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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
UCL-Confidential 2
• 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
UCL-Confidential 3
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 Cani unpublished data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
UCL-Confidential 4
Proof of concept preclinical studies
A. Everard
Akkermansia, obesity and type 2 diabetes
UCL-Confidential 5
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
UCL-Confidential 6
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?
=
UCL-Confidential 7
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.
UCL-Confidential 8
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
UCL-Confidential 9
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
UCL-Confidential 10
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
UCL-Confidential 11
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.
UCL-Confidential 12
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
UCL-Confidential 13
Future readings