Intestinal permeability during pregnancy - maintained by Vitamin D, Omega-3, etc. - March 2025

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Mechanisms underlying changes in intestinal permeability during pregnancy and their implications for maternal and infant health

Journal of Reproductive Immunology Vol. 168, March 2025 https://doi.org/10.1016/j.jri.2025.104423 PDF is behind a $25 paywall

Highlights

• During pregnancy, increased intestinal permeability is influenced by uterine enlargement, hormonal changes, altered gut motility, prolonged gallbladder emptying, and changes in gut microbiota and inflammation.
• Pregnancy-induced increased intestinal permeability boosts nutrient absorption, supporting maternal health, fetal growth, and microbiota establishment in breast milk, placenta, and fetal gut.
• Periodic changes in intestinal permeability during pregnancy may help regulate immune transitions and influence the initiation of labor.
• Abnormal elevation of intestinal permeability during pregnancy is linked to immune dysregulation, metabolic disorders, and pregnancy-related complications.
• Moderate intestinal permeability can be maintained with probiotics, prebiotics, dietary fiber, omega-3 fatty acids, and vitamin D.

Abstract
Proper regulation of intestinal permeability is essential for maintaining the integrity of the intestinal mucosal barrier. An abnormal increase in permeability can significantly contribute to the onset and progression of various diseases, including autoimmune disorders, metabolic conditions, allergies, and inflammatory bowel diseases. The potential connection between intestinal permeability and maternal health during pregnancy is increasingly recognized, yet a comprehensive review remains lacking. Pregnancy triggers a series of physiological structural adaptations and significant hormonal fluctuations that collectively contribute to an increase in intestinal permeability. Although an increase in intestinal permeability is typically a normal physiological response during pregnancy, an abnormal rise is associated with immune dysregulation, metabolic disorders, and various pregnancy-related complications, such as recurrent pregnancy loss, gestational diabetes mellitus, overweight and obesity during pregnancy, intrahepatic cholestasis of pregnancy, and preeclampsia. This paper discusses the components of the intestinal mucosal barrier, the concept of intestinal permeability and its measurement methods, and the mechanisms and physiological significance of increased intestinal permeability during pregnancy. It thoroughly explores the association between abnormal intestinal permeability during pregnancy and maternal diseases, aiming to provide evidence for the pathophysiology of disease development in pregnant women. Additionally, the paper examines intervention methods, such as gut microbiota modulation and nutritional interventions, to regulate intestinal permeability during pregnancy, improve immune and metabolic states, and offer feasible strategies for the prevention and adjuvant treatment of clinical pregnancy complications.

Introduction
The intestine plays a key role not only in digesting food and absorbing nutrients, but also in forming a selective barrier through its epithelial cells. This intestinal barrier permits the passage of small molecules, nutrients, water, and ions, while limiting the entry of potentially harmful pathogens and bacterial toxins (Groschwitz and Hogan, 2009, Turner, 2009a). The integrity of this barrier is essential for protecting the body from external threats, thereby helping to maintain internal balance. However, when the intestinal mucosal barrier is compromised and permeability is increased, there is a risk that microorganisms, allergens, and endotoxins from the gut may cross into the bloodstream. This translocation can allow these substances to reach distant organs via systemic circulation, potentially contributing to a range of health issues, including systemic inflammatory response syndrome or multiple organ dysfunction syndrome (Epstein et al., 1992, Ghosh et al., 2020, Kinashi and Hase, 2021, Van Leeuwen et al., 1994). Increased intestinal permeability is often considered a marker of mucosal barrier dysfunction, sometimes referred to as "leaky gut." This condition has been linked to the development of various health disorders, including autoimmune diseases, metabolic conditions, allergic reactions, and inflammatory bowel diseases (IBD), all of which involve underlying immune disturbances (Camara-Lemarroy et al., 2018, Fasano and Shea-Donohue, 2005, Michielan and D’Incà, 2015, Oshima and Miwa, 2016, Portincasa et al., 2021, Poto et al., 2023). Increased intestinal permeability facilitates the translocation of gut bacteria, toxins, and other substances, triggering abnormal immune responses that promote autoimmune diseases (Camara-Lemarroy et al., 2018, Fasano and Shea-Donohue, 2005). This disruption also causes gut microbiota imbalances, leading to systemic inflammation. Such dysregulation affects metabolic processes, promoting fat accumulation, insulin resistance, and other disturbances that contribute to obesity, type 2 diabetes, and metabolic syndrome (Cox et al., 2017, Portincasa et al., 2021). In IBD, impaired gut barrier function is marked by epithelial cell death, altered mucus composition, tight junction protein dysfunction, and reduced antimicrobial peptide expression, collectively resulting in diarrhea, bacterial translocation, and inflammation (Holmberg et al., 2018, Michielan and D’Incà, 2015).

Pregnant women represent a special population in which intestinal permeability undergoes changes during pregnancy (Ribeiro et al., 2023, Zhou et al., 2019). Several factors contribute to the increased intestinal permeability observed during this time.

• As the uterus expands, it compresses abdominal organs, affecting intestinal motility.
• Elevated progesterone levels relax smooth muscles, slowing intestinal movement and delaying gastric emptying (Alqudah et al., 2022, Wang et al., 2003).
• Rising estrogen levels cause mesenteric vasodilation, potentially increasing intestinal permeability (Kuate Defo and Daskalopoulou, 2023).
• Prolonged gallbladder emptying leads to thicker bile, further slowing digestion and increasing the risk of constipation.
• In addition to these physiological changes, alterations in the gut microbiota and increased gut inflammation further contribute to the heightened intestinal permeability (Collado et al., 2008).

These changes in intestinal permeability can trigger significant physiological effects, including alterations in immune responses. While some of these changes are normal physiological adaptations, others may lead to health issues.
An abnormal increase in intestinal permeability is closely linked to immune dysregulation, contributing to serious metabolic disorders and pregnancy-related complications such as

• recurrent pregnancy loss (RPL),
• gestational diabetes mellitus (GDM),
• obesity during pregnancy,
• intrahepatic cholestasis of pregnancy (ICP), and
• preeclampsia (PE) (Bawah et al., 2020, Clark et al., 1993, Fernández-Valero et al., 2023, Mokkala et al., 2016, Oral et al., 2024, Reyes et al., 2006, Ribeiro et al., 2023, Srugo et al., 2019, Tersigni et al., 2018).

Table 1 summarizes the changes in intestinal permeability and associated indicators in pregnancy-related diseases. These changes not only affect maternal health but can also negatively impact fetal growth and development. Therefore, it is essential to accurately identify pregnant women with increased intestinal permeability and implement early interventions. Early detection and assessment of increased intestinal permeability can facilitate targeted treatments, help prevent or delay disease progression, and ensure the health of both the mother and the fetus.

This article explores the mechanisms underlying changes in intestinal permeability during pregnancy and their implications for maternal health. It also reviews various intervention strategies, including nutritional adjustments and modulation of the gut microbiota, aimed at regulating intestinal permeability. By highlighting these aspects, this review aims to provide new insights and directions for future research in improving maternal and infant health. Fig. 1 summarizes the changes in intestinal permeability during pregnancy and their impact on maternal and infant health.

Section snippets
Mechanical barrier
The intestine is the largest organ surface through which the body interacts with the external environment. Maintaining an intact intestinal mucosal barrier is crucial for gut homeostasis and disease prevention (Farhadi et al., 2003). The intestinal barrier system comprises four components: mechanical, chemical, immune, and biological barriers, which work together to maintain stability between internal and external environments (J et al., 2022). The mechanical barrier is formed by tight . . . .

Disaccharide test
The disaccharide test was the first technique developed to assess intestinal permeability. In this test, subjects orally ingest both a monosaccharide and a disaccharide, then collect their urine while fasting. The concentrations of these sugars in the urine are measured. When intestinal integrity is intact, monosaccharides are easily absorbed, whereas disaccharides are poorly absorbed and remain in the gut, resulting in a high monosaccharide ratio in the urine. However, when intestinal . . . .

Changes in intestinal permeability during pregnancy and their mechanisms
Compared to non-pregnant women, pregnant women experience increased intestinal permeability (Kerr et al., 2015a, Ribeiro et al., 2023, Zhou et al., 2019). This heightened permeability is attributed to a combination of physiological and anatomical changes during pregnancy, including uterine enlargement, hormonal fluctuations, and alterations in gut microbiota (Fig. 2).
Firstly, the expanding uterus exerts pressure on or displaces the intestines, impacting their normal motility and function.
The role of the gut barrier in immune regulation . . . .

The vast microbial community in the gut maintains the balance of intestinal microecology through symbiotic and competitive relationships. Intestinal permeability regulates the rate and amount of translocation of gut bacteria and their metabolites. When the penetration of bacterial LPS increases, it can lead to endotoxemia and systemic inflammatory responses (Fuke et al., 2019). Additionally, changes in the gut microbiota can affect the types and amounts of SCFAs, which in turn influence the . . . .

Nutritional needs of the pregnant woman and requirements for fetal growth and development
During pregnancy, increased intestinal permeability optimizes nutrient absorption to meet the heightened metabolic demands of the mother, support fetal development, and facilitate pregnancy-related physiological processes. Elevated permeability enhances the absorption of key nutrients, including proteins, carbohydrates, fats, vitamins, and minerals, which are critical for fetal growth and the maturation of tissues and organs. Simultaneously, it supports maternal nutritional needs, contributing . . . .

Recurrent pregnancy loss
In clinical practice, approximately 15 %-20 % of pregnancies end in spontaneous miscarriage (Ford and Schust, 2009). The incidence of RPL is 3–5 %, with about 30 % of cases having no identifiable cause (Ford and Schust, 2009, Tersigni et al., 2018). As early as 1984, researchers began investigating the association between intestinal status and female pregnancy outcomes. A study examined infertility and pregnancy outcomes in 112 married women under 45 years old with Crohn's disease, ultimately . . . .
Probiotics and prebiotics
Probiotics are a class of beneficial active microorganisms that colonize the human body and alter the microbiota composition in certain areas. Ingesting probiotics can maintain the stability of the gut microbiota, enhancing the intestinal epithelial barrier function by promoting mucin secretion, increasing the expression of tight junction proteins, and boosting mucosal immunity (Mutluoglu et al., 2023). This process reduces endotoxemia and inflammatory responses, alleviating insulin resistance . . . .

Conclusions and perspectives
Pregnant women, as a special group, experience increased intestinal permeability during pregnancy. This increase is necessary to meet the heightened nutritional needs required for fetal development, pregnancy-related physiological processes, and the overall metabolic demands of pregnancy. Additionally, increased intestinal permeability may facilitate the formation and transmission of specific microbiota, which are foundational for the microbiota present in breast milk and the placenta. Changes . . . .

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