New Cardiovasculaire zorgen van morgen: Diabetes · 2019. 2. 11. · DNA, urine samples, vaginal...
Transcript of New Cardiovasculaire zorgen van morgen: Diabetes · 2019. 2. 11. · DNA, urine samples, vaginal...
Cardiovasculaire zorgen van morgen: Diabetes .
Prof dr Max Nieuwdorp MD PhD internist – endocrinoloog/vasculaire geneeskunde
Chair Diabetes AMC and VUMC, head of Experimental Vascular Medicine Lab
NVF meeting Friday 23rd November 2018 10:15 till 1045
|
Research contracts: Astra Zeneca
Consulting: -Astra Zeneca, Eli-lilly, Sanofi, MSD, Danone, Johnson&Johnson
Employment in industry: -
Advisory board of a healthcare company:
- Caelus Health
Disclosure slide
• 1. Gutmicrobiota composition is driven by manyconfounders including ethnicity
• 2.Interstinal microbiota may indeed play a small but causal role in human (metabolic) disease
• 3. Donor bacterial ENGRAFTMENT (responders) differsbetween human subjects and can be predicted on baseline fecal sample
• 4.. reconstitution of single/multiple beneficial bacterialstrain(s) in combination with diet to increaseengraftment might be a solution for human metabolicdisease (more than orally replenishing missing SCFA)
Take home message
Emerging Risk Factors collaboration, NEJM 2011 364:829-841
Diabetes are physically 10 years older than their non affected peers
What factors drive obesity to metabolic syndrome?
Hyperglycemia: the tip of the metabolic syndrome/ type
2 diabetes iceberg
Abdominal obesity
Atherogenicdyslipidemia
Satiety
Insulin resistance----------------------
Hyperinsulinemia
High fat/sugardiet
Gutmicrobiota
Hyperglycemia
Role of intestinal microbiota in (human) metabolism
Schroeder and Backhed, Nature Medicine 2016
Most produced metabolites are Short chain fatty acids
Human microbiome project 2008
1.Core human microbiome (approx 4000-6000 different bacteria species)
2.Changes in the human microbiome correlate with changes in human health
(an)aerobic culture
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16s sequencing
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Geboren: 1947, New Orleans, Louisiana, Verenigde
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Veld: Geneeskunde
Prijzen: Keio Medical Science Prize, Robert Koch-prijs
Selman A. Waksman Award in Microbiology
Opleiding: Universiteit van Chicago, Oberlin College
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Short chain fatty acids (ScFA) are best studiedmicrobial metabolites in relation to metabolism
SCFA-acetate (50%) 2
-butyrate (30%) 1
-propionate (20%): 1
Backhed, Nature 2012,Vrieze 2014
Holmes E, Cell Metabolism 2012 16, 559-564
1. Pitfalls in microbiota research and potential new confoundersin association studies
Figure 1
Cell Metabolism 2012 16, 559-564DOI: (10.1016/j.cmet.2012.10.007)
Copyright © 2012 Elsevier Inc. Terms and Conditions
Acknowledge the pink elephant in the room of current microbiota research
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A pink elephant in a room
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Caveats• 1. Gutmicrobiota and ethnicity; does
gene-environment interaction drive differential gutmicrobiota dietaryprocessing?
• 2. Large Sample size (~1700 subjects) is probably needed to adequately assesthe relationship between obesity andmicrobiota composition in a cohort studywhen one corrects for age, gender andother variables eg. (medication and diet)
• 3. Are gutmicrobiota and their derivedmetabolites causally involved in human obesity and its sequelae?
• 4. If so, can we restore this intestinalmicrobial balance?
Falony/Raes, Science 2016
Fecal gutmicrobiome: knownconfounders and more than just
bacterial strains• 16S sequencing
Bojanova, Plos Biology 2016
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Confounders:Diet/medication/age
What about other confunders
Age-adjusted means of BMI during 20 years of follow-up among 78,419 US women by ethnic
group.
Iris Shai et al. Dia Care 2006;29:1585-1590
• Data collected:
✓ Questionnaire: sociodemographics, ethnicity, lifestyle, dietary habits, health, physical activity
✓ Physical examination: anthropometric measurements, clinical measurements, blood draw, medications,
DNA, urine samples, vaginal and oral swabs for microbiome analyses
✓ Morning feces samples > 6000 subjects
✓ Detailed Food Frequency Questionnaires
Multiethnic HELIUS cohort (Healthy Life in an Urban Setting) in Amsterdam, the Netherlands
(Dekker, BMC Public Health 2011; Stronks, BMC Public Health. 2013)
• 22,165 participants (18-70 years)
included between 2011 and 2016
✓ 6 ethnic groups in similar
proportions: Dutch, Surinamese
(African and South-Asian descent),
Turkish, Moroccan and Ghanaian
✓ Preferably 3 generations from one
family (grandparents-children-
grantchildren) included
✓ Otherwise healthy (at baseline visit
30-50% obese with signs of
metabolic syndrome)
** **
***
Currently sequenced 2048 out of 6048 fecal samples in collaboration Fredrik Backhed (Gothenburg
Gutmicrobiota diversity across different Ethnicities in all currently sequenced (n=2048) HELIUS subjects
Deschaschaux/Nieuwdorp , Nature Medicine 2018
RichnessversusEthnicity–OTUlevel
lm p<2e-16
Wilcoxon G M AS SAS T
D p<2.2e-16p=1.0e-06p<2.2e-16p<2.2e-16 P=2.11e-06
G p=0.0016p=1 P=2.868e-11p=0.01
M p=0.001 p=5.241e-13p=0.7
AS p=3.253e-11p=0.01
SAS p=6.46e-12
lm p<2e-16
Wilcoxon G M AS SAS T
D p<2.2e-16p=2.9e-05p<2.2e-16p<2.2e-16 p=3.9e-06
G p=0.006 p=0.99 p=1.0e-10 p=0.07
M p=0.006 p=8.9e-12 p=0.5
AS p=2.49e-10p=0.052
SAS p=1.3e-10
lm p<2e-16
Wilcoxon G M AS SAS T
D p<2.2e-16p=1.18e-05p<2.2e-16p<2.2e-16 p=6.78e-06
G p=0.007 p=0.9 p=1.872e-09p=0.04
M p=0.0098p=8.026e-11p=0.7
AS p=2.15e-09 p=0.04
SAS p=1.07e-09
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Bekijk het volledige profiel van Andrei Prodan
Ervaring
AMC Medical Research BV
maart 2017 – heden (4 maanden) Amsterdam en omgeving, Nederland
Analysis of gut microbiome 16S rRNA sequencing data and other omics from clinical studies
ACTA (academisch centrum tandheelkunde amsterdam)
september 2012 – februari 2017 (4 jaar 6 maanden)
Studying oral biochemistry and its relationship to oral health (part of theTI Food & Nutrion Oral
Health project)
Canadian Research Institute for Food Safety
2011 – 2011 (minder dan een jaar)
Projecten
Startdatum: augustus 2013
The oral cavity is receiving increasing interest from the food, food ingredient and personal care
industries. The human oral cavity is the entry point for all food and drink and the first active part of
the digestive system. Furthermore, the health and hygiene status of the mouth can play a prominent
role in the social comfort of individuals during verbal and non-verbal communication. Reduced oral
health can have a significant negative impact on systemic health, social functioning and wellbeing.
The TI Food and Nutrition theme Oral Health aims to identify the biological processes in the oral
ecosystem responsible for maintaining oral health and to develop in vitro and in vivo technologies
for the development of novel preventative strategies and to evaluate their efficacy. The project is
based on the hypothesis that oral health reflects the ability of the oral ecosystem to adapt to and
counteract perturbing stresses, where the oral ecosystem is defined as the oral microbiota, the
saliva and host (mucosal) immunity.
The past year has been marked by the initiation of the project, completion of the full project proposal
and recruitment of the project leader, principal investigators and team members. Currently, a clinical
inventory study has been initiated aiming to provide a detailed description of the oral ecosystem.
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Melanie Deschasaux Andrei Prodan Evgeni levin
Diversity in different ethnicities
Eve
Holmes E, Cell Metabolism 2012 16, 559-564
2. Causality of intestinal microbiota composition in human (glucose) metabolism and obesity?
Figure 1
Cell Metabolism 2012 16, 559-564DOI: (10.1016/j.cmet.2012.10.007)
Copyright © 2012 Elsevier Inc. Terms and Conditions
Koch’s postulates
for causality of bacteria in human
metabolic disease
• The microorganism must be identified/isolatedfrom a diseased organ(ism).✔
• The microorganism should be associated withdisease (association/intervention) in people. ✔
• The introduced microorganism should reproduce fenotype (inoculation). X
De groot/Nieuwdorp, Gut Microbes 2017
4th Century BC: FMT in Chinese medicine for
food poisoning and diarrhea
1958: Eiseman, antibiotics-induced chronic diarrhea
Fecal transplant in the press 19- 07- 15 11:30FMT Fees and Treatment Costs | Taymount Clinic
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Initial Consultation
Price subject to UK VAT at 20%
120+VAT
This can be by Skype or Telephone
consultation and A formal consultation must be
carried out to establish suitability and to discern
which program is more likely to be the most
beneficial, before an FMT program can be
booked.
Please note: Consultation Fee is deductible
against the cost of treatment if you decide to
make a booking
FMT Fees for 10+2 Programme
£4500
10 implant treatments over 2 weeks and 2
additional implants to take away with you
and use at home.
Included in the price of the program above is a pre-
treatment QOL questionnaire call and follow-up
call(s) 3 months after FMT program is completed.
Dependent upon the presenting condition (as
directed by our CMO), you may be asked to take
a stool test and full details of this will be given if
applicable.
FMT Fees and Treatment Costs
Our Recommended Treatment Plan
Initial consultations must be completed before treatment programs can be arranged.
We recommend patients take up our 10 day, in-clinic treatment plan to achieve the best outcome but we
also recognise that there are advantages to home treatment (being in your own environment, eating your
own food etc) and that some patients are better equipped to use the implants at home than others. We
also understand that cost can be an issue for some patients and that some countries will not allow
implants to be taken across their borders. All of these factors will be considered when preparing a
treatment plan.
During the consultation we will discuss your suitability for FMT and if you and your consultant agree that
FMT is a good option for you, they will recommend a treatment plan for you based on a combination of
treatments in clinic and implants to take away with you and use at home once our fully trained nursing staff
have shown you how and you feel ready to continue treatment at home. Permutations on the 10+2
program can include 5+5 or 5+15 etc. We recommend a minimum of 5 days in clinic so that we can monitor
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Urge to educate (with proper studies) public about therapeutic or non therapeutic effects of FMT
Fecal transplant to study causality of fecal
microbiota in human disease
PRO
• Small groupsizes
sufficient to study
causality
• Every subjects is its own
control (less variation)
• Intervention allows taking
intestinal biopsies next to
fecal samples
CON
• No consensus for donor screening and fecal material treatment
• Only one or two FMTs allowed
• Variation of donor feces composition
• Potential risk of transferring (multiresistant)bacteria/viruses/phages
Van Nood,/Nieuwdorp NEJM 2013
Effects of donor FMT in Clostridium
difficile associated diarrhoea
Reproduced many times and FMT for rec CDiff now in (European) Guidelines
Kelly ANN Int Medicine 2016Lee JAMA 2016Youngster/Homann, JAMA 2014
187
Altering cardiometabolic phenotype in humans
using fecal microbial transplant (FMT)• at AMC >500 FMT’s since 2006, predominantly
in RCT due to large placebo effect
• Long term side effects not observed
• Large placebo effect
• At AMC ongoing/finished RCT’s with single/ multiple FMT using hard clinical endpoints for:
- C difficile diarrhoea
- ESBL (multiresistant bacteria)
- atherosclerosis (TMAO and PETCT)
- metsyn/type 2 diabetes (stable isotope clamp)
- NAFLD/NASH (liverbiopsy)
- anorexia (fMRI)
- cancer cachexia
- type 1 diabetes (T cel autoimmunity)
Smits/Nieuwdorp, Gastroenterology 2013 [; van Nood/Nieuwdorp, NEJM 2013 Rossen, Gastro 2015;Singh/Nieuwdorp, Clin Microbiol Infect. 2014 ; Rossen, Gastro 2015
Microbiota in CVD via TMAO
Koeth et al; Nature Med 2013:Gregory JBC 2015
Vegan FMT affects fecal microbiota composition but has no effect on TMAO production and vascular inflammation
Smits/Kootte/Groen/Stroes/Nieuwdorp, JAHA 2018
FMT is not a panacea!
Autoimmune diseases (DM1/ coeliakie)
IBD and IBS
C difficile
Relation microbiota and disease
most likely not always causal
ESBL/VRE/post AB dysbiosis
Insulin resistance/DM2
Gut-brain axis diseases (autism)
Level of complexityCourse of disease
Responders-non responders
Influence of genetics and diet
Multiple FMT or real failures
Concomitant medication
Causal
microbiota
Disease modifier
Scheihauer/Nieuwdorp, Mol Metabolism 2016
Overnight fast
Insulin prime0 min Steady state the last 20 min
[6,6-2H2]glucose bolus
Basal Step 1 Clamp Step 2
Constant [6,6-2H2]glucose infusion (0.11 µmol · kg–1 · min–1 )
2h Constant insulin infusion (20 mU · m–2
· min–1)
Variable 10% glucose infusion for plasma glucose 5 mmol/l
Hyperinsulinemic euglycemic clampEndogenous (hepatic) glucose production and (peripheral) glucose utilization
12h fast
2h Constant insulin infusion (60 mU · m–2
· min–1)
2h 2h 2h
Effect lean microbiota (FMT) on insulinsensitivity (23%) in metsyn subjects
Vrieze, Gastroenterology 2012
Lean donor FMT increased SCFA butyrate producers
Anne Vrieze
Reproduced that lean donor feces improves insulin sensitivity
(Rd) by 15% but only at 6 weeks (NOT 18 weeks) in Metsyn
• Transient effect (NO LONG TERM EFFECT) at 18 weeks of single or multiple lean donor FMT on fecal microbiotacomposition and(peripheral) insulinsensitivity
• However, significant changes in fecalmicrobiota andIimprovement of insulinsensitivity at 6 weeks upon lean donor FMT (n=26) vs own (n=12) feces
t=0 t=6 t=0 t=610
20
30
40
Rd
(u
mo
l/kg
min
)
autologous allogenic
ns
p<0.05ns
Kootte/Nieuwdorp, Cell Metabolism 2017
Duodenal fecal
Ruud Kootte
Lean donor FMT variable with studies, but
similar effect of oral diabetes medication
on peripheral insulin sensitivity (Rd)
Merovci A, J Clin Invest. 2014;124(2):509-14
SGLT2 inhibition:
insulin sensitivity (Rd)
increase 22%
Karlsson, Diabetes. 2005;54(5):1459-67.
PPARgamma agonist:
insulin sensitivity (Rd)
increase 18%
Lean donor FMT:
insulin sensitivity (Rd)
increase 23% (FATLOSE1)
Effect donor faeces on
periferal insulin sensitivity
A.Vrieze, Gastroenterology 2012
Muscle (periferal) insulin resistance ê
Vrieze, Gastroenterology 2012. Kootte, Cell Metabolism 2017
t=0 t=6 t=0 t=610
20
30
40
Rd
(u
mo
l/kg
min
)
autologous allogenic
ns
p<0.05ns
insulin sensitivity (Rd)
increase 15% (FATLOSE2)
Responders and non responders
Kootte/Nieuwdorp, Cell Metabolism 2017
Engraftment of donor strains after FMT can be studied
By studying bacterial SNPs
Engraftment
Intermediate
No engraftment
Li/Nieuwdorp/deVos/Bork, Science 2016
Li/Nieuwdorp/de Vos/Bork, Science 2016
Donor FMT Engraftment of new microbiotavaries greatly between metsyn subjects
Same lean donor
Lean donor FMT affects fastingplasma metabolites profile
Cystathione
PGA2
LPA C16:0
Homocitrulline
8,12-iPF2alpha VI
LPA C20:1
LPA 483
Sphingosine-1-phosphate C18:1
Homocysteine
Putrescine
L-Arginine
L-Threonine
Sphingosine C18:1 Low Trans
8-iso-PGF2alpha
L-4-hydroxyproline
L-Phenylalanine
L-Kynurenine
Gamma-L-glutamyl-L-alanine
Platelet-activating factor C16:0
Serotonine
L-alpha-aminobutyric acid
L-Homoserine
3-Methylhistidine
LPA C22:5
cLPA C16:0
O-Acetyl-L-serine
LPA C20:3
L-Tryptophan
LPA C18:1
Gamma-aminobutyric acid
-0.6 -0.4 -0.2 0.0 0.2 0.4 0.6 0.8
Metabolite Biomarkers
Model weights/importances
autologous FMT allogenic FMT
autologous FMT allogenic FMT
LEAN FMT increases plasma metabolites involved in serotonin/dopamineOWN FMT increases oxidative stress related metabolites
Cervenka, Science 2017
Kootte/Nieuwdorp, Cell Metabolism 2017
Holmes E, Cell Metabolism 2012 16, 559-564
3. Effect of replenishing missing intestinal metabolites or microbial strains on human (glucose) metabolism and
obesity?
Figure 1
Cell Metabolism 2012 16, 559-564DOI: (10.1016/j.cmet.2012.10.007)
Copyright © 2012 Elsevier Inc. Terms and Conditions
SodiumButyrate improves glucose metabolism DIO mice
• No side effects!
Gao et al, Diabetes , 2009/ Wang/Rensen, Gut 2018
Effect of 4 grams oral butyrate daily during one
month on peripheral and hepatic insulin
sensitivity
in lean and metabolic syndrome subjects (n=10)15% increase in peripheral insulin sentivity
Only in leans10% increase in hepatic insulin sensitivity
Only in leans
Bouter/Nieuwdorp, Clin Translational Gastroenterology 2018
Correlations between clinical markers and and SCFAs in feces andplasma 4 weeks of butyrate significantly different in leans vs
metsyn
Lean Metsyn
MetsynLean
Positive correlation posttreatment fecal butyrate levels (but no other SCFA) with Rd in lean
negative correlation with all SCFA and Rd + LDL cholesterol in metsyn
Bouter/Nieuwdorp, Clin Translational Gastroenterology 2018
FMT allows to mine for beneficial and adverse intestinal bacteria in diabetes/insulin resistance
Eiseman (Surgery 1958)
Reverse engineering to achieve (personalized)
optimal gutmicrobiota composition
Vrieze/Nieuwdorp, Gastroenterology 2012; Nieuwdorp/de Vos, Nature 2013
Nieuwdorp/Groen, Embo 2016
Replenishing (missing) intestinal microbiota or metabolites might improve metabolism in human
obesity
Pitfalls and hurdles
• HACCP/GMP production bacteria as novel probiotics (culture medium and> 80 liter of production)
• Single vs multiple strains (GMP) andlocated delivery (small-large intestine)
• Large and expensive phase I-IV clinical trials for validity (mouse ≠ men)
• No one size fits all …(personalizedmedicine)
Khan/Nieuwdorp/Backhed, Cell Metab 2014
Stratification of patients to personalized
treatments based on gutmicrobiome?
• 1. Gutmicrobiota composition is driven by manyconfounders including ethnicity
• 2.Interstinal microbiota may indeed play a small but causal role in human (metabolic) disease
• 3. Donor bacterial ENGRAFTMENT (responders) differsbetween human subjects and can be predicted on baseline fecal sample
• 4.. reconstitution of single/multiple beneficial bacterialstrain(s) in combination with diet to increaseengraftment might be a solution for human metabolicdisease (more than orally replenishing missing SCFA)
Take home message
Acknowledgments
Willem de VosWUR/Helsinki
Nieuwdorp Group AMC VUMc:Ruud Kootte MDPim Gilijamse, MDKasper ter Horst, MDLoek Smits, MDKristien Bouter, MDPieter de Groot, MDAnnick Hartstra MDGuido Bakker, MDMarcel Tonneijk, MDMark Smits, MDMarcel Muskiet, MDErik van Bommel, MDAnnicke van Baar, MDCasper van Olden, MDNicolien de Clercq, MDTorsten Scheithauer, MscStijn Meijnikman, MDAnnefleur Koopen, MDJulia Witjes MDMichiel van Baar, MDOmrum Ayden, MDMadelief Wijdeveld MDHilde Herrema, PhDDaniel van Raalte, MD PhDEvegeni Levin, PhDAndrei Prodan, PhDMelanie Deschascaux, PhDHan Levels PhDAlinda Schimmel, BscMaaike Winkelmeijer, Bsc
Fredrik backhedGothenborg
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Acknowledgments
Willem de Vos WUR/Helsinki
AMC-VU Nieuwdorp Group: Ruud Kootte MD Fleur van der Valk, MD
Pim Gilijamse, MD
Kasper ter Horst, MD Loek Smits, MD Sophie Bernelot Moens, MD Kristien Bouter, MSc
Pieter de Groot, MD
Annick Hartstra MD Guido Bakker, MD Marcel Tonneijk, MD Mark Smits, MD
Marcel Muskiet, MD
Casper van Olden, MD Nicolien de Clerq, MD Hilde Herrema, PhD Daniel van Raalte, MD PhD
Han Levels PhD
Jing Zhao, PhD Geesje Dallinga, PhD
Alinda Schimmel, Bsc Stefan Havik, Bsc
Petia Kovatcheva, PhD
Gothenborg
Fredrik backhed Gothenborg
Louise Manneras PhD
Gothenborg
Erik Stroes AMC
Bert Groen AMC
Gothenborg lab
John Kastelein AMC
Erwin Zoetendal
Stan hazen Geesje Dallinga-Thie
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