The document discusses risk factors for multiple sclerosis (MS), emphasizing environmental influences such as vitamin D levels, smoking, diet, and genetic predispositions. It explores various studies linking these factors to the prevalence and progression of MS. Strategies for patient management and counseling regarding these risk factors are also suggested.

1. Risk
factors
in
Mul0ple
Sclerosis:
Detec0on
and
Treatment
in
Daily
Life
Caroline
Pot
Patrice
Lalive
Unit
of
Neuroimmunology
and
Mul0ple
Sclerosis
Geneva
University
Hospital
16th
State
of
the
Art
Lucerne,
January
11th,
2014
Workshop
C

2. Alimenta0on
Socioeconomic
level
Age
Industrialisa0on
Climate
Gene0c
Predisposi0on
Race
Geography
Hygiene
Virus
Mul$ple
sclerosis
Mul0ple
Sclerosis
Mul0factorial
origin?

3. Mul0ple
Sclerosis

4. Mul0ple
Sclerosis
• Environmental risk factors:
-> Who is guilty & which level of demonstration ?
-> Can we have an impact on it ?
-> Counseling for the patient and the family
-> Future research direction with high potential

5. Mul0ple
Sclerosis
-> How do you manage “Environmental risk factors” with patients ?
- Give advices (only if asked) ?
- Blood test ?
- Vit. D ?
- Diet ?
- Smoking ?
- Follow specific protocol?
- > Do you believe this can have an impact on the disease course or the
risk of MS?

6. Mul0ple
Sclerosis
:
Risk
factors
1. Environmental climatic factors and Vitamin D
2. Smoking
3. Diet
Obesity
Salt intake
4. Gut immunology
Parasite infection
Gut flora
5. Conclusion

7. Mul0ple
Sclerosis
:
mul0factorial
disease
Gene$c
Twin
studies:
Monozygo0c
twin:
20%
MHC-­‐suscep0bility:
HLA-­‐DRB1
locus
non-­‐MHC
suscep0bility
genes:
(IL2RA,
IL7R,
IRF8,
and
TNFRSF1A)
Environment
Pathogens
(viral
exposi0on)
Vitamin
(D)
Smoking
Diet
Commensal
flora
Epigene$c
MS
Introduc0on

8. World
Distribu0on
of
Mul0ple
Sclerosis
Introduction

9. hence limiting ascertainment bias. Treatment costs for
values” heading. The d
daily sums for UVB ra
latitude and longitude
MSA regions in France
by the service were use
tion. The “all sky” UV
the latter provides the
vides an average value.
used for analysis as the
tion. Verification of th
have been previously p
A map of France ill
irradiation was produc
vices.18
The quantitie
(kWh/m2
) calculated f
puted from satellite ob
ergy that reaches the
Oldenburg, MINES P
Data analyses. Pears
relationship of overall
MSA region. This was
Both annual and wint
rately in males and fem
assess the association o
mean UVB.
Sex ratio was calcu
Figure 1 Annual mean ultraviolet B (Wh/m2
) radiation in France
Multiple sclerosis prevalence rates (per 100,000) for each Mutualite´ Sociale Agricole re-
gion are shown.
Neurology. 2011 Feb 1;76(5):425-31.
1. Environmental risk factor
MS
prevalence
rates
(per
100
000
for
each
region
of
France)
Environmental
clima0c
risk
factors
for
MS

10. Figure 3 Environmental climatic risk factors for multiple sclerosis and links between them. The r- and P-values illustrate the example of
France and correspond to the Pearson correlation tests reviewed in this article or performed by the authors, based on data for French
regions concerning (A) mean latitude, (B) mean global annual sunshine (Suri et al., 2007), (C) mean serum level of vitamin D in normal
Hypovitaminosis D in multiple sclerosis Brain 2010: 133; 1869–1888 | 1875
Brain 2010: 133; 1869-1888
Environmental
clima0c
risk
factors
for
MS
1. Environmental risk factor and Vitamin D

11. Mul0ple
Sclerosis
Vitamin D ?

12. Vitamin D and Multiple Sclerosis: risk of developing MS
Neurology 2004 Jan 13, vol. 62 (1) 60-65
Prospective study
Nurses’ Health Study
Women who took vitamin D
( ≥400
interna0onal
units/day)
had a 40% lower risk of MS than women
who did not use vitamin D supplements.
(rela0ve
risk
0.59,
95%
CI
0.38-­‐0.91)
JAMA. 2006;296(23):2832-2838.
Prospective, nested case-control study among
more than 7 million US military personnel
1. Vitamin D

13. Genome Wide Association Studies (GWAS)
Nature. 2011 Aug 10;476(7359):214-9
cyp27B1
cyp24A1
1. Vitamin D

14. Genome Wide Association Studies (GWAS)
1. Vitamin D

15. Ann Neurol 2010(68):193-203. Neurology. 2012 Jul 17;79(3):261-6.
August and nadirs in mid February. The
soidal curve resulted in a geometric mean
concentration of 69 nmol/L. There was
able variation in mean levels between pa
ficient of variation 41%).
Association between serum 25-OH-D co
Figure 2 Monthly exacerbation rates for the different groups
(A) Monthly exacerbation rates for the different groups of serum 25-hydro
(25-OH-D) concentrations, and (B) for at-risk period for infections. Error
95% confidence intervals. Serum 25-OH-D concentrations: p (trend) ϭ
tions p Ͻ 0.001.
Vitamin
D:
risk
factor
for
disease
progression
1. Vitamin D

16. Vitamin
D
levels
and
Brain
MRI
Longitudinal
cohort
study
of
469
subjects
with
MS
Vitamin
D
levels
are
inversely
associated
with
the
risk
of
new
lesion
Ann
Neurol.
2012;72(2):234.
1. Vitamin D

17. What do we measure?
Vitamin D in practice in Geneva University Hospital
25(OH)D (calcidiol) in the serum
Optimal ≥ 75 nmol/L
Sub-optimal: ≥50 nmol/L et < 75 nmol/L
Moderate deficit: >25 nmol/L et <50nmol/L
Severe deficit : < 25 nmol/l
1. Vitamin D

18. Vitamin D in practice in Geneva University Hospital
1. Before starting a substitution exclude a:
Hypercalcemia
Subclinical hyperparathyroidism
Measure : Calcium and PTH
2. If PTH and calcium normal but 25(OH)D decreased
Severe deficit : < 25 nmol/l
Cholecalciférol 300 000UI per os (vitamine D3 Streuli)
then 1000 IU cholecalciferol/jour per os: Vi-De3
Moderate deficit: >25 nmol/L et <50nmol/L
Sub-optimal: ≥50 nmol/L et < 75 nmol/L
1000 IU cholecalciferol/day per os (Vi-De3)
1. Vitamin D

19. Mul0ple
Sclerosis
Smoking?

20. Smoking and Multiple Sclerosis: risk of developing MS
2. Smoking
Cross-sectional study
22312 subjects in the general population of Hordaland County in Norway
years. Exclusion of these cases from the analyses did not
change the results.
The RR estimated by the Cox model comparing ever-
smokers with never-smokers was 1.81 (p ϭ 0.014) (table).
The RR was 2.75 for men and 1.61 for women. An analysis
excluding the patients who started to smoke less than 4
years prior to the onset of disease gave an RR of 1.74 (p ϭ
0.024). Further, an analysis including educational level
per 100,000 people 40 to 49 years old.8
This is
slightly lower than the rate found in the current
study, assuming the same frequency of nonresponse
among patients with MS as the rest of the popula-
tion (390 per 100,000). This could reflect a small
increase in the prevalence rate during these 4 years
or that the patients with MS in the current study
had a slightly higher response rate than did the total
Table The number of smokers and risk estimate (rate ratio) for six common diseases among 22,312 subjects in the general population of
Hordaland County, Norway
Disease No. of patients* Never smoker, n (%) Current or past smoker, n (%) Ratio ratio† (95% CI)
Multiple sclerosis 86 21 (24.4) 65 (75.6) 1.81 (1.13–2.92)
Myocardial infarction 76 9 (11.8) 67 (88.2) 4.53 (2.26–9.01)
Angina pectoris 108 17 (15.7) 91 (84.3) 3.30 (1.96–5.55)
Stroke 93 27 (29.0) 66 (71.0) 1.48 (0.94–2.35)
Asthma 1,350 446 (33.0) 904 (67.0) 1.21 (1.05–1.39)
Diabetes 216 85 (39.4) 131 (60.6) 0.86 (0.65–1.13)
Total population 22,240 8,239 (37.0) 7,892 (35.5) 1.00
* Information on smoking was missing for 72 individuals including one patient with multiple sclerosis.
† Rate ratio estimated in a Cox proportional hazard regression model with smoking as a time-dependent covariate. Smoking individuals
are being compared with nonsmoking individuals at the same age for the risk of developing the disease. All analyses were performed
stratified by sex.
Neurology 2003; 61: 1122-1124

21. Smoking
and
risk
of
MS:
popula0on-­‐based
studies
anese17
but not in Canadian18
patients. Ongoing
work associating vitamin D exposure, ultraviolet ir-
radiation, and MS is under way in Australia, as is
research examining dietary vitamin D supplementa-
tion as a possible preventive treatment strategy for
the disease.
unsaturated fatty acids and vitamin D foods may be
encouraged.
Acknowledgment
The authors thank Dr. Stephen Reingold, National MS Society,
and Dr. Annette-Langer-Gould, Stanford University, for their
input.
Table Smoking and the risk of MS: Findings from population-based studies
Study Design, location Smoking measure
Odds ratio
(95% CI)
Reference 4 Prospective cohort study of incident cases among
British women
Ͼ 15 cigarettes/day* 1.4 (0.9–2.2)
Reference 5 Prospective cohort study of incident cases among
British women
Ͼ15 cigarettes/day* 1.4 (0.9–2.2)
Reference 6 Case-control study of incident cases in Montreal ever vs never smoked 1.6 (1.0–2.4)
20–40 cigarettes/day* 1.9 (1.2–3.2)
Reference 7 Prospective cohort study among U.S. women ever vs never smoked 1.6 (1.2–2.1)
Ն25 pack-years* 1.7 (1.2–2.4)
Reference 3 Case-control study of prevalent cases in
Hordaland, Norway
ever vs never smoked
(dose response not reported)
1.8 (1.1–2.9)
* Comparison group for cigarette dosage categories is never smokers.
Smoking and Multiple Sclerosis: risk of developing MS
2. Smoking
Neurology 2003; 61: 1032-1034

22. 7 for current smokers
rd ratio, 0.95; 95% CI,
ver-smokers). In con-
etween smoking status
of 2 years; the percent-
was 23.3% in smokers,
never-smokers(P=.57,
ase duration, and treat-
ed progression also was
the groups (adjusted
nd for progression at 5
alyses restricted to pa-
nd T2-weighted lesion
e 2). Current smokers
d a significantly greater
volume (P=.02, ad-
ase duration, and dis-
greater decrease in the
ex-smokers and never-
ant difference on either
ion; EDSS, Expanded Disability Status Scale score; ellipses, no data available; IQR, interquartile range; MS, multiple
core.
ups.
ups adjusting for age, sex, and disease duration as appropriate. Twenty-five patients had missing number of
patients stopped smoking before the study but were missing age at smoking initiation; data for these patients are
.70
.75
.80
.85
.90
.95
.99
Study Time, y
SurvivalProbability
0 2 4 6 8
Figure 1. Kaplan-Meier curve for time to conversion from relapsing-remitting
to secondary progressive multiple sclerosis. Smoking status was defined at
study entry. Disease in current smokers progressed significantly faster than
in never-smokers (P=.002). Red line indicates current smokers; green line,
ex-smokers; and black line, never-smokers.
Smoking
as
risk
factor
for
disease
progression
2. Smoking
Arch Neurol. 2009; 66 (7): 858-864
Current
smokers
Ex-­‐smokers
Never-­‐smokers
Time
to
conversion
from
RR-­‐MS
to
SP-­‐MS

23. Neurology 2009; 73;504-510
Smoking
as
risk
factor
for
disease
progression
2. Smoking

24. Smoking in practice in Geneva University Hospital
Question about smoking
It is never too late to quit smoking
2. Smoking
Counseling for the family :
Avoid exposure to smoke

25. Mul0ple
Sclerosis
Specific Diet?

26. Diet and MS
?
3. Diet

27. Diet
and
MS
3. Diet
No
Diet
has
been
proven
to
alter
the
evolu0on
of
the
disease
HOWEVER

28. Obesity
and
risk
of
developing
Mul0ple
sclerosis
Body
size
and
risk
of
MS
in
two
cohorts
of
US
women.
Table 2 Pooled relative risks and 95% confidence intervals (CIs) for body mass index (BMI) at age 18 and
baseline and risk of multiple sclerosis, Nurses’ Health Study (NHS) (1976–2002), and Nurses’
Health Study II (NHSII) (1989–2003)
NHS, cases/
person-years
NHSII, cases/
person-years
Pooled relative risks (95% CI)
Age-adjusted
Age-, smoking-
adjusted
Multivariate*
adjusted
BMI age 18 (kg/m2
)
<18.5 21/292,421 45/231,006 0.94 (0.71–1.24) 0.94 (0.71–1.24) 0.96 (0.73–1.27)
18.5–<21 77/963,413 134/656,714 1 (ref) 1 (ref) 1 (ref)
21–<23 55/648,273 84/347,962 1.15 (0.92–1.42) 1.13 (0.91–1.40) 1.13 (0.91–1.40)
23–<25 24/281,999 31/161,737 1.00 (0.74–1.35) 0.97 (0.72–1.31) 0.97 (0.72–1.31)
25–<27 20/130,338 17/72,559 1.51 (0.90–2.52) 1.45 (0.86–2.43) 1.44 (0.87–2.39)
27–<30 8/72,619 16/50,889 1.47 (0.96–2.24) 1.40 (0.92–2.14) 1.40 (0.92–2.14)
>30 6/45,583 21/39,839 2.41 (1.61–3.60) 2.26 (1.50–3.38) 2.25 (1.50–3.37)
Total 211/2,434,647 348/1,560,707
p, trend Ͻ0.001 Ͻ0.001 Ͻ0.001
p, het 0.98 0.96 0.997
Baseline BMI (kg/m2
)
<18.5 7/74,199 14/53,541 1.11 (0.70–1.75) 1.10 (0.69–1.74) 1.13 (0.71–1.78)
18.5–<21 68/656,533 81/396,203 1 (ref) 1 (ref) 1 (ref)
21–<23 66/816,791 68/377,321 0.87 (0.69–1.10) 0.87 (0.69–1.10) 0.87 (0.69–1.10)
23–<25 45/574,546 59/266,505 1.00 (0.78–1.28) 1.00 (0.78–1.28) 1.00 (0.78–1.29)
25–<27 32/344,643 42/157,999 1.22 (0.92–1.62) 1.22 (0.92–1.61) 1.23 (0.93–1.62)
27–<30 9/263,744 36/134,424 0.78 (0.28–2.19) 0.78 (0.29–2.11) 0.79 (0.30–2.12)
“High
body
mass
index
before
age
20
is
associated
with
increased
risk
for
mul0ple
sclerosis
in
both
men
and
women”
Neurology
2009:73:1543.
3 Diet Obesity
Mult.
Scler.
2012
Sep
18(9)

29. Salt
intake
and
animal
model
of
Mul0ple
sclerosis
3 Diet Salt

30. Salt
intake
and
animal
model
of
Mul0ple
sclerosis
Sodium Chloride Drives Autoimmun
NIH Public Access
Author Manuscript
Nature. Author manuscript; available in PMC 2013 A
Published in final edited form as:
Nature. 2013 April 25; 496(7446): 518–522. doi:10.1038
NIH-PAAu
3 Diet Salt

31. Ectrims
2013;
abstract
119
Salt and risk of disease progression
Es0mated
daily
sodium
intake:
spot
urine
collec0on
to
es0mate
daily
sodium
excre0on
Salt
intake
classified
as:
high:
>
4.8
g/day
intermediate:
2
to
4.8
g/day
Low:
<
2
g/day
Relapse
rate
were
3.95
0mes
greater
(95%
CI
1.39-­‐11.21)
in
high
salt
intake
than
those
with
intakes
less
than
2
g/day
Par0cipants
with
daily
intake
of
2.0
to
4.8
g/day
had
relapse
rates
that
were
2.75
0mes
that
of
the
low-­‐intake
group
(95%
CI
1.30-­‐5.81).
Each
increment
in
intake
of
1
g
above
the
cohort
average
was
associated
with
3.65-­‐
lesion
increase
in
T2
count
(SD
0.77,
P<0.001).
122
RR-­‐MS
pa0ents
3 Diet Salt

32. Diet in practice in Geneva University Hospital
3. Diet

33. Mul0ple
Sclerosis
Future promising research direction?

34. The
gut-­‐brain
axis
4 Gut immunology
Nat
reviews
Neuroscience
October
2012,
vol
13.
701-­‐712

35. Gut
immunology
and
MS
Nature Reviews | Immunology
BasophilB cell
iNKT cell
Gut
lumen
Lamina
propria
IgE
Pancreas Lungs
↓ Firmicutes
↑ Bacteroidetes
TReg cell
IL-1β
CNS Joint
TH17
cell IL-1R
antagonist
TH17 cell
TH17 cell
Peripheral blood
Multiple sclerosis
EAE
Type 1 diabetes
Pancreatitis
Allergic
Arthritis
commensal bacteria
SFB
mice with KRN T cell receptor-
transgenic mice on the C57BL/6
background. As the KRN
receptor on T cells recognizes a
peptide from the autoantigen
glucose-6-phosphate
isomerase, these mice develop
an arthritis that is mediated,
and transferable, by circulating
antibodies against glucose-6-
phosphate isomerase.
erbation. However, it is unclear whether the disease is
caused by the migration of SFB-specific TH
17 cells into
the CNS or by the expansion of pathogenic autoantigen-
specific T cells that are promoted by intestinal TH
17
cell responses (FIG. 4). By contrast, certain populations
of commensal bacteria are capable of attenuating CNS
inflammation. For example, PSA+
B. fragilis, which
are reduced in a germ-free environment136,153
. As in EAE,
TH
17 cell responses are implicated in promoting disease,
and SFB-mediated enhancement of TH
17 cell immunity
stimulates autoantibody production by B cells, which
leads to arthritic symptoms153
(FIG. 4). TH
17 cell immunity
is also a key factor in spontaneous rheumatoid arthri-
tis in IL-1R antagonist (Il1rn)−/−
mice, which exhibit
Figure 4 | Gut microbiota affects extra-intestinal autoimmune diseases. Segmented filamentous bacteria (SFB)
colonization induces T helper 17 (TH
17) cell development in the intestine. These TH
17 cells might migrate to the periphery
toaffectsystemicandcentralnervoussystem(CNS)immunity;increasedintestinalTH
17cellsenhancetheexpansion
commensalbacteriacanattenuateCNSinflammationthroughtheinductionofforkheadboxP3(FOXP3)+
regulatoryT(TReg
)
cells. Induced T
Nat
review
may
2013,
vol
13.
335
Gut
microbiota
affects
extra-­‐intes0nal
autoimmune
diseases
4 Gut immunology

36. The
gut-­‐brain
axis
Gut immunology : a new risk factor for MS?
4 Gut immunology

37. to autoimmunity include (i) a primary
which normally promote immunological
tral tolerance and peripheral tolerance) (
2011), (ii) infections or other exogenou
inflammation and thereby override toler
2009; Sener and Afsar, 2012), (iii) an abn
tissues themselves (e.g., inappropriate re
nals or aberrant antigen presentation
2010), or (iv) a combination of processes
In this regard, Dobzhansy observed
makes sense except in the light of evoluti
giene or microbial deprivation hypothe
based explanation (Pollard, 2008) for the
autoimmunity which has been observed
during the last century (Bach, 2002) an
be occurring in the developing world (C
et al., 2011; Etemadifar and Maghzi, 2
2011). Rook (2012) has summarised how
hygienic environment in the developed w
lutionarily ancient microbes, including p
he coined the term ‘‘Old Friends’’ (Rook e
as recently as 1947, it was estimated that
ulation was colonised by intestinal hel
these infections are virtually absent in
1947; Gale, 2002). It may sound paradox
as friends or beneficial, given the major
constitute, especially in tropical regions
less, from an evolutionary perspective, t
most parasitic diseases is relatively low
worm (Brooker et al., 2004)); the relatio
flict and morbidity, but over millions
0 20 40 60 80
0
20
40
60
80
100
120
TT Prevalence (%)
MSPrevalence(per100,000)
Fig. 2. The prevalence of multiple sclerosis (patients per 100,000 general popula-
tion) and the human whipworm, Trichuris trichiura (TT) (percentage of surveyed
population infected) by country or region. North America: northern United States
(1), southern United States (2), Canada (3). Latin America: Brazil (4), Mexico (5),
Paraguay (6), Honduras (7), Cuba (8), Jamaica (9), Panama (10), Argentina (11), Chile
(12). Oceania: Australia (13). Africa: Ethiopia (14), Kenya (15), Cameroon (16),
Nigeria/Ghana (17), Ivory Coast/Senegal (18). Middle East: Iran/Iraq (19), Lebanon/
Jordan (20), Jerusalem–Jewish (21), Jerusalem–Arab (22). Europe: Italy (23), Poland
(24), Belgium (25), East Germany (26), United Kingdom (27). Asia: Indonesia (28),
J.O. Fleming / International Journal for Parasitology 43 (2013) 259–274
Neurology 2006, 67, 2085-2086
inflamm
2009; Se
tissues t
nals or
2010), o
In th
makes s
giene or
based ex
autoimm
during t
be occu
et al., 2
2011). R
hygienic
lutionar
he coine
as recen
ulation
these in
1947; G
as friend
constitu
less, fro
0 20 40 60 80
0
20
40
60
80
100
TT Prevalence (%)
MSPrevalence(per100,000)
Fig. 2. The prevalence of multiple sclerosis (patients per 100,000 general popula-
tion) and the human whipworm, Trichuris trichiura (TT) (percentage of surveyed
population infected) by country or region. North America: northern United States
(1), southern United States (2), Canada (3). Latin America: Brazil (4), Mexico (5),
Paraguay (6), Honduras (7), Cuba (8), Jamaica (9), Panama (10), Argentina (11), Chile
(12). Oceania: Australia (13). Africa: Ethiopia (14), Kenya (15), Cameroon (16),
Parasites
infec0on
and
prevalence
of
MS
4 Gut immunology Parasites

38. Observa0onal
study,
no
immunomodulatory
or
immunosuppressive
treatment
Annals of Neurology Vol 61 No 2 February 2007
Fig 1. Number of exacerbations (A) and changes in extended disability status scale (EDSS; B) and magnetic resonance imaging (C
Fig 1. Number of exacerbations (A) and changes in extended disability status scale (EDSS; B) and magnetic resonance imaging (C
and D) parameters observed over time in parasite infected (squares) and uninfected (diamonds) multiple sclerosis (MS) patients.
. Number of exacerbations (A) and changes in extended disability status scale (EDSS; B) and magnetic resonance imaging (C
D) parameters observed over time in parasite infected (squares) and uninfected (diamonds) multiple sclerosis (MS) patients.
Helminths
infec0on
decreases
MS
progression
4 Gut immunology Parasites

39. Table 2
Clinical studies of helminth therapy in multiple sclerosis: completed, in progress or anticipated.
Type of
investigationa
Studyb
Statusc
Subjectsd
Helminthe
ClinicalTrials.govf
Results Publicationsg
Observational
Correale
and
Farez
C 12 RRMS Natural gastrointestinal
infections with human
helminths, see text
Dramatic reduction in clinical, MRI, and
immunological measures of MS activity
found
Correale and
Farez (2007,
2011)
Exploratory
HINT 1 C 5 RRMS Trichuris suis ova 2,500 q
2 weeks  12 weeks orally
NCT00645749 Treatment was safe; MRI and
immunological outcomes favourable
Fleming et al.
(2011)
Charite C 4 SPMS T. suis ova 2,500 q
2 weeks  24 weeks orally
Treatment was safe; moderate positive
immunomodulatory impact
Benzel et al.
(2012)
TRIMS A C 10 RRMS T. suis ova 2,500 q
2 weeks  12 weeks orally
NCT01006941 Treatment was safe; no clinical, MRI,
immunological benefit
AAN (2012)
Phase 1/2
HINT 2 P 15 RRMS T. suis ova 2,500 q
2 weeks  10 months orally
NCT00645749 Safety confirmed; interim MRI and
immunological measures positive; final
results expected 2013
AAN (2012)
ACTRIMS
(2012)
TRIOMS P 50 RRMS T. suis ova 2,500 q
2 weeks  12 months orally
NCT01413243 Trial enrolling
WIRMS A 36 RRMS 25 live Necator americanus
dermally
NCT01470521 Trial initiation anticipated in near future Edwards and
Constantinescu
(2009)
MRI, magnetic resonance imaging.
a
Studies are classified as observational (field study, naturally-acquired infections), exploratory (preliminary pilot first-use safety clinical trials), or early phase 1/2 (follow
up clinical trials).
b
Each study is designated by location, investigators or acronym.
c
Study status is indicated by C (completed), P (in progress or enroling), or A (initiation anticipated in near future).
d
The number and type of subjects are noted (RRMS = relapsing-remitting MS; SPMS = secondary progressive MS); only the number of subjects with MS are shown,
exclusive of subjects in placebo or observational arms.
e
The heminth infection or treatment indicated by agent, dose, duration and route.
f
Clinical trial listings are provided by study number on the clinicaltrials.gov website; these listings provide details of study design and periodic updates on study progress.
g
Publications or meeting presentations (AAN, American Academy of Neurology, 2012; ACTRIMS, Americas Committee for Treatment and Research in Multiple Sclerosis,
2012) are indicated.
266 J.O. Fleming / International Journal for Parasitology 43 (2013) 259–274
International Journal for Parasitology 43 (2013) 259–274
Contents lists available at SciVerse ScienceDirect
International Journal for Parasitology
Helminth
therapy
trials
4 Gut immunology Parasites

40. Gut
immunology
and
Mul0ple
sclerosis
uto-
how
cing
vail-
yco-
ions
une
.
SJL/J
ans-
–106
elop
ssive
NS)
hich
cells
pon-
ther
90%
also
cific
SPF mice (Supplementary Table 1). Moreover, germ-free and SPF SJL/J
mice immunized with rMOG produced comparable levels of anti-
MOG antibodies in their serum (Fig. 1d).
Recent studies established that components of the commensal micro-
biota profoundly shape the gut-associated lymphatic tissue (GALT),
a b
c d
4
5 GF WT
SPF WT
lscore
0 10 20 30 40 50
0
20
40
60
80
100 GF
SPF
Time (weeks) after birth
SpontaneousEAEincidence(%)
SpontaneousEAEincidence(%)
0
20
40
60
80
100
0 5 10 15 20 25 30
Colonization
6–12 weeks
Time (weeks) after
colonization
2.0
2.5 GF WT
SPF WT
m
Nature 2011 Nov 24, 279, 538-542
auto-
show
ducing
avail-
glyco-
ations
mune
ets.
c SJL/J
trans-
2–106
evelop
cessive
(CNS)
which
B cells
spon-
other
5–90%
at also
pecific
SPF mice (Supplementary Table 1). Moreover, germ-free and SPF SJL/J
mice immunized with rMOG produced comparable levels of anti-
MOG antibodies in their serum (Fig. 1d).
Recent studies established that components of the commensal micro-
biota profoundly shape the gut-associated lymphatic tissue (GALT),
a b
c d
4
5 GF WT
SPF WT
lscore
0 10 20 30 40 50
0
20
40
60
80
100 GF
SPF
Time (weeks) after birth
SpontaneousEAEincidence(%)
SpontaneousEAEincidence(%)
0
20
40
60
80
100
0 5 10 15 20 25 30
Colonization
6–12 weeks
Time (weeks) after
colonization
2.0
2.5 GF WT
SPF WT
m
4 Gut immunology Gut flora

41. From Mouse to Man (MS >RR)
0 2 4 6 8 10 12 14 16
0
20
40
60
80
100 MS Patient feces (n = 5)
Healthy Control feces (n = 5)
Time (wk) after colonization
SpontaneousEAE[%]
State
of
the
art
Luzern
26.01.2013
Presenta0on
from
Prof
Wekerle
Fecal
Microbiota
Transplanta0on
and
Mul0ple
sclerosis
4 Gut immunology Gut flora

42. The new england
journal of medicine
established in 1812 january 31, 2013 vol. 368 no. 5
Duodenal Infusion of Donor Feces for Recurrent
Clostridium difficile
Els van Nood, M.D., Anne Vrieze, M.D., Max Nieuwdorp, M.D., Ph.D., Susana Fuentes, Ph.D.,
Erwin G. Zoetendal, Ph.D., Willem M. de Vos, Ph.D., Caroline E. Visser, M.D., Ph.D., Ed J. Kuijper, M.D., Ph.D.,
Joep F.W.M. Bartelsman, M.D., Jan G.P. Tijssen, Ph.D., Peter Speelman, M.D., Ph.D.,
Marcel G.W. Dijkgraaf, Ph.D., and Josbert J. Keller, M.D., Ph.D.
Abstr act
From the Departments of Internal Medi-
cine (E.N., A.V., M.N., P.S.), Microbiology
(C.E.V.), Gastroenterology (J.F.W.M.B.,
J.J.K.), and Cardiology (J.G.P.T.) and the
Clinical Research Unit (M.G.W.D.), Aca-
demic Medical Center, University of Am-
sterdam, Amsterdam; the Laboratory of
Microbiology, Wageningen University,
Background
Recurrent Clostridium difficile infection is difficult to treat, and failure rates for anti-
biotic therapy are high. We studied the effect of duodenal infusion of donor feces
in patients with recurrent C. difficile infection.
Methods
We randomly assigned patients to receive one of three therapies: an initial vanco-
Fecal
Microbiota
Transplanta0on
4 Gut immunology Gut flora

43. Risk factors and multiple sclerosis
Summary in one slide!

44. Conclusion
:
risk
factors
and
mul0ple
sclerosis
Gene$c
Environment
Pathogens
(viral
exposi0on)
Vitamin
(D)
Smoking
Diet
Commensal
flora
Epigene$c
MS
Earn Free CME Credits by reading the latest medical news
in your specialty.
Register Today
Sign Up
Dietary Salt Associated With MS
Activity
Published: Oct 4, 2013 | Updated: Oct 4, 2013
By John Gever, Deputy Managing Editor, MedPage
Today
Reviewed by Zalman S. Agus, MD; Emeritus Professor,
Perelman School of Medicine at the University of
Pennsylvania and Dorothy Caputo, MA, BSN, RN, Nurse Planner
save | A A
Action Points
Note that this study was published as
an abstract and presented at a
conference. These data and
conclusions should be considered to be
preliminary until published in a peer-
reviewed journal.
This study suggests that higher sodium
intake is associated with increased
clinical activity and MRI lesions in
patients with multiple sclerosis.
COPENHAGEN -- Sodium intake was
positively correlated with risk of increased
disease activity in patients with multiple
sclerosis, according to a small study
reported here.
Each gram of estimated daily sodium
intake above the average in a 52-patient
sample was associated with an increase of
3.65 in MRI lesion counts, said Mauricio
Farez, MD, PhD, of Fundación para la
Lucha contra las Enfermedades
Neurológicas de la Infancia in Buenos
Aires.
Also, patients with estimated salt intake
classified as high -- more than 4.8 g daily --
showed relapse rates that were 3.95 times
greater (95% CI 1.39-11.21) than those
with intakes less than 2 g/day, he told
attendees at the European Committee for
Treatment and Research in Multiple
Sclerosis annual meeting.
Farez emphasized repeatedly that the
findings did not prove that high salt intake
caused the increased disease activity. He
ADVERTISEMENT
Conclusion

45. Ques0ons?
Thank
you
for
your
alen0on