Received: 27 August 2021 | Accepted: 7 October 2021

DOI: 10.1111/ene.15150

S H O R T C O M M U N I C AT I O N

Short-­chain fatty acids during pregnancy in multiple sclerosis:

A prospective cohort study

Juan Pablo Cuello1 | María Luisa Martínez Ginés1 | José Manuel García Domínguez1 |
Amalia Tejeda-­Velarde2 | Alberto Lozano Ros1 | Yolanda Higueras1 |
Ariana Meldaña Rivera1 | Haydee Goicochea Briceño1 | Santiago Garcia-­Tizon1 |
Juan de León-­Luis1 | Silvia Medina Heras2 | José Ignacio Fernández Velasco2 |
Silvia Pérez-­Pérez3 | María Ángel García-­Martínez3 | Beatriz Pardo-­Rodríguez3 |
3 4 4
María Inmaculada Domínguez-­Mozo | Estefanía García-­Calvo | Héctor Estévez |
Jose Luis Luque-­García4 | Luisa Maria Villar2 | Roberto Alvarez-­Lafuente3

Abstract
1
Gregorio Marañón University General
Hospital, Madrid, Spain
2 Background and purpose: Short-­chain fatty acids (SCFAs) can have pro-­ or anti-­
Ramón y Cajal University Hospital,
Madrid, Spain inflammatory properties, but their relationship with multiple sclerosis (MS) relapses
3
Research Group on Environmental during pregnancy remains unknown. This study aimed to explore SCFA profiles in MS
Factors in Degenerative Diseases,
Health Research Institute of the San
patients during pregnancy and to assess their association with the appearance of relapses
Carlos Clinical Hospital/Spanish Multiple during pregnancy and postpartum.
Sclerosis Network, Madrid, Spain
4
Methods: We prospectively included 53 pregnant MS patients and 21 healthy control
Department of Analytical Chemistry,
Faculty of Chemical Sciences, women. Patients were evaluated during pregnancy and puerperium. SCFAs were meas-
Complutense University of Madrid, ured by liquid chromatography–­mass spectrometry.
Madrid, Spain
Results: Sixteen patients (32%) had relapses during pregnancy or puerperium, and 37
Correspondence (68%) did not. All MS patients showed significant increases in acetate levels during preg-
Luisa Maria Villar, Hospital Universitario
Ramón y Cajal. Ctra. Colmenar Viejo, km. nancy and the postpartum period compared to non-­MS women. However, propionate
9, 100, 28034 Madrid, Spain. and butyrate values were associated with disease activity. Their values were higher in
Email: luisamaria.villar@salud.madrid.org
nonrelapsing patients and remained similar to the control group in relapsing patients. The
Funding information variable that best identified active patients was the propionate/acetate ratio. Ratios of
The authors received no financial support
for the research, authorship, and/or <0.36 during the first trimester were associated with higher inflammatory activity (odds
publication of this article ratio = 165, 95% confidence interval = 10.2–­239.4, p < 0.01). Most nonrelapsing patients
showed values of >0.36, which were similar to those in healthy pregnant women.
Conclusions: Low propionate/acetate ratio values during the first trimester of gestation
identified MS patients at risk of relapses during pregnancy and the postpartum period.

KEYWORDS
intrapartum, multiple sclerosis, pregnancy, puerperium, short-­chain fatty acids

Eur J Neurol. 2022;29:895–900. wileyonlinelibrary.com/journal/ene

© 2021 European Academy of Neurology | 895
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I NTRO D U C TI O N
In multiple sclerosis (MS), pregnancy causes a reduction in the annu-
alized relapse rate, especially during the third trimester, although in-
flammatory activity temporarily increases during the first trimester
postpartum. However, pregnancy does not seem to affect disability
progression in the long term [1,2]. The exact mechanism underlying
this clinical observation remains unknown.
The composition of the microbiota determines short-­chain fatty
acid (SCFA) serum levels, as their concentrations are closely related
to the genus present in the gut flora [3]. Acetate, propionate, and
butyrate acids are the main SCFAs, and they are derived from mi-
crobial fermentation of plant fiber polysaccharides in the human
colon. Dysbiosis leading to changes in serum SCFA concentrations
has adverse effects on different immunological mechanisms, such as
epithelial barrier integrity, cell energy homeostasis, and activated/
regulatory T-­cell balance [4]. In MS patients, the microbiota are as-
sociated with the disease course [5], and part of this effect could be
mediated by SCFAs. Along this line, a decrease in different genera,
such as Butyricimonas, that produce high levels of some SCFAs was
observed in MS patients compared to healthy controls [6]. We aimed
to explore whether SCFA levels are associated with clinical activity
in a cohort of pregnant MS patients and to assess their putative role
as biomarkers for predicting disease activity during pregnancy and
the postpartum period.
PATI E NT S A N D M E TH O D S
Patients
This prospective, longitudinal study was conducted at Gregorio
Marañón University General Hospital, Madrid, Spain. We con-
secutively included 63 patients who gave their informed consent
to participate in the study. Five were lost during follow-­up, and
another five with missing blood samples were excluded from the
study. We finally included 53 pregnant MS patients as diagnosed
using the McDonald criteria [7], who gave birth between January
2007 and July 2018 at our center. As a control group, we in-
cluded 21 healthy age-­matched pregnant women (HCW). We had
prepregnancy serum samples in 15 cases (five who presented with
disease activity during pregnancy and 10 who did not). No dif-
ferences in the elapsed time from sample collection to pregnancy
were observed.
Pregnant MS patients were evaluated every trimester and during
puerperium, with additional visits in case of a relapse. We studied
demographic and clinical variables at the first visit, including age,
disease duration, reproductive history, annualized relapse rate be-
fore pregnancy, Expanded Disability Status Scale (EDSS), and previ-
ous MS treatments. During follow-­up, we monitored disease activity
and changes in EDSS score. A relapse was defined as the appearance
or worsening of focal neurological dysfunction of >24-­h duration
in the absence of fever. The pregnant cohort with MS was further
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CUELLO et al.
divided into two groups: (i) patients who had clinical activity during
pregnancy or puerperium (ACT group) and (ii) those without clini-
cal activity during this period (No-­ACT group). The study was ap-
proved by the ethics committee of the Gregorio Marañón University
General Hospital, and written informed consent was obtained from
all participants.
Sample collection
Serum samples were collected between 8 and 10 AM in fasted par-
ticipants during the first (Weeks 8–­12) and third (Weeks 29–­37)
trimesters of pregnancy and during the first postpartum trimester.
After collection, samples were aliquoted and stored at −80°C until
analyzed. Neurologists were blind to laboratory results during the
study.
Sample analysis
We prospectively studied levels of acetate, propionate, and butyrate
in serum samples using liquid chromatography coupled to mass spec-
trometry in an 8030 Shimadzu triple-­quadrupole mass spectrom-
eter. The chromatography was performed in a Phenomenex Gemini
C18 (5 µm, 150 × 2 mm) column using 0.01% formic acid in water and
0.01% formic acid in acetonitrile. We used the same methodology as
described in a previous study [8]. Data were obtained and processed
with LabSolution software.
Statistical analyses
We used nonparametric Mann–­Whitney U tests to explore differ-
ences in continuous variables. When needed, cutoff values were
established using receiver operating characteristic (ROC) curves.
Fisher tests were used for categorical variable analyses. All analyses
were conducted with the Stata statistical package. Probability val-
ues < 0.05 were considered significant.
R E S U LT S
Fifty-­three pregnant MS patients and 21 healthy pregnant women
were analyzed. No differences in pregnancy and delivery data were
observed between groups, except for a higher percentage of primi-
parous subjects in the control group (Table 1).
All MS patients had a relapsing form of the disease. Thirty-­three
(63%) of them were undergoing disease-­modifying therapy before
conception. Treatment was suspended in 24 cases (45%) at the man-
ifestation of pregnancy desire (median = 12 weeks [interquartile
range = 5.25–­4 0] before pregnancy). In the remaining nine cases
(16%), treatment was maintained until the patient received a positive
pregnancy test.
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INTRAPARTUM SHORT-­CHAIN FATTY ACIDS IN MS 897

TA B L E 1 Clinical and demographic data

Participants MS patients, n = 53 HCW, n = 21 p

Age, years, median (IQR) 33 (31–­37) 35 (30–­37) 0.9

Abortion history, n (%) 14 (26.4%) 4 (19%) 0.15
Primiparous, n (%) 9 (16.9%) 8 (38%) 0.04
Delivery mode: vaginal, n (%) 42 (79%) 18 (85%) 0.7
GA at birth, weeks, median (IQR) 39 (38–­4 0) 39 (38–­4 0) 0.9
Birthweight, g, median (IQR) 3090 (2080–­3 450) 3150 (2330–­3600) 0.8

MS patients ACT group, n = 16 No-­ACT group, n = 37 p

Disease duration, years (range) 9 (4.3–­15) 7.5 (5–­13) 0.68

EDSS score, median (range) 0.5 (0–­1.75) 1 (0–­1) 0.8
ARR 2 years before pregnancy, median (IQR) 0.5 (0–­0.5) 0.5 (0–­0.5) 0.33
Patients with relapses during pregnancy, n 10 –­ –­
Patients with puerperium relapses, n 11 –­ –­
Patients with relapses in both pregnancy and puerperium, n 5 –­ –­
Treatment status, n (%)
Treatment naïve 7 (44%) 13 (35%) 0.7
Patients on DMT before pregnancy 9 (56%) 24 (65%)
7 on 1st line 19 on 1st line
2 on 2nd line 5 on 2nd line

Abbreviations: ACT, patients with disease activity during pregnancy and puerperium; ARR, annualized relapse rate; DMT, disease-­modifying
treatment; EDSS, Expanded Disability Status Scale; GA, gestational age; HCW, healthy control pregnant women; IQR, interquartile range; MS,
multiple sclerosis; No-­ACT, patients without disease activity during pregnancy and puerperium.

In the first trimester, we observed clear differences in acetate
values among our three groups of patients. Acetate levels signifi-
cantly increased in MS patients compared to HCW independently
of relapse occurrence (Figure 1a). Similar results were observed in
the third trimester and in postpartum samples. A different pattern
was observed in relapsed MS patients after measuring propionate
and butyrate levels. The highest values of both SCFAs were ob-
served in the No-­ACT group compared to the ACT group and HCW
(Figure 1a). No differences were observed between the latter two
groups. Again, the pattern remained the same in the third trimester
and postpartum period. We explored the values of the three SCFAs
in prepregnancy samples of five ACT and 10 No-­ACT patients. No
significant differences were observed (Figure S1).
The best variables for identifying active patients were the pro-
pionate/acetate and butyrate/acetate ratios (Figure 1b). In both
cases, ACT patients clearly showed lower values than the No-­ACT
(p < 0.0001 propionate/acetate; p < 0.0001 butyrate/acetate) and
HCW groups (p = 0.0002 propionate/acetate) during the first tri-
mester of pregnancy. Differences were more evident when using the
propionate/acetate ratio. No differences were found between the
No-­ACT and HCW groups.
We next analyzed whether the propionate/acetate ratio in the
first trimester of pregnancy could be used to identify patients with
disease activity during our study. We established a cutoff value
using an ROC curve analysis. We identified a ratio of 0.36 as the best
cutoff point (area under the curve = 0.96, p < 0.0001, sensitivity =
94%, specificity = 92%). These cutoff values clearly discriminated
first trimester patients who had relapses during pregnancy and pu-
erperium (odds ratio = 165, 95% confidence interval = 10.2–­239.4,
p < 0.0001) from the others who did not.
DISCUSSION
SCFAs are volatile acids produced by the gut microbiome in the large
bowel as fermentation products from food components that are
not absorbed in the small intestine. The primary sources of SCFAs
are carbohydrates [9]. After SCFA production, SCFAs are absorbed
and used by the host in different biosynthetic routes [10]. The most
abundant acids in the colon are acetate, propionate, and butyrate,
which represent up to 95% of the colonic SCFAs. Their proportion
depends on the microbiota profile. Interestingly, the patient's diet
can modify gut microbiota composition; therefore, the profile of
synthesized SCFAs can consequently change patient immunological
responses [11]. Along this line, it has previously been published that
SCFAs can alter host antibody responses via gene expression modu-
lation, enhancement of cellular metabolism, and induction of plasma
B-­cell differentiation. Also, SCFAs can boost mucosal and systemic
antibody responses during steady state or infection [12]. Specifically,
butyrate and propionate induce the differentiation of regulatory T
cells by assisting in control of intestinal inflammation [9]. Specifically,
butyrate influences colon motility, modulates inflammation, and pro-
duces an increase in intestinal irrigation, induction of cell apoptosis,
and inhibition of tumor cell progression.
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898 CUELLO et al.

(a)
1 Trimester 3 Trimester Puerperium

45
30 30
Serum Acetate ( M)

Serum Acetate ( M)
30 30

Serum Acetate ( M)
20 20
20

10 10 10

0 0 0
ACT No-ACT HCW ACT No-ACT HCW ACT No-ACT HCW

15
15
Serum Propionate ( M)

15
Serum Propionate ( M)

Serum Propionate ( M)
10 10
10

5 5
5

0 0
No-ACT HCW ACT No-ACT HCW 0
ACT
ACT No-ACT HCW

10
10 10
Serum Butyrate ( M)

Serum Butyrate ( M)
Serum Butyrate ( M)

8
8 8

6 6
6

4 4 4

2 2 2

0 0 0
ACT No-ACT HCW ACT No-ACT HCW ACT No-ACT HCW

(b)
Ratio Prop/Acet Ratio But/Acet
1.5 0.5

0.4
1.0
0.3

0.2
0.5
0.1

0.0 0.0
ACT No-ACT HCW ACT No-ACT HCW

F I G U R E 1 (a) Acetate, propionate, and butyrate concentrations during pregnancy and puerperium in pregnant multiple sclerosis (MS)
patients. We measured serum concentrations of acetate, propionate, and butyrate during the first and third trimesters of pregnancy and
puerperium in MS patients showing (ACT) or lacking (No-­ACT) disease activity during pregnancy and puerperium and in healthy control
pregnant women (HCW). (b) Ratio of propionate/acetate (Prop/Acet) and butyrate/acetate (But/Acet) during the first trimester of pregnancy.
Serum proportions of propionate/acetate and butyrate/acetate during the first trimester of gestation correlated with the incidence of
relapses during pregnancy and puerperium. Nonparametric Mann–­Whitney tests were used to determine statistical significance (*p < 0.05,
**p < 0.01, ***p < 0.001, ****p < 0.0001)

INTRAPARTUM SHORT-­CHAIN FATTY ACIDS IN MS
During gestation, the gut microbiome undergoes a progressive
change in its composition. Those changes are mainly connected
with more efficient energy homeostasis that favors fat storage and
gestational insulin resistance. The progressive microbiome adap-
tation during pregnancy includes an increase in the proportion of
Actinobacteria and Proteobacteria phyla strains and a reduction in
bacterial diversity [13]. Intriguingly, it has been proven that gut mi-
crobiota remain stable between the third trimester of conception
and lactation progress [14]. Other variables, such as diet intake or
estradiol levels during pregnancy, are also associated with gut micro-
biota composition during pregnancy [15].
On the other hand, limited information on SCFAs levels during
pregnancy in healthy women as been reported. It was proposed
that the changes that occur in the gut microbiota composition can
affect maternal serum SCFA production, which might consequently
affect maternal weight gain, glucose metabolism, and various hor-
mone levels. Specifically, acetic acid concentration is associated with
maternal weight gain and maternal adiponectin levels, and propio-
nate concentrations were inversely correlated with maternal leptin
levels [13]. Also, propionate and butyrate were shown to be asso-
ciated with a decrease in proinflammatory cytokine expression in
the human placenta and adipose tissue in humans [16]. In MS, the
influence of SCFAs remains unknown, but it was previously demon-
strated that propionic acid could enhance T-­reg cell function and
ameliorate the disease course [6]. In this field, investigating differ-
ent SCFA levels is essential for broadening the understanding of the
tolerogenic mechanisms that occur in the disease during pregnancy
and to help design new tools for controlling MS activity. In addition,
studying the SCFA correlations with postpartum patient outcomes
could provide us with biomarkers to prevent disease exacerbations
during this period.
In our study, we evaluated serum acetate, propionate, and butyr-
ate levels in our cohort to assess their association with disease activ-
ity during pregnancy and/or puerperium. We found higher acetate
levels in MS patients compared to healthy women, thus confirming
the association of this SCFA with the disease [8]. By contrast, pro-
pionate and butyrate levels remained low in relapsing patients and
healthy women, whereas increased values were found in nonactive
patients. This apparent conundrum could be explained by explor-
ing the propionate/acetate and butyrate/acetate ratios. They were
similar in healthy women and No-­ACT MS patients but remained sig-
nificantly lower in the ACT group. This finding seems to indicate an
augmentation in the regulatory mechanisms, which is responsible for
MS patient amelioration during pregnancy and reinforces previous
findings on the association of interleukin 10 with a better pregnancy
outcome [17]. Finally, we identified the propionate/acetate ratio as
an accurate biomarker for predicting disease activity during preg-
nancy in MS. As a limitation, the patient's diet and stool samples
were not evaluated in our study.
Although these results should be validated in multicenter co-
horts, our data strongly suggest that different SCFA indices during
the first trimester of pregnancy can be used to predict the incidence
of pregnancy and postpartum relapses in MS. Also, the results
|
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899
may contribute to tailoring individual treatment during pregnancy.
Finally, these data might contribute to revealing the immune mech-
anism underlying disease amelioration occurring in MS patients
during pregnancy. Further studies with other molecules that contrib-
ute to triggering tolerogenic responses may demonstrate whether
there is any influence on the relapse incidence during pregnancy and
puerperium.
C O N FL I C T O F I N T E R E S T
The authors declare no conflict of interest.
AU T H O R C O N T R I B U T I O N S
Juan Pablo Cuello: Conceptualization (equal), data curation (equal),
funding acquisition (lead), methodology (equal), project admin-
istration (equal), resources (equal), supervision (equal), writing–­
original draft (lead), writing–­review & editing (equal). María Luisa
Martínez Ginés: Investigation (supporting), methodology (support-
ing), supervision (equal). José Manuel García Domínguez: Formal
analysis (equal), methodology (equal), supervision (equal). Amalia
Tejeda-­Velarde: Formal analysis (equal), validation (equal). Alberto
Lozano Ros: Data curation (equal), investigation (equal), method-
ology (equal), validation (equal). Yolanda Higueras: Investigation
(equal), methodology (equal), validation (equal). Ariana Meldaña
Rivera: Investigation (equal), methodology (equal), validation (equal).
Haydee Goicochea Briceño: Data curation (equal), formal analy-
sis (equal), validation (equal). Santiago Garcia-­Tizon: Data curation
(equal), methodology (equal), validation (equal). Juan de León-­Luis:
Data curation (equal), methodology (equal), validation (equal).
Silvia Medina Heras: Data curation (equal), formal analysis (equal),
validation (equal). José Ignacio Fernández Velasco: Formal analysis
(equal), validation (equal). Silvia Pérez-­Pérez: Formal analysis (equal),
supervision (equal). María Ángel García-­Martínez: Formal analysis
(equal), validation (supporting). Beatriz Pardo–­Rodríguez: Formal
analysis (equal), validation (equal). María Inmaculada Domínguez-­
Mozo: Formal analysis (equal), validation (equal). Estefanía García-­
Calvo: Formal analysis (equal), validation (equal). Héctor Estévez:
Formal analysis (equal), validation (equal). Jose Luis Luque-­García:
Formal analysis (equal), validation (equal). Luisa Maria Villar:
Conceptualization (equal), data curation (equal), investigation
(equal), methodology (equal), project administration (equal), supervi-
sion (equal), writing–­original draft (equal), writing–­review & editing
(lead). Roberto Alvarez-­L afuente: Formal analysis (equal), investiga-
tion (equal), visualization (equal).
DATA AVA I L A B I L I T Y S TAT E M E N T
Anonymized data not published within the article will be shared over
the next 5 years upon request.
ORCID
Juan Pablo Cuello https://orcid.org/0000-0003-0209-8227
Silvia Pérez-­Pérez https://orcid.org/0000-0002-3899-8932
Beatriz Pardo-­Rodríguez https://orcid.
org/0000-0002-7163-0726
 |
900
María Inmaculada Domínguez-­Mozo https://orcid.
org/0000-0001-9236-5717
Luisa Maria Villar https://orcid.org/0000-0002-9067-3668
Roberto Alvarez-­Lafuente https://orcid.
org/0000-0002-3132-1486
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S U P P O R T I N G I N FO R M AT I O N
Additional supporting information may be found in the online ver-
sion of the article at the publisher’s website.
Fig S1
How to cite this article: Cuello JP, Martínez Ginés ML, García
Domínguez JM, et al. Short-­chain fatty acids during pregnancy
in multiple sclerosis: A prospective cohort study. Eur J Neurol.
2022;29:895–­900. https://doi.org/10.1111/ene.15150