Devkota- Cardiometabolic Cong.ppt
Transcript of Devkota- Cardiometabolic Cong.ppt
Joslin Diabetes CenterPrimary Care Congress for Cardiometabolic Health 2013The GI Tract in the Etiology of the Cardiometabolic Syndrome
Copyright © 2013 by Joslin Diabetes Center, Inc. All rights reserved. These materials may be used for personal use only. Any distribution or reuse of this presentation or any part of it in any form for other than personal use without the express written permission of Joslin Diabetes Center is prohibited.
The microbiome: A historical perspective
> 1985‐1991 Norman Pace pioneered use of PCR to explore diversity of rRNA seq’s. First report of bulk isolation and cloning of DNA from environmental samples.
> 1991 David Relman uses new sequencing methods to discover bacterial causes of many diseases (cat scratch fever, Whipple’s disease).
The human microbiome
Me, myself, usLooking at human beings as ecosystems that contain many collaboratingand competing species could change the practice of medicine
The human microbiome
Me, myself, usLooking at human beings as ecosystems that contain many collaboratingand competing species could change the practice of medicine
Aliens Inside Us: A (Mostly Friendly) Bacterial Nation
New School
2006
2007
2006
2005
2007
20012004
> 2007‐ NIH created the Human MicrobiomeProject to span 5 years and $150 million
> Europe and China joined to form MetaHIT Consortium
> 2012‐ Conclusion of HMP. Series of reports in Nature, PloS One, Science.
> 2013‐ HMP 2.0?
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Joslin Diabetes CenterPrimary Care Congress for Cardiometabolic Health 2013The GI Tract in the Etiology of the Cardiometabolic Syndrome
Copyright © 2013 by Joslin Diabetes Center, Inc. All rights reserved. These materials may be used for personal use only. Any distribution or reuse of this presentation or any part of it in any form for other than personal use without the express written permission of Joslin Diabetes Center is prohibited.
The gut mucosa is our only protection from the outside world
Food particles
Bacteria, virus, fungi Toxins
Microbial byproducts
> There are more bacteria in our guts than cells in our entire body
> Dense microbial community interacts with your largest immune and endocrine organ
> Acquired from the environment from birth onwards
> Educates your immune system
> Breakdown otherwise indigestible dietary components
A hundred trillion of your closest friends
…but you must treat your friends well
Microbial influences on cardiometabolism
> Bacteria are absolutely required for energy harvest in the gut
Backhed et al. PNAS (2004)
• High fat feeding increases gut permeability
• Chronic permeability leads to impaired metabolism
(Cani et al, Diabetes 2008).
• Type 2 diabetics exhibit a unique microbial profile similar to individuals with chronic gastritis (Qin et al. Nature 2012)
> Does Type 2 Diabetes start in the gut?
Microbial influences on cardiometabolism
Whatever is Driving the Autoimmunity Underlying Type 1 Diabetes Begins Early in Life
Geneticsusceptibility
% I
slet
Cel
l Ma
ss
100
50
0
IncitingEvent(s)
“Brittle”Diabetes
Time (years)
“Silent” �Cell Loss
DiabetesOnset
A microbial fingerprint for Type 1 Diabetes risk?
Microbial influences on cardiometabolism
Dumas et al.PNAS (2006)
Pluznick et al.PNAS (2013)
Koeth et al.Nat Med (2013)
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Joslin Diabetes CenterPrimary Care Congress for Cardiometabolic Health 2013The GI Tract in the Etiology of the Cardiometabolic Syndrome
Copyright © 2013 by Joslin Diabetes Center, Inc. All rights reserved. These materials may be used for personal use only. Any distribution or reuse of this presentation or any part of it in any form for other than personal use without the express written permission of Joslin Diabetes Center is prohibited.
Koenig et al. PNAS (2010),
Diet shapes gut bacterial profile in humans
> Burkina Faso, AfricaDietary intake, ages 1‐6
• 672.2 ‐ 996.1 kcal/d
• Protein: 30.9 ‐ 40.2 g/d
• Fat: 18.9 ‐ 31.2 g/d
• Carbohydrates: 102.6 ‐ 148.6 g/d
BacteroidetesBacteroidetes
FirmicutesFirmicutes
BacteroidetesBacteroidetes
FirmicutesFirmicutes
De Filippo et al. PNAS (2010)
> EU, ItalyDietary intake, ages 1‐6
• 1068.7 – 1512.7 kcal/d
• Protein: 41.9 – 66.7 g/d
• Fat: 56.1 – 73.9 g/d
• Carbohydrates: 190.0 – 290.0 g/d
Genetic susceptibility
Immuneresponse
Environmentaltriggers
Luminal and Microbial adjuvants
Multiple hits creating the perfect storm
Cardiometabolicdiseases
Characteristics of the American diet(NHANES, 2001)
> 2,618 kcal/d
> 49% carbohydrate
> 15.5% protein
> 32.8% fat
> 10.9% saturated fat (of total kcal)
Study DietsLow-fat
(AIN-93M)Saturated-
Milk FatSaturated-Lard Fat
PUFA(Safflower oil)
Fat (%kcal)-Saturated (%total)-PUFA
ProteinCarbohydrateMicronutrients/Fiber
50.63.9
1966
*ND
38653.5
1647
*ND
383911
1647
*ND
38978
1647
*ND
Can dietary fat alter the enteric microbiome?
LF PUFA MF
> C57BL/6 mice fed three diets for 21 days
Devkota et al. Nature (2012)
% in
cide
nce
of c
oliti
s
Time (weeks)
MF
PUFA
LF
> IL10‐/‐mice fed three diets for 21 days
Arumugam et al. Nature (2011)
> Low‐abundance species with high function?
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Joslin Diabetes CenterPrimary Care Congress for Cardiometabolic Health 2013The GI Tract in the Etiology of the Cardiometabolic Syndrome
Copyright © 2013 by Joslin Diabetes Center, Inc. All rights reserved. These materials may be used for personal use only. Any distribution or reuse of this presentation or any part of it in any form for other than personal use without the express written permission of Joslin Diabetes Center is prohibited.
Bilophila wadsworthia?
> Discovered in 1988
> Bilophila = “bile‐loving”
> Sulfite‐reducing bacteria (SRB‐ dsrA)
> Input sulfite, output H2S
> Often recovered from a variety of infections (pathobiont)
> Bile must be the sulfite source
Key = Taurocholic acid
Diet-derived bile
MFLF PUFA
% T
auro
chol
ate
of total bile
***
Op
tical d
en
sity
MF Bile
PUFA BileLF BileControl Media
Time (hrs)
Devkota et al. Nature (2012)
> A symbiont that turns pathogenic given the right stimulus
> Present in healthy individuals
> These bacteria have evolved the ability to survive harsh environments
What is a pathobiont?
Complications of modern society
> Antibiotic overuse
• MRSA
> Hospital acquired infections
• C. difficile
> The “hygiene hypothesis” and autoimmunity
• Food allergies
B. wadsworthia induces TH1-mediated colitis
a
c bc bcbc
b
a
bb
ccc
a
bbcbcbcc
LF + Bw MF + Bw0% 0%
PUFA + Bw23%
MF + Bw
CD4
IFN
-γ
CD4
Isot
ype
0% 0% 28%
Devkota et al. Nature (2012)
% C
D4+
IFNγ+
cel
ls
**
LF + Bw
PUFA + Bw
MF + Bw
Num
ber
of I
FNγ
prod
ucin
g C
D4+
cel
ls (
105)
**
LF + Bw
PUFA + Bw
MF + Bw
Can we re‐shape the gut microbiotathrough diet?
Design:
1. SPF IL10‐/‐mice fed 4 diets for 8 weeks:
Low‐fat High Saturated‐fatHigh Saturated‐fat + 5% fish oil High Saturated‐fat + 5% safflower oil
2. Germ‐free IL10‐/‐mice monoassociated w/ B. wadsworthia and fed test diets for 4 weeks
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Joslin Diabetes CenterPrimary Care Congress for Cardiometabolic Health 2013The GI Tract in the Etiology of the Cardiometabolic Syndrome
Copyright © 2013 by Joslin Diabetes Center, Inc. All rights reserved. These materials may be used for personal use only. Any distribution or reuse of this presentation or any part of it in any form for other than personal use without the express written permission of Joslin Diabetes Center is prohibited.
Omega‐3 supplementation inhibits bloom of Bw in SPF IL10‐/‐ mice
0102030405060708090
100
Bacteroidetes
Firmucutes
Proteobacteria
Cyanobacteria
Actinobacteria
Tenericutes
LF MF MF + -3 MF + -6
% B
.wad
swor
thia
LF MF
MF +
ω-6
MF +
ω-3
0
1
2
3
4
5*
*
#LF MF
MF +
! -6
MF +
! -30
1
2
3
4C
oliti
s S
core
***
*
#
LF MF
MF +
ω-6
MF +
ω-3
0
50
100
150
pg/m
L IF
N * *
#
LF MF
MF +
ω-6
MF +
ω-3
0
200
400
600
800
pg/m
L IL
12p7
0
*
*
#
LF MF
MF +
ω-6
MF +
ω-3
0
50
100
150
200
pg/
mL
IL6 *
#
LF MF
MF +
ω-6
MF +
ω-3
0
200
400
600
800
pg/m
L IL
17 *
#
Bw growth and inflammation is attenuated by omega‐3 supplementation
LF MF
MF +ω-6
MF +
ω-3
0.0
0.5
1.0
20
40
60
80
100
120
Rel
ativ
e fo
ld c
hang
e (d
srA
)
*
*
#
CD4
IFN
-γ
10% 5% 1%
CD4
Isotyp
e
MF MF + ω -6 MF + ω -3
>Current drug therapy for diabetes is poor and narrowly focused
>Targeting bacterial populations and intestinal inflammation offer new avenues for treating and curing metabolic diseases.
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>Pathobionts: Understand the triggers that turn a benign bacteria into a pathogen
>Prebiotics: Develop nutrient therapy that selectively eliminates harmful bacteria or promotes growth of beneficial bacteria.
>Probiotics: Design robust bacterial cocktails tailored to an individual’s microbiome.
The future of personalized medicine:Prebiotics, Probiotics, and Pathobionts
Clinical Implications
> The intestinal microbiota are absolutely required for intestinal health and homeostasis
> Dysbiosis results from an array of external influences, namely diet and antibiotics, that can provide fertile ground for pathobiont expansion
> In the presence of pathobionts, the intestinal barrier may become compromised, leading to luminal antigens passing through systemic circulation
> This phenomena is responsible for an array of inflammatory diseases and may explain others of unknown origin
Future therapies for treating systemic inflammation must begin to consider re‐shaping the gut microbiota
Acknowledgements
Joslin Diabetes CenterSteven ShoelsonJongsoon Lee
The University of ChicagoEugene ChangBana Jabri
Matthew BradyChris RhodesMark MuschYunwei WangVanessa Leone
Anuradha NadimpaliHannah Fehlner‐Peach
Romain BouziatDigestive Diseases Research
Core CenterCommittee on Molecular Metabolism and Nutrition
Argonne National LaboratoryDionysios Antonopoulos
Folker MeyerJack Gilbert
Michigan State UniversityJames TiedjeMarius Vital
UCLA‐Wadsworth VASidney Finegold
UCSDLee Hagey
Alan Hofmann
Questions?
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