New Cardiovasculaire zorgen van morgen: Diabetes · 2019. 2. 11. · DNA, urine samples, vaginal and oral swabs for microbiome analyses Morning feces samples > 6000 subjects Detailed

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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and... Read more. Jeffrey N.

Geboren: 1947, New Orleans, Louisiana, Verenigde

Staten

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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Jeffrey gordon

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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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


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


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

Deschaschaux/Nieuwdorp,manuscriptinpreparaFon

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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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Diversity in different ethnicities

Eve


2. Causality of intestinal microbiota composition in human (glucose) metabolism and obesity?

Figure 1



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

Download ourBrochure

Click the button below to download

our Faecal Microbiota Transplant

brochure and find information and

answers to many common

questions.

Schedule YourConsultation

Use the online booking facility below

to schedule your initial consultation.

How To Contact Us

The Taymount Clinic

Croft Chambers, 11 Bancroft

Hitchin, Hertfordshire

SG5 1JQ, United Kingdom

Tel: +44 (0)1462 712 500

Email: [email protected]

Clinic Hours

Monday to Friday

9.00 am to 5.30 pm (UK Time)

Gut Health Pioneers

"We are proud to say that we have

developed a processing and

administering protocol which is

highly effective without being

excessively invasive or

uncomfortable and which is the

result of many hours’ research,

study and trials."

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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:


increase 18%

Lean donor FMT:


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


increase 15% (FATLOSE2)

Responders and non responders


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



3. Effect of replenishing missing intestinal metabolites or microbial strains on human (glucose) metabolism and

obesity?

Figure 1



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

Peer Bork

EMBLBart Roep, LUMC/LA

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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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New Cardiovasculaire zorgen van morgen: Diabetes · 2019. 2. 11. · DNA, urine samples, vaginal and oral swabs for microbiome analyses Morning feces samples > 6000 subjects Detailed