Introduction

Have you ever found yourself dreading allergy season, sniffling and sneezing while your friends blissfully enjoy the blooming flowers unaffected? It may seem like bad luck, but one potential explanation can be found in the events that happened before you were even born. Emerging research studies are  exploring the origins of our immune system, uncovering its surprising connection with, and lasting impact on the maternal-fetal gut microbiome axis.

The Connection Between the Gut Microbiome and Pregnancy

The gut microbiome is a collection of trillions of microorganisms—including bacteria, archaea, and fungi—residing in the gastrointestinal tract. The maternal-fetal gut microbiome axis refers to the close relationship between the gut microbiota of a pregnant mother and its influence on fetal development.  Complex interactions in the axis play a critical role in shaping the health of both mother and child. 

During pregnancy, the maternal gut microbiome undergoes significant changes, driven by hormonal shifts and physiological adaptations that the maternal body experiences during pregnancy. These changes support the metabolic and immunological needs of the growing fetus, especially in the later stages of pregnancy. However, by the third trimester, the gut microbiota changes rapidly. One characteristic of a third-trimester maternal gut microbiome is an increase in bacterial load, defined as the amount of bacteria in a specific area or organism. 

Another component of a third-trimester gut microbiome is an altered microbial diversity, or the variety of microorganisms in the maternal gut microbiome. The abundance of bacteria in the taxonomic groups of Actinobacteria and Proteobacteria phyla noticeably rises. Additionally, levels of Faecalibacterium, a butyrate-producing bacterium with anti-inflammatory properties, are depleted. One measure of altered microbial diversity is a reduction in species richness or alpha diversity, defined as the number of different species in the gut. A second measure of microbial diversity is the reduction in beta diversity, which describes the variation in microbial composition across individuals. 

Furthermore, levels of bacterial metabolites or  certain beneficial products from bacterial metabolism such as short-chain fatty acids (SFCAs), diminish during pregnancy. SFCAs are a type of fatty acid-important components of lipids-with less than six carbons. SCFAs, including acetate, propionate, and butyrate, are among the most abundant metabolites produced as by-products of bacterial fermentation of dietary fibers in the gut. SCFAs play an important role in aiding metabolism and reducing inflammation.

Although the decrease in bacterial metabolites might seem detrimental — characterized by inflammation, insulin resistance, and weight gain — they are crucial for supporting fetal development. The physiological effects of the microbial changes include enhanced absorption of glucose and fatty acids, increased secretion of fasting-induced factors for adipocytes (fat cells), and stimulation of catabolic pathways. Catabolic pathways are necessary to sustain the fetus’s growth and metabolism of nutrients absorbed through the maternal placenta. These changes, accompanied by a heightened immune response, are important for maintaining maternal and fetal health.

Evidence from research studies supports the differential characterization of gut microbiota in different stages of pregnancy. In a research study conducted by the Ley Lab at Cornell,  mice that received fecal transplants from third trimester human microbiotas exhibited greater insulin resistance and inflammatory responses than those receiving transplants from first trimester microbiotas. The physiological effects of the microbial changes, though seemingly harmful, play an essential role in enhancing nutrient availability and storage, ultimately benefiting the developing fetus.

Effects of Gut Bacteria on Shaping Fetal Immunity

One of the primary ways the maternal gut microbiome impacts the fetus is through microbial metabolites, particularly SCFAs. A current hypothesis for this mechanism suggests that SCFAs enter the maternal bloodstream and travel through the placenta to reach the developing fetus, and by crossing the placental barrier, the SCFAs influence fetal metabolism and immune system development.

The immunological connection between the mother and fetus is central to the fetal-maternal gut axis, as it influences the development of the fetus’s immune responses both in utero – in the womb – and after birth. At the start of development, the fetus lacks immune cells—cells necessary for defending the body against pathogens and other toxic molecules. However, fetal immune cells begin to form as early as the first trimester, gradually developing the capacity to recognize foreign substances in the intrauterine environment, or the environment inside the uterus. The early immune development caused by interactions between the mother and fetus is crucial for establishing immunological “memory,” which helps the fetus respond to pathogens after birth. These memories can be more effectively developed through “priming” or early exposure to pathogens. 

New research suggests that the fetus may encounter microbial signals from the maternal microbiome while in the womb. Early exposure helps shape the fetal immune system, fine-tuning its response to potential threats in the postnatal environment. Immunological priming may play a role in reducing the risk of immune-related conditions, such as allergies and autoimmune disorders, later in life.

During pregnancy, maternal regulatory T cells (Tregs) play a critical role in maintaining immune tolerance towards the fetus, which could otherwise be recognized as a foreign body inside the mother’s uterus. Tregs suppress excessive maternal immune responses by secreting anti-inflammatory cytokines—molecules secreted by the immune system, like IL-10—and modulating the activity of other immune cells. The balance between the maternal immunological response protecting the fetus while not rejecting it as a foreign body is essential to preventing fetal rejection while still allowing the mother’s immune system to protect against harmful pathogens that could have a detrimental effect on the mother and the fetus. 

The maternal gut microbiome is a key player in regulating Treg activity. Metabolites produced by gut bacteria, including SCFAs, help promote immune tolerance by supporting Treg development and function. A healthy and diverse microbiome encourages the production of SCFAs, fostering an environment conducive to maternal-fetal immune harmony. 

Multiple research studies have shown that maternal gut-derived SCFAs can cross the placenta and influence the fetal immune system. These maternal SCFAs enhance epigenetic modifications, or changes to DNA that turn genes on and off, such as acetylation, on immune-related genes, like FoxP3, which are essential for Treg cell function. By strengthening the fetal Treg response, SCFAs support immune tolerance, reduce the likelihood of allergic reactions and foster immune system adaptability after birth.

Gut Microbiome Dysbiosis and Immunological Complications

When the maternal gut microbiome is imbalanced, a condition called dysbiosis can lead to  reduced bacterial diversity and fewer SCFA-producing microbes. Decreased SCFA levels impair the development of both maternal and fetal Treg cells. A compromised Treg response then increases the risk of immune overreactions, such as allergies and asthma in the offspring.

Studies in mice have demonstrated that maternal diets high in microbiota-accessible carbohydrates (MACs) or SCFAs during pregnancy can reduce the likelihood of asthma and allergies in their offspring. In one study conducted by the Charles McKay Lab at USC, mice receiving higher amounts of SCFAs or MACs produced offspring that showed less severe allergic reactions and airway inflammation. A subsequent study found that the protective effect lasted into adulthood and is associated with an increased presence of fetal Tregs, which promote immune tolerance. 

Similarly, human studies suggest a link between lower maternal fiber intake, reduced blood acetate (an SCFA), and increased rates of respiratory issues. In another study by the McKay Lab, researchers found an association between reduced recalled maternal dietary fiber intake and reduced serum acetate levels in humans. The scientists also showed an association between serum acetate below median level and increased doctor visits for cough in children during their  first year of life. While further studies are deemed necessary to better understand the connection in humans, these findings emphasize the importance of a healthy maternal microbiome in shaping the long-term immune health of offspring.

Gut microbiome dysbiosis during pregnancy may serve as an early warning sign for increased allergy and asthma risk in infants, highlighting the importance of maternal gut health. Dietary interventions, such as adopting a high-fiber vegetarian diet rich in vegetables, have shown promise in promoting a healthy microbiome by increasing the production of SCFAs, which play a key role in regulating immune health. Emerging evidence also suggests that SCFA supplementation during pregnancy may have protective effects against allergy development in offspring–though this area is still under active investigation. Additionally, probiotics—beneficial bacteria that support gut health—offer another potential strategy for modulating the maternal microbiome to enhance immune outcomes in infants. Collectively, these interventions could pave the way for reducing the prevalence of allergies and asthma in future generations.