The Involvement of Gut Microbiota and Their Key Metabolites in Regulating Fetal Development via the Gut–Placental Axis

Composition of gut microbiota during pregnancy

The microbiome is a diverse community comprising bacteria, viruses, fungi, archaea, and other microorganisms (Vemuri and Herath, 2023). The gut harbors a complex, dynamic, and highly diverse microbial population, forming a robust ecosystem of nearly 100 trillion bacteria (Simrén et al., 2013). This assemblage consists of 500–1500 distinct species of bacteria, archaea, fungi, and viruses, which influence intestinal physiology and participate in essential life activities (Simrén et al., 2013). The gut microbiome and its metabolites play a crucial role in regulating numerous physiological processes and contribute significantly to the maintenance of human health (Jin et al., 2022). During pregnancy, the composition and activity of the gut microbiota change across different gestational stages, exhibiting shifts in microbial diversity and metabolic function. These variations are notably influenced by maternal body weight, though their specific roles require further evaluation (Koren et al., 2012). Concurrently, maternal gut microbes support key physiological processes in pregnancy, such as promoting embryo survival and modulating growth and developmental pathways, particularly during critical windows in early gestation (Bazer et al., 2004).

Pregnancy is a complex and delicate process during which the mother undergoes substantial physiological adaptations—including hormonal, immune, and metabolic changes—that support fetal development (Yao et al., 2020; Giugliano et al., 2025). It has been demonstrated that pregnancy influences the composition of the maternal gut microbiome, which differs between early and late gestation (Koren et al., 2012). These physiological and metabolic adjustments are often accompanied by a significant restructuring of the maternal gut microbial community, characterized by shifts in taxonomic composition and overall diversity (Ziętek et al., 2021; Coley-O’Rourke et al., 2025). Certain maternal changes during pregnancy may be closely linked to alterations in gut microbiota composition and diversity. For example, the rise in mucin-degrading bacteria after conception reflects a dynamic host-microbiome interaction (Gohir et al., 2015; Wang et al., 2025a). This interplay suggests that maternal microbial restructuring represents an important physiological adaptation in pregnancy, one that may subsequently affect fetal development (Martínez Sánchez et al., 2025).

The maternal gut microbiota undergoes essential changes during pregnancy, characterized by an increase in total bacterial abundance and profound compositional shifts, particularly in the late gestational period (Koren et al., 2012; Mesa et al., 2020). These alterations contribute to the metabolic changes typical of pregnancy, modulate inflammatory markers, and are associated with increased energy harvest. During the first trimester, the composition of the maternal gut microbiome remains similar to that of healthy nonpregnant women (Koren et al., 2012; Nuriel-Ohayon et al., 2016). From mid-pregnancy onward, the abundances of Actinobacteria, Bifidobacterium, and certain strains of Lactobacillus increase, whereas butyrate-producing bacteria decline (Adak and Khan, 2019). In late pregnancy, the maternal gut microbiota shows a higher proportion of Proteobacteria, a phylum often linked to inflammation (Koren et al., 2012). Overall, from early to late gestation, there is an increase in Bifidobacterium, Proteobacteria, and lactic acid-producing bacteria, accompanied by a reduction in butyrate-producing bacteria (Koren et al., 2012). In summary, the maternal gut microbiota undergoes significant compositional changes throughout pregnancy. These include an overall increase in the abundance of Actinobacteria at the phylum level, along with a reduction in the diversity of certain individual bacterial groups (Nuriel-Ohayon et al., 2016). Concurrently, the increased diversity of the gut microbial community during pregnancy may be influenced by factors such as hormonal fluctuations, immune system adaptation, and maternal nutritional status.

The microbiota and host engage in a mutually beneficial symbiotic relationship (Belkaid and Harrison, 2017). Through nutrient- and metabolite-dependent mechanisms, the microbiota modulates host immunity (Brestoff and Artis, 2013). It can transmit signals not only to adjacent organs and tissues but also to distant sites in the body, thereby influencing the host’s immune and hormonal systems (Schroeder and Bäckhed, 2016). Examples include communication along the gut–brain axis, gut–liver axis, and gut–placenta axis. Conversely, the host actively shapes its microbiota. These interactions are crucial for maintaining physiological homeostasis (Liu et al., 2016); however, ecological dysbiosis—characterized by microbial imbalance, a reduction in beneficial microbes, or an expansion of harmful ones—promotes inflammation and heightens susceptibility to various diseases (Schroeder and Bäckhed, 2016; Zeng et al., 2017). The gut microbiota produces diverse bioactive metabolites, such as short-chain fatty acids (SCFAs), bile acids (BAs), amino acid metabolites, and lipopolysaccharides (LPS). These molecules circulate through the bloodstream, the intestine, and multiple extraintestinal organs, regulating a wide range of physiological processes (Qi et al., 2021) (Fig. 2).

OPEN IN VIEWER

FIG. 2.

Parent gut microbes interact with the host. Microbiome in the gut and the bioactive substances they produce bind to the appropriate receptors and then act as signaling molecules. Signals are sent through the blood circulation to influence the host, e.g., brain (brain–gut axis), liver (liver–gut axis), placenta (gut–placenta axis). The host also shapes the microbiota in the body; for example, changing the diet can affect microbiome composition, as discussed in the final section of this review.

Short-chain fatty acids

SCFAs, including acetate, propionate, and butyrate, are produced through microbial activity and subsequently translocated into the bloodstream, where they participate in various host metabolic processes (Ferguson, 2020). These SCFAs serve not only as an energy source for the host but also function as signaling molecules (Koh et al., 2016). During pregnancy, SCFAs—particularly acetate, propionate, and butyrate—play a crucial role in maintaining maternal homeostasis and modulating immune function, carbohydrate metabolism, and lipid metabolism (Ziętek et al., 2021). In humans, the protective effects of SCFAs such as butyrate are mediated through the inhibition of histone deacetylase activity and signaling via free fatty acid receptors (Chang et al., 2014). Furthermore, SCFAs (butyric, propionic, and acetic acids) help regulate host energy homeostasis by acting on the sympathetic nervous system, adipose tissue, pancreas, and intestine through receptors G-protein coupled receptor (GPR) 41 and GPR43 (Ziętek et al., 2021).

SCFAs, which include acetic acid (C2:0), propionic acid (C3:0), butyric acid (C4:0), valeric acid (C5:0), and hexanoic acid (C6:0), are the primary end products of bacterial metabolism on the luminal surface of the intestine (He et al., 2020; Parada Venegas et al., 2019). Among these, acetic, propionic, and butyric acids are the most abundant in the human body and are commonly studied in microbiome metabolite research (Ziętek et al., 2021). The quantity and proportion of SCFAs—particularly acetate and butyrate—produced in the gastrointestinal (GI) tract vary depending on diet, the composition and abundance of the host microbiome, and intestinal transit time (Macfarlane and Macfarlane, 2003). Acetic acid constitutes more than 50–60% of total SCFAs (Schwiertz et al., 2010) and is produced by intestinal bacteria such as Bifidobacterium, Lactobacillus, Mucor, and Ruminalococcus (Dao et al., 2016; Feng et al., 2018). The main producers of propionic acid are fermentative bacteria belonging to the phylum Fimicutes and the family Lachnospiraceae, which can also generate butyric acid (Ziętek et al., 2021); however, the specific output of propionate or butyrate is ultimately determined by the available substrates. Butyric acid, on the other hand, is produced by intestinal bacteria such as E. faecalis, Fusobacterium rectum, and Rosa rosa-sinensis (Liu et al., 2018). Although butyrate is produced in smaller amounts compared with acetate and propionate, it exerts significant beneficial effects on cellular energy metabolism and intestinal homeostasis, serving as the primary energy source for colonocytes (Tan et al., 2014). Pregnancy has been associated with increased abundance of acetic and propionic acids, with acetate being the predominant SCFA in both pregnant women and their infants (Nilsen et al., 2020). Elevated maternal serum levels of SCFAs—acetate, propionate, and butyrate—may positively influence maternal weight gain, glucose metabolism, and various metabolic hormone levels (Priyadarshini et al., 2014; Kim et al., 2025).

Bile acids

Extensive communication occurs between the liver and the gut microbiome, forming the gut–liver axis (Simbrunner et al., 2021). Primary BAs are synthesized by hepatocytes and stored in the gallbladder, whereas secondary BAs are produced by the gut microbiome through the metabolism of primary BAs (Konturek et al., 2018; Tripathi et al., 2018). Synthesized from cholesterol in the liver, BAs serve as important endocrine regulators and signaling molecules in both the liver and the intestine (Shao et al., 2021). They help maintain the homeostasis of BAs and intestinal barrier function and regulate hepatic and intestinal circulation via receptors such as the farnesoid X receptor (FXR) and G-protein coupled bile acid receptor 5 (TGR5), among others (Zhu et al., 2023). BAs transported into the intestinal lumen via the enterohepatic circulation are hydrolyzed and oxidized by intestinal microbes. These modifications alter their physicochemical properties and can also disrupt the ecological balance of the gut flora, promoting the overgrowth of pathogenic bacteria. Such dysbiosis may trigger inflammation and compromise the intestinal barrier (Simbrunner et al., 2021; Zhu et al., 2023). The homeostasis of the gut microbiota is influenced by multiple factors, including BAs, diet, certain medications (e.g., probiotics and antibiotics), and disease states (Vassallo et al., 2015). The gut microbiota participates in the synthesis of BAs and the modulation of their signaling pathways. Conversely, BAs also play a fundamental role in shaping the composition and function of the gut microbiota (Zhu et al., 2023).

The intestinal microbiota not only converts primary BAs into secondary BAs through desulfation and modification but also suppresses hepatic BA synthesis by modulating the ileal FXR-FGF19 signaling pathway (Chiang, 2013). These processes influence the levels and physiological functions of BAs in vivo, thereby affecting lipid metabolism, hepatobiliary function, and intestinal health—all of which play crucial roles in maintaining the health of humans and animals. BAs contribute to intestinal epithelial integrity and modulate mucosal immune responses, which in turn indirectly shape the composition of the gut microbial community (Wahlström et al., 2016). As key regulators of intestinal microecology, BAs can promote the proliferation of Gram-negative bacteria; this shift may favor the overgrowth of pathogenic species, triggering the release of inflammatory markers and enhancing hepatic inflammatory responses (Islam et al., 2011). Alterations in the gut microbiome and increased intestinal permeability may coincide with dysfunctional bidirectional communication between the brain and the gut (Vilstrup et al., 2014). BAs influence the microbiota directly via their antimicrobial properties and indirectly by engaging nuclear and membrane receptors involved in gut homeostasis and immunity (Wahlström et al., 2016; Bustos et al., 2018). By modulating the BA pool, the microbiota supports the maintenance and renewal of the intestinal barrier and governs the maturation of both innate and adaptive immune responses in the host (Zarrinpar et al., 2018). Furthermore, microbial modification of BAs can impact host metabolism by altering signaling through BA receptors and simultaneously shifting the composition of the microbiota itself (Wahlström et al., 2016).

Lipopolysaccharide

LPS, a bioactive molecule derived from the intestinal microbiome, can be released by bacteria and lead to endotoxemia, thereby contributing to ecological dysregulation (Miko et al., 2022). LPS activates specific pattern recognition receptors, most notably Toll-like receptors (TLRs), which recognize microbial and infectious agents and initiate downstream signaling. This process promotes the release of pro-inflammatory cytokines and triggers inflammatory activation. Both LPS and SCFAs of intestinal bacterial origin can modulate macrophage polarization and inflammation via inhibition of histone deacetylases (Jin et al., 2022). Microbial metabolites, such as butyrate, also supply energy to support epithelial metabolism (Kelly et al., 2015). In addition, the microbiota degrades host-indigestible food components, including complex carbohydrates, thereby maximizing nutrient utilization and generating health-promoting metabolites (Bäckhed et al., 2005). Chang et al. (2014) demonstrated that butyrate, acting through G protein-coupled receptors (GPCRs), suppresses the production of pro-inflammatory cytokines induced by endotoxin or LPS from Gram-negative bacteria, including interleukin-6 (IL-6) and IL-12. In summary, butyrate attenuates the inflammatory response by reducing the release of cytokines such as IL-6 and IL-12.

Microbial–host interactions take place within the gut, where crosstalk and feedback loops shape microbiome composition, host physiology, and disease susceptibility (Ali Mubaraki et al., 2018). Host-gut microbiota interactions, particularly in the intestinal environment, exert a profound influence on overall human health, affecting processes such as energy reabsorption and immune system development (Hillman et al., 2017). Therefore, maintaining a symbiotic microbial community is critical for host health (Table 1).

OPEN IN VIEWER

Table 1.

Summary of Major Metabolites during Pregnancy and Their Receptors in Fetal or Placental Tissue

Metabolite category	Specific metabolite examples	Major producing bacterial genera in pregnancy (references)	Targeted receptors in fetal/placental tissues (references)
SCFAs	Acetate, propionate, butyrate	Bifidobacterium, Lactobacilluus. Roseburia, Faecalibacterium, Lachnospiraceae (Koren et al., 2012; Ziętek et al., 2021; Liu et al., 2018)	GPR41 (FFAR3), GPR43 (FFAR2), GPR109A (Ziętek et al., 2021; Chang et al., 2014)
BAs	Primary BAs (e.g., CA, CDCA), Secondary BAs (e.g., DCA, LCA)	Bacteria involved in biotransformmation: Bacteroides, Clostridiun, Lactobacillus, Bifidobacterium, Eubacteriuum (Konturek et al., 2018; Wahlström et al., 2016)	FXR (NR1H4), TGR5 (GPBAR1) (Shao et al., 2021; Zhu et al., 2023; Wahlström et al., 2016)
LPS	LPS (endotoxin)	Gram-negative bacteria (e.g., Enterobacteriaceae, Bacteroidetes) (Miko et al., 2022)	Toll-like Receptor 4 (TLR4) (Jin et al., 2022; Miko et al., 2022)

BAs, bile acids; CA, cholic acid; CDCA, chenodeoxycholic; DCA, deoxycholic acid; FFAR3, free fatty acid receptor 3; FFAR2, free fatty acid receptor 2; FXR, farnesoid X receptor; GPR41, G protein-coupled receptor 41; GPR43, G protein-coupled receptor 43; GPR109A, G protein-coupled receptor 109 A; GPBAR1, G protein-coupled bile acid receptor 1; LCA, lithocholic acid; LPS, lipopolysaccharides; NR1H4, nuclear receptor subfamily 1, group H, member 4; SCFAs, short-chain fatty acids; TGR5, takeda G protein-coupled receptor 5; TLR4, toll-like receptor 4.

Maternal SCFAs and fetal–placental development

Bioactive metabolites of the maternal microbiome, specifically SCFAs, regulate placental growth and vascularization, thereby promoting placental development (McDonald and McCoy, 2019). SCFAs influence fetal developmental and metabolic programming during pregnancy (Spor et al., 2011). Circulating SCFAs derived from the maternal gut microbiota can cross the placental barrier and reach the developing embryo (Kimura et al., 2020). Once transferred, they play functional roles; for instance, propionate can serve as an energy source via lipid and glucose synthesis. Substantial alterations in the maternal gut microbiota occur during late gestation, a critical period for fetal brain development encompassing processes such as synaptogenesis, myelination, and maturation of specific brain regions (Jašarević et al., 2018). The expression of uteroplacental receptors GPR41 and GPR43, along with their involvement in inflammatory pathways during pregnancy and parturition, may represent one mechanism through which SCFAs affect fetal metabolic programming (Soderborg et al., 2020).

During pregnancy, metabolic changes associated with the maintenance of energy homeostasis are critical for fetal development, the future metabolic fate of the offspring, and maternal health (Kimura et al., 2014). The sympathetic nervous system, intestinal epithelium, and pancreas of the embryo highly express GPR41 and/or GPR43, which sense SCFAs derived from the maternal gut microbiota (Kimura et al., 2020). Activation of the SCFA-GPR41 and SCFA-GPR43 axes promotes the development of neuronal cells, GLP-1-expressing enteroendocrine cells in the small intestine, and pancreatic β-cells, thereby shaping embryonic energy metabolism (Kimura et al., 2020). Maternal microbiota-derived SCFAs cross the placenta to promote sympathetic nervous system development and regulate insulin secretion in the embryo via GPR41 and GPR43 signaling (Kimura et al., 2020). In particular, propionate stimulation of GPR41 effectively activates sympathetic neurons to modulate energy expenditure. In addition, the maternal gut microbiota and Bifidobacterium breve can influence fetal growth by altering the expression of key placental nutrient transporters (Lopez-Tello et al., 2024).

Among these, propionate serves as the primary metabolite of Akkermansia muciniphila, and the abundance of intestinal Akkermansia muciniphila is markedly reduced in numerous metabolic and inflammatory diseases (Jin et al., 2022). Akkermansia muciniphila is a highly prevalent intestinal bacterium that produces acetic and propionic acids and supplies substrates for butyrate production by other SCFA-producing bacteria (Zhai et al., 2019). In addition, Akkermansia muciniphila contributes to host immune homeostasis and intestinal barrier integrity (Everard et al., 2013). Propionate may modulate macrophage autophagy via a receptor-independent mechanism involving AMP-activated protein kinase (AMPK) and GPR109A (Jin et al., 2022). The mammalian target of rapamycin (mTOR), which inhibits autophagy, is negatively regulated by AMPK. Meanwhile, propionate promotes macrophage M1 polarization through the GPR2-STAT43 pathway (Jin et al., 2022). AKT pathway activation plays a crucial role in trophectoderm invasion. Propionate significantly increases the p-AKT/AKT ratio and downregulates the expression of the AKT inhibitory phosphatase and tensin homolog, thereby counteracting the effects of LPS in the trophectoderm. This suggests that propionate activates GPR41-AKT signaling and promotes trophoblast invasion. Acetate crosses the placenta (Fukuda et al., 2011) and, upon translocation to the fetus, exerts systemic metabolic and immunological effects on fetal development (Hu et al., 2019).

Lipid metabolism and inflammation are key processes during pregnancy. Maternal diet-induced obesity has been shown to be associated with reduced expression of genes encoding the tight-junction-associated proteins claudin-1 and zonula occludens-1 (ZO-1) in the maternal gut, which are critical for regulating intestinal permeability (Wang et al., 2012). This impairs the protective effects of SCFAs and their receptors—particularly GPR43—on maternal gut barrier function, thereby affecting both maternal and fetal health. Alterations in the maternal gut may lead to adverse metabolic adaptations in the mother and placenta, consequently changing maternal gut microbiota metabolites such as SCFAs. Butyrate, for example, modulates inflammatory and angiogenic factors in the placenta via gut microbiota interactions, thereby alleviating hypertension in preeclampsia (Yong et al., 2022). It also suppresses the expression of cytokines IL-6, interleukin-1β (IL-1β), and tumor necrosis factor-α (TNF-α), demonstrating anti-inflammatory properties (Pirozzi et al., 2018). In animal models, SCFAs such as propionate derived from the maternal gut microbiota are detected by GPR41 and GPR43 receptors in fetal sympathetic nervous tissue, GI tract, and pancreas (Kimura et al., 2011). Moreover, butyrate produced by maternal gut microbiota through dietary fiber fermentation is delivered to the embryo via the maternal circulation (Yu et al., 2022; Wang et al., 2025b), improving fetal glucose homeostasis and conferring obesity resistance in offspring.

SCFAs exert a significant influence on the developing immune system, particularly on immunoregulatory mechanisms. By modulating and balancing immune responses, SCFAs help prevent excessive inflammation and autoimmunity (Yang et al., 2015). Specifically, SCFAs—such as butyric acid, propionic acid, and acetic acid—promote regulatory T cell proliferation, differentiation, cytokine synthesis, Foxp3 expression, and anti-inflammatory activity (Ziętek et al., 2021; Yang et al., 2015). Studies in mice have demonstrated the beneficial role of SCFAs (mediated by propionate) during embryonic development, and their positive effects on metabolism, primarily through the regulation of insulin levels, have also been observed in the fetus (Kimura et al., 2020). Bioactive substances derived from the maternal microbiome may regulate gene expression within the Wnt signaling pathway in the fetal gut via m6A modifications. This mechanism may explain how their absence impairs fetal intestinal development (Xiao et al., 2025), thereby affecting normal gut maturation. Furthermore, SCFAs contribute to the maintenance of intestinal barrier integrity largely through the transcriptional regulation of tight junction-associated proteins (Korsten et al., 2023).

LPS impacts on fetal–placental development

LPS, a major component of the Gram-negative bacterial cell wall, is a potent inducer of inflammatory responses. During normal pregnancy, the maternal immune system undergoes intricate remodeling to establish a state of immune tolerance toward the semi-allogeneic fetus (Mor and Cardenas, 2010). However, elevated circulating LPS levels—resulting from maternal infection, gut microbiota dysbiosis, or other causes—can severely disrupt this delicate equilibrium. LPS primarily triggers innate immune responses by binding to its pattern recognition receptor, TLR4. Within placental tissue, TLR4 is widely expressed on trophoblasts, placental macrophages, and vascular endothelial cells. Upon binding to TLR4, LPS activates key downstream signaling pathways, such as NF-κB and MAPK, which drive substantial production of proinflammatory cytokines—including TNF-α, IL-1β, and IL-6—both locally in the placenta and systemically in the mother (Koga and Mor, 2010). This excessive inflammatory response creates a deleterious microenvironment. Such an inflammatory milieu directly impairs multiple placental functions. It disrupts normal trophoblast biological behavior and, through inflammatory mediators, induces dysfunction in placental vascular endothelial cells, increases vascular permeability, and promotes the expression of procoagulant factors, potentially leading to local placental thrombosis (Ramma and Ahmed, 2011). Moreover, activated immune cells generate substantial reactive oxygen species, inducing oxidative stress that further exacerbates cellular damage and apoptosis (Jauniaux and Burton, 2016). Collectively, this cascade of pathological alterations compromises the placental barrier function and material exchange capacity, impairing efficient delivery of oxygen and nutrients to the fetus as well as removal of metabolic wastes, thereby laying the groundwork for adverse pregnancy outcomes.

As the sole hub connecting the mother and fetus, impaired placental function directly affects fetal development. LPS-induced intense inflammatory response and oxidative stress significantly disrupt placental transport mechanisms. The expression and activity of specific transporters mediating the cross-placental transfer of nutrients—such as glucose and amino acids—may be suppressed. At the same time, the integrity of the placental barrier is compromised, resulting in an inadequate supply of nutrients to the fetus (Jansson and Powell, 2013). Such intrauterine malnutrition represents one of the core causes of FGR.

Amino acid metabolites in fetal–placental development

Alterations in the composition and abundance of gut bacteria involved in amino acid metabolism during pregnancy, along with the translocation of their amino acid metabolites to the uterus, may influence uterine function and induce epigenetic modifications in maternal physiology and metabolism. These changes are critical for pregnancy recognition and fetal development (Dai et al., 2015). For example, tryptophan metabolites, including kynurenine and serotonin, are known to regulate maternal immune tolerance at the fetal–maternal interface, influence placental vascular development, and serve as precursors for neurotransmitter synthesis in the developing fetal brain (Van Zundert et al., 2022). The presence of maternal microbiota in the intrauterine environment—such as in the endometrium and placenta—as well as in breast milk may represent a distinctive aspect of whole-body microbiome and metabolic programming in fetuses and infants (Donnet-Hughes et al., 2010). The roles and mechanisms of amino acid metabolites in placental development and function are diverse and warrant further in-depth investigation.

Placental microbiome: From paradigm shift to scientific debate

Traditional medical perspectives have long considered the uterus and placenta to be strictly sterile environments—a fundamental physiological assumption that protects the developing fetus from pathogen exposure. However, this classical paradigm is now being substantially challenged by emerging scientific evidence. Pioneering work by scholars such as Donnet-Hughes has laid the groundwork for investigating the possibility of maternal microbial presence within the intrauterine environment (Donnet-Hughes et al., 2010). They hypothesize that maternal microbiota resident in the endometrium, placenta, and even breast milk may constitute a unique source for the colonization and metabolic programming of the fetal and infant microbiome. If confirmed, this hypothesis would fundamentally reshape our understanding of early immune development, metabolic initiation, and the establishment of long-term health trajectories.

Although the “in utero colonization” hypothesis is highly compelling, it has been entangled in scientific controversy since its inception. The core of the dispute lies in methodological limitations and the reproducibility of its conclusions. The most pointed criticism concerns sample contamination. The collection, dissection, and processing of placental and other tissue samples are highly susceptible to contamination from vaginal, skin, or environmental microbiomes. Highly sensitive PCR and sequencing techniques cannot reliably distinguish exogenous contaminant DNA from genuine endogenous microbial signals. Multiple rigorous studies have shown that under strictly controlled, low-biomass sterile conditions—such as obtaining placental tissue in sterile operating rooms and employing extensive decontamination controls—the “placental microbiome” signals reported in many earlier studies diminish significantly or disappear entirely (Kennedy et al., 2023). This finding has been further substantiated by a recent systematic reanalysis by Panzer et al., who examined multiple published placental microbiota datasets and concluded that the detected signals are indistinguishable from background DNA contamination in technical controls, thus failing to support the existence of a resident placental microbial community (Panzer et al., 2023). These signals closely resemble contaminants introduced through laboratory reagents and procedures. Furthermore, critics raise physiological and immunological objections: why would a functional immune system permit a substantial microbiome to reside long-term within critical reproductive organs without triggering inflammation or rejection? This appears to contradict fundamental immunological principles (Lewis et al., 2017). Consequently, many scientists argue that existing evidence falls far short of demonstrating the existence of a physiologically functional, stable microbial community within the placenta. A more plausible explanation is that the detected microbial DNA originates from transient, low-level bacteremia during pregnancy. These microbes are effectively cleared and degraded by the placenta, with residual nucleic acid fragments being captured by modern sensitive technologies (Lauder et al., 2016). This does not equate to the presence of an active, symbiotic “microbiome.”

The critical role of dietary fiber and specific short-chain fatty acids

Dietary fiber effectively regulates the composition of intestinal microbiota and induces the production of SCFAs through fermentation (Kundi et al., 2021). Maternal high-fiber diets can modulate offspring immune and neurocognitive functions by altering SCFA levels, particularly butyrate (Yu et al., 2020). In a sow model, Liu et al. demonstrated that dietary fiber intake during pregnancy stimulated SCFA production (especially butyrate), increased beneficial bacterial abundance, and limited harmful bacterial proliferation, thereby promoting a healthier intestinal environment (Liu et al., 2021). Dietary fiber intake also influences the synthesis of peripheral 5-hydroxytryptamine (5-HT), a key monoamine neurotransmitter involved in central neurotransmission and intestinal physiology (Kundi et al., 2021; Keski-Rahkonen et al., 2019), with positive effects on placental development and pregnancy maintenance. In addition, 5-HT can be converted into melatonin, which is essential for placental function and fetal development (Lanoix et al., 2012). Maternal gut microbes remotely regulate placental structure and nutrient transport proteins, which are important for fetal blood glucose and growth (Lopez-Tello et al., 2022). A fiber-rich diet is known to increase the abundance of Bifidobacteria, Prebiotics, and Lactobacillaceae, while reducing Porphyromonas and Lactobacillus (David et al., 2014). Studies in mice indicate that maternal diet before and during pregnancy significantly shapes intestinal microbiota (Gohir et al., 2015). Maternal SCFAs supplementation (acetate, propionate, and butyrate) during pregnancy prevents fetal placental disorders induced by maternal microbiome deficiency or protein malnutrition. These SCFAs are directly transferred from maternal to fetal circulation (Erny et al., 2015). SCFAs can act via direct receptor-mediated signaling (Kimura et al., 2020) and have been shown to stimulate angiogenesis in cultured umbilical vein endothelial cells (Robles-Vera et al., 2020); for instance, propionate supplementation promotes placental vascularization in vivo. In mouse models, exogenous SCFA supplementation reduced hepatic fat reserves and suppressed the expression of lipid synthesis-related genes (Shimizu et al., 2019). Moreover, SCFA supplementation, particularly propionate, reversed birth weight reduction in hypoxia-induced FGR (Chen et al., 2022). In summary, maternal SCFAs play a key role in regulating disease susceptibility.

The impact of specific amino acids and micronutrients

During pregnancy, maternal dietary supplementation with specific amino acids—such as arginine, glutamine, leucine, glycine, and methionine—has been shown to improve fetal survival and growth in humans and other animals. These effects are mediated through the modulation of key signaling and metabolic pathways, leading to beneficial outcomes in reproductive performance (Zeng et al., 2023). Differences in the maternal microbiota during gestation have also been associated with variations in serum biochemical markers related to nutritional and health status, including reduced levels of cholesterol, folate, ferritin, and transferrin (Santacruz et al., 2010). In a study using cirrhotic rats, folic acid was found to reverse the reduction in ileal FXR signaling, improve the mucus layer integrity, and stabilize the intestinal vascular barrier (Sorribas et al., 2019), suggesting potential implications for fetal health planning. Overall, host–microbe interactions during pregnancy influence host metabolism in ways that can be beneficial (Koren et al., 2012).

Specifically, dietary supplementation with specific amino acids, including arginine, glutamine, leucine, glycine, and methionine, has been shown to directly or indirectly enhance fetal survival and growth (Zeng et al., 2023). Their mechanisms of action extend well beyond their role as mere nutrients. For example, these amino acids can act as signaling molecules that activate key pathways such as mTOR, thereby optimizing placental nutrient transport efficiency (Jansson and Powell, 2007). Importantly, they also serve as essential metabolic substrates for the gut microbiota. Specific microbial communities utilize these amino acids to produce beneficial metabolites, such as SCFAs (e.g., butyrate) and polyamines (Dai et al., 2011). These microbial metabolites can be absorbed into the maternal circulation, transported across the placenta, and directly participate in regulating fetal energy metabolism, immune development, and even neurological development (Gomez de Agüero et al., 2016). At the same time, a healthy microbial community structure, supported by beneficial amino acid metabolism, suppresses the growth of potential pathogens, maintains intestinal barrier integrity, and reduces the translocation of harmful substances such as endotoxins into maternal circulation. This helps establish a stable and healthy intrauterine environment for the fetus.

On the other hand, the importance of micronutrients such as folate (vitamin B9) is equally significant. Research indicates that the gut microbial composition in pregnant women is closely correlated with biochemical markers like serum folate and ferritin (Santacruz et al., 2010), suggesting that the microbiota may be involved in the metabolism and absorption of these nutrients. More direct evidence comes from studies on folate function. In a rat model of liver cirrhosis, folate was shown to reverse the reduction in the FXR signaling pathway in the ileum (Sorribas et al., 2019). As a core nuclear receptor regulating BA metabolism and intestinal homeostasis, restored FXR activity helps improve the intestinal mucus layer and strengthen the intestinal vascular barrier. An intact intestinal barrier effectively prevents the translocation of gut bacteria and their fragments, thereby averting chronic low-grade maternal inflammation—a condition known to impair placental function and restrict fetal growth (West et al., 2015). Thus, folate stabilizes the intestinal microenvironment by repairing key signaling pathways (such as FXR) that govern microbiota–host interactions, indirectly safeguarding fetal nutrition and immune tolerance.

Supplementation with probiotics and prebiotics

Probiotics are live beneficial microorganism found in certain foods and supplements (Hill et al., 2014). They are thought to help restore the physiological balance of the intestinal microbiota. Currently, most probiotic products contain strains such as Bifidobacterium, Lactobacillus, and other lactic acid bacteria (e.g., Lactococcus and Streptococcus) (Azad et al., 2018). The beneficial effects of these strains are multifaceted: they can promote colonization resistance, limit mucosal adhesion of pathogens, enhance mucosal integrity, and strengthen local immune defenses, thereby potentially reducing inflammation. Maternal dietary intake of probiotics has been shown to regulate TLR-related gene expression in the placenta and fetal gut (Rautava et al., 2012), thereby influencing the development of the fetal immune system. Prebiotics are food compounds that promote the growth or activity of beneficial microorganism (Miko et al., 2022). A common example is non-digestible oligosaccharides that reach the small intestine intact. In studies of diet-induced obese pregnant rats, treatment with the prebiotic oligofructose was found to reduce maternal energy intake, lower gestational weight gain (Klancic et al., 2020), and prevent increased obesity in offspring. Supplementation with multi-strain probiotics containing Bifidobacterium and Lactobacillus may improve health outcomes by modulating gut microbiota composition and maintaining normal concentrations of SCFAs, even when lifestyle changes related to diet and exercise are insufficient (Ziętek et al., 2021). Transplacental effects of the maternal gut microbiota on the developing fetus occur through several mechanisms, including transplacental transport of bacterial components, cytokine signaling, and immune programming mediated by microbiota-derived metabolites (Constância et al., 2005).

Potential of bioactive plant extracts

Plant extracts have also emerged as a prominent area of research, with a growing body of evidence indicating their positive influence on gut microbiota, primarily attributed to the bioactive compounds they contain. Rich in natural antibiotics and antioxidants, certain plant extracts can inhibit the growth and proliferation of harmful bacteria, mitigate intestinal inflammatory responses, and protect the integrity of the intestinal mucosa. Through these mechanisms, they modulate the composition and metabolic functions of gut microbes, thereby exerting both health-promoting and therapeutic effects. For instance, polyphenols—plant metabolites found in vegetables, fruits, spices, and medicinal plants—exhibit a broad spectrum of biological activities, including antioxidant, antimicrobial, anticancer, and anti-inflammatory properties (Milutinović et al., 2021). Supplementation with polyphenol-rich pomegranate extract has been shown to preserve maternal intestinal barrier structure, restore gut microbiota dysbiosis, and further enhance placental function and fetal development (Deckmann et al., 2024). Similarly, Pueraria lobata root and Chuanqi rhizoma, traditional medicinal and food plants in Asia, may alleviate preeclampsia—a serious pregnancy complication—by reversing gut flora dysbiosis and protecting intestinal and placental barriers (Huang et al., 2022). Thus, plant extracts hold considerable potential for modulating gut microbiota composition and supporting maternal and fetal health.

Modulation of the gut microbiome is beneficial to both maternal and fetal health. Moreover, such microbial alterations can be readily achieved. Interventions such as adjusting maternal dietary fiber intake and supplementing with prebiotics and probiotics are safe and effective strategies for restoring maternal health and enhancing fetal growth and development. Regulating the gut microbiota of pregnant women through these approaches can therefore promote maternal intestinal health while further supporting placental function integrity and fetal development (Table 2).

OPEN IN VIEWER

Table 2.

Methods for Maintaining a Healthy Gut Microbiome During Pregnancy

Strategy classification	Primary intervention/component	Core mechanism of action	Key maternal and fetal health effects	References
Dietary fiber and SCFAs	Dietary fiber, SCFAs (butyric acid, propionic acid, acetic acid)	1. SCFAs are produced through fermentation by intestinal flora. 2. SCFAs, as signaling molecules (e.g., through receptor mediation), regulate host physiology 3. Regulate the synthesis of serotonin (5-HT) and its derivative melatonin 4. Directly transferred to the fetal circulation	1. Regulate maternal microbiota: increase beneficial bacteria (such as Bifidobacteria) and inhibit harmful bacteria 2. Improve placental function: promote angiogenesis and regulate nutrient transporters 3. Affect offspring: regulate the immune and neurocognitive development of offspring, improve FGR, and regulate fetal metabolism	Kundi et al. (2021); Yu et al. (2020); Liu et al. (2021); Lopez-Tello et al. (2022); Kimura et al. (2020); Chen et al. (2022)
Probiotics and prebiotics	Probiotics: Lactobacillus, Bifidobacterium, etc. Prebiotics: Indigestible oligosaccharides such as fructooligosaccharides	1. Probiotics: Enhance colonization resistance, maintain mucosal integrity, and regulate local and systemic immunity 2. Prebiotics: Selectively promote the growth and activity of beneficial bacteria 3. Transplacental signals: Influence fetal immune programming through bacterial components, cytokines, or metabolites	1. Regulate maternal microbiota and metabolism: maintain the normal proportion of SCFAs and control weight gain during pregnancy 2. Program fetal immunity: regulate the expression of TLR-related genes in the placenta and fetal intestine 3. Long-term health: prevent obesity in offspring	Hill et al. (2014); Rautava et al. (2012); Klancic et al. (2020); Ziętek et al. (2021); Constância et al. (2005)
Specific amino acids and micronutrients	Amino acids: arginine, glutamine, leucine, etc. Micronutrients: folic acid (vitamin B9)	1. Amino acids: act as signaling molecules to activate key pathways (such as mTOR) and serve as substrates for microbial metabolism to produce beneficial metabolites (such as SCFAs and polyamines) 2. Folic acid: repairs the ileal FXR signaling pathway and strengthens the intestinal vascular barrier	1. Supporting fetal development: directly or indirectly improving fetal survival and growth 2. Stabilizing the maternal intestinal environment: enhancing intestinal barrier function, reducing endotoxin translocation and inflammation 3. Optimizing placental function: indirectly ensuring fetal nutrition and immune tolerance by improving the maternal microenvironment	Zeng et al., (2023); Santacruz et al., (2010); Sorribas et al., (2019); Jansson and Powell, (2007)
Plant bioactive extracts	Polyphenols (such as pomegranate extract), traditional medicinal plants (such as Pueraria lobata, Ligusticum chuanxiong)	1. Exhibit anti-inflammatory, antioxidant, and antibacterial activities 2. Directly regulate the composition of intestinal flora 3. Protect the structure and function of the intestinal and placental barriers	1. Correcting dysbiosis: restoring the disturbed intestinal flora 2. Protecting the barrier: maintaining the integrity of the maternal intestinal barrier and placental barrier 3. Improving pregnancy complications: such as potentially alleviating preeclampsia and promoting fetal development	Milutinović et al. (2021); Deckmann et al. (2024); Huang et al. (2022)