Microbiote et Obésités - Académie Nationale de Pharmacie...Academie de pharmacie 2019 / Clément. Higher baseline A. muciniphila is associated with a healthier metabolic status,

Professeur Karine Clément MD, PhDNutriOmics team

Inserm/ Sorbonne Université Pitié-Salpêtrière, faculté de Medecine,

Académie de Pharmacie, 6 février 2019

Microbiote et Obésités

Nutrition & Obesity; Systemic approaches

Progression of severe obesity?

2

Obesity epidemiology:

2014: 2.3% of the world’s men and 5.0% of women were severely obese

(age-standardized data)

… with an important increase since 1975

Men Women

Data from the French

national survey

ESTEBAN (2015):

3.3% of men, 5.8% of

women

Academie de pharmacie 2019 / Clément

Genome/Epigenome/metagenome 3

Lifestyle

Hypertrophy

Immune/inflammatoryunbalance

Altered angiogenesis

Altered extra-cellular matrix

Perturbedendocrinesecretions

Organelledysfunctions

Brain

Energy balanceEndocrine functionmood

Muscle

Energy balance

Endocrine function

Heart injuries

Epicardial fat

Vascular system

atherosclerosis

Immune systemCytokine production

Liver Injuries

Intestine

Gut microbiota

Obesities : organ & systemic disease

Pancreas Injuries

LEPR Clément K, Nature. 1998 Lahlou N, Clement K, Diabetes. 2000Rolland V, Clément K, Obes Res. Le Beyec J, JCEM. 2013Nizard, Dommergue, Clement NEJM, 2012

Huvenne H, et al, JCEM, 2015

POMC & αMSH Dubern B, el al . Pediatr Res. 2008 Clément K, Dubern B, ET AL.. JCEM 2008.

Kuhnen, Clément et al, NEJM, 2016Clément et al, Nature Médecine 2018

MC4R et MC3RVaisse C, Clement K, Nature Genetics 1998Dubern B, Clément K J Pediatr, 2001Lubrano-Berthelier C, Dubern B, JCEM 2006Dubern B, J Pediatr 2007Roubert P, Dubern B, J Endocrinol 2010Mencarelli, Dubern, Hum Mol Genet 2011Valette M, Poitou C, Plos one 2012Collet, Dubern, Mol Metabl 2017

New therapies (agonists MC4R-Selmelanotide)Deep phenotypes , New genes

Prader-Willi SyndromeLloret-Linares C, IJO 2013Coupaye M, JCEM 2013Lacroix D, JCEM 2015Coupaye M, 2016Burnett LC, JCI 2017

Severe early-onset obesityHyperphagia

+/- endocrine /Neurodevelopmental abnormalities

Genetic obesities ; success of genetic approaches

Change of society : complex disorders

GUT MICROBIOTA MAY BE A MISSING LINK?

INFECTION

TOXIC SMOKE

DRUGS

URBANIZATION

SOCIO-ECONOMICAL

CONTEXT

SEDENTARITY

FOOD

PSYCHOSOCIAL STRESS

ENVIRONMENT-SOCIETYGENETICS/EPIGENETICS

TISSUE BIOLOGY

GUT MICROBIOTA

Academie des Sciences 2018 / Clément

Protective role of gut microbiota from lean donnor in presence of healthy diet, Protection lost with unhealthy diet

Ridaura et al. Science 2013; Walker and Parkhill. Science 2013

Is obesity/diabetes a non communicable ?


Gut Microbiota initiates insulin resistance and inflammation

(Metabolic endotoxemia)

Cani P.D. et al. Diabetes 2007, Cani P.D. et al. Diabetologia 2007,

Tsukumo et al. Diabetes 2007, Cani P.D. et al. Diabetes 2008, Kim et al. Circ. Res. 2007

GUT Leaking?


X1.5

Increased surface

of absorption More inflammation

(jejunum)

n/mm2 Ob vs.Lean

Mature DC 5 X 5NK cells 12 X 6Macrophage 150 X 1.5

n/mm2 Ob vs. Lean

Lamina propria 350 X 1.75Epithelium 1200 X 1.5

Corpulence, liver disease and dyslipidemia

Links with obesity & complications

Altered function

(insulin resistance)

CD8αβ

Jejunum immunity is altered in obesity

Monteiro-Sepulveda et al. Cell Metab 2015

SCFA: fermentation of dietary fiber

Insulin sensitivity, and secretion

Anti-inflammatory

Decrease food intake

Koh et al, Cell metab 2016;

Ridaura et al science 2013

Maslowski et al., Nature 2009

De Vadder et al., Cell Metab

2014

Chambers et al., Gut 2015

Secondary bile acids

Insulin secretion

Sayin et al., Gut 2013

Li et al., Nature Comm 2013

Jiang et al., JCI 2015

Wahlström et al., Cell metab

2016

Branched chain amino-acids

(BCAA) produced by « LGC »

microbiota

Associated with insulin resistance

Wang et al., Nat Med 2011

Lee et al., Diabetes Care

2016

Pedersen, et al., Nature

2016

TMAO

from bacterial metabolism of cholin

and L-carnitin

Associated with cardiovascular risk

Tang, et al NEJM

Wang et al., Nature 2011

Koeth et al., Nature Med 2013

Wu et al. Gut 2016

Interaction of diet, microbiota function and host metabolism

Sonnenburgetal.,Nature2016

Gut microbiota derived metabolites from diet may play a key role in the regulation of host

metabolism


• There are many obesities (diabetes) :

Different phenotypes in obese people living in different conditions from different genetic background involving different environmental triggers

• Not a matter of BMI (Body fat distribution)• Degree of severity (different disease vs. continuum?)• Different trajectories• Tissue & signal disease• Different responses to treatments ?• Importance of therapies (complications)

Obesity: High phenotypic Heterogeneity

GUT MICROBIOTA

Help in patient stratification?

Pathophysiology

Targeted treatments ?


LGC: ↗ Pro-

inflammatory

HGC: ↗ Anti-

inflammatory

Microbial richness : A phenotype ?

Le Chatelier et al. Nature 2013

Cotillard et al. Nature 2013

Kong & Holmes et al. PLoS ONE, 2015

METAHIT 292 subjects

MicroObes49 subjects

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

LGC = Low

gene count

HGC = High

gene count

Ovw/Ob

MICROBIAL

RICHNESS

MICROBIAL RICHNESS

And healthier diet

LGC associates with CMD risks

dyslipidemia

adiposity

insulin resistance

inflammation (circulating

and adipose tissue)


Gut Microbiota Richness ?

Le Chatelier et al. Nature 2013

292 participants (obese/overweight)


49 participants (obese/overweight)

LGC (23%)

LGC (40%) HGC (60%)

HGC (77%)

Ovw/Ob

MICROBIAL RICHNESS

MICROBIAL RICHNESS

LGC (19%) HGC (81%)

MICROBIAL RICHNESS

Prifti et al. Unpublished

276 participants

Healthy

Severe

obesity

Aron & Prifti 1 Belda et al. Gut 2018

MICROBIAL RICHNESS

LGC prevalence increases

with obesity severity

(More severe phenotype)

Threshold

480 K Genes

Aron-Wisnewsky J*, Prifti E*, Belda E*…Clément K GUT 2018

MicroBaria61 subjets with severe obesity

Severe obesity : LGC individuals had a more severe phenotype

Characteristics of LGC patients:More severe forms of obesity Fat trunck mass (DXA) DT2HTA and severity (as seen with N°

drugs) Obstructive Sleep ApneaDespite same overall BMI

Characteristics of LGC patients:Confirmation: Triglycerides * Insulin resistance *Systemic inflammation (fibrinogen,

neutrophil count) *Despite same overall BMI

LGC patients: New findings:

Strong correlation with softer stools (BSS)“inflammatory stools”(R= -0.42, p= 0.005)

No association with birth modePPI, or smoking

Interaction with Enterotypes ?

Aron-Wisnewsky J*, Prifti E*, Belda E*…Clement K GUT 2018

4 Enterotypes in Severe obesityB2 :lower MGR

Ruminococcus : higher MGR

Enterotypelinked to lowgene richness

(MGR)

Bacteroides B2

dec. cell count Cell moisture Bristol stool ScaleVandeputte et al Nature 2017

Aron-Wisnewsky J*, Prifti E*, Belda E*…Clement K Gut 2018

Markers of dysbiosis & metabolic alteration

78 MGS associates with LGC (blue +, red -) & corpulence & metabolic alterations

Mostly Firmicutes /Clostridiales

As well as metabolic & CV Risks

Metabolomic signature of LGC

Aron-wisnewsky J*, Prifti E*, Belda E*…Clement K Gut 2018

78 MGS-related LGC : 50% associated with metabolic traits (severe obesity)

GU 373 Coprococcus Spx5

GU 183 Erysipelatoclostridium

GU G6 Bacteroides Vulgatus

(Pedersen et al, Nature 2016)

GU 115 Eubacterium

GU 121 Ruminococcus Bacterium

GU 82 Faecalibacterium_6

GU 373 Coprococcus

GU 195 Faecalibacterium_1

GU 163 Clostridiales

GU 95 Firmicutes ..

GU 71 Blautia

GU 82 LachnospiraceaeButyrate producers

Weight loss programs: Reversion ?

Models:

Bariatric Surgery(PHRC microbaria)

Furet at al, Diabetes, 2010

Kong, Am J Clin Nutr, 2013

Kong, Plos One, 2014

Aron-Wisnewsky J,

Curr Atheroscler Rep et al 2014

Review Nat Rev Gastroenterol

Hepatol, et al 2012

Magalhaes I, JCI, 2015

Monteiro-Sepulveda M, Cell Metab

2015

Aron, GUT 2018

Future Probiotics ?

Cotillard A, Nature, 2013

Kong LC, AM J Clin Nut 2013

DAO, MC, GUT, 2015

Schoaie, Cell Metab, 2015

Dao, Frontiers Physiol 2019Dietary Intervention

“MicroObese”

Akkermansia

& others ..


Dietary changes impact on richness

HGC

LGC

↑30%


Obese or overweight patients (N=49)

Diet: High fiber and protein,

low carbohydrate index


Better Focus on ecosystem rather than one species?

Too follows…

Is Akkermansia Muciniphila case: a candidate to improve metabolic health ?


Everard et al., 2013, PNAS

Bacteria

Verrucomicrobia

Verrucomicrobiae

Verrucomicrobiales

Verrucomicrobiaceae

Akkermansia

Akkermansia muciniphila

Derrien et al. IJSEM

2004

Health implications• Mouse studies: maintenance of glucose

homeostasis. Everard et al. PNAS 2013

• Links with Metformin. Shin et al. Gut 2013

• Membrane Protein (Amuc_1100); recap effect of Akk (Plovier H, Nature Med, 2017)

Diversity & “beneficial” bacteria : Akkermansia muciniphila (Akk)


Higher baseline A. muciniphila is associated with a healthier

metabolic status, and more insulin sensitivity

Dao et al. Gut 2015

OGTT

Glucose


Subjects with higher A. muciniphila abundance

and microbial richness have healthier metabolic profile

Dao et al., 2015, Gut

0

0 0

0

*p<0.05, **p<0.01; Kruskal-Wallis, Wilcoxon

rank sum test, Bonferroni adjustment

Need to consider overall richness ?

Carlota

Dao


Akk LO Akk HI

PRE-OP N Median (IQR) N Median (IQR)

Glucose (mM) 32 5.1 (0.9)3

35.0 (1.0)

Insulin (µIU/mL) 32 17.2 (14.7)3

218.5 (9.8)

HOMA2-IR 32 2.6 (2.0)3

22.7 (1.6)

HOMA2-%B 32 186.0 (101.2)3

2184.6 (112.4)

HOMA2-%S 32 39.1 (27.4)3

237.5 (20.1)

HbA1c (%) 32 5.8 (0.7)3

35.7 (0.5)

No significant differences, Wilcoxon test.

Baseline insulin sensitivity and glucose tolerance markers

by A. muciniphila category in severe obesity

Dao et al, review

75 % Low diversity


Microbial gene richness after RYGB and AGB

Aron-wisnewsky J*, Prifti E*, Belda E*…Clement K GUT, 2018

Overall gene richness?

Enterotypes ?

After 5 years ?

Confirmation group

X 1.39

X 1.27

To the future ?

Can the microbiome be a treatmentfor human metabolic disease ? Efficiency ?

For which

objective ?

Microbiome ?

Gut barrier ?

Derived-molecules?

Host targets?

Combined?

Prevention ?

Patient trajectories?

Stage of

progression?

Food ?

Prebiotics?

Probiotics?

Metabolites ?

Feces transfer ?

Combination?

Patients Phenotypes

Heterogeneity

Healthy stages of

obesity?


Precision Nutrition (IA)

Microbial richness

Microbial function

Species (A. muciniphila)

Metabolites (SCFA, TMAO)

Environmental factors (diet)

Shoaie et al. Cell Metab 2015 & Dao et al. CNX 2016Academie de pharmacie 2019 / Clément

Transfer (?)

M Nieuwdorp team, Cell Metab, 2017

Jean-Daniel Zucker, Judith Aron, Sébastien André

Christine Poitou, Véronique Pelloux, Edi Prifti, Jean

Debedat, Pierre Bel Lassen

Rohia Alili.. Karen Assemann, Favien Jacque

Carlota Dao, Brandon Kayser, Nataliya Sokolovska

…...

INRA – MGPHervé BlottièreNicolas PonsEmmanuelle Le Chatelier….Florence LevenezJoel DoréStanislav Dusko Ehrlich

Dr. Patrice CaniDr. Amandine Everard

Dr. Armelle LeturqueDr. Edith Brot-Laroche

Equipe Integromics

-JD Zucker

- E Belda

- E Prifti

Documents

Microbiote et Obésités - Académie Nationale de Pharmacie...Academie de pharmacie 2019 / Clément. Higher baseline A. muciniphila is associated with a healthier metabolic status,