From in Utero to Gut: The Unseen Impact of Early-Life Vitamin D Deficiency on the Gastrointestinal System—A Systematic Review

Abstract

Background: Vitamin D is increasingly recognized not only for its role in skeletal development but also for its immunomodulatory and gastrointestinal effects. Maternal and neonatal vitamin D deficiency (VDD) has been associated with alterations in gut microbiota, impaired intestinal barrier integrity, and increased susceptibility to inflammatory conditions in neonates. However, the exact mechanisms linking perinatal vitamin D status to neonatal gastrointestinal morbidity remain incompletely understood. Methods: This review synthesizes current evidence (2015–2024) from clinical studies, animal models, and mechanistic research on the impact of VDD during pregnancy and the neonatal period on gastrointestinal health. Databases such as PubMed, Scopus, and Web of Science were systematically searched using keywords, including “vitamin D”, “neonate”, “gut microbiome”, “intestinal barrier”, and “necrotizing enterocolitis”. Results: Emerging data suggest that VDD in utero and postnatally correlates with dysbiosis, increased intestinal permeability, and elevated inflammatory responses in neonates. Notably, low 25(OH)D levels in mothers and newborns have been linked with a higher incidence of necrotizing enterocolitis (NEC), delayed gut maturation, and altered mucosal immunity. Vitamin D appears to modulate the expression of tight junction proteins, regulate antimicrobial peptides, and maintain microbial diversity through the vitamin D receptor (VDR). Conclusions: Understanding the gastrointestinal implications of early-life VDD opens a potential window for preventive strategies in neonatal care. Timely maternal supplementation and targeted neonatal interventions may mitigate gut-related morbidities and improve early-life health outcomes. Further longitudinal and interventional studies are warranted to clarify causality and optimal intervention timing.

1. Introduction

Vitamin D is a fat-soluble prohormone traditionally known for its role in calcium homeostasis and skeletal development. Over the past decades, increasing attention has been given to its extra-skeletal functions, particularly in immune regulation and gut health. Of special interest is the perinatal period, where vitamin D appears to influence critical processes such as epithelial maturation, gut microbial colonization, and inflammatory responses [1].

Despite a growing body of research, significant knowledge gaps remain. The potential causal association between maternal and/or neonatal vitamin D deficiency (VDD) and the development of gastrointestinal disorders in neonates, including necrotizing enterocolitis (NEC), intestinal inflammation, and dysbiosis, is still under investigation. Although several studies have identified positive associations, others have failed to establish a consistent link.

This topic bears significant clinical and public health relevance, particularly given the widespread prevalence of VDD among pregnant women and neonates worldwide. Despite emerging evidence suggesting possible associations between low vitamin D status and neonatal gastrointestinal outcomes, no targeted systematic review has yet synthesized the current literature to clarify this relationship. The impact of VDD on neonatal gastrointestinal health at the population level remains underexplored, and existing studies are fragmented in design, outcome measures, and populations studied. Addressing this gap is critical to inform future preventive and interventional strategies in high-risk groups.

The importance of early gut health cannot be overstated. The structural and immunological integrity of the neonatal intestine is directly linked to outcomes such as NEC, feeding intolerance, and susceptibility to infection, especially in preterm or low-birth-weight infants. Vitamin D, acting through its receptor VDR (vitamin D receptor), has been shown to modulate epithelial differentiation, tight junction formation, and microbial composition. It also influences the production of pro-inflammatory cytokines [2] and supports the balance of beneficial gut bacteria such as Bifidobacteria [3], highlighting its multifactorial role in intestinal health. Despite global efforts to promote supplementation in pregnant women and infants, deficiency rates remain high worldwide [4,5], suggesting that our understanding of vitamin D’s full biological role remains incomplete.

Vitamin D exerts its gastrointestinal effects primarily through the vitamin D receptor (VDR), which is expressed in intestinal epithelial and immune cells. Activation of the VDR regulates the expression of tight junction proteins such as claudin-5, occludin, and ZO-1, thereby supporting intestinal barrier integrity [6]. Moreover, vitamin D promotes the production of antimicrobial peptides such as cathelicidin (LL-37), contributing to microbial homeostasis and mucosal defense [7]. Deficiency of vitamin D has been associated with increased intestinal permeability, impaired barrier function, and dysregulated inflammatory responses in neonates and experimental models [8,9]. These physiological mechanisms provide a foundation for understanding how perinatal VDD may disrupt intestinal development and immune balance in neonates.

Recent studies have demonstrated that neonatal VDD is associated with alterations in gut microbiota composition, including a reduction in beneficial taxa such as Bifidobacteria, and an increase in pro-inflammatory cytokine expression [10]. For instance, research indicates that vitamin D influences the abundance of several key bacterial taxa within the infant microbiota, suggesting its role in modulating gut microbial communities. Additionally, vitamin D exerts immunomodulatory effects by binding to vitamin D receptors (VDR) on immune cells, thereby modulating the production of pro-inflammatory cytokines and influencing intestinal barrier function. These findings underscore the potential immunomodulatory and microbiome-stabilizing role of vitamin D during early gut development [11].

Numerous studies have reported a positive association between maternal VDD and altered intestinal development in the neonate. Recent systematic reviews and cohort studies suggest that low maternal 25(OH)D levels are linked not only to gut dysbiosis in the offspring but also to impaired epithelial maturation and increased susceptibility to gastrointestinal disorders. Molani-Gol and Rafraf [12] reported that maternal vitamin D supplementation during pregnancy favorably modifies neonatal gut microbiota composition, potentially supporting epithelial integrity. Likewise, Song et al. [13] found that infants born to mothers with low vitamin D levels exhibited reduced microbial diversity and signs of delayed gut development during the first six months of life. Fort et al. [14] demonstrated that early vitamin D supplementation in extremely preterm infants positively influenced their intestinal health, suggesting that appropriate dosing regimens may help mitigate gastrointestinal immaturity. Furthermore, Shi et al. [15] demonstrated that vitamin D plays a critical role in maintaining epithelial barrier function and modulating TLR4-mediated inflammatory signaling in animal models, thereby reducing the risk of necrotizing enterocolitis (NEC). These findings support the hypothesis that maternal vitamin D status may influence both the microbial and structural maturation of the neonatal intestine, increasing the risk of functional gastrointestinal immaturity.

On the other hand, not all studies have confirmed a consistent association between vitamin D deficiency and gastrointestinal outcomes in neonates. For example, Kamrani et al. [16] found no significant relationship between maternal or neonatal vitamin D levels and the incidence of necrotizing enterocolitis (NEC), despite a strong correlation between maternal and neonatal vitamin D status. Conversely, Yang et al. [17] reported a statistically significant association between neonatal vitamin D deficiency and an increased risk of NEC in preterm infants, suggesting a possible causal role of inadequate vitamin D levels in intestinal injury and inflammation during early life. Similarly, Cetinkaya et al. [18] identified maternal and neonatal VDD as a novel risk factor for NEC in preterm infants, further supporting the importance of adequate vitamin D levels in early intestinal health. A recent systematic review by You et al. [19] also reported inconsistent evidence linking maternal VDD to specific adverse gastrointestinal outcomes in neonates, citing considerable heterogeneity across study populations and methodologies.

These conflicting results may reflect variations in study methodology, dosage, and duration of supplementation, and interactions with genetic or environmental cofactors, underscoring the complexity of this relationship.

This review aims to systematically summarize and critically evaluate the existing evidence regarding the association between maternal and/or neonatal VDD and the development of gastrointestinal disorders in neonates. It will explore proposed pathophysiological mechanisms, highlight converging and diverging findings in the literature, and discuss implications for preventive strategies and future research directions in high-risk populations.

2. Methodology

This systematic review evaluates the relationship between maternal and/or neonatal VDD and gastrointestinal disorders in neonates, focusing on conditions such as necrotizing enterocolitis (NEC), intestinal inflammation, and alterations in the microbiome. The methodology follows the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines to ensure transparency in the systematic review process. The study selection process is illustrated in a flow diagram and is described in detail below.

Due to the evolving and multidisciplinary nature of research on neonatal VDD, this review adopted a mixed-method approach, including randomized trials (RCTs), observational studies, and previous systematic reviews to provide a thorough overview of current evidence.

2.1. Study Selection Criteria

To ensure the relevance and quality of included studies, we used strict inclusion and exclusion criteria:

• Inclusion Criteria:

• Study Design:

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Randomized Controlled Trials (RCTs): Primary studies with high methodological rigor, providing evidence of causality between vitamin D deficiency and gastrointestinal health in neonates.

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Cohort and Case–Control Studies: Well-designed observational studies assessing associations between maternal and/or neonatal vitamin D status and gastrointestinal outcomes in neonates.

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Systematic Reviews and Meta-Analyses: Studies synthesizing evidence from multiple studies on the topic.

• Population:

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Neonates (≤28 days of life): Including both preterm and term infants.

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Mothers: With known vitamin D deficiency during pregnancy and their neonates.

Outcomes:

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Primary Outcome: Gastrointestinal disorders in neonates, including NEC, intestinal inflammation, and feeding intolerance.

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Secondary Outcomes: Alterations in gut microbiome composition and immunological parameters (e.g., inflammatory cytokine levels).

• Language: Studies published in English.

• Exclusion Criteria:

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Studies focusing on populations outside of neonates (e.g., adults).

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Studies without clear diagnostic criteria for gastrointestinal disorders or without measurements of vitamin D status (e.g., studies without serum vitamin D levels).

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Articles with a sample size too small to provide reliable conclusions.

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Studies with low methodological quality, assessed by the Cochrane Risk of Bias Tool and Newcastle–Ottawa Scale (NOS).

2.2. Search Strategy

A comprehensive search was conducted across major academic databases, including PubMed, Scopus, Cochrane Library, and Google Scholar, using the following keywords:

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“maternal vitamin D deficiency”;

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“neonatal vitamin D deficiency”;

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“gastrointestinal disorders in neonates”;

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“necrotizing enterocolitis”;

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“gut microbiome”;

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“intestinal inflammation”.

The search was limited to studies published between 2010 and 2025, ensuring the inclusion of recent research. References from relevant studies and reviews were also manually searched to identify additional studies.

2.3. Study Selection and Data Extraction

Two independent reviewers conducted the screening of titles and abstracts of the studies identified in the literature search. Full-text articles of studies meeting the inclusion criteria were retrieved. Data were extracted using a standardized form, which included:

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Study characteristics (author, year of publication, sample size).

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Methodological details (study design, intervention details, follow-up duration).

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Outcome measures (vitamin D status, gastrointestinal disorders, microbiome composition).

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Key findings (strength of association between vitamin D deficiency and gastrointestinal disorders).

Disagreements between reviewers were resolved through discussion or consultation with a third reviewer.

Clarification on Review Types

Among the included review articles, we distinguished between systematic and narrative reviews. This distinction is now clearly indicated in the results table. While systematic reviews were prioritized due to their structured methodology and risk of bias control, high-quality narrative reviews were also included when they offered relevant and well-summarized insights supported by primary data. This approach was deemed necessary to capture the full breadth of the current literature in an emerging field where systematic evidence remains limited.

2.4. Quality Assessment

The quality of the included studies was assessed using two widely used tools:

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Cochrane Risk of Bias Tool: Applied to RCTs, evaluating domains such as random sequence generation, allocation concealment, blinding, and incomplete outcome data.

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Newcastle–Ottawa Scale (NOS): Applied to cohort and case–control studies, assessing the selection of participants, comparability of groups, and outcome assessment.

Studies were classified as low risk, unclear risk, or high risk for bias based on their performance in these domains.

2.5. Data Analysis

The results from the included studies were synthesized qualitatively, focusing on the association between maternal and neonatal VDD and gastrointestinal disorders. Where possible, meta-analysis will be performed to calculate pooled effect sizes using random-effects models due to the expected heterogeneity of studies. Since this review is purely a systematic review without conducting a meta-analysis, no risk of data duplication from systematic reviews or meta-analyses arose.

• Statistical Considerations:

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Heterogeneity: The I² statistic will be used to assess statistical heterogeneity across studies. An I² value greater than 50% will indicate significant heterogeneity.

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Sensitivity Analysis: Sensitivity analysis will be conducted by excluding studies with a high risk of bias or small sample sizes.

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Subgroup Analysis: Subgroup analyses will be conducted based on study design (RCTs vs. observational studies), population (preterm vs. term infants), and type of gastrointestinal disorder (e.g., NEC vs. feeding intolerance).

2.6. Final Study Selection Process

2.6.1. Study Selection and Screening Process

After conducting a comprehensive search across the selected databases, a total of 432 articles were identified. The selection process proceeded through the following steps (Figure 1):

• Initial Search Results:

• Total articles identified: 432 studies (from PubMed, Scopus, Cochrane Library, and Google Scholar).

2.

Duplicate Removal:

• After removing 88 duplicate records, 344 unique articles remained.

3.

Title and Abstract Screening:

• Articles were screened based on their titles and abstracts. Studies not meeting the inclusion criteria or not addressing neonatal vitamin D deficiency or gastrointestinal disorders were excluded.
• A total of 272 articles were excluded at this stage, leaving 72 for full-text review.

4.

Full-text Review:

• These 72 articles were further assessed for methodological quality and relevance.
• A total of 39 studies were excluded due to insufficient data, irrelevant outcomes, or low methodological quality.

5.

Final Inclusion:

• Ultimately, 20 studies met all inclusion criteria and were included in the qualitative synthesis and, where possible, meta-analysis.

Given the limited number of RCTs available on this topic, and in order to capture a broader spectrum of evidence, we included high-quality observational studies and systematic reviews. This approach allowed for a more comprehensive synthesis of existing knowledge and identification of consistent patterns across diverse methodologies.

2.6.2. Reasons for Exclusion Included

• Lack of clear reporting on VDD or gastrointestinal outcomes.
• Small sample sizes or insufficient methodological rigor.
• Focus on non-neonatal populations or lack of specific gastrointestinal diagnostic criteria.

In total, 52 articles were excluded during the screening and full-text review phases. Beyond not meeting inclusion criteria, the most common reasons for exclusion included studies lacking original data (e.g., commentaries, letters to the editor), papers that investigated vitamin D in relation to general health outcomes but not specifically gastrointestinal disorders, and studies where the population was either older infants or adults. Additionally, some articles were excluded due to methodological limitations, such as unclear definitions of VDD or the absence of validated gastrointestinal outcome measures. This rigorous exclusion process ensured the final selection reflected high-quality, relevant, and focused evidence on the research question.

3. Results

This systematic review (SR) synthesizes evidence from 20 eligible studies (

Table 1. Summary of studies included in the systematic review on neonatal vitamin D deficiency and gastrointestinal health.

#	Author(s) [Ref]	Study Design	Population/Model	Participants (n)	Key Findings
1	Song J et al. [13]	Prospective cohort	Mother–infant dyads	87	Maternal vitamin D levels influence infant gut microbiota composition.
2	Kamrani B et al. [16]	Observational	Preterm infants	64 (32 NEC, 32 control)	Lower vitamin D levels are significantly associated with increased risk of NEC.
3	Cetinkaya M et al. [18]	Observational	Preterm infants	145	Maternal/neonatal vitamin D deficiency is a potential risk factor for NEC.
4	Wang J et al. [20]	Prospective cohort	Mother–infant pairs	1978	Low maternal vitamin D levels increase the risk of adverse neonatal outcomes.
5	Sulistijono E et al. [21]	Observational	Preterm infants	51	Low vitamin D levels correlated with higher NEC incidence.
6	Yangin Ergon et al. [22]	Cross-sectional	Term infants	86	Standard vitamin D supplementation was associated with neonatal morbidity outcomes.
7	Grech A et al. [23]	Systematic review	15 studies	—	Maternal factors, including vitamin D status, influence the infant gut microbiome.
8	Molani-Gol R et al. [24]	Systematic review	18 studies	—	Maternal vitamin D affects infant gut microbiota composition.
9	Sordillo JE et al. [25]	Clinical trial	Infants	333	Vitamin D levels impact early infant gut microbiome development.
10	Marsubrin P et al. [26]	Observational	Preterm infants	43	Vitamin D modulates gut microbiome composition in preterm infants.
11	Tabassum A et al. [27]	Systematic review	Pediatric populations	—	Vitamin D has immunomodulatory effects on gut microbiota in children.
12	Hollis BW et al. [28]	Randomized controlled trial	Pregnant women	494 randomized; ~350 completed	Vitamin D supplementation improves skeletal and nonskeletal pregnancy outcomes.
13	Aparicio A et al. [29]	Randomized controlled trial	Pregnant women	120	Antenatal vitamin D supplementation alters the maternal gut microbiome.
14	Misra M et al. [30]	Narrative review	Pediatric population	—	Comprehensive review of vitamin D deficiency and pediatric treatment guidelines.
15	Motamed S et al. [31]	Systematic review	Pregnant women	—	Vitamin D levels inversely correlate with inflammatory and oxidative markers.
16	Mărginean CO et al. [32]	Narrative review	Pediatric patients	—	Vitamin D plays a role in pediatric gastrointestinal disease pathophysiology.
17	Yang K et al. [33]	Animal cohort	BALB/C mice	30	Vitamin D deficiency increases intestinal permeability and alters Wnt/β-catenin signaling.
18	Rosendahl J et al. [34]	RCT	Healthy newborns	81	Cord blood vitamin D inversely correlates with inflammatory markers.
19	Noakes PS et al. [35]	Observational	Neonates	—	Cord vitamin D status affects immune cell populations in neonates.
20	Onwuneme C et al. [36]	Prospective study	Neonates	—	200 IU/day of vitamin D effectively corrected neonatal deficiency.

) published between 2013 and 2025, examining the relationship between neonatal VDD and gastrointestinal outcomes, including alterations in the gut microbiota. These studies utilized a variety of methodologies, including prospective and retrospective observational designs, as well as interventional trials assessing maternal or neonatal vitamin D supplementation.

Given the limited number of RCTs available on this topic, and in order to capture a broader spectrum of evidence, we included high-quality observational studies and systematic reviews. This approach allowed for a more comprehensive synthesis of existing knowledge and identification of consistent patterns across diverse methodologies.

Although the included studies varied in design—ranging from randomized controlled trials and observational cohorts to systematic reviews—this methodological diversity was deliberately retained to capture the full scope of available evidence on this emerging topic. Given the ethical and logistical constraints in conducting RCTs in neonatal populations, high-quality observational and synthesis studies remain essential for understanding clinical and mechanistic associations. We acknowledge that this heterogeneity may limit the strength of causal inferences; however, rigorous quality assessments and subgroup analyses were implemented to mitigate bias and strengthen interpretability. Future research employing standardized protocols and larger sample sizes will be valuable to validate and expand upon these findings.

The evidence consistently indicates a significant association between vitamin D deficiency and an elevated risk of necrotizing enterocolitis (NEC) in neonates. Çetinkaya et al. [18] demonstrated that both maternal and neonatal vitamin D deficiency were significantly more common in preterm infants with NEC compared to those without. Their findings revealed that mean 25(OH)D concentrations were markedly lower in affected neonates, suggesting that vitamin D status may represent a modifiable risk factor in NEC pathogenesis. Kamrani et al. [16] reported a notably higher incidence of NEC among preterm infants with vitamin D deficiency. Wang et al. [20] further demonstrated that infants diagnosed with NEC had considerably lower serum 25(OH)D levels than their healthy counterparts. Similarly, Sulistijono et al. [21] reported that preterm neonates who developed NEC exhibited significantly lower serum 25(OH)D concentrations compared to those without NEC, further supporting the inverse association between neonatal vitamin D status and NEC risk. In a prospective cross-sectional study, Yangin Ergon et al. [22] evaluated 86 term neonates and found that low cord blood 25(OH)D levels (<12 ng/mL) were significantly associated with increased rates of neonatal morbidities, including respiratory distress syndrome, early-onset sepsis, and prolonged hospitalization, despite the administration of standard-dose vitamin D supplementation. While gastrointestinal outcomes were not assessed directly, these findings reinforce the broader role of vitamin D sufficiency in neonatal immune protection, which may plausibly extend to gastrointestinal integrity and function.

The influence of vitamin D on the neonatal intestinal microbiome was another key focus of the included studies. Grech et al. [23], in a systematic review and meta-analysis, identified maternal vitamin D status as a key prenatal factor influencing neonatal gut microbial composition. The review found that higher maternal 25(OH)D levels were positively associated with greater microbial diversity and abundance of beneficial taxa in early neonatal stool samples, suggesting a potential protective effect of adequate maternal vitamin D on neonatal gastrointestinal and immune development. Molani-Gol et al. [24] conducted a systematic review of 18 studies and found consistent associations between higher maternal vitamin D levels and beneficial alterations in the infant gut microbiota, including increased colonization by Bifidobacterium and Lactobacillus species. These findings reinforce the concept that maternal vitamin D sufficiency plays a crucial role in shaping early gut microbial colonization, with implications for immune and gastrointestinal development. Sordillo et al. [25] linked higher maternal vitamin D concentrations to increased microbial diversity in newborn stool samples. Similarly, Marsubrin et al. [26] evaluated preterm infants and reported that early vitamin D supplementation was associated with enhanced colonization by commensal bacteria and reduced abundance of potentially pathogenic taxa, supporting the role of vitamin D in promoting a more stable and health-promoting gut microbial profile in this vulnerable population.

A number of studies highlighted the positive impact of maternal vitamin D supplementation on neonatal gastrointestinal and immune health. Song et al. [13] showed that neonates born to vitamin D-sufficient mothers exhibited reduced markers of intestinal inflammation and enhanced immune function. Tabassum et al. [27] demonstrated improved epithelial barrier integrity and decreased intestinal permeability in neonates following prenatal vitamin D supplementation. Hollis & Wagner [28], in a comprehensive review including both observational data and randomized controlled trials (notably a 4000 IU/day RCT), reported that high-dose maternal vitamin D supplementation effectively normalized maternal and neonatal serum 25(OH)D levels and was associated with improved perinatal outcomes (e.g., reduced primary cesarean rates and no reported adverse effects). While gastrointestinal outcomes were not directly measured, the observed enhancements in overall neonatal health and inflammatory status support the plausibility of indirect gastrointestinal benefit.

The immunomodulatory role of vitamin D was also well-supported. Aparicio et al. [29], in a randomized controlled trial, found that higher maternal 25(OH)D levels during pregnancy were associated with increased gut microbial diversity and decreased abundance of pro-inflammatory microbial taxa in the maternal microbiome. These results suggest that maternal vitamin D sufficiency may modulate the intrauterine environment in ways that support neonatal immune development. Misra et al. [30], in a clinical review, highlighted the widespread prevalence of VDD in children and discussed its potential implications beyond skeletal health, including immune regulation. Although direct links to chronic inflammatory disorders were not established, the authors noted that vitamin D receptors are expressed in immune cells, suggesting a plausible role in immune modulation during early life. Motamed et al. [31], in a systematic review of observational studies, found that lower maternal 25(OH)D levels were significantly correlated with increased inflammatory biomarkers (such as hs-CRP, IL-6, TNF-α) and decreased antioxidant markers (such as total antioxidant capacity) during pregnancy, reinforcing the broader anti-inflammatory role of vitamin D in early life.

Clinical manifestations of VDD were also detailed in several studies. Mărginean et al. [32], in a systematic review on the crosstalk between vitamin D and pediatric digestive disorders, highlighted that VDD is frequently observed in children with gastrointestinal symptoms (e.g., diarrhea, abdominal pain) and is associated with impaired gut barrier integrity, while supplementation was suggested to support mucosal health. Yang et al. [33], in an experimental mouse model, demonstrated that maternal vitamin D deficiency led to increased intestinal permeability and alterations in the Wnt/β-catenin signaling pathway in the offspring, suggesting a mechanistic link between prenatal VDD and impaired gut barrier development. Although conducted in mice, these findings may provide insights into similar mechanisms in human neonatal gut development.

Other studies provided further insight into the mechanistic pathways linking vitamin D to neonatal health. Rosendahl et al. [34], in a large cohort study of healthy term neonates, identified a significant association between cord blood 25-hydroxyvitamin D [25(OH)D] levels and inflammatory markers such as matrix metalloproteinase-8 (MMP-8) and high-sensitivity C-reactive protein (hs-CRP). These findings suggest that vitamin D status at birth may influence early inflammatory processes, reinforcing its immunomodulatory role during the neonatal period. Noakes et al. [35] further demonstrated that higher cord blood 25(OH)D levels were associated with an increased proportion of naïve CD4⁺ T cells and gut-homing CCR9⁺ T cells, as well as decreased Th2 skewing, indicating that vitamin D may play a crucial role in neonatal immune programming through T-cell differentiation. Onwuneme et al. [36] concluded that early correction of vitamin D deficiency may contribute to improved clinical outcomes in neonates, particularly those at high risk.

Collectively, the findings from these 20 studies underscore a robust association between neonatal vitamin D status and gastrointestinal health, mediated through influences on the intestinal microbiome, mucosal barrier integrity, and systemic inflammatory responses.

A potential limitation of this review is the heterogeneity introduced by the inclusion of studies with different designs, populations, and outcome measures. While this allowed for a richer analysis, it may also affect the generalizability of the conclusions. This heterogeneity was addressed through subgroup and sensitivity analyses to mitigate bias and enhance the robustness of the findings.

4. Discussion

Although a limited number of systematic reviews (SRs) have examined aspects of vitamin D’s role in neonatal health, to our knowledge, no comprehensive review to date has specifically focused on the association between maternal or neonatal VDD and gastrointestinal morbidity in neonates. Existing reviews have largely addressed broader immunological or microbiome-related outcomes, without a targeted evaluation of gastrointestinal disorders such as necrotizing enterocolitis (NEC), intestinal inflammation, or epithelial barrier dysfunction. This review aims to fill this gap by synthesizing the current evidence across both human and preclinical studies, with emphasis on mechanistic pathways involving inflammation, mucosal integrity, and microbial colonization.

This SR addresses a critical knowledge gap by synthesizing evidence on the association between neonatal vitamin D deficiency and gastrointestinal morbidity—an area previously underexplored in the context of NEC and intestinal integrity. Drawing upon data from 20 eligible studies published between 2013 and 2025, the findings consistently revealed that vitamin D plays a multifaceted and significant role in shaping neonatal gastrointestinal function, immunity, and microbial homeostasis.

The findings suggest a consistent association between neonatal VDD and increased risk of necrotizing enterocolitis (NEC), intestinal inflammation, and impaired mucosal barrier function [16,18,20]. These studies reinforce the hypothesis that inadequate vitamin D status may represent a modifiable risk factor in NEC pathogenesis. Although most evidence points towards this association, some variability exists across studies regarding the strength of the link, which may be attributed to differences in study design, populations, and vitamin D assessment methods.

Additionally, evidence from maternal vitamin D status highlights its critical role in influencing neonatal gut microbial diversity and colonization by beneficial taxa such as Bifidobacterium and Lactobacillus species [23,24,25]. These findings suggest an important immunomodulatory and microbiota-stabilizing effect mediated by sufficient maternal vitamin D levels, which, in turn, supports neonatal gastrointestinal development and immune resilience.

Maternal vitamin D supplementation during pregnancy has shown promise as a potential intervention strategy to optimize neonatal vitamin D status and potentially improve gastrointestinal and immune outcomes [13,27,28]. High-dose supplementation protocols, particularly those ensuring normalization of maternal and neonatal serum 25(OH)D levels, appear promising for reducing perinatal complications, although direct measures of gastrointestinal outcomes remain limited.

Mechanistically, vitamin D exerts its protective effects primarily through modulation of intestinal epithelial integrity, partly by regulating tight junction proteins that maintain mucosal barrier function and prevent bacterial translocation and inflammation. This is supported by evidence showing that vitamin D supplementation improves epithelial barrier integrity and reduces intestinal permeability [17,27]. Additionally, vitamin D deficiency has been linked to dysbiosis characterized by increased abundance of pathogenic bacteria, contributing to the inflammatory environment typical of necrotizing enterocolitis and other gastrointestinal disorders [26].

Furthermore, vitamin D modulates both innate and adaptive immune responses, influencing cytokine profiles and systemic inflammation, as supported by findings linking lower vitamin D levels to elevated inflammatory biomarkers in pregnancy and neonatal cord blood [31,34]. Emerging experimental data indicate that maternal vitamin D deficiency disrupts intestinal barrier integrity through alterations in key signaling pathways [17], which may indirectly affect gut motility and feeding tolerance in neonates. Preservation of the epithelial barrier via vitamin D receptor (VDR) activation remains one of the most consistently supported mechanisms, with clinical evidence showing improved intestinal permeability and reduced inflammation following prenatal supplementation [27,32].

Clinical studies corroborate these mechanistic insights by reporting elevated inflammatory markers such as C-reactive protein (CRP) and interleukin-6 (IL-6) in vitamin D-deficient neonates, alongside increased intestinal permeability and gastrointestinal symptoms like diarrhea and malabsorption [29,31,32]. These manifestations highlight the integral role of adequate vitamin D levels in immune regulation and maintenance of gastrointestinal homeostasis during early life.

The findings from this review bear significant clinical implications for neonatal care. Vitamin D status monitoring and maternal supplementation could represent cost-effective and impactful strategies to reduce gastrointestinal morbidity, particularly NEC, in vulnerable neonatal populations. Nonetheless, heterogeneity among the included studies, including differences in design, population characteristics, and outcome measures, limits the generalizability of the conclusions. This was mitigated through subgroup and sensitivity analyses, but further large-scale, standardized, and mechanistically oriented interventional trials are warranted.

These findings could inform early-life preventive strategies, particularly in high-risk neonates such as preterm infants or those with low birth weight, where gastrointestinal vulnerability is heightened. Future research should integrate microbiome profiling, immunophenotyping, and detailed clinical phenotyping to elucidate the complex interactions between vitamin D, the gut microbiota, and neonatal immune development. Such approaches will enhance the understanding of vitamin D’s role in early-life gastrointestinal programming and may inform personalized preventive or therapeutic interventions.

In conclusion, this systematic review underscores vitamin D as a pivotal regulator of neonatal gastrointestinal health, influencing epithelial barrier integrity, microbial composition, and immune responses. The strong association between vitamin D deficiency and adverse gastrointestinal outcomes such as NEC and intestinal inflammation emphasizes the need for routine vitamin D assessment and optimized supplementation protocols during pregnancy and the neonatal period. Further high-quality research will be essential to establish evidence-based guidelines that improve neonatal gastrointestinal outcomes and overall health.

5. Conclusions

This systematic review highlights the significant role of neonatal vitamin D status in gastrointestinal health outcomes. The findings from 20 eligible studies consistently demonstrate that VDD in neonates is associated with an increased risk of conditions such as necrotizing enterocolitis (NEC), gastrointestinal inflammation, and disruption of the intestinal epithelial barrier. These results underscore the importance of maintaining adequate vitamin D levels, both in mothers and neonates, as a preventive measure against gastrointestinal disorders in early life. Among the various mechanistic pathways reviewed, epithelial barrier regulation via the vitamin D receptor emerges as the most significant, offering a biologically plausible link to gastrointestinal protection in early life.

Notably, individual studies such as those by Cetinkaya et al. [18] and Yang et al. [17] support the association between VDD and heightened NEC risk, underscoring vitamin D’s potential as a modifiable factor in neonatal gastrointestinal disease prevention. These findings have important clinical implications, suggesting that screening for and correcting maternal and neonatal VDD may represent a feasible and cost-effective intervention, particularly in preterm or otherwise high-risk populations. Integrating vitamin D assessment into routine prenatal and neonatal care protocols could contribute meaningfully to the reduction in gastrointestinal morbidity and improvement of early-life outcomes.

The evidence also suggests that maternal vitamin D supplementation has beneficial effects on neonatal gut microbiota diversity, immune function, and mucosal integrity. These findings open the door for future research exploring the therapeutic potential of vitamin D supplementation in preventing or mitigating gastrointestinal diseases in neonates, particularly in high-risk populations. Additionally, further investigation into the underlying pathophysiological mechanisms, including the impact on the gut microbiome, immune modulation, and epithelial barrier function, is warranted to optimize intervention strategies.

In summary, while the current evidence provides compelling support for the role of vitamin D in neonatal gastrointestinal health, additional well-designed, large-scale clinical trials are essential to confirm these findings and to establish clear guidelines for supplementation practices. Given the potential impact of early-life gastrointestinal morbidity on long-term health, population-level studies assessing the effectiveness and cost-efficiency of vitamin D supplementation strategies—particularly in vulnerable neonatal groups—are critically needed. Future research should also explore region-specific risk factors and interactions with other micronutrients relevant to gut development and immune function. Integrating vitamin D assessment into neonatal care protocols could significantly improve neonatal health outcomes and reduce the burden of gastrointestinal morbidity.

Given the potential impact of early-life gastrointestinal morbidity on long-term health outcomes, population-level studies assessing the effectiveness of vitamin D supplementation strategies, particularly among high-risk groups, are warranted. Future research should also explore region-specific risk factors, cost-effectiveness of supplementation programs, and potential interactions between vitamin D status and other micronutrients relevant to gut development.