kong et al AJCN 2013; Cotillard et al, Nature 2013

LGC subjects HGC subjects

Kong et al AJCN 2013; Cotillard et al, Nature 2013

LGC subjects HGC subjects

Cotillard et al nature medicine 2013

• II- microbiota obesity, cardiometabolism and nutrients

• III- modulation of gut microbiota with different nutrient

• IV- modulation using prebiotcs

David et al, nature 2014

David et al, nature 2014

David et al, nature 2014

David et al, nature 2014

• II- microbiota obesity, cardiometabolism and nutrients

• III- modulation of gut microbiota with different nutrient

• IV- modulation using prebiotcs

cesar et al cell metab 2015

cesar et al cell metab 2015

Singh et al, J transl med 2017; cesar et al cell metab 2015

• II- microbiota obesity, cardiometabolism and nutrients

• III- modulation of gut microbiota with different nutrient

• IV- modulation using prebiotcs

African children: European children:

Philippo et al PNAS 2010; clarke et al gut 2014

Singh et al, J transl med 2017

• II- microbiota obesity, cardiometabolism and nutrients

• III- modulation of gut microbiota with different nutrient

• IV- modulation using prebiotcs

Oral gavage with Akkermanisia muciniphila

CT Improves intestinal barier

HFD + akker Pasterized akk protect

Currently tested in humans

Plovier et al Nature medicine 2016