Prof. Caroline Pot Rôle de la nutri-on et de la flore intes-nale dans les maladies auto-immunes
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Rôle
de
la
nutri-on
et
de
la
flore
intes-nale
dans
les
maladies
auto-‐immunes
Prof.
Caroline
Pot
Service
de
Neurologie
Département
des
Neurosciences
Cliniques
UNIL/CHUV
Contact:
caroline.pot-‐kreis@chuv.ch
Jeudi
30.01.2020
QUADRIMED
Crans-‐Montana
2/10/20
1
Plan
de
la
présentaIon
-‐ IntroducIon
flore
intesInale
(microbiote
intesInal)
et
maladies
auto-‐
immunes
-‐ Maladies
auto-‐immunes:
axe
intesIn-‐cerveau
et
sclérose
en
plaques
-‐ Autres
maladies
auto-‐immunes
2/10/20
2
Le microbiote intesInal 2/10/20 3
Le microbiote intesInal = flore intesInale -‐ 1-‐2 kg de bactéries dans notre corps (Whitman et al, Prokaryotes: The unseen majority, PNAS 95: 6578, 1998) -‐ 100’000 milliard de microorganismes : 10 x plus que de cellules dans le corps humain -‐ Au moins 1’000 espèces bactériennes -‐ Plus de 3 millions de gènes, soit 150 X plus que le génome humain Human microbiota 2/10/20 The human microbiome: Me, myself, us; The Economist: Microbes maketh man, August 18th 2012 4
Microbiote intesInal et réparIIon dans les intesIns 2/10/20 5
Microbiote
intesInal
et
rôle
des
facteurs
environnementaux
Sandhu
et
al.,
Feeding
the
microbiota-‐gut-‐brain
axis:
diet,
microbiome,
and
neurpsychiatry.
Transl
Res.
2017
Jan;179:223-‐244
2/10/20
6
NutriIon
et
Microbiote
intesInal
Sandhu
et
al.,
Feeding
the
microbiota-‐gut-‐brain
axis:
diet,
microbiome,
and
neurpsychiatry.
Transl
Res.
2017
Jan;179:223-‐244
2/10/20
7
Obésité et dysbiose
• Dysbiose: un
déséquilibre
du
microbiote
intesInal
Shift lors de l’obésité
2/10/20
8
Transplantation fécale et obésité 2/10/20 9
Quid des maladies autoimmunes? 2/10/20 10
maladies autoimmunes 2/10/20 11
IntesIn-‐autoimmunité: quel lien? 2/10/20 12
Microbiote intesInal et les cellules immunitaires 2/10/20 13
Dialogue
entre
flore
intesInale
et
les
cellules
immunitaires
Jangi
et
al.,
AlteraIons
of
the
human
gut
microbiome
in
mulIple
sclerosis,
Nat
Commun.
2016
Jun
28;7:12015
2/10/20
14
Plan
de
la
présentaIon
-‐ IntroducIon
Microbiote
et
maladies
auto-‐immunes
-‐ Maladies
auto-‐immunes:
axe
intesIn-‐cerveau
et
sclérose
en
plaques
-‐ Autres
maladies
auto-‐immune
2/10/20
15
Axe
intesIn-‐cerveau:
quel
lien?
David J. Durgan. Stroke. Examining the Role of the Microbiota-Gut-Brain Axis in Stroke,
Volume: 50, Issue: 8, Pages: 2270-2277, DOI: (10.1161/STROKEAHA.119.025140)
2/10/20
16
© 2019 American Heart Association, Inc.DéfiniIon
de
la
sclérose
en
plaques
(SEP)
• SEP : maladie «auto-immune »
• Affection neurologique chronique du système nerveux central (SNC)
• Facteurs démographiques:
- 1ère manifestation généralement entre 20 et 40 ans
- Incidence (pays occidentaux): 3-7/100.000
- Prévalence: 50-200/100.000
- Suisse: env. 10.000 personnes atteintes
- Ratio femmes/hommes 2:1 (formes progressive: 1:1)
2/10/20
17
Sclérose
en
plaques:
maladie
mulIfactorielle
Géné-que
Environnement
Risque
de
développer
la
SEP:
ExposiIon
à
la
lumière/
vitamine
D
-‐
Sans
histoire
familiale:
1
/
700
Cigareje
-‐
Fratrie
:
1
/
25
-‐
Jumeaux
monozygotes:
1
/
5
SEP InfecIeux
(EBV)
Microbiote
intesInal?
NutriIon
?
Métabolisme
?
2/10/20
18
Gradient
Nord-‐Sud
pour
la
prévalence
de
la
SEP
• Gradients Nord-Sud
dans l’hémisphère Nord
140/100 000 en Ecosse
40/100 000 en Sicile
Atlas
of
MS
2013
2/10/20
19
2/10/20
ֺ
InfecIon
parasitaire
et
prévalence
de
la
SEP
MS
Hookworm
20
Helminthes
et
acIvité
de
la
SEP
rbations (A) and changes
Correale
in
et
al.,
extended disability
AssociaIon
Between
status
Parasite
InfecIon
scale
and
Immune
(EDSS;
Responses
B) and
in
MulIple
Sclerosis,
Annals
omagnetic resonance
f
Neurology
2007
February
Vol
61:97-‐108
infected (squares) and uninfected (diamonds) multiple sclerosis (MS
rved over time in parasite
2/10/20
21
Sclérose
en
Plaques
et
dysbiose
Ø
Dysbiose
chez
des
personnes
ajeintes
de
SEP
Ø
Corréla-on
entre
dysbiose
intesInale
les
variaIons
dans
l’expression
des
gènes
inflammatoires
impliqués
dans
la
SEP
Jangi
et
al.,
AlteraIons
of
the
human
gut
microbiome
in
mulIple
sclerosis,
Nat
Commun.
2016
Jun
28;7:12015
2/10/20
22
Sclérose
en
Plaques
-‐
Dysbiose
-‐
Dysimmunité
Jangi
et
al.,
AlteraIons
of
the
human
gut
microbiome
in
mulIple
sclerosis,
Nat
Commun.
2016
Jun
28;7:12015
2/10/20
23
ARTICLE Sclérose
en
Plaques
/Dysbiose
NATURE COMMUNICATIONS | DOI: 10.1038/ncomm
a b Low_abundance
Akkermansia
Euryarchaeota Verrucomicrobia Bacteria;unclassified
Mollicutes;unclassified
0.15 * 4 *** Firmicutes;unclassified
3
groupes:
Relative abundance (%) 0.10
3
Megasphaera
Dialister
* ***
2
Erysipelotrichaceae;unclassif
Clostridiales;unclassified
454
Ruminococcaceae;unclassifie
• ParIcipants
contrôles
0.05
1 Ruminococcus
Faecalibacterium
0.00 0 Ethanoligenens
Unclassified
S
ol
ed
ed
l
nt S
T d
ed
o
M
e
M
tr
tr
Oscillibacter
at
at
at
at
on
on
re
re
re
re
• Personnes
souffrant
de
SEP
:
C
C
T
nt
Lachnospiraceae;unclassified
U
U
Roseburia
Dorea
-‐
pas
traitées
* 3
Euryarchaeota
20
Verrucomicrobia Coprococcus
Blautia
-‐
traitées
(Interféron,
GlaIramère
d’acétate)
Anaerostipes
Relative abundance (%)
Gracilibacter
15
* ** 2 Eubacterium
Sarcina
MiSeq
10 Streptococcus
1
5
Bacteroidales;unclassified
Alistipes
0 0
Prevotella
Porphyromonadaceae;unclas
Parabacteroides
S
S
ol
ed
ed
ol
ed
ed
M
M
tr
tr
at
at
at
at
Barnesiella
on
on
re
re
re
re
C
C
T
T
nt
nt
Bacteroides
U
U
HC MS-U MS-T HC MS-U MS-T Bifidobacterium
Methanobrevibacter
454 MiSeq
c Jangi
et
al.,
AlteraIons
MS–effect of
the
human
gut
microbiome
in
mulIple
sclerosis,
&NTreatment–effect
MS–effect at
Commun.
2016
Jun
28;7:12015
Treatment–effe
Methanobrevibacter Akkermansia Butyricimonas Prevotella Sutterella Sarcina
0.15 4 ** 0.20 4 0.15 4
* * #
2/10/20
24
ance (%)
** **
3 0.15 3 3
0.10 # 0.10 ***
** ***0.05
1 0.05 1
Microbiome
intesInal
et
SEP
0 0.00 0 0.00
20 * 0.20 ** 5 0.03
** ***
4
15 0.15
** * 0.02
3
10 0.10 ***
2
0.01
5 0.05
1
0 0.00 0 0.00
n t MS
nt MS
S
n t MS
l
d
l
ed
Tr d
d
l
Tr d
d
l
Tr d
d
l
tro
ro
ro
ro
te
e
te
e
te
e
te
M
M
at
t
at
t
at
t
at
ea
on
ea
on
ea
on
ea
on
re
re
re
re
Tr
C
C
C
C
FermentaIon
nt
U
U
U
U
U
sitional differences in faecal microbiota Butyrates
between MS patients and healthy subjects.
Développement
(a) Relat
cellules
Butyricimonas
sécréIon
IL-‐6
n the faecal microbiota of
healthy controls (n ¼ 43, grey bar), all MS patients Th17
(n ¼ 60, red) and
t (n ¼ 32, blue) subgroups
as analysed by two independent sequencing technologies, 454 (top)
alent microbiota (41% in (acide
any sample group)
gras
à
chaine
determined from MiSeq and 454 high-throughput
courte)
l microbiota that are significantly altered between healthy controls (n ¼ 43) and MS patients (n
ed MS Possible
hypothèse
à
patients (n ¼ 32) entre
la
relaIon
(disease microbiote,
effect) as
analysed
système
immunitaire
by two eindependent t
pathologie
de
la
SEP
sequencing technolo
mini–Hochberg corrected P values o0.05 with a false discovery rate threshold of 0.1. Bars repre
2/10/20
Chang
et
al.,
The
microbial
metabolite
butyrate
regulates
intesInal
macrophage
funcIon
via
histone
25
deacetylase
inhibiIon,
PNAS
February
11,
2014
111(6)
2247-‐2252
Régimes
alimentaires
et
neuroinflammaIon
modèle
murin
-‐Régime
riche
en
acide
gras
courte
chaîne
SCFA
(C6):
lauric
acid
[LA],
palmiSc
acid
Haghikia
et
al.,
Dietary
Fajy
Acids
Directly
Impact
Central
Nervous
System
Autoimmunity
via
the
Small
IntesIne,
Immunity
2015
Oct
20;43(4):817-‐29
2/10/20
26
Biopsie duodenale dans la SEP 2/10/20 27
2/10/20 28
Microbiome
intesInal
et
immunité
PaIents
SEP
Contrôles
INTESTIN
SANG
Cosorich
et
al.,
High
frequency
of
intesInal
TH
17
cells
correlates
with
microbiota
alteraIons
and
disease
acIvity
in
mulIple
sclerosis,
Sci
Adv.2017
Jul
12;3(17):e1700492
2/10/20
29
Cellules
Th17
intesInales
et
évoluIon
de
la
SEP
Cosorich
et
al.,
High
frequency
of
intesInal
TH
17
cells
correlates
with
microbiota
alteraIons
and
disease
acIvity
in
mulIple
sclerosis,
Sci
Adv.2017
Jul
12;3(17):e1700492
2/10/20
30
Présence
de
lymphocytes
reconnaissant
la
myéline
dans
le
colon
Duc
D
et
al,
Cell
reports,
2019,
2/10/20
31
Importance
de
l’axe
intesIn-‐cerveau
dans
un
modèle
murin
Neuro-‐inflammaIon
Myelin-‐specific
TH17
IntesInal
dysbiosis
Duc
D
et
al,
Cell
reports,
2019
2/10/20
32
Présence
de
Plasmocytes
IgA
dans
le
cerveau
de
paIent
SEP
• DiminuIon
des
bactéries
fécales
liées
au
IgA
lors
de
poussée
• Présence
de
plasmocytes
IgA+
dans
le
cerveau
de
paIents
avec
une
SEP
Cell.
2019
Jan
24;176(3):610-‐624.e18.
doi:
10.1016/j.cell.2018.11.035.
Epub
2019
Jan
3.
2/10/20
33
- SPF mice (Supplementary Table 1). Moreover, germ-free and SPF SJL/J
wWe show mice immunized with rMOG produced comparable levels of anti-
mice immunized
groducing MOG antibodies
MOG antibodies
with rMOG
in theirinserum
produced
their serum
(Fig. 1d).
comparable
(Fig. 1d).
Dysbiosis:
cause
ou
conséquence?
levels of anti-
-on avail- Recent studies
Recent studies established
established that components
that components of theofcommensal
the commensal micro-
micro-
Encephalomyélite
-te glyco- Autoimmune
E xpérimentale
( EAE)
biota profoundly
biota profoundly shape shape the gut-associated
the gut-associated lymphatic
lymphatic tissue
tissue (GALT),
(GALT),
ervations
s
e
oimmunea a b b
Spontaneous EAE incidence (%)
Spontaneous EAE incidence (%)
Spontaneous EAE incidence (%)
Spontaneous EAE incidence (%)
rgets. 100 100GF(Environnement
GF stérile)
100 100
J SPF SPF
enic SJL/J 80 80 80 80
-, a trans-
6 92–106 60
de 60 60 60
py develop 40 40
euccessive 40 40
Colonization
Colonization
)m (CNS) 20 20
20 6–12 weeks
20 6–12 weeks
h
lls, which 0 0
s 0 0
ng B cells 0 10 20 30 40 50 0 5 10 15 20 25 30
Time (weeks) after birth 40
0 10 20 30 50
Time0(weeks)
5 10 15 20 25 30
after
- Time (weeks) after birth Time (weeks) after
colonization
red Øspon-
Modula-on
du
microbiote:
exacerbaIon
ou
amélioraIon
des
symptômes
c d
colonization
%e in other 5 c GF WT 2.5
d cooperate
Berer
et
al.,
Commensal
microbiota
and
myelin
autoanIgen
GF WT
to
trigger
autoimmune
demyelinaIon,
Nature
2011
Oct
26;479(7374):538-‐41
m 5 2.5 GF WT
o 35–90% 4 SPF WTGF WT SPF WT
score
SPF WT 2.0 SPF WT34
cthat also
2/10/20
ore
4 2.0Facteurs
de
risque
pour
la
SEP
:
dysbiose
intesInale
Transplanta-on
fécale
de
microbiome
intes-nal
Pourcentage
de
souris
avec
symptômes
neurologies
Jumeaux
monozygoIques
discordants
pour
la
SEP
Temps
(sem)
après
transplantaIon
fécale
Berer
K
et
al.
Proc
Natl
Acad
Sci
U
S
A.
2017.
2/10/20
35
Microbiote et cellules immunitaires 2/10/20 36
Spectre de la neuromyélite opIque (NMOSD) 2/10/20 37
RAPID COMMUNICATION
NMOSD et
dysbiosis
Aquaporin 4-Specific T Cells in
Neuromyelitis Optica Exhibit a Th17 NMOSDaugmentaIon
de
Bias and Recognize Clostridium clostridium
perfringens
ABC Transporter
Michel Varrin-Doyer, PhD,1 Collin M. Spencer, BS,1 Ulf Schulze-Topphoff, PhD,1
Patricia A. Nelson, PhD,1 Robert M. Stroud, PhD,2 Bruce A. C. Cree, MD, PhD,1
and Scott S. Zamvil, MD, PhD1
bjective: Aquaporin 4 (AQP4)-specific autoantibodies in neuromyelitis optica (NMO) are immunoglobulin (Ig)G1, a
cell-dependent Ig subclass, indicating that AQP4-specific T cells participate in NMO pathogenesis. Our goal was
o identify and characterize AQP4-specific T cells in NMO patients and healthy controls (HC).
Methods: Peripheral blood T cells from NMO patients and HC were examined for recognition of AQP4 and
roduction of proinflammatory cytokines. Monocytes were evaluated for production of T cell-polarizing cytokines
nd expression of costimulatory molecules.
esults: T cells from NMO patients and HC proliferated to intact AQP4 or AQP4 peptides (p11–30, p21–40, p61–80,
131–150, p156–170, p211–230, and p261–280). T cells from NMO patients demonstrated greater proliferation to
QP4 than those from HC, and responded most vigorously to p61–80, a naturally processed immunodominant
eterminant of intact AQP4. T cells were CD4þ, and corresponding to association of NMO with human leukocyte
ntigen (HLA)-DRB1*0301 and DRB3, AQP4 p61–80-specific T cells were HLA-DR restricted. The T-cell epitope
ithin AQP4 p61–80 was mapped to 63–76, which contains 10 residues with 90% homology to a sequence within
lostridium perfringens adenosine triphosphate-binding cassette (ABC) transporter permease. T cells from NMO
atients proliferated to this homologous bacterial sequence, and cross-reactivity between it and self-AQP4 was
bserved, supporting molecular mimicry. In NMO, AQP4 p61–80-specific T cells exhibited Th17 polarization, and
urthermore, monocytes produced more interleukin 6, a Th17-polarizing cytokine, and expressed elevated CD40 and
D80 costimulatory molecules, suggesting innate immunologic dysfunction.
nterpretation: AQP4-specific T-cell responses are amplified in NMO, exhibit a Th17 bias, and display cross-reactivity
o a protein of an indigenous intestinal bacterium, providing new perspectives for investigating NMO pathogenesis.
ANN NEUROL 2012;72:53–64
2/10/20
38
Microbiote et cellules immunitaires 2/10/20 39
48
Bactéries
comme
source
de
métabolites
Autoimmunity
Figure 2
Dietary tryptophan Tryptophanase posi!ve gut bacteria
(e.g. Lactobacillus reuteri)
Tryptophanase Indole
O
OH
NH2 HN
HN
O Indoxyl-
S
O O O
- 3-sulfate
I3S I3S
HN
Liver
I3S
Blood brain barrier
Astrocyte
I3S I3S AHR
SOCS2
NF-κB
Monocyte Monocyte / Microglia
Neurotoxicity
recruitment ac!va!on
Current Opinion in Immunology
Magalam
et
al.,
Human
Gut-‐Derived
Commentsal
bacteria
Suppress
CNS
Inflammatory
and
DemyelinaIng
Disease,
Cell
Rep.
2017
Aug
8;20(6):1269-‐1277
Metabolites of dietary tryptophan control autoimmune inflammation in the CNS. The essential amino acid tryptophan is broken down to indole by
tryptophanase-positive, ampicillin-sensitive, vancomycin-resistant bacteria in the gut. One of the bacterial strains exhibiting these features is
Lactobacillus reuteri. Thereafter, indole is metabolized to indoxyl-3-sulfate (I3S) and other metabolites in the liver and released into the circulation.
These indole derivatives are capable of crossing even the intact blood brain barrier and enter into the CNS, where they bind and activate the
cytosolic Aryl hydrocarbon receptor (AHR). AHR interacts with SOCS2 to inhibit NF-kB activation and nuclear translocation. Ultimately, NF-kB
dependent pro-inflammatory pathways, including monocyte recruitment, neurotoxicity, and activation of monocytes and microglia are inhibited.
2/10/20
Together, these pathways confer down-modulatory actions on acute and chronic inflammation in the CNS and integrate dietary and microbial 40
signals into CNS inflammation.Comment influencer notre microbiote intesInal? 2/10/20 41
TransplantaIon
fécale
pour
traiter
les
maladies
neurologiques?
2/10/20
42
Essai
clinique
en
cours
MS-‐BIOME
Fecal
Microbiota
TransplantaIon
(FMT)
of
FMP30
in
Relapsing-‐
Remiung
MulIple
Sclerosis
ClinicalTrials.gov
IdenIfier:
NCT03594487
University
of
California,
San
Francisco
Début:
16
novembre
2018,
fin
novembre
2020
hjps://clinicaltrials.gov/ct2/show/NCT03594487?cond=NCT03594487&rank=1
2/10/20
43
AlimentaIon
et
microbiote
…
Contenu
de
l’alimentaIon
2/10/20
44
Régimes et SEP" 2/10/20 45
ARTICLE
Diet quality is associated with disability and
symptom severity in multiple sclerosis
Kathryn C. Fitzgerald, ScD, Tuula Tyry, PhD, Amber Salter, PhD, Stacey S. Cofield, PhD, Gary Cutter, PhD, Correspondence
Robert Fox, MD, and Ruth Ann Marrie, MD, PhD Dr. Fitzgerald
fitzgerald@jhmi.edu
Neurology® 2018;90:e1-11. doi:10.1212/WNL.0000000000004768
Abstract RELATED ARTICLE
Objective Editorial
To assess the association between diet quality and intake of specific foods with disability and
Basé
s ur
u n
registre:
N
symptom severity in people with multiple sclerosis (MS). orth
A merican
R esearch
C ommijee
o n
M S
( NARCOMS)
Diet in multiple sclerosis:
Science takes a seat at the
table
Methods Page 14
6,989
parIcipants
In 2015, participants in the North American Research Committee on MS (NARCOMS)
Registry completed a dietary screener questionnaire that estimates intake of fruits, vegetables
CME Course
and legumes, whole grains, added sugars, and red/processed meats. We constructed an overall NPub.org/cmelist
diet Score
quality p lus
élevé
=
alimentaIon
plus
saine
score for each individual based on these food groups; higher scores denoted
a healthier diet. We assessed the association between diet quality and disability status as
measured using Patient-Determined Disease Steps (PDDS) and symptom severity using
proportional odds models, Fitzgerald
et
al.,
Diet
for
adjusting quality
age,is
sex,
associated
income, with
body disability
massaindex,nd
symptom
smoking severity
status, in
mulIple
and sclerosis,
Neurology
2018;90:e1-‐11
disease duration. We assessed whether a composite healthy lifestyle measure, a healthier diet,
healthy weight (body mass indexRégimes alimentaires suivis par les paIents 2/10/20 47
Score
plus
élevé
=
alimenta-on
plus
saine
• Plus
de
fruits
et
légumes
• Céréales
complètes
• Faible
consommaIon
d’aliments
sucré
(avec
ou
sans
édulcorant)
et
viande
rouge
est
associée
à
• DiminuIon
de
dépression
sévère
• DiminuIon
des
douleurs
• DiminuIon
de
la
faIgue
• Moins
d’ajeinte
“dite
cogniIve”
Fitzgerald
et
al.,
Diet
quality
is
associated
with
disability
and
symptom
severity
in
mulIple
sclerosis,
Neurology
2018;90:e1-‐11
2/10/20
48
Sclérose
en
plaques
pédiatriques
• Prevalence
du
début
de
la
SEP
dans
l’enfance
/
adolescence
:
2.2%-‐4.4%.
• Plus
de
poussées
(par
rapport
aux
adultes)
Tremlej
et
al.,
Gut
microbiota
composiIon
and
relapse
risk
in
pediatric
MS:
A
pilot
study,
Journal
of
Neurological
Sciences
363
(201)
153-‐157
2/10/20
49
Nutrition"
Downloaded from http://jnnp.bmj.com/ on March 5, 2018 - Published by group.bmj.com
Multiple sclerosis
RESEARCH PAPER
Contribution of dietary intake to relapse rate in early
paediatric multiple sclerosis
Saeedeh Azary,1 Teri Schreiner,2 Jennifer Graves,1 Amy Waldman,3 Anita Belman,4
Bianca Weinstock Guttman,5 Gregory Aaen,6 Jan-Mendelt Tillema,7 Soe Mar,8
Janace Hart,1 Jayne Ness,9 Yolanda Harris,9 Lauren Krupp,10 Mark Gorman,11
Leslie Benson,11 Moses Rodriguez,7 Tanuja Chitnis,11 John Rose,12 Lisa F Barcellos,13
Tim Lotze,14 Suzan L Carmichael,15 Shelly Roalstad,16 Charles T Casper,16
Emmanuelle Waubant1
For numbered affiliations see ABSTRACT MS susceptibility may be higher in individuals with
end of article. Objective The role of diet in multiple sclerosis (MS) higher saturated fat intake,6 while consumption of
course remains largely unknown. Children with MS have fruit and vegetables may be associated with reduced
Correspondence to
Dr Emmanuelle Waubant,
Azary
et
al.,
aChigher
ontribuIon
relapse of
rate
dietary
comparedintake
with
to
relapse
MS in radults.
ate
in
eThus,
arly
paediatric
mulIple
sclerosis,
patient-reported relapse J
Nrate
eurol
and Neurosurg
disability. Psychiatry
7
Neither
studying the effect of diet on relapse rate in this age
2018;89:28-‐33
Department of Neurology, of these reports have been confirmed nor have used
University of California San group is likely to provide more robust answers. medically confirmed MS relapses or longitudinal
Francisco, San Francisco, CA Methods This is a multicentre study done at 11 prospectively collected data.
2/10/20
94158, USA; emmanuelle. Children have a 50
higher relapse rate compared
paediatric MS centres in the USA. Patients with
waubant@ucsf.eduNutriIon
et
risque
de
poussées
dans
la
SEP
• SEP
forme
poussée
rémission
ou
syndrome
clinique
isolé
• Début
de
la
maladie
<
18
ans
• Durée
de
la
maladie
<
4
ans
• Suivi:
maximal
de
4
ans
Temps
jusqu’à
la
prochaine
poussée?
Inclusion
FFQ
Azary
et
al.,
ContribuIon
of
dietary
intake
to
relapse
rate
in
early
paediatric
mulIple
sclerosis,
J
Neurol
Neurosurg
Psychiatry
2018;89:28-‐33
2/10/20
51
Conclusion
de
ceje
étude
• Chaque
augmentaIon
de
10%
increase
de
graisses
saturées
triple
le
risque
d’appariIon
d’une
poussée:
• Chaque
porIon
équivalente
de
légumes:
• Diminue
le
risque
d’une
poussée
50%
• Reste
à
confirmer
mais
indicaIon
que
la
nutriIon
joue
un
rôle
• Régime:
Swank
diet,
Terry
Wahls
diet:
riche
graisses
non
saturatées
et
en
légumes
Azary
et
al.,
ContribuIon
of
dietary
intake
to
relapse
rate
in
early
paediatric
mulIple
sclerosis,
J
Neurol
Neurosurg
Psychiatry
2018;89:28-‐33
2/10/20
52
Journal of the Neurological Sciences 363 (2016) 153–157
Contents lists available at ScienceDirect
Journal of the Neurological Sciences
journal homepage: www.elsevier.com/locate/jns
Clinical short communication
Gut microbiota composition and relapse risk in pediatric MS:
A pilot study☆
Helen Tremlett a,⁎, Douglas W. Fadrosh b, Ali A. Faruqi b, Janace Hart b, Shelly Roalstad c, Jennifer Graves b,
Susan Lynch b, Emmanuelle Waubant b, on behalf of the, US Network of Pediatric MS Centers
Greg Aaen 1, Anita Belman 2, Leslie Benson 3, Charlie Casper 4, Tanuja Chitnis 3, Mark Gorman 3, Yolanda Harris 7,
Lauren Krupp 2, Tim E. Lotze 6, Sabina Lulu 7, Jayne Ness 5, Cody Olsen 4, Erik Roan 4, Moses Rodriguez 5,
John Rose 4, Timothy C. Simmons 4, Jan-Mendelt Tillema 5, Wendy Weber 4, Bianca Weinstock-Guttman 8
1
Loma Linda University, Loma Linda, CA, United States
2
Stony Brook University, Stony Brook, NY, United States
3
Harvard University, Cambridge, MA, United States
4
University of Utah, Salt Lake City, UT, United States
5
Mayo Clinic, Rochester, MN, United States
6
Baylor College of Medicine, Houston, TX, United States
7
University of California, San Francisco, San Francisco, CA, United States
8
State University of New York at Buffalo, Buffalo, NY, United States
a
University of British Columbia, Vancouver, BC, Canada
b
University of California, San Francisco, San Francisco, CA, United States
c
University of Utah, Salt Lake City, UT, United States
a r t i c l e i n f o a b s t r a c t
Article history: We explored the association between baseline gut microbiota (16S rRNA biomarker sequencing of stool samples)
Received 4 January 2016 in 17 relapsing-remitting pediatric MS cases and risk of relapse over a mean 19.8 months follow-up. From the
Received in revised form 11 February 2016 Kaplan-Meier curve, 25% relapsed within an estimated 166 days from baseline. A shorter time to relapse was as-
Accepted 16 February 2016
sociated with Fusobacteria depletion (p = 0.001 log-rank test), expansion of the Firmicutes (p = 0.003), and
Available online 20 February 2016
presence of the Archaea Euryarchaeota (p = 0.037). After covariate adjustments for age and immunomodulatory
Keywords:
drug exposure, only absence (vs. presence) of Fusobacteria was associated with relapse risk (hazard ratio = 3.2
Pediatric multiple sclerosis (95% CI: 1.2–9.0), p = 0.024). Further investigation is warranted. Findings could offer new targets to alter the MS
Tremlej
et
al.,
Gut
microbiota
composiIon
and
relapse
risk
in
pediatric
MS:
A
pilot
study,
Journal
of
Neurological
Gut microbiota disease course.
© 2016 Elsevier B.V. All rights reserved.
Sciences
363
(201)
153-‐157
16S rRNA
Relapse risk
Survival analyses
Kaplan-Meier
Cox regression
2/10/20
53
1. Background relapsing-remitting MS, for instance, a germ-free environment
has been associated with a milder disease course [1,2]. In addition,Tremlej et al., Gut microbiota composiIon and relapse risk in pediatric MS: A pilot study, Journal of Neurological 2/10/20 Sciences 363 (201) 153-‐157 54
Autres
facteurs:
taux
de
vitamine
D
et
du
tabac
• Cohorte
barcelonaise
de
CIS
• 2
facteurs
de
risques
(FR)
environnementaux
modifiables
• Vit.
D
dans
les
6
mois
du
CIS
:
<
8
ng/ml
(
<
20nmol/l)
• CoInine
:
>
14
ng/ml
→
fumeur
acIf
• 1
062
paIents
CIS
(entre
1995
et
2016):
sous-‐groupe
avec
données
disponibles
:
472
(vitamine
D)
435
(coInine)
ECTRIMS 2018 – Tintoré M, abstr. 170
2/10/20
55
PrédicIon
du
pronosIc
du
CIS
en
tenant
compte
du
taux
de
vitamine
D
et
du
tabac
Risque
d’aLeindre
EDSS
3.0
HR (IC 95 %)
Risque bas Vit D > 8 & cotinine < 14 1,00 ( - )
Risque bas Vit D > 8 & cotinine > 14 5,78 (0,65-51,76)
Risque bas Vit D < 8 & cotinine < 14 12,47 (0,78-199,39)
Risque bas Vit D < 8 & cotinine > 14 33,20 (2,08-531,05)
Risque interm Vit D > 8 & cotinine < 14 10,73 (1,42-81,21)
Risque interm Vit D > 8 & cotinine > 14 21,78 (2,94-161,24)
Risque interm Vit D < 8 & cotinine < 14 30,80 (3,20-296,36)
Risque interm Vit D < 8 & cotinine > 14 39,73 (4,89-322,97)
Risque élevé Vit D > 8 & cotinine < 14 19,86 (1,80-219,00)
Risque élevé Vit D > 8 & cotinine > 14 108,15 (12,54-932,77)
Risque élevé Vit D < 8 & cotinine < 14 32,32 (2,02-516,74)
Risque élevé Vit D < 8 & cotinine > 14 78,96 (4,93-1 264,53)
0,05 0,1 0,5 1 2 5 10 20 40
ECTRIMS 2018 – Tintoré M, abstr. 170
2/10/20
56
PrédicIon
de
l’ajeinte
cogniIve
après
11
ans
:
taux
de
vitamine
D
et
du
tabac
ExposiIon
(années
0-‐2):
coInine
(tabagisme),
25-‐hydroxyvit.D
(vitamine
D),
EBNA-‐1
IgG
(EBV)
Outcome
(année
11):
PASAT,
sNfL
• Des
taux
élevés
de
vitamine
D
dans
les
deux
premières
années:
Meilleurs
scores
cogniIfs
pour
des
augmentaIon
de
50nmol/l:
65%
ont
des
amélioraIons
du
score
PASAT
NfL:
20%
NfL
20%
plus
bas
si
taux
de
vitamine
D
50nmol
higher
vitamin
D
• Co-nite:
<
10ng/ml;
>
25ng/ml
fumeur
-‐ fumeurs
ont
des
scores
z-‐PASAT
significaIvement
plus
bas
après
11
ans
NfL:
20%
plus
haut
si
taux
de
coInine
>
25
• EBNA-‐1
IgG:
pas
associé
à
des
changements
de
score
PASAT
ni
de
changement
en
NfL
ECTRIMS 2018 – Cortese M, abstr. 321
2/10/20
57
Moment
de
la
prise
alimentaire…
• Project
in
collaboraIon
with:
• Dr.
Tinh-‐Hai
Collet
• Service
of
Endocrinology,
Diabetes
&
Metabolism
• CHUV,
Lausanne
2/10/20
58
Downloaded from http://science.sciencemag.org
old ad- circadian clock oscillates in a cell-autonomous genes, such as Bmal1, in non-SCN regions of the
ertains manner and is tuned to a 24-hour period by multi- brain can also render that tissue transcription-
hythms,
rcadian Etude
de
l’alimentaIon
au
sens
large
ple layers of posttranslational regulation. The posi-
tive limb of the clock regulates transcription of
ally arrhythmic without altering the animal’s
sleep-wake cycle or behavioral rhythms (12).
ympto- hundreds or thousands of transcripts in a tissue- One caveat is that Bmal1 can exert developmen-
neuro- and cell type–specific manner (8). In mice and tal effects, and regulates many genes that are
eimer’s
nd Hun-
SCN (suprachiasmatic nucleus)
vidence
rcadian
urse of
not only
so may
genesis
ta link-
eurode- Cellular circadian clocks Sleep Peripheral circadian clocks
olecular
to neu-
erapeu-
is hier-
circuit-
he core
ed clock
lational Brain homeostasis With
the
courtesy
of
Dr
TH
Collet
Peripheral metabolism
tions in
he posi- Redox status Glymphatic flow Glucose homeostasis
2/10/20
59
Vascular regulation
n clock Inflammation Neuronal metabolismUne
applicaIon
sur
son
téléphone
‘Feedogram’
Chaque
photo
permet:
• Heure
de
la
prise
alimentaire
(OpIonal)
annotaIon
Research
work
in
progress,
Prof.
Pot’s
lab,
Lausanne,
2019
2/10/20
60
Plan
de
la
présentaIon
-‐ IntroducIon
Microbiote
et
maladies
auto-‐immunes
-‐ Maladies
auto-‐immunes:
axe
intesIn-‐cerveau
et
sclérose
en
plaques
-‐ Autres
maladies
auto-‐immunes
2/10/20
61
receptor on T cells recognizes a the CNS or by the expansion of pathogenic autoantigen- and SFB-mediated enhancement of TH17 cell immunity
IntesIns
et
autoimmunité
peptide from the autoantigen specific T cells that are promoted by intestinal TH17 stimulates autoantibody production by B cells, which
glucose-6-phosphate cell responses (FIG. 4). By contrast, certain populations leads to arthritic symptoms153 (FIG. 4). TH17 cell immunity
isomerase, these mice develop
of commensal bacteria are capable of attenuating CNS is also a key factor in spontaneous rheumatoid arthri-
an arthritis that is mediated,
and transferable, by circulating
inflammation. For example, PSA+ B. fragilis, which tis in IL-1R antagonist (Il1rn)−/− mice, which exhibit
antibodies against glucose-6-
phosphate isomerase.
CNS Joint
Multiple sclerosis Arthritis
EAE
TH17
TH17 cell cell IL-1R
TReg cell antagonist
IL-1β
TH17 cell
commensal bacteria
Gut Lamina
lumen propria
SFB IgE Peripheral blood
↓ Firmicutes B cell Basophil
↑ Bacteroidetes
iNKT cell
Type 1 diabetes Allergic
Pancreatitis
Pancreas Lungs Nat
review
may
2013,
vol
13.
335
Figure 4 | Gut microbiota affects extra-intestinal autoimmune diseases. Segmented filamentous bacteria (SFB)
colonization induces T helper 17 (TH17) cell development in the intestine. These TH17 cells might migrate to the periphery
2/10/20
to affect systemic and central nervous system (CNS) immunity; increased intestinal TH17 cells enhance the expansion 62
Nature Reviews | ImmunologyPolyarthrite
rhumatoide
inflammaIon
(douleur,
chaleur,
gonflement,
rougeur)
des
arIculaIons,
principalement
des
mains
et
des
pieds
2/10/20
63
Polyarthrite rhumatoide • maladie rhumaIsmale inflammatoire autoimmune la plus fréquente • prévalence d’environ 1 % dans la populaIon générale • touche de manière préférenIelle les femmes • Pic d’incidence autour de la ménopause • le risque de développer la PR est mulIplié par 3 avec HLA-‐DRB1 2/10/20 64
Polyarthrite
rhumatoide
et
nutriIon
• Tabagisme
:
facteur
de
risque
le
plus
associé
à
la
PR
• Boissons
sucrées:
nurses
health
study
consommaIon
quoIdienne
de
sodas
sucrés
2x
plus
de
risque
de
PR
• AssociaIon
entre
sirop
de
glucose
et
boissons
sucrées
• Dietary
long-‐chain
n-‐3
polyunsaturated
fajy
acids
(LC-‐PUFAs,
fish)
of
>
0.21
g/day
:
associated
with
a
35%
decreased
risk
of
developing
RA
compared
with
a
lower
intake
in
women
2/10/20
65
Conclusion: mes recommandaIons 2/10/20 66
Mes
recommandaIons
(pour
la
SEP)
subsIIon
en
vitamine
D
si
carence
2/10/20
67
Mes
recommandaIons:
Arrêter
de
fumer
2/10/20
68
• Merci
pour
votre
ajenIon
• QuesIons?
2/10/20
69
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