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THE ENTEROBIOME

WHO WE ARE

COMPETITIVITY

COMPETITIVITY

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Construction of a world-scale library of
‘Akkermansia mucininphila’
and ‘Faecalibacterium prausnitzii’

Providing personalized treatment

- Isolation of all Akkermansia mucininiphila distinct clades (AmI to IV)

- Isolation of major Faecalibacterium prausnitzii phylogrup (I and II)

Libraries of various anaerobic species

Libraries of over 30 anaerobic species with high potential
for development as microbiome therapeutics

Next Generation Probiotics

  • · AM
  • · FP
  • · Bacteroides fragilis
  • · B. thetaiotaomicron
  • · B. uniformis
  • · Eubacterium halli
  • · E. limosum
  • · E. rectale
  • · Roseburia intesnalis
  • · Ruminococcus bromii

continuous expansion

Personalized microbiome preparations

Strain Library

Libraries for AM, FP, B.
uniformis, B.
thetaiotaomicron, E.
rectale, etc.

Patent registration for 2 AM
strains and 2 FP strains

Overcome competitors 'prior technologies (medium components)
‘Media Optimization’ Improve cultivability (number of viable cells)
by more than 1000 times

Technology for Akkermansia muciniphila

Initial phase
Late log phase
  • Incubation time: <20h
  • Number of viable bacteria: 1000 times or more improvement compared to competitors
Mucin media
Competitor’s media
Enterobiome media
  • Patents : Completion of domestic registration/PCT application (entry into USA, Europe, Australia, China, Japan, Canada

Improving cultivability (number of viable cells) by more than 1000 times compared to prior technology

Technology for Faecalibacterium prausnitzii

Initial phase
Late log phase
  • Number of viable bacteria: 1000 times or more improvement compared to prior technology
Before
After
  • Induction of cell morphology (chain→single cell) change through medium improvement
  • increase the number of viable cells
  • Domestic patent registration

‘Patent-based production of culture medium’ CDMO and self-production

  • Prototype production in progress through technology transfer to CDMO companies
  • Present : DS production for pharmaceutical and functional food development
  • 2022 early : DS production completed
  • 2025 : In-house production after completion of cGMP and GMP production facilities
High-concentration culture technology
CDMO incubator

NEXT generation microbiome Akkermansia muciniphila

Correlation between Akkermansia muciniphila and disease in animals

No.
Subject
Study type (Diet/Reagent)
Relevance conclusion
Reference
1
Nine-week-old male
C57Bl/6J (WT) and Apoe/ (KO) mice
High Fat diet Prebiotics (DEF, ITF)
· After prebiotic treatment of inulin-type fructans, the endothelial dysfunction was improved in mice, and the abundance of A. muciniphila was increased
Catry et al., 2018
2
Six-week-old male
C57BL/6J mice
Fructo-oligosaccharides (FOS)와 inulin
(prebiotics), 6weeks gavage
· A. muciniphila became a dominant species in Verrucomicrobia phylum after treatment with fructo-oligosaccharides and inulin. It played an important role on maintaining balance between mucin and short-chain fatty acids
Zhu et al., 2017
3
male Swiss albino mouse
High Fat diet
Green tea extract
Isomalto-oligosaccharide
· A combination of green tea extract with isomalto-oligosaccharide exerted beneficial effects on HFD-induced alterations in mice and improved A. muciniphila abundances
Singh et al., 2017
4
Male C57BL/6J mouse
High Fat diet
200 mg/kg HPBN
· Red pitaya betacyanins protect from diet-induced obesity and its related metabolic disorders, and increase the relative abundance of A. muciniphila
200 mg/kg HPBN
5
Six-week male C57BL/6 mice
High Fat diet
· A. muciniphila abundance was reduced in obese mice induced by a high-fat diet
Schneeberger et al., 2015
6
Two-week BALB/c mice
maternal milk or infant formula
· Compared with the infant formula group, A. muciniphila abundance was increased in the breastfeeding group
Gomez-Gallego et al., 2014
7
NOD (non-obese diabetic) mouse
Vancomycin (antibiotic)
· Transplanting the gut microbiota of mice with low diabetes incidence to mice with high diabetes incidence did not reduce the morbidity of diabetes but transplanting the single strain A. muciniphila to mice with high incidence of diabetes can reduce the morbidity of diabetes
Hansen et al., 2012
8
Male 6–8 week C57BL/6 mice
High Fat diet
10 μg AmEV (A. muciniphila extracellular vesicles)
·A. muciniphila extracellular vesicles may improve metabolic function by altering intestinal permeability and barrier integrity in high-fat diet mice
Chelakkot et al., 2018
9
10- to 11-week- old male
C57BL/6J mice; Human subjects
with excess body weight
High Fat diet
A. muciniphila live or pasteurized cells
· A. muciniphila retains its efficacy when grown on a synthetic medium. Pasteurization of A. muciniphila enhanced its capacity to reduce fat mass development, insulin resistance and dyslipidaemia in mice. Administration of live or pasteurized A. muciniphila grown on the synthetic medium is safe in humans
Plovier et al., 2017
10
NNon-obese diabetic mice
FMT (normal)
A. muciniphila
· FMT transplantation or A. muciniphila gavage reduced morbidity of diabetes.
Hanninen et al., 2017
11
Eight-week-old
male Apoe-/-mice
Western diet
A. muciniphila
· Oral gavage with A muciniphila protected against western diet- induced atherosclerotic lesion formation in Apoe-/- Mice
Li et al., 2016
12
C57BL/6 mouse
High Fat diet
Metformin
A. muciniphila
· Oral administration of Akkermansia muciniphila to HFD- fed mice without metformin
significantly enhanced glucose tolerance and attenuated adipose tissue inflammation by inducing Foxp3 regulatory T cells (Tregs) in the visceral adipose tissue
Shin et al., 2014
13
10-week C57BL/6 mice
High Fat diet
A. muciniphila Live and heat-killed
cells
· A. muciniphila abundance was decreased in mice with diabetes and obesity caused by high-fat diet, and the metabolic function of mice could be improved by intragastric administration of live A. muciniphila
Everad et al., 2013

Correlation between Akkermansia muciniphila and disease in humans

No.
Subject
Study type
Relevance conclusion
Reference
1
81 patients with T2D
Reduced-energy diet
· Increased levels of A. muciniphila
· Improvement of glycaemic control, dyslipidaemia and inflammation
Medina-Vera et al., 2019
2
60 overweight and obese diabetic patients
Administration of
600 mg/d butyrate, 10 g/d inulin powder
· Increased levels of A. muciniphila
· Significant decreased TNF-α mRNA expression and diastolic blood pressure levels
Roshanravan et al., 2017
3
28 obese men with the metabolic syndrome
Oral administration of 1 g polyphenol resveratrol twice daily
· Increased levels of A. muciniphila
· Improvement of glucose homeostasis
Walker et al., 2019
4
268 Danish individuals with prediabetes or normal glucose regulation
Case-control study
· Lower abundance of A. muciniphila in individuals with prediabetes
Allin et al., 2018
5
49 participants with overweight or obese
Calorie restriction for 6 weeks
· Increased levels of A. muciniphila
· Improvement in fasting plasma glucose, plasma triglycerides and body fat distribution
Dao et al., 2016
6
42 hypercholesterolemic patients and 19 healthy
subjects
Atorvastatin (a cholesterol-lowering agent)
· Increased levels of A. muciniphila
Khan et al., 2018
7
70 female T2DM patients and 70 healthy females
Case-control study
· Confirmed the correlation between decreased A. muciniphila and type 2 diabetes mellitus (fasting blood glucose and urine glucose)
Liu et al., 2017
8
16 infants of overweight women and 34 infants of
normal-weight women
Case-control study
· Lower abundance of A. muciniphila in women with excessive weight gain during pregnancy.
Santacruz et al., 2010
9
28 participants with diabetes (14 taking metformin) and the 84 participants without diabetes
Metformin (diabetes treatment)
· Higher relative abundance of A. muciniphila in participants with diabetes taking metformin compared with participants without diabetes.
De La Cuesta-Zuluaga et al.,
2017
10
13 morbidly obese patients who underwent RYGB
(Roux-en-Y gastric bypass)
Roux-en-Y gastric bypass (RYGB)
· ∙ Incresed 31 strains including A. muciniphila within the first 3 months
after RYGB and maintained their abundances.
Palleja et al., 2016
11
Obese females (n=53)
Case-control study
· Identification of 140 metagenomic species (including A. muciniphila)
linked to metabolic risk markers in obesity.
Brahe et al., 2015
12
32 overweight/obese insulin-resistant volunteer
A. muciniphila bacteria either live or pasteurized
· Reduced the levels of the relevant blood markers for liver dysfunction and inflammation by oral supplementation of A. muciniphila bacteria
Depommier et al., 2019
13
3 individuals of normal weight, 3 morbidly obese
individuals and 3individuals who had undergone RYGB
at least 6 months earlier
Case-control study
· Abundance of Verrucomicrobia (Akkermansia) is variable in normal weight, undetaectable in obese patients, and very high in patients undergone RYGB
Zhang et al., 2009
14
21 patients with ASH (Alcoholic steatohepatitis) and
16 non-obese healthy individuals
Case-control study
· Decreased abundance of A. muciniphila in patients with ASH compared with healthy controls
∙ A. muciniphila promotes intestinal barrier integrity and ameliorates experimental ASH
Grander et al., 2018
15
13 overweight individuals
Probiotics intervention
· After fasting and probiotics intervention, Increased levels of A. muciniphila
Remely et al., 2015
16
33 obese individuals
A dietary intervention over a four month.
· After weight reduction, increased abundance of A. muciniphila
Remely et al., 2015
17
7 women with obesity
Intake of ephedra for 8 weeks
· Alteration of gut microbiota (A. muciniphila) by ephedra intake showed correlation with loss of body weight and BMI
Kim et al., 2014
18
44 normal glucose tolerance, 64 prediabetes, and 13
newly diagnosed T2DM
Case-control study
· Lower abundance of Verrucomicrobiae in both the pre-DM and T2DM.
Zhang et al., 2013
19
Twenty overweight or obese children and twenty
children with BMI within the normal range (age: 4-5 years)
Case-control study
· Significantly lower levels of A. muciniphila in the obese/overweight children
Karlsson et al., 2012

Development of personalized therapeutics
Individual targets of disease-specific strains

Providing personalized microbiome therapeutics based on AM and FP libraries

obese/NASH
Expansion of Indication
AM/FP
Phenotype
  • qPCR
  • Genome analysis
Customized
treatment (strain)
  • Single/multi
    strain
Selection
excellent
therapeutic effect
Libraries of AM and FM, etc.
Libraries of AM and FM, etc.

Secured technology for screening efficacious microbiome strain

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    Fecal sample
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    02
    Next generation Sequencing
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    03
    Gut microbiota analysis
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    A. muciniphila
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    05
    Securing microbial
    and genetic resources
    beneficial for human use
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    Strain library, safety
    evaluation, animal model
    study, product development
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    Mass production via
    optimization of cultivation
In vitro

BMDC, PBMC
3T3L-1 : ELISA, PCR

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Control
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BAA-835
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EB-AMDK19
EX vivo

Splenocyte, organoid

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Laboratory rat
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Spleen, ELISA
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Control
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EB-AMDK19
In vivo

HFD-induced
obesity model

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Oral administration
of bacteria

Efficacy evaluation
in animal models