(2024) 24:588
Marsubrin et al. BMC Pediatrics
https://doi.org/10.1186/s12887-024-05055-9

BMC Pediatrics

RESEARCH

Open Access

Vitamin D and gut microbiome in preterm
infants
Putri Maharani Tristanita Marsubrin1,2,3* , Agus Firmansyah1^, Rinawati Rohsiswatmo1, Yuditiya Purwosunu4,
Saptawati Bardosono5^, Safarina G. Malik6,7, Zakiudin Munasir1, Ina S. Timan8,9, Tetty Yuniati10 and Maya Yulindhini1
Abstract
Background The incidence of vitamin D deficiency among pregnant women remains high and is associatedwith vitamin D deficiency in infants. In normally breastfed infants, Bifidobacteriaceae and Lactobacillaceae are known
to help in maintaining immunotolerance and prevent infection. Vitamin D in the gastrointestinal tract plays a rolein determining the composition and function of intestinal bacteria. Preterm infants are vulnerable to intestinal dysbiosis and sepsis due to bacterial translocation. This study aimed to determine the association between vitamin D levels
and intestinal dysbiosis.
Methods It was a cohort study conducted in the Neonatal Unit, Cipto Mangunkusumo Hospital, Tertiary hospital in Indonesia, from November 2019 to January 2021. The inclusion criteria in this study were preterm infants
with a gestational age of less than 32 weeks or a birth weight of less than 1500 g. Total 25-hydroxyvitamin D (25(OH)D) levels were collected from the umbilical cords of very preterm or very low birth weight infants. A fecal examination
was performed on the seventh day of life to assess intestinal bacteria using real-time PCR for four bacterial genera:
Bifidobacteriaceae, Lactobacillaceae, Enterobacteriaceae, and Clostridiaceae.
Results A total of 43 infants were included in this study. Among the subjects, 53.4% had vitamin D deficiency. There
was no association identified between vitamin D deficiency and intestinal dysbiosis (RR 0.67; 95% CI (0.15–2.82),
p-value = 0.531). However, the ratio of Lactobacillacecae to Enterobacteriaceae was lower in those with vitamin D
deficiency.
Conclusion Vitamin D deficiency was not associated with dysbiosis in preterm infants. However, this study foundthat the ratio of Lactobacillaceae to Enterobacteriaceae in those with vitamin D deficiency was lower than in those
without vitamin D deficiency. Further research is warranted to confirm this finding.
Keywords Dysbiosis, Preterm infants, Vitamin D^

Agus Firmansyah and Saptawati Bardosono are deceased.

*Correspondence:
Putri Maharani Tristanita Marsubrin
putristanita2806@yahoo.com
1
Department of Child Health, Faculty of Medicine Universitas Indonesia,
Dr. Cipto Mangunkusumo Hospital Indonesia, 6 Salemba Road,
Jakarta 10430, Indonesia
2
Doctoral Program in Medical Science, Faculty of Medicine Universitas
Indonesia, Jakarta, Indonesia
3
Neonatal Unit, Universitas Indonesia Hospital, Depok, Indonesia
4
Department of Obstetrics and Gynecology, Faculty of Medicine
Universitas Indonesia, Dr. Cipto Mangunkusumo Hospital, Jakarta,
Indonesia

5
Department of Nutrition, Faculty of Medicine Universitas Indonesia,
Jakarta, Indonesia
6
Mochtar Riady Institute for Nanotechnology, Tangerang, Indonesia
7
Eijkman Institute for Molecular Biology, Jakarta, Indonesia
8
Department of Clinical Pathology, Faculty of Medicine and Health
Sciences Universitas Kristen Krida Wacana, Jakarta, Indonesia
9
Human Genetic Research Center Indonesian Medical Education
and Research Institute, Faculty of Medicine Universitas Indonesia, Jakarta,
Indonesia
10
Department of Paediatrics, Faculty of Medicine Universitas Padjadjaran,
Dr. Hasan Sadikin Central General Hospital, Bandung, Indonesia© The Author(s) 2024. Open Access This article is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0
International License, which permits any non-commercial use, sharing, distribution and reproduction in any medium or format, as longas you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if
you modified the licensed material. You do not have permission under this licence to share adapted material derived from this article orparts of it. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicatedotherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not
permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To
view a copy of this licence, visit http://creativecommons.org/licenses/by-nc-nd/4.0/.

Marsubrin et al. BMC Pediatrics(2024) 24:588

Background
The incidence of maternal vitamin D deficiency is high.
Several studies have found that 18–84% of pregnant
women have vitamin D deficiency [1]. The prevalenceof vitamin D deficiency among first trimester pregnant
women in Indonesia was 99.6% [2]. This deficiency isconsequentially associated with low vitamin D levels in
infants, with approximately 79% of preterm infants suffering from this condition [3]. Very preterm infants (bornbefore 32 weeks) have a higher risk of vitamin D deficiency than late preterm and full-term infants. Notably,Indonesia has a premature birth rate of approximately
15%, making it the fifth highest in the world [4]. However,
the association between gestational age and vitamin D
status remains unclear [5]. Hospitalized preterm infants
are at an increased risk for vitamin D deficiency due tofactors such as limited sun exposure during hospital stay,
delayed initiation of oral feeding, prolonged fasting, lowvitamin D levels in breast milk, and insufficient maternal
vitamin D levels [5, 6].
Preterm and very low birth weight infants are vulnerable to intestinal dysbiosis and bacterial translocation
through the intestines [7]. Intestinal dysbiosis is defined
as an imbalance in microbiota composition, changes in
the metabolic activity of the microbiota, or changes inthe distribution of the microbiota in the gut [6, 8]. Several factors that may affect this include age, genetics,
use of antibiotics, delivery method, nutritional intake(breast milk or formula milk), and postnatal environment(such as neonatal intensive care unit) [9, 10]. Preterm
birth causes a delay in gut colonization. Additionally, it
results in abnormal pattern of gut microbiota colonization compared with term birth [11]. In normal breastfed infants, Bifidobacteriaceae and Lactobacillaceaeplay
a role in maintaining immunotolerance and preventing
infection. The composition and function of those intestinal bacteria are regulated by the status of the vitamin D
receptors [12]. This study aims to determine the association between vitamin D levels and intestinal dysbiosis bycomparison of commensals and pathogens ratio.
Methods
This is a prospective cohort study conducted in the
Neonatal Unit, Cipto Mangunkusumo Hospital (CMH),
Jakarta, from November 2019 to January 2021. The
inclusion criteria in this study were preterm infants gestational age < 32 weeks or birth weight of < 1500 g parental or legal guardian consent to participate in the study.
The exclusion criteria were infants with lethal congenitalabnormalities, suspected of syndrome, and incompletematernal data. Follow up will be continue until patientdischarged or die for a minimum of 7 days.

Page 2 of 6

The dependent variable in this study is intestinal dysbiosis. Independent variable is umbilical cord serum vitamin D level measured as 25-hydroxyvitamin D (25(OH)D). Potential confounding variables for intestinal dysbiosis are maternal vitamin D supplementation, severe
preeclampsia, maternal infection, delivery method, gestational age, birth weight, nutritional intake, sepsis, andantibiotic use during hospitalization.
The assessment of total 25‑hydroxyvitamin D (25(OH)D)

Determination of total circulating 25(OH)D in umbilicalcord was performed using DiaSorin (Liaison®, Saluggia,
Italy) analyzer, using a direct competitive chemiluminescence immunoassay (CLIA) method, which was tested
in Prodia Child Laboratory. American Academy of Pediatrics (AAP) categorizes the vitamin D status into three
categories, deficient (5–15), insufficient (16–20), and sufficient (21–100) [12]. For analysis purposes in this study,
vitamin D status was categorized into two categories,
deficient ≤ 15 ng/mL and not deficient (insufficient andsufficient) > 15 ng/mL.
Assessment of faecal samples and DNA extraction

Faecal samples were collected from 7-day-old infants(180–220 mg), and were stored at the Gastrohepatology
Biomolecular Laboratory of the Department of Child
Health, Faculty of Medicine Universitas Indonesia at-20 °C. Samples were added with 1 mL of sterile buffer
TN150 (nM Tris–HCl, 150 mM NaCl (pH 8)) and 300 mg
of zirconium beads (0.1 mm in diameter) [13].
The real‑time PCR examination

All samples were examined at the Gastrohepatology Biomolecular Laboratory of the Department of Child and
Health, Faculty of Medicine University Indonesia. Intestinal bacteria from faecal samples were assessed using
quantitative real-time PCR (qPCR). The fecal examination was performed on four bacterial genera, i.e., Enterobacteriaceae and Lactobacillaceae, as well as Clostridium
and Bifidobacteriaceae. The results were presented incopy numbers/200 mg of faeces for each type of bacteria. Quantitative real-time PCR was performed using the
ABI 7500 Fast system on MicroAmp Fast Optical 96-Wellplates with an optical adhesive film (Biosystems, Foster City, CA, USA). The primer used was working stockprimer forward (Aliquor primer). The primer target fromthe PCR was the 16S rRNA gene from all bacteria, which
is a common bacterial structure in human faecal microbiota. All reactions were conducted in a final volume of
20 mL, which contained 1 × Fast SYBR® Green PCR Mastermix (Biosystems), 300 nM each primer, and a 2 mL
DNA template. The thermocycling program included
polymerase activation at 95°C for 30 s, followed by 40

Marsubrin et al. BMC Pediatrics(2024) 24:588

cycles that consisted of denaturation at 95°C for 10 s,annealing, and elongation at 60°C for 30 s. The fluorescence level was measured after annealing at 60°C. Concentration and purity of the DNA were evaluated using ananodrop spectrophotometer (Thermo Fisher Scientific),
and was then stored in a freezer at -20°C and diluted 10
times from 5 × 106 to 5 × 101 genome, calculated using
a copy of gene target per genome, which was obtained
from genome sequence information (NCBI). All reactions were performed twice in two stages with separate
plates. The qPCR results were normalized according to
the total target abundance of the 16S rRNA gene, measured with qPCR using primer [13].
Assesment of intestinal dysbiosis

Intestinal dysbiosis describes changes in the intestinal
microbiota in relation to a disease [14]. An abundanceof Enterobacteriaceaeis one of the characteristics of dysbiosis [15]. Low numbers of Bifidobacteriaceae and highnumbers of Enterobacteriaceae and Clostridiaceae canbe a sign of dysbiosis within the first month of life. For
analysis purposes, a comparison between Lactobacillaceae (representing commensal bacteria) and Enterobacteriaceae (representing pathogenic bacteria) was
performed, and a ratio of Lactobacillaceae to Enterobacteriaceae < 1 indicates the presence of intestinal dysbiosis,
modified from Paterson et al. [16].
Statistical analysis

All obtained data were recorded using a pre-prepared
form. Data entry was performed using the Statistical
Package for the Social Sciences (SPSS) program version 20.0 for Windows. Univariate and bivariate analyses
were performed. Data which followed normal distribution were presented in mean (± SD), while those which
did not follow normal distribution were presented using
median (interquartile range). The chi-square test wasused to analyze data between two categorical variables.
Multivariate analysis was conducted using modified cox
proportional hazard regression. Effect size was measured
using relative risk (RR) and 95% confidence interval. The
significance level for all hypotheses was p < 0.05, with aconfidence interval of 95%.

Results
This is a secondary analysis as a part of study “The Roleof Vitamin in Determining the Morbidity of Very Premature or Very Low Birth Weight Babies: A Review on
Regulatory T Cells and Intestinal Dysbiosis”. Sample size
calculation was address based on that study. The original cohort recruited 119 very preterm and/or very low
birth weight infants but a proportion of subject could not

Page 3 of 6

undergo fecal examination due to technical issues related
to COVID-19 pandemic.
A total of 43 infants of the original cohort were eligible for this analysis. The mean gestational age was
29.56 ± 2.67 weeks, and the mean birth weight was
1,138.21 ± 262.70 g. As many as 53.4% (23 out of 43)
subjects were found to have vitamin D deficiency. The
infants whose mother received vitamin D supplementation had lower proportion of vitamin D deficiency (40%)
than those whose mothers did not (55.2%). There were nodifferences in the baseline characteristics of subjects inboth groups (Table 1).
In the microbiota examination, no Bifidobacteriaceae
was found from the faecal samples collected. The mean
total bacteria were 2,520,300 copy numbers/200 mg offaeces. Detailed bacteria number were 232.26 (± SD)
copy numbers/200 mg faeces for Lactobacillaceae, 5.25(± SD) copy numbers/200 mg of faeces for Clostridiaceae, and 37,711 (± SD) copy numbers/200 mg of faeces
for Enterobacteriaceae. A difference in proportion wasseen between subjects with vitamin D deficiency and novitamin D deficiency (Fig. 1). The proportion Lactobacillaceae was 67.66% in the group no vitamin D deficiency,
whereas it was only 13.16% in the group with vitamin D
deficiency.
In our study, 61.1% subjects had intestinal dysbiosis.
Subjects with vitamin D deficiency had lower proportionof intestinal dysbiosis although statistically not significant(60.87% vs 70%, p-value = 0.531) (Table 2). There was no
association between vitamin D deficiency in newborns
and intestinal dysbiosis (RR 0.49; 95% CI (0.10–2.37),
p-value = 0.38) after being adjusted by confounding factors (Table 3). On the other hand, we found that sepsis
significantly increase the risk of intestinal dysbiosis (OR8.18 95% CI 1.41–47.23, p-value = 0.01) (Table 3).

Discussion
Vitamin D deficiency was found in 53.4% among very
preterm and/or very premature infants in this study. We
found no Bifidobacteriaceae and only a few Clostridium
in subject fecal analysis. Dysbiosis, defined as a ratio
between Lactobacillaceae and Enterobacteriaceae, wasfound in 60.87% subjects and tend to be lower among
subjects with vitamin D deficiency. On the other hand,
this study did not find association between vitamin D
deficiency and intestinal dysbiosis.
There is a high prevalence of vitamin D deficiency invery premature infants. Previous study reported thatmost of preterm infants had vitamin D insufficiency
and half of them were severely vitamin D deficient [4].
In this cohort, vitamin D status was not associated withmaternal vitamin D supplementation, pre-eclampsia,
and maternal infections (p> 0.05). Most of the mothers

Marsubrin et al. BMC Pediatrics(2024) 24:588

Page 4 of 6

Table 1 Baseline characteristics of study participants
Characteristics

Vitamin D deficiency

No vitamin D deficiency

n (%)

n (%)

p-value

Maternal vitamin D supplementationNo

21 (55)17 (44.7)

Yes

2 (40)

3 (60)

0.43

Severe pre-eclampsia
Yes

10 (58.8)

7 (41.1)

No

13 (50)13 (50)0.57

Maternal infectionYes

13 (48.1)

14 (51.8)No

10 (62.5)

6 (37.5)

0.36

Delivery method
Caesarean section

21 (53.8)

18 (46.1)

Spontaneous delivery

2 (50)

2 (50)

0.64

Gestational age (weeks)

30.00 ± 2.93

29.05 ± 2.30

0.25

Birth weight (grams)

1,147.17 ± 252.14

1,127.90 ± 280.59

0.81
0.26

Nutritional intake
Breast milk

16 (55.1)

13 (44.8)

Formula milk

7 (50)

7 (50)

Antibiotic use
Yes

22 (52.3)

20 (47.6)No

1 (100)

0 (0)

0.53

SepsisYes

13 (52)12 (48)No

10 (55.5)

8 (44.4)

0.81

Fig. 1 Show comparison of Lactobacillaceae/Enterobacteriaceae between groups with and without vitamin D deficiency

in this study did not consume vitamin D supplementation during pregnancy. In contrast to this study, maternal vitamin D supplementation was positively correlated

to maternal serum and cord blood 25(OH)D concentrations [14]. Matejek et al. reported that there is a strong
correlation between maternal and cord blood 25(OH)Marsubrin et al. BMC Pediatrics(2024) 24:588

Page 5 of 6

Table 2 Bivariate analysis between infant vitamin D andIntestinal dysbiosis
Vitamin D status

Intestinal dysbiosis
Yes
n (%)

No
n(%)

Deficiency

14(60.87)

9(39.13)

No deficiency

14(70.00)

6(30.00)

RR 95%CI

p-value

0.67(0.15–2.82)

0.531

Table 3 Association between vitamin D and intestinal dysbiosis
after adjusted by confounding factors for intestinal dysbiosis
Confounding factors

RR 95% CI

p-value

Maternal vitamin D

1.68(0.15–18.01)

0.66

Gestational Age

1.15(0.84–1.57)

0.37

Infant Vitamin D

0.49(0.10–2.37)

0.38

Nutritional Intake

0.76(0.17–3.32)

0.72

Sepsis8.18(1.41–47.23)

0.01

D levels indicating inadequate vitamin D stores during
pregnancy and the presence of vitamin D deficiency inpreterm newborns [15]. Previous studies have indicatedthat infections can lead to vitamin D deficiency, as infections increase the physiological demand for vitamin D,
which plays a crucial role in modulating both innate andadaptive immune responses. Consequently, we hypothesized that maternal infections may lower maternal vitamin D levels, thereby impacting transplacental transfer
and potentially resulting in vitamin D deficiency in neonates [16, 17].
This study demonstrated that there were no associations between gestational age or birth weight and vitamin D status (p> 0.05), which was similar to the findingsof several previous studies [15, 18]. There were no significant differences in serum 25(OH)D concentrationsor the incidence of severe vitamin D deficiency between
early, moderate, and late preterm infants. Therefore, it
was hypothesized that vitamin D status may be related toother factors such as maternal serum levels during pregnancy. No endogenous production of 25(OH)D occurs in
the fetus, and hence its levels depend on transplacental
transfer [19].
Intestinal dysbiosis is defined as low microbiota diversity, lack of commensal microbiota, and excessive growthof pathogenic microbiota [6, 20]. Intestinal dysbiosis
describes changes in the intestinal microbiota in relation to a disease [20]. In general, low Bifidobacteriaceae
and high Enterobacteriaceae and Clostridiaceaeproportion can be a sign of dysbiosis within the first month oflife. This pattern is often found in various conditions,

including premature infants, full-term infants requiringlong-term treatment or antibiotics, and infants with goodclinical conditions with an increased risk for dysbiosisassociated diseases [20]. Based on the definition above,
we found all of the subjects in our study were dysbiotic,
characterized by low number of Bifidobacteriaceae andhigh number of Enterobacteriaceae.
The microbiota composition in newborns can beaffected by many factors from pregnancy to birth. Previously, the intestines of an infant were thought to besterile before birth. However, with time, several studies
identified the presence of bacteria inside the meconium,
amniotic fluid, and placenta [7]. This finding opened
a possibility that intrauterine factors can also affect thecomposition of intestinal microbiota in newborns. One
mechanism for the presence of microbiota in the intestine of newborns is through the process of ingestingamniotic fluid. The diversity and abundance of microbiota in newborns increases along with their development.
Vitamin D deficiency causes a decrease in microbiota
clearance in intestine, decreased expression of intestinal
epithelial tight junctions, and increased Th1 cell-mediated inflammation [21]. Intestinal microbiota imbalancecan be influenced by the number of vitamin D receptors[12]. Premature and/or very low birth weight infants arethought to be more susceptible to intestinal dysbiosis [7].
An interesting trend was also observed in this study
regarding the ratio between commensal and pathogenic
bacteria in preterm neonates with vitamin D deficiency,with a lower proportion of commensal bacteria comparedto pathogenic bacteria (13.16%: 86.84%). In contrast,
opposite results were observed in the group no vitamin D
deficiency in preterm neonates (67.66%: 32.34%) (Fig. 1).
Low levels of vitamin D in premature infants can cause
an imbalance in gastrointestinal microbiota, leading tointestinal dysbiosis [12, 21].
Intestinal microbiota also played an important role
for the development of the immune system and immune
responses following birth [22]. Vitamin D modulates theimmune system by regulating one of its main roles (antimicrobial peptide, AMP). The antimicrobial peptide hasvarious functions aside from its microbiocidal activity,
which include chemotaxis of inflammatory immune cells.
This means that the level of AMP expression will affectthe relative composition of intestinal microbiota. The
role of vitamin D in regulating AMP production showsthat vitamin D status can affect intestinal microbiota
composition [23].
A limitation of this study is that it did not perform
microbiota sequencing to better assess intestinal dysbiosis through higher analytical sensitivity, greater resolutionof genomic variants, and more data from smaller DNA
amounts. We realize that the number of the sample wasMarsubrin et al. BMC Pediatrics(2024) 24:588

small but yet valuable for the study. This was the first study
in Indonesia which correlated vitamin D and neonatal dysbiosis in premature infant.

Conclusion
Vitamin D was not associated with dysbiosis in prematureinfants. However, this study found that the ratio of Lactobacillaceae to Enterobacteriaceae in those with vitamin D
deficiency was lower than in those without vitamin D deficiency. Further research is warranted to confirm this finding.
Abbreviations
CMH	Cipto mangunkusumo hospital
AMP	Antimicrobial peptide
SPSS	Statistical package for the social sciences
RR	Relative risk
SD	Standard deviation
Acknowledgements
The authors would like to thank the doctors, nurses, and all team members at
the Neonatal Unit of Cipto Mangunkusumo Hospital (CMH), Jakarta for their
participation in this study.
Authors’ contributions(PMTM): Conceptualization, Methodology, Validation, Format analysis, Investigation, Writing-original draft, Writing-review and editing. (AF): Conceptualization, Methodology, Validation, Supervision, Writing-original draft. (RR):
Conceptualization. (YP): Conceptualization. (SB): Methodology, Format analysis. (SGM): Methodology, Validation, Writing-review and editing, Supervision.
(ZM): Investigation. (IST): Investigation. (TY): Investigation. (MY): Investigation,
Writing-original draft, Writing-review and editing.
Funding
The authors would like to thank Universitas Indonesia for funding this study
through the PUTI Grant, with the following contract number: NKB-3517/UN2.
RST/HKP.05.00/2020.
Availability of data and materials
The data are available from the corresponding author on reasonable request.
Medical records are available in the Archive of Neonatal Unit, Cipto Mangunkusumo Hospital.

Page 6 of 6

2.
3.
4.
5.
6.
7.
8.
9.
10.
11.
12.
13.

14.
15.

16.
17.

Declarations
Ethics approval and consent to participate
This study obtained ethical clearance from the Ethical Committee of theFaculty of Medicine, Universitas Indonesia with the following registration
number: 617/UN2.F1/ETIK/PPM.00.02/2019. Informed consent to participate
was obtained from the parents or legal guardians, as our study involved a
population of children under the age of 16.
Consent for publication
Not applicable.
Competing interests
The authors declare no competing interests.
Received: 7 June 2024 Accepted: 4 September 2024

18.

19.
20.
21.
22.
23.

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