A hidden universe: how bacteria
keep the world in shape
Bacteria inside the body
Gut microbiota and obesity
Karine Clément, MD, PhD
Institute of Cardiometabolism and Nutrition
(ICAN)
INSERM UMRS 1166, Team 6
University Pierre & Marie Curie
Pitié-Salpêtrière Hospital, APHP, Paris
[email protected]
Cardio-metabolic and Nutrition-Related diseases
Heavy burden for the Society
According to WHO estimates,
Noncommunicable diseases contributed to 36 million
deaths globally in 2008, accounting for 63% of 57 million total deaths.”
(From Hunter DJ et al. N Engl J Med 2013; 369: 1336-1343)
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Individual Trajectories Matter
=> Toward Chronic diseases
– Phenotype heterogeneity?
- Stage of progression (worsening, acute , relapse) ?
- Response to treatments (variable)
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Obesity: an organ disease and a systemic disease
Lifestyle Dietary
Changes
Brain
Energy balance
Endocrine function
mood
Immune system
Cytokine production
Perturbed
endocrine
secretions
Hypertrophy
Altered
extra-cellular matrix
Intestine
Gut microbiota
Muscle
Energy balance
Endocrine function
Immune
/inflammatory
unbalance
Altered
angiogenesis
Heart injuries
Epicardial fat
Organelle
dysfunctions
Vascular system
atherosclerosis
Liver
injuries
The gut is the largest reservoir
of live bacteria communities (1-2 kg)
An organ as active as the liver
There is a similar number of bacteria in 1g
(fecal sample) than cells in human brain!
Microbiota & Diseases: a Quick Overview
Microbiota as an asset
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Defense - bacterial antagonism
Priming of mucosal immunity
Peristalsis
Metabolism of dietary carcinogens
Synthesis of B & K vitamins
Epithelial nutrients (e.g. SCFAs)
Conversion of prodrugs
Utilisation of indigestible (CH2O)n
Microbiota as a liability
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Thanks to J. Marchesi
Procarcinogens  carcinogens
Overgrowth syndromes
Opportunism – Translocation
Implicated in obesity, metabolic syndrome
and colorectal cancer, IBD and other
diseases
Happy World of Microbiome
Gut Microbiome & Obesity: Diet matters
Protective role of
gut microbiota from
lean donnor in
presence of
« healthy diet »
Protection lost with
« unhealthy
diet
»
From Walker et al.
Science 2013
Ridaura et al.
Science 2013
 Gut Microbiome could be one of the causes of Obesity
Human metagenomic in the world
Canadian
Microbiome Initiative
Human Microbiome
Project (US)
MetaHit (EU and China)
Human MetaGenome
Consortium (Japan)
MicroObes
(France)
Meta-GUT (China)
Human Gastric
Microbiome Project
(Singapore)
Australian Urogenital
Microbiome Consortium
Adapted from Nicolas Pons, Ecole NGS INRA, Lyon, january 2012
Gut microbiome and physiological composition
4.9 M de
gènes
“Common metagenome” for a part
>>> but huge individual variability
Qin et al; Nature 2010; Qin et al Nature 2012,
Nielsen et al Nature techno 2014
An equilibrium between Health and Disease
Fibromyalgia
IBD
Diabetes Colon Cancer
T I & T II
NASH
Obesity
CVD
CVD
Depression
Kidney stones
Atopic disease
Concepts in Nutrition –related diseases
Gut
microbiota
Composition:
Bacterial
Metabolites
(i.e. SCFA, TMA,
TMA0)
Brown & Hazen, Ann Rev med
2015
Gene
richness
Specific
species or
bacterial
groups
Energy harvest, lipid
metabolism,
markers for increased risk of
chronic disease (CVD, T2D)
Bacterial
Components
(i.e. LPS)
Others
Innate immunity stimulation
Inflammation
Insulin resistance
Metabolic syndrome
Chronic disease
(CVD, T2D)
Tremaroli et al. Nature 2012
Adapted from Harris et al. J Obes 2012
Gut Microbiome and Obesity: Diversity matters
METAHIT
MicroObes
292 subjects
49 subjects
LGC (23%)
HGC (77%)
LGC (40%)
HGC (60%)
Ovw/Ob
LGC = Low
gene count
HGC = High
GENE RICHNESS
gene count
GENE RICHNESS
LGC associates with CMD risks
LGC: ↗ Pro-
↑ ↑ dyslipidemia
inflammatory
↑ adiposity
↑ insulin resistance (surrogates)
LGC: ↘ Antiinflammatory
↑ inflammation (circulating
and adipose tissue)
Le Chatelier et al. Nature 2013;
Cotillard et al. Nature 2013
Stratify subgroups of patients to identify optimal treatments.
Ex: Low gene richness
20-40% in overweight & obese
Dietary intervention => Improved richness
75 % in severe obesity
Novel treatment ?
• Enrich gut microbiota in obese
& diabetic subjects ?
• Personalized Nutrition
Cotillard, Nature 2013
« Individual Probiotics » ?
Is Akkermansia Muciniphila a candidate to
improve metabolic health ?
Better Focus on ecosystem
rather than one species?
Akkermansia muciniphila (Akk): a candidate?
Bacteria
Verrucomicrobia
Verrucomicrobiae
Verrucomicrobiales
Verrucomicrobiaceae
Akkermansia
Akkermansia muciniphila
Derrien et al. IJSEM 2004
Main characteristics:
• Mucin-degrading function, Anaerobic,
gram negative.
• Main products from mucin degradation:
Acetate, propionate, sulfate, amino acids,
cofactors, vitamins.
Health implications
• Inversely related to GI conditions such as ulcerative colitis and Crohn’s disease (Vigsnaesn LK 2012)
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Mouse studies : maintenance of glucose in homeostasis (Everard A, PNAS, 2013).
There is some evidence of inverse association between Akk and weight in humans (more clear in mice).
Carlota Dao et al., GUT 2015
Subjects with higher A. muciniphila abundance and
gene richness have healthier metabolic profile
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*p<0.05, **p<0.01; Kruskal-Wallis, Wilcoxon rank sum test, Bonferroni adjustment
Dao et al. Gut 2015
A core of MGS associated with Akk
over time
13 Firmicutes, 5 Bacteroidetes, 1 Actinobacteria and 1 Euryarchaeota
Dao et al. Gut 2015
Multiple players
Immunity
Adapted from Khan MT, et al, Cell Metab 2014
Bacterial metabolites as biomarkers ex TMAO?
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Aron & Clément, Nature Nephr, 2016
Actionnable models for personnalized nutrition
(modeling the gut microbiota ecosystem)
Need more on food intake record !
Schoaie, Cell Metab 2015
Losing weight for a better health: Role for the gut microbiota (Dao et al, 2016)
Whats’ next? European initiative
?
14 Partners-6 Europeans countries
Multidisciplinary
Patient Association
INSERM coordination (K Clément)
2000 EU patients
Healthy
Metabolic syndrome
Obese
Diabetics
Coronaropathy
Heart Failure
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Future strategies ……
THANK YOU!
Dr. Eric
Verger
Dr. Salwa
Rizkalla
Dr. Judith AronWisnewsky
Carlota
Dao
Dr. Brandon
Kayser
ICAN
Sylvie Le Mouhaër
Agathe Arlotti
Ludovic Le Chat
Florence Marchelli
Véronique Pelloux
Rohia Alili
Valentine Lemoine
Nutriomique Team
Dr. Edi Prifti
Dr. JeanDaniel
Zucker
Dr. Tuong
Nguyen
Dr. Nataliya
Sokolovska
Dr. Aurelie
Cotillard
Dr. Patrice Cani
Dr. Amandine Everard
INRA - MGP
Sean Kennedy
Nicolas Pons
Jean-Pierre Furet
Emmanuelle Le Chatelier
Mathieu Almeida
Benoit Quinquis
Florence Levenez
Nathalie Galleron
Jean-Michel Batto
Pierre Renault
Joel Doré
Stanislav Dusko Ehrlich
A hidden universe: how bacteria
keep the world in shape
Prof. Dr. Shinichi Sunagawa
European Molecular Biology Laboratory, Heidelberg, Germany
Now: Institute of Microbiology, D-BIOL, ETH Zurich, Switzerland
Ocean Microbial Diversity at Global Scale
• Plankton are microbes that power our earth
• Much of ocean biodiversity still unknown
• Composition of plankton is driven by temperature
The power of plankton
How much of biosphere is oceanic?
71% of Earth‘s surface (2D), but >98% of the
biosphere‘s volume (3D)
What is plankton?
passively transported, mostly microscopic organisms
What is the biological content of seawater?
Each litre contains
What are some major roles of plankton?
small animals: 10 - 10 k
single-celled eukaryotes: 100 k - 10 M
bacteria and archaea: 1 G - 10 G
viruses: 10 G - 100 G
• oxygen source / carbon sink: CO2 + H2O -> CH2O + O2
• impact on atmosphere
• basis of food chain
Exploring the oceans
Eric Karsenti
Charles
Darwin
Senior scientist CBB, EMBL
Scientific director of Tara Oceans
Etienne Bourgois
CEO agnes
1836)b.
Co-founder of TARA Expeditions
HMS
(183121Beagle
partner
institutions
>260 scientific contributors
Tara Oceans Expedition 2009-2013
210 stations
35,000 biological samples
1,200 environmental samples
3 depth layers
How do we describe organisms invisible to the naked eye?
 Imaging (microscopy, movies)
 High-throughput DNA sequencing
+ (lots of) bioinformatics
Genomic revolution
apply (meta)genomics to ocean ecosystem
Human genome < $1000
5 research articles
1) Eukaryotic biodiversity
De
Vargas, et al., 2015
2) Species and gene diversity of bacteria and archaea
Sunagawa, et al., 2015
3) Biodiversity of viruses
Brum, et al., 2015
Special issue May 2015
4) Interactions between species
Lima-Mendez, et
al., 2015
5) Dispersal potential of plankton
Villar, et al., 2015
detected ‘species’
Number of
Enormous eukaryotic biodiversity
Number of detected cells
10,000+ newly detected species
 Genomic potential hardly explored
de Vargas et al., Science, 2015.
Species interactions are complex
 microbes create highly interactive networks
 most of them cannot be cultured
 but their DNA can be de-coded (metagenomics)!
Lima-Mendez et al., Science, 2015.
Towards a genetic inventory of the ocean
• 243 representative samples
• 3 depth layers
• 7.2 Tbp of DNA sequence
Sunagawa et al., Science, 2015.
Temperature drives surface microbial composition
Reconstruct and catalogue the genetic
Microbial composition of surface sea-
diversity of the ocean
water is largely driven by temperature
Sunagawa et al., Science, 2015.
• Plankton are microbes that power our earth
•
oxygen production, carbon sink, base of food web
• Much of ocean biodiversity still unknown
• global census of biodiversity emerging
• complex species interactions identified
• genetic inventory has begun
• Composition of plankton is driven by temperature
Future outlook: predictive models and functional understanding
Thank you!
Prof. Dr. Shinichi Sunagawa
European Molecular Biology Laboratory, Heidelberg, Germany
Now: Institute of Microbiology, D-BIOL, ETH Zurich, Switzerland