Microbiote et Obésités - Académie Nationale de Pharmacie...Academie de pharmacie 2019 / Clément....
Transcript of Microbiote et Obésités - Académie Nationale de Pharmacie...Academie de pharmacie 2019 / Clément....
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 ?
Academie de pharmacie 2019 / Clément
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?
Academie de pharmacie 2019 / Clément
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
Academie de pharmacie 2019 / Clément
• 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 ?
Academie de pharmacie 2019 / Clément
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)
Academie de pharmacie 2019 / Clément
Gut Microbiota Richness ?
Le Chatelier et al. Nature 2013
292 participants (obese/overweight)
Cotillard et al. Nature 2013
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 ..
Academie de pharmacie 2019 / Clément
Dietary changes impact on richness
HGC
LGC
↑30%
Cotillard et al. Nature 2013
Obese or overweight patients (N=49)
Diet: High fiber and protein,
low carbohydrate index
Academie de pharmacie 2019 / Clément
Better Focus on ecosystem rather than one species?
Too follows…
Is Akkermansia Muciniphila case: a candidate to improve metabolic health ?
Academie de pharmacie 2019 / Clément
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)
Academie de pharmacie 2019 / Clément
Higher baseline A. muciniphila is associated with a healthier
metabolic status, and more insulin sensitivity
Dao et al. Gut 2015
OGTT
Glucose
Academie de pharmacie 2019 / Clément
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
Academie de pharmacie 2019 / Clément
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
Academie de pharmacie 2019 / Clément
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?
Academie de pharmacie 2019 / Clément
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