UCL-Confidential 1

Brussels Belgium

@MicrObesity

Royal Academyof Medicine of Belgium

Patrice D. CaniUCLouvain, Brussels, Belgium

NeuroMicrobiota Lab (LEA Pr. Knauf INSERM/UCL)

Serendipity….

The « Akkermansia » story

Isolated in 2004 by Prof. Willem de Vos

and Dr. Muriel Derrien

Akkermansia muciniphila

Laura Huskonen & Willem M de Vos

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• Naturally present in gut lining of healthy humans

Slide kindly provided by Dr Hubert Plovier

Derrien et al ISJEM 2004

Prebiotics

MORE THAN 100 TAXA MODIFIED

some of them more than 10 Fold

Microbiome sequencing revealed

novel taxa

MORE THAN 1000 COG’s

FUNCTIONS MODIFIED !!!

Everard et al Diabetes 2011 Everard et al ISME J 2014 epub ahead of print April 3th

Akkermansia muciniphila was

Increased by about 100 fold

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level 2 Ratio obese vs lean pvalue

Akkermansia muciniphila -342.94 0.0073

L. salivarius et rel. -11.65 0.0127

Subdoligranulum et rel. -4.01 0.0055

Bilophila et rel. -3.14 0.0063

Desulfovibrio et rel. -2.47 0.0158

Cl. leptum et rel. -1.95 0.0031

B. distasonis et rel. -1.93 0.0059

R. callidus et rel -1.70 0.0147

Cl. herbivorans et rel. -1.32 0.0188

Faecalibacterium prausnitzii et rel. -1.32 0.0084

Cl. perfringens et rel. -1.15 0.0450

Staphylococcus aureus et rel. -1.14 0.0203

Enterococcus 1.10 0.0192

Dialister et rel. 1.10 0.0019

Olsenella et rel. 1.20 0.0048

Sutterella wadsorthia et rel. 1.21 0.0217

Labrys methylaminiphilus et rel. 1.27 0.0186

Unc. Clostridiales. II 1.29 0.0044

Coprobacillus et rel. 1.32 0.0302

Unc. Clostridiales. XIVa 1.33 0.0151

Cl. difficile et rel. 1.39 0.0046

Catenibacterium 1.43 0.0074

L. plantarum et rel. 1.59 0.0001

Allobaculum et rel. 1.72 0.0469

Atopobium 1.74 0.0000

Mucispirillum schaedleri et rel. 1.77 0.0371

Unc. Clostridiales. IV 1.86 0.0442

Acholeplasma et rel. 2.02 0.0005

Butyrivibrio crossutus et rel. 2.09 0.0217

L. delbrueckii et rel. 2.58 0.0098

Prevotella ruminicola et rel. 2.75 0.0073

L. gasseri et rel. 3.01 0.0000

Fibrobacter succinogenes et rel. 5.94 0.0006

Unc. Clostridiales. I 8.07 0.0047

L. acidophilus et rel. 17.17 0.0010

OK

but is it relevant?

Year 2008vs

Everard ….. Cani unpublished data

In mice

A. muciniphila

A. muciniphila

Everard et al Diabetes 2011, PNAS 2013 Everard et al ISME J 2014Schneeberger et al Sci Rep 2015Neyrinck et al Mol Nutr Food Res 2016Grander et al GUT 2017

Alcohol

Liou et al Sci Trans Med 2013

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Proof of concept preclinical studies

A. Everard

Akkermansia, obesity and type 2 diabetes

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Gastric bypass

Clinical Data have shown…

A. muciniphila

A. muciniphila

Dao, Everard ….. Cani, Clément, GUT March 2016

Dao, Everard, Clément and Cani Clin Exp Nutr 2016

Metformin RespondersNon-Responders

Akkermansia GOOD or BAD?

Abundance subjected to confounding factors !

Adapted from Cani PD GUT IN PRESS 2018

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Challenges!

Many problems remain

to be solved before a

PoC in Humans !

The major issues:

1) Preferred growth medium of Akkermansia

contains animal-derived compounds (i.e.

mucus)! Strongly limits the translational

approach for human test…

2) Akkermansia is relatively sensitive to oxygen!

3) But what about pasteurization?

Can we maintain at least in part the activity of

Akkermansia?

=

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Pasteurised Akkermansia stop the

development of obesity and diabetes

Plovier et al Nature Medicine 2017

The future: using molecules from bacteria

that exhibit therapeutic properties ?

Pharmacognosy and « Microbiognosy »

Can

i P

.D.

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January 2017

Dr. Hubert PlovierProf. Willem de Vos

Reviewed in Cani and de Vos Front Microbiology september 2017

Everard A et al PNAS 2013, Li J et al Circulation 2016, Grander et al GUT 2017 Plovier H et al Nature Medicine 2017, Hanninen et al GUT 2017, Routy et al Science 2017

In humans?

First administration of

Akkermansia muciniphilaAkkermansia muciniphila

Laura Huskonen & Willem M de Vos

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NCT02637115

Placebo

Live A. muciniphila 1010/day

Live A. muciniphila 109/day

Pasteurized A. muciniphila

Randomization

15daysSafety check

Informedconsent

3 monthsof treatment

39

BMI ≥ 25, insulin resistance and metabolic syndrome

Randomized, single-blind, parallel, placebo-controlled

100 subjects

Key Outcomes : insulin-resistance, inflammation, dyslipidemia, body-weight, type-2 diabetes, gut microbiota, gut barrier function

ClinicalTrials.gov Protocol Record 2015/02JUL/369

ERC-PoC-2016

Prof. Jean-Paul Thissen

Prof. Michel Hermans

Prof. Dominique Maiter

Dr. Audrey Loumaye

Dr. Amandine Everard

Dr. Céline Druart

Mlle Clara Depommier

Mme Marie de Barsy

Prof. Willem de Vos

First Spin OFF project

Microbes4U pilot-study: the first

A. muciniphila supplementation in human volunteers

Total 54 subjects

Liver enzymes

Designed in Q3 2013Approved in 2015

Production ready 12/2015 Started in Q1 2016

Three or more comorbidities associated to Metabolic syndrome

Caucasian Aged between 18 and 70 Overweight or obese BMI > 25 kg/m2 Pre-diabetic state : Insulin sensitivity < 75 %

According to the NCEP ATP III definition

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Exclusion criteria

Acute or chronic progressive or chronic unstabilized diseases

Crohn disease or a other intestine inflammatory disease

Being pregnant or pregnancy planned

Previous bariatric surgery

Alcohol consumption (> 2 glasses / day)

Regular physical activity(> 30 min of sports 3 times a week)

Consumption of dietary supplements in the month prior the study

Consumption of more than 30 g of dietary fibers per day

Consumption of vegetarian or unusual diet

Lactose intolerance / milk protein allergy

Gluten intolerance

Taking medicine affecting measured metabolic parameters

Insulin

Sensitivity

Liver enzymes Hip

Total cholesterol

Microbes4U : the first exploratory study on

Akkermansia

UNPUBLISHED DATA

LPS levels

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Not designed for efficacy! The study is an exploratory study

Limited power of the study (but still clear effects or trends

observed)

Overselection of the population due to the criteria

Non stabilized phenotype! Explaining the trends ? Effect due to

placebo deterioration?

General critics

What’s next!

• Preparation of a dossier to introduce the approval of

pasteurized Akkermansia as a Novel Food (EFSA =

EU regulatory)

• Deeper analysis of the current MICROBES4U samples

• Preparation of novel studies to investigate the effect

of pasteurized Akkermansia on larger cohort of

volunteers.

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Pitié-Salpêtrière hospitalICANProf K. Clément Dr Dao and Microbes consortium

INSERM, Toulouse, France

Prof C. KnaufProf. R. Burcelin

LDRI, UCL, Belgium

Prof G. Muccioli

IREC

Prof Y. Guiot

Rose-Marie Gobbels

Walloon Excellence in Life Sciences and BIOtechnology

Gothenburg University, SwedenProf F. BackhedDr. R. CaesarDr. M. StahlmanDr. M. Johansson

Université de Genève, Hopitaux universitaires

Prof J. SchrenzelProf P. FrançoisProf V. Lazarevic

Wageningen URProf W. de VosDr M. DerrienDr. C. BelzerDr. J Owerkerk

Dr. J. Klievink

Former members of Cani’s teamD. NaslainA. BeverT. PringelsO. RottierF. PierardM. Van RoyeA. DegrooteDr. M. OstoDr. S. Matamoros Dr. T. Duparc Dr G. TrincheseDr. L. Geurts

DDUV, UCL, Belgium

Prof JB Demoulin, Dr A. Essaghir

Prof JC Renauld, Prof. L Dumoutier

ERC-StG-ENIMGO-2013

and

ERC-PoC-Microbes4U-2016

St Luc Hospital, BrusselsProf. Jean-Paul ThissenProf. Michel HermansProf. Dominique MaiterDr. Audrey LoumayeMarie de Barsy

Fondation FRANCQUI

Special thanks to Gaudichon et Philippon

Special thanks to Benoit Lambert

ww.visible.be

Université de Lyon, Prof G. MithieuxAnd his team

The future is inside!

In gut we trust ©

@MicrObesityFollow on

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Future readings