The maternal and infant gut microbiome: implications for pregnancy outcomes, immune development, and health in the first 1000 days

Abstract

Background

The maternal microbiota is recognized as an important regulator of pregnancy outcomes and early infant immune programming. Across gestation, microbial communities in the gut, vaginal, oral, and putative placental niches undergo dynamic changes driven by hormonal, metabolic, and environmental factors, with important consequences for maternal–fetal health. These microbial transitions shape maternal immune-metabolic balance and are associated with major pregnancy complications, including gestational diabetes mellitus, preeclampsia, intrahepatic cholestasis of pregnancy, fetal growth restriction, and preterm birth.

Main body

Emerging yet debated evidence suggests that microbial DNA signatures may be detected in the placenta and uterus, raising critical questions about in utero microbial transmission and its role in neonatal microbiota establishment. The first 1,000 days, spanning prenatal life through early childhood, represent a critical window during which the infant gut microbiota is established and immune programming begins. Maternal–infant microbial transfer occurs through delivery, breastfeeding, and early-life environmental exposures, seeding the neonatal gut with beneficial taxa such as Bifidobacterium and shaping immune tolerance through mediators including IgA, TGF-β, and human milk oligosaccharides. Perturbations during this period via cesarean delivery, antibiotic exposure, or maternal dysbiosis have been associated with higher risks of allergy, autoimmunity, obesity, and neurodevelopmental abnormalities later in life. This review synthesizes current findings on maternal–infant microbiome interactions, emphasizing their role in immune maturation and disease susceptibility. It also discusses emerging therapeutic strategies—including probiotics and prebiotics, fecal microbiota transplantation, next-generation microbial ecosystem therapeutics, and CRISPR-based approaches that are under investigation for modulating the maternal and infant microbiome.

Conclusions

Despite significant advances, key gaps remain in establishing the existence of a true placental microbiome, the mechanisms of maternal immune–microbial signaling, and the long-term efficacy of microbiome-targeted therapies. Understanding the intricate crosstalk between microbiota, hormones, and immunity provides a foundation for developing approaches to improve maternal and child health.

Introduction

Pregnancy is a highly complex natural process in which multiple physiological systems adapt in coordination to assist in the growth and development of the fetus [1]. These changes range from hormonal fluctuations and weight gain to immune system modulation, all of which are crucial for safeguarding maternal and fetal health [2]. Alterations are not limited to systemic physiology but are also mirrored in the maternal microbiota, particularly within the gut, vaginal, and oral environments [3, 4]. The maternal microbiome has emerged as an important regulator of placental and fetal development, although the underlying mechanisms remain unclear [5]. Together, these adaptations position the maternal microbiome as a dynamic interface linking endocrine, immune, and metabolic regulation during pregnancy.

The maternal gut microbiota plays a central role in fetal and neonatal immune development through its interactions with reproductive hormones [6, 7]. Consequently, gut microbial dysbiosis may exert adverse effects on both maternal and offspring health [8]. Despite its importance, the contribution of microbial alterations to fetal immune maturation and neonatal microbiota–immune interactions remains underexplored. The urgency of this research is underscored by World Health Organization (WHO) data indicating that in 2020 alone, around 287,000 women worldwide died from pregnancy-related conditions, equivalent to one death every two minutes [9].

Equally important is the early postnatal period, particularly the first 1000 days of life, which serves as a key window for immune system maturation and gut microbiota establishment [10]. Humans coexist with a diverse microbiota consisting of bacteria, fungi, and viruses, distributed across multiple body sites [11]. Although microbial detection in prenatal remains controversial due to contamination risks, substantial evidence demonstrates that gut colonization begins soon after birth [12, 13].

The gut microbiota, frequently referred to as the body’s “second genome” and the largest endocrine organ, harbors a genetic repertoire that rivals the human host [14]. It is indispensable for regulating immunity, metabolism, endocrine function, neural signaling, and reproductive health [15, 16]. Evidence from multiple studies demonstrates that microbial dysbiosis contributes to diverse pathological processes and is associated with the development of cardiovascular, metabolic, and immune-mediated diseases [17, 18].

This review highlights the importance of maternal gut microbiota in pregnancy complications by examining its dynamic changes, mechanistic pathways, and etiological significance. It further addresses controversial findings regarding microbial presence in the placenta and uterus, which are central to ongoing debates on maternal–infant microbial transmission and early-life microbiome establishment. Finally, it considers the first 1,000 days of life as a critical developmental window and evaluates the diagnostic and therapeutic potential of microbiota-targeted interventions for pregnancy-associated disorders.

This review is structured around a unifying conceptual framework in which the maternal microbiome functions as a dynamic interface linking hormonal regulation, immune adaptation, and metabolic homeostasis during pregnancy, with lasting implications for infant immune programming across the first 1,000 days of life. Rather than treating maternal, placental, and infant microbiomes as isolated entities, we synthesize evidence supporting a coordinated maternal microbiome–hormone–immune axis that shapes pregnancy outcomes, microbial transmission, and early-life disease susceptibility. By critically evaluating mechanistic pathways, evidence quality, and translational potential, this review aims to move beyond descriptive cataloging toward a more integrative understanding of microbiome-driven maternal–infant health. Collectively, current evidence suggests the maternal microbiome as a dynamic and potentially modifiable regulator of pregnancy outcomes and early-life immune development through integrated hormonal, immunological, and metabolic pathways.

The microbiome

The human body hosts a vast array of microorganisms, including bacteria, archaea, fungi, and viruses- collectively referred to as the human microbiome [19, 20]. Each body site supports a distinct microbial community, with differences shaped by local environmental factors including oxygen availability, pH, nutrient supply, temperature, and humidity [21]. These conditions allow specific microbial populations to establish themselves, carry out specialized roles, and maintain complex interactions with the host [22]. Collectively, these organisms influence essential aspects of human health, including metabolism, immune responses, and hormonal regulation [7, 23].

Although microbial communities are found throughout the body, the gut serves as their primary reservoir, housing hundreds of bacterial species, mainly Firmicutes and Bacteroidetes [24]. Similarly, unique bacterial populations inhabit other body sites, such as the skin, oral cavity, and reproductive tract, where they contribute to immune defense by preventing colonization by harmful pathogens [25]. Disruption of these communities, known as dysbiosis, is frequently linked to negative health effects and long-term disease susceptibility [26], including diabetes, obesity, and inflammatory bowel disease (IBD) [27–29].

Beyond disease states, natural shifts in the microbiome also occur as part of human development and physiology. Microbial composition changes from infancy through adulthood, continues to evolve with aging, and undergoes further modifications during pregnancy [30]. These dynamic transitions highlight the microbiome’s adaptability across the human life cycle, including during pregnancy, when microbial changes occur alongside profound endocrine, immune, and metabolic remodeling of the host.

Maternal microbiome during pregnancy

During pregnancy, the maternal microbiome undergoes profound shifts that are thought to influence both maternal health and neonatal outcomes, extending beyond the pregnancy period itself [31]. This microbiome is composed of several specialized microbial communities, each dominated by distinct bacterial groups. For instance, a vaginal microbiota largely comprised of Lactobacillus species is generally considered beneficial and has been linked with favorable pregnancy outcomes [32]. In contrast, when the vaginal environment is dominated by more complex community structures such as Community State Type IV (CST-IV), characterized by the presence of Gardnerella, Prevotella, Chlamydia, and bacterial vaginosis-associated bacterium I (BVAB-I), there are higher chances of adverse pregnancy outcomes, notably fetal infection [33, 34]. Beyond the vaginal microbiome, both the gut and oral microbial populations also experience notable alterations during gestation [35]. These include a measurable decline in alpha diversity and an enrichment of Actinobacteria and Proteobacteria [36]. Such changes highlight the systemic nature of microbiome modulation in pregnancy. Maintaining a firm relation between these microbial communities and the maternal immune system, balancing tolerance with defense, is considered critical for healthy pregnancy outcomes [37]. Disruption of this equilibrium has been implicated in a range of complications that may affect both maternal physiology and fetal development.

Immunological and hormonal adaptations in pregnancy

Pregnancy requires finely coordinated immunological and hormonal adaptations to support fetal development while preserving maternal immune competence. The developing embryo, although genetically distinct and antigenic to the mother, must be protected by finely tuned immune regulation to preserve its immune privilege, which is vital for pregnancy success [38]. Before conception, inflammatory mediators remain relatively low; however, once the fertilized ovum implants, minor damage to the endometrium and exposure of trophoblast human leukocyte antigens (HLAs) activate innate immune pathways, initiating a controlled proinflammatory cascade [39]. Early placental development is further supported by the increased levels of human chorionic gonadotropin (hCG), which promotes decidual NK cell proliferation and cytokine-mediated spiral artery remodeling [40]. In parallel, group 3 innate lymphoid cells release inflammatory mediators that reinforce the proinflammatory environment of the implantation phase and early pregnancy [41].

All through the second trimester, the maternal immune system transitions into a state of heightened tolerance. This phase is marked by the expansion of regulatory T (Treg) cells and rising levels of progesterone and estrogen, which together enhance anti-inflammatory immune responses [42]. At the maternal–fetal interface, the T-cell balance shifts from proinflammatory effector responses toward regulatory and anti-inflammatory phenotypes, reinforcing immune tolerance [43]. Together, these changes consolidate fetal immune tolerance and support placental homeostasis.

As pregnancy advances into the third trimester, immune dynamics shift toward a proinflammatory profile that supports parturition through activation of innate immune pathways [44]. Following delivery, immune parameters gradually normalize, with restoration of pre-pregnancy immune balance over subsequent weeks to months [45, 46].

Alongside immune changes, dynamic hormonal regulation underpins pregnancy maintenance and fetal development. Trophoblast-derived hCG, progesterone, estrogen, and thyroid hormones coordinate placental development, immune modulation, and metabolic adaptation during gestation [47–52]. Beyond their physiological roles, these hormonal fluctuations also influence gut microbial composition and metabolic adaptation, thereby indirectly shaping host–microbiome interactions during pregnancy [37].

Physiological adaptation in the maternal gut microbiota

Across the different stages of pregnancy, the maternal gut microbiota undergoes substantial compositional and functional remodeling. Research by Koren et al. reported that, at the start of pregnancy, the gut microbial community is largely dominated by Firmicutes and Bacteroidetes, resembling the profile typically observed in non-pregnant women [37]. Similarly, across the trimesters, the microbial landscape shifts: alpha diversity progressively declines while beta diversity increases, accompanied by an enrichment of Actinobacteria and Proteobacteria [53]. Within these changes, the abundance of Enterobacteriaceae rises, whereas Clostridiales populations decrease. Because Clostridiales produce butyrate, a metabolite essential for intestinal barrier integrity and anti-inflammatory effects, their reduction has been associated with impaired gut function [54]. Conversely, elevated Enterobacteriaceae levels have been linked to the stimulation of inflammatory signaling pathways [55], suggesting that late-pregnancy microbiota alterations may predispose to complications.

Further evidence indicates that gut microbial shifts in the third trimester can influence maternal metabolism. For instance, fecal microbiota collected during this stage has been shown to induce features of metabolic syndrome, highlighting the functional distinction between early and late pregnancy microbial profiles [56]. Hormonal fluctuations during pregnancy, particularly rising progesterone, influence gut microbial composition, with notable enrichment of Bifidobacterium [57]. This enrichment is thought to benefit the neonate by facilitating the breakdown of human milk oligosaccharides (HMOs), which are critical for immune development and protection against disease [58]. Collectively, these findings suggest that pregnancy-associated microbial remodeling represents an adaptive response, optimizing maternal metabolism and immune function to support fetal growth and ensure a successful pregnancy.

Vaginal microbiota during pregnancy

The vaginal microbiota acts as a first line of defense against bacterial and viral pathogens, thereby reducing susceptibility to infections and associated diseases [59]. This ecosystem is dominated primarily by Lactobacillus species, although taxa from Bacteroidetes, Actinomycetes, and Clostridiales are also present [60]. Among the Lactobacillus group, L. gasseri, L. crispatus, L. iners, and L. jensenii are most frequently isolated, and each has been linked to maintaining vaginal health during pregnancy [60].

The composition of the vaginal microbiome shifts over the course of gestation. Studies indicate that communities in later pregnancy more closely resemble those of non-pregnant women [61]. Importantly, the dominant Lactobacillus species can vary across ethnic populations [62]. For example, Romero et al. observed that African-American women often exhibit the predominance of a single Lactobacillus strain throughout pregnancy, which suppresses competing bacteria and enhances protection against infections [63]. Postpartum changes are also notable. Approximately six weeks after delivery, around 40% of women display reduced Lactobacillus abundance, accompanied by greater microbial diversity and increased colonization by vaginosis-associated bacteria, such as Actinobacteria. In contrast, only about 2% of women show such microbial patterns during pregnancy [64]. Furthermore, a consolidated overview of key human cohort studies, animal models, and interventional trials examining maternal and infant microbiota in relation to pregnancy outcomes is provided in Table 1, highlighting study design diversity and evidence heterogeneity.

Table 1.

Representative studies examining maternal and infant microbiomes in pregnancy

Study type	Microbiome niche	Key findings	Clinical relevance	Limitations	Ref
Human cohort (91 pregnant women)	Maternal gut	3rd trimester → ↑Proteobacteria, Actinobacteria; ↓diversity	Associated with insulin resistance, inflammation	Small cohort, observational	[37]
Human cohort (1,500 samples)	Vaginal, gut, saliva	Vaginal microbiota shifts predict preterm birth	Early diagnostic potential	Regional population	[65]
Human cohort (Pregnancy & diet study)	Gut	Women with GDM → ↑ Enterobacteriaceae, ↓ Akkermansia	Links to hyperglycemia, maternal metabolic health	Cross-sectional	[66]
Mouse model	Gut	Dysbiosis induced hypertension and PE-like features	Mechanistic insight for preeclampsia	Translational gap	[67]
Human placental samples	Placental	Detected low-biomass microbes; possible contamination	Debate over placental microbiome existence	Contamination risk	[68]
Human cohort	Gut	Dysbiosis → linked to preeclampsia and systemic inflammation	Suggests gut-immune axis role in PE	Small sample size	[69]
Review + meta-analysis	Maternal gut/vaginal	Vaginal microbiota stability is protective against PTB	Vaginal microbiome as a biomarker	Heterogeneous studies	[36]
RCT	Maternal gut & infant gut (diet + probiotics)	Infant α-diversity is lower in the intervention group; maternal Prevotella ↑	Shows maternal diet/probiotic combo can modulate early gut microbiota	Short follow-up; small sample size	[70]
Cohort (36 mothers, 32 infants)	Maternal & infant stool samples	Mode of delivery, gestational age, and breastfeeding strongly influence infant microbiota; maternal changes postpartum	Helps identify modifiable birth/delivery practices	Small cohort; short duration	[71]
Observational	Maternal stool	Trends that specific nutrients (macro/micro) affect maternal gut diversity; the influence varies with risk status	Points to dietary counselling as an intervention potential	No causality; diversity measures only	[72]

Although the studies summarized in Table 1 consistently associate maternal and infant microbiome alterations with pregnancy outcomes, the strength of evidence varies substantially. Most human data are derived from observational cohort studies, which limit causal inference, while animal models provide mechanistic insight but face translational constraints. Additional limitations include heterogeneity in sampling time points, sequencing methodologies, population characteristics, and control of confounding variables. These factors underscore the need for rigorously designed, longitudinal, and contamination-aware human studies integrating microbiome, immune, and metabolic data.

Oral microbiota during pregnancy

The oral cavity harbors a highly diverse microbiome, comprising up to 600 distinct microbial species [11]. During pregnancy, women exhibit increased levels of viable oral bacteria across all stages, with the most pronounced elevation occurring in early gestation when compared with non-pregnant counterparts [73]. Borgo et al. reported that the abundance of Actinomycete was significantly higher during the third trimester compared to non-pregnant women [74]. In addition, levels of Candida were observed to rise substantially during mid- and late-pregnancy, suggesting a greater colonization of periodontal pathogens in this period [75].

Placental microbiota during pregnancy

For decades, the placenta was considered a sterile organ, and any microbial detection was attributed to infection or contamination [76, 77]. More recent studies have reported the presence of microbial DNA or bacterial structures in placental tissues; however, these findings remain highly controversial, and their biological significance is unclear. Early culture-based studies have identified aerobic bacteria in approximately 16% of placental samples, suggesting that microbial presence is possible even under normal conditions [78]. Using whole-genome sequencing, Aagaard et al. analyzed placental samples from 320 pregnant women and reported low-abundance microbial DNA signals, predominantly from Proteobacteria, interpreted as a potential placental microbial signature [79]. Observed overlaps between oral and placental microbial signatures have been interpreted as evidence of possible microbial translocation from the oral cavity [80]. However, such interpretations remain speculative, as similar taxonomic profiles may also arise from shared contamination sources or sequencing bias rather than true biological transfer.

Additional investigations further support microbial detection within placental tissue. In one study comprised of 195 patients, intracellular Gram-positive and Gram-negative bacteria were identified in the basal plate in 27% of cases [81]. Likewise, Cao et al. described various bacterial morphologies within trophoblastic cells, reinforcing the concept of bacterial colonization in the placenta [82]. Nonetheless, methodological limitations complicate interpretation. Morphological and culture-based techniques are restricted in their ability to detect microbes, especially in low-biomass environments like healthy placenta, where many species remain unculturable under standard aerobic conditions [83]. Figure 1 summarizes trimester-specific shifts in maternal oral, gut, vaginal, and placental microbial communities, emphasizing coordinated microbial remodeling aligned with hormonal and immunological adaptations during pregnancy rather than isolated taxonomic changes. Despite these reports, the existence of a true, resident placental microbiome remains highly controversial. Placental tissue represents a low-biomass environment [84], making microbiome analyses particularly vulnerable to contamination from reagents, laboratory environments, and sequencing workflows. Large, well-controlled studies incorporating stringent negative controls and contamination-aware analytical pipelines have failed to identify a consistent or biologically coherent placental microbial community, instead detecting sporadic microbial signals consistent with contamination or transient microbial presence. Consequently, current evidence does not support the presence of a stable, resident placental microbiome analogous to the gut or vaginal microbiota. Resolving this debate will require rigorously designed studies integrating contamination-aware sequencing, spatial imaging, culture-independent validation, and functional analyses.

Fig. 1.

Trimester-specific alterations in maternal oral, gut, vaginal, and placental microbiota during pregnancy, highlighting coordinated microbial shifts aligned with gestational adaptations

Microbiota–hormone crosstalk in pregnancy

This section highlights hormone–microbiome interactions with demonstrated mechanistic and translational relevance to pregnancy outcomes.

Estrogen and the gut microbiota

Estradiol, the predominant form of estrogen, plays a central role in female physiology and reproductive health. The gut microbiota both regulates and is regulated by estrogen [85]. Within the gut metagenome, numerous microbial genes encode enzymes involved in estrogen metabolism, collectively termed the estrobolome, defined as the microbial gene repertoire involved in estrogen biotransformation [86]. These enzymes, including β-glucuronidases and β-glucosidases, deconjugate estrogen and facilitate its intestinal reabsorption. When microbial diversity is reduced, β-glucuronidase activity diminishes, leading to impaired estrogen deconjugation, reduced reabsorption, and ultimately decreased systemic estrogen concentrations [87]. In contrast, enrichment of bacterial populations with strong β-glucuronidase activity can elevate circulating estrogen levels [88].

Similarly, estrogen influences both the composition and functional activity of the gut microbiota. Estrogen receptor-β (Erβ), expressed in colonic epithelial cells, is essential for maintaining microbial balance [89]. For example, experimental Erβ knockout models demonstrate that loss of estrogen signaling disrupts microbial homeostasis and promotes inflammatory phenotypes [90]. Moreover, 17β-estradiol treatment in experimental models reduced lipopolysaccharide-producing Proteobacteria, suggesting improved intestinal barrier integrity [91]. These alterations suggest that estrogen may limit LPS production by reshaping gut microbial communities, thereby improving intestinal barrier integrity. Together, these findings demonstrate a bidirectional interaction between estrogen and the gut microbiota that influences systemic hormone availability and intestinal homeostasis, with potential relevance for pregnancy outcomes.

Progesterone and microbial shifts

During pregnancy, rising progesterone levels promote an anti-inflammatory immune environment that indirectly influences gut microbial composition [92, 93]. Experimental work by Nuriel-Ohayon and colleagues demonstrated that sustained progesterone exposure in non-pregnant female mice led to marked alterations in gut microbial composition, most notably an enrichment of Bifidobacterium [57]. Enrichment of Bifidobacterium has been associated with improved metabolic and inflammatory profiles in experimental models [94–96]. Clinically, higher progesterone-driven Bifidobacterium abundance has been linked to improved pregnancy outcomes, while reduced levels correlate with elevated risk of preterm birth (PTB) [46]. This observation aligns with clinical studies demonstrating that progesterone supplementation in women with a history of PTB can lower recurrence rates by approximately one-third [97]. In addition, progesterone-driven microbial remodeling has also been shown to influence host physiology in experimental models [57]. Together, these findings support a role for progesterone-driven microbial remodeling, particularly enrichment of Bifidobacterium, in metabolic and immunological adaptation during pregnancy.

Androgens and microbial regulation

Emerging evidence indicates that the gut microbiota can modulate systemic androgen availability through multiple metabolic pathways [7, 98]. For instance, fecal microbiota transplantation from male to germ-free mice has been demonstrated to raise circulating testosterone concentrations [99]. Like estrogens, androgens undergo hepatic conjugation and enterohepatic cycling, processes that can be modulated by gut microbial enzymes. Some microbes, such as Escherichia coli, encode enzymes capable of deconjugating androgens, which enhances their reabsorption and consequently elevates systemic hormone levels [37, 86]. Beyond deconjugation, common intestinal bacteria, including E. coli and Bacteroides species, have also been shown to synthesize androgenic compounds from bile acid precursors [100]. These observations suggest that the microbiota can regulate epithelial and systemic exposure to sex hormones through multiple, complementary mechanisms.

Excessive androgen production is also closely linked to polycystic ovarian syndrome (PCOS) [101]. Experimental studies demonstrate that transplanting gut microbiota from women with PCOS, or directly colonizing mice with B. vulgatus, induces PCOS-like features. These alterations are accompanied by disrupted bile acid metabolism, impaired insulin sensitivity, ovarian dysfunction, and reduced fertility [53, 102]. Conversely, androgens also exert influence on the gut microbiota. Work by Organki and colleagues revealed that gonadectomized male rats exhibited markedly different gut microbial profiles compared with sham-operated controls, highlighting the bidirectional nature of androgen–microbiome interactions [99].

Thyroid hormones and microbial interactions

Thyroid hormones play key roles in metabolic regulation and reproductive physiology and are increasingly recognized to interact with the gut microbiota [7]. The pregnant women with TPOAb-positive SCH, treatment with levothyroxine (LT4) has been shown to reshape microbial communities [103]. Specifically, enrichment of Streptococcus salivarius, Blautia, and Bifidobacterium longum was observed in the third trimester, whereas reductions in Bacteroidota, Bacteroidales, and Prevotella occurred during the second trimester, along with a decline in Agathobacter in the third trimester [104]. Similarly, their protective associations have also been reported: the phylum Actinobacteria appears to confer resilience against hypothyroidism, while the class Deltaproteobacteria demonstrates protective effects against hyperthyroidism [105].

Beyond compositional shifts, intestinal bacteria contribute functionally to thyroid hormone metabolism. In germ-free mice, the absence of a microbiota has been associated with reduced intestinal surface area, impairing the enterohepatic recycling of orally administered T4 and consequently lowering absorption efficiency [106]. These findings underscore the clinical relevance of microbiota–thyroid hormone interactions, as thyroid dysfunction during pregnancy is associated with increased risks of miscarriage and preterm birth [107]. Collectively, these hormone–microbiome interactions highlight that pregnancy-associated endocrine shifts can indirectly remodel maternal microbial communities, influencing metabolic adaptation, inflammatory tone, and maternal–infant microbial transmission. Framing these pathways in a translational context is essential for developing microbiome-targeted strategies to improve pregnancy outcomes.

Microbiome dysbiosis and pregnancy complications

Gestational diabetes mellitus

Gestational diabetes mellitus (GDM) is a temporary form of hyperglycemia that arises during pregnancy, affecting between 5 and 14% of women [108]. It is frequently regarded as a prediabetic condition due to its strong association with future metabolic complications. GDM is characterized by systemic insulin resistance and low-grade inflammation, processes that are increasingly linked to alterations in gut microbial composition and function [109]. Women with GDM exhibit distinct gut microbiota compositions compared with healthy pregnancies, frequently mirroring patterns seen in non-pregnant individuals with type 2 diabetes [110]. Kuang et al. examined an increased abundance of Bacteroides, Klebsiella variicola, and Parabacteroides distasonis in women diagnosed with GDM, whereas normoglycemic pregnancies showed enrichment of Alistipes spp., Methanobrevibacter smithii, Bifidobacterium, and Eubacterium species [111]. Additional studies have identified specific microbial signatures linked to GDM: taxa such as Bifidobacterium dentium and Alistipes putredinis were negatively correlated with GDM, while Escherichia coli, a potential endotoxin (LPS)-producing pathobiont, displayed a positive association [112], consistent with inflammation-related metabolic dysfunction. Although individual studies vary in their findings, consistent patterns have emerged. Women with GDM typically exhibit higher levels of Desulfovibrio, Enterobacteriaceae, Ruminococcaceae, Collinsella, P. distasonis, and Prevotella, coupled with lower abundances of Bifidobacterium, Alistipes, and Faecalibacterium, taxa commonly associated with SCFA production and anti-inflammatory functions have also been reported [113]. Importantly, the overrepresentation of endotoxin-producing Enterobacteriaceae has been strongly linked to GDM and may promote TLR4-mediated inflammatory signaling that contributes to insulin resistance, while the reduction of beneficial microbes—such as Bifidobacterium and Alistipes, which contribute to short-chain fatty acid production, starch metabolism, and anti-inflammatory pathways correlates negatively with the condition [112]. Moreover, GDM has also been associated with a decline in bacteria capable of degrading aromatic amino acids, suggesting that disrupted microbial amino acid metabolism may influence host metabolic signaling and glycemic regulation [114]. Taken together, these findings highlight the pivotal role of gut microbiota alterations in driving the pathophysiology of GDM, linking microbial dysbiosis to insulin resistance and impaired metabolic regulation.

Intrahepatic cholestasis of pregnancy

Intrahepatic cholestasis of pregnancy is the most prevalent liver disorder during pregnancy, typically arising during the second and third trimester [115], and is characterized by pruritus and elevated serum bile acids and transaminases, and is linked with spontaneous preterm birth, fetal growth restriction (FGR), and intrauterine death [116]. Women with ICP display significant alterations in gut microbiota composition. Notably, there is an elevation of Enterobacteriaceae, Bacteroidetes, Turicibacter, Olsenella, Escherichia_Shigella (potential endotoxin-producing taxa), as well as bile acid–associated genera such as Parabacteroides and Bilophila. In contrast, beneficial short-chain fatty acid-producing microbes such as Blautia, Eubacterium hallii, and Faecalibacterium, important for intestinal barrier integrity and anti-inflammatory signaling, are consistently reduced [117].

Importantly, alterations in gut microbial composition in ICP include changes in bile salt hydrolase (BSH)–active taxa, which influence bile acid deconjugation and farnesoid X receptor (FXR) signaling [116]. A decrease in BSH-active bacteria may impair FXR signaling, subsequently increasing hepatic bile acid synthesis and contributing to disease pathogenesis [118]. Collectively, these findings support a model in which gut microbiota dysbiosis contributes to ICP pathogenesis by disrupting bile acid metabolism and FXR-mediated signaling, thereby exacerbating maternal cholestasis and increasing fetal risk.

Preeclampsia (PE)

Preeclampsia (PE) is a major pregnancy complication and a leading cause of maternal and perinatal morbidity and mortality globally [119]. It is clinically defined as the onset of hypertension after 20 weeks of gestation accompanied by proteinuria, multi-organ dysfunction, or uteroplacental complications [120]. Studies have indicated that alterations in the maternal gut microbiota may contribute to the pathophysiology of PE by influencing inflammatory and vascular regulatory pathways [121]. For example, supplementation with Bifidobacterium, commonly associated with anti-inflammatory and barrier-supportive functions, has been linked with a decreased risk of developing PE [122]. Conversely, increased levels of Clostridium perfringens and decreased abundances of Coprococcus catus have been identified in women with the condition [123].

More broadly, pathogenic taxa such as Clostridium (excluding the beneficial C. butyricum), Dialister, Veillonella, and Fusobacterium frequently associated with pro-inflammatory metabolites and endotoxin production, are enriched in PE patients, while beneficial microbes, including Lachnospira, Akkermansia, and Faecalibacterium, are reduced. These shifts correlate with clinical markers such as blood pressure, renal function, proteinuria, and hepatic parameters, consistent with a link between microbial dysbiosis, systemic inflammation, and vascular dysfunction [69]. Overall, PE is associated with a distinct pattern of gut microbial imbalance in which enrichment of pro-inflammatory taxa and depletion of protective microbes may amplify systemic inflammation and endothelial dysfunction, thereby contributing to hypertensive pathology [124].

Sepsis

Sepsis is a life-threatening syndrome marked by multi-organ dysfunction that results from an uncontrolled systemic inflammatory response to infection [125]. Pregnancy heightens susceptibility to severe sepsis, making it a fundamental contributor to maternal morbidity and mortality. In addition, sepsis can complicate conditions such as preeclampsia, further increasing clinical risks [126]. Recent studies suggest that maternal gut microbiome dysbiosis plays a key role in sepsis development and progression. Chen et al. demonstrated that fecal microbiota transplantation (FMT) from pregnant women exacerbated inflammation and accelerated mortality in septic mice, supporting a causal role for dysbiotic microbial communities in sepsis severity [127]. During sepsis, profound microbial disruption is observed, with a decline in microbial diversity, a marked loss of commensal taxa, and an abundance of opportunistic pathogens, including Staphylococcus, Enterococcus, and Enterococcus durans—opportunistic pathogens associated with epithelial barrier disruption, microbial translocation, and exaggerated inflammatory responses [128, 129].

Clinical data further support this connection. Analysis of a retrospective cohort of 10,996 patients revealed that individuals hospitalized with Clostridium difficile infection, a condition closely associated with gut microbiota disturbances, had a 70% higher likelihood of readmission due to severe sepsis compared with patients admitted for other infectious disease, however, this association may be confounded by antibiotic exposure, which independently predisposes to both Clostridioides difficile infection and subsequent sepsis risk [128]. Similarly, Zhang et al. identified 37 distinct gut microbial taxa causally linked with an increased risk of sepsis [130]. Together, these findings support a model in which gut microbiota dysbiosis promotes sepsis susceptibility and severity by impairing intestinal barrier integrity, facilitating pathogen overgrowth and translocation, and amplifying systemic inflammatory responses.

Preterm birth (PTB)

Preterm birth (PTB), defined as birth before 37 weeks’ gestation, contributes substantially to neonatal morbidity and mortality worldwide [131]. It is linked to multiple maternal and fetal factors, including immune dysregulation, vascular complications, cervical insufficiency, intrauterine infection, and premature membrane rupture [132]. Multiple studies have examined the link between maternal gut microbiota and PTB. Comparative analyses of microbiota from preterm and full-term neonates, as well as their mothers, reveal significant differences in the initial microbial composition [133]. Neonates born preterm often display reduced alpha and distinct beta diversity compared to full-term infants, with variations noted between spontaneous and medically induced PTB [134]. Emerging evidence suggests that maternal gut microbiome dysbiosis may contribute to PTB primarily by disrupting immune tolerance and promoting inflammation-driven initiation of labor [135].

Shiozaki et al. reported gut microbiota changes in mothers at 28 weeks’ gestation who subsequently delivered preterm infants. Specifically, Bacteroides and Clostridium levels were reduced, whereas Lactobacillus was significantly elevated in the PTB group [132]. Since Clostridia and Bacteroides promote regulatory T cell (Treg) activation, their depletion may impair IL-10–mediated immune tolerance, thereby increasing susceptibility to inflammation-associated PTB [133]. Similarly, Dahl et al. further observed reduced abundances of Bifidobacterium, Streptococcus, and Clostridial taxa in women who delivered preterm [136]. Given that Bifidobacterium species exert strong anti-inflammatory effects, including inhibition of lipopolysaccharide (LPS)-induced NF-κB activation and suppression of IL-8 and COX-2 expression, their decline may predispose women to infection-driven PTB [137]. Whether Bifidobacterium confers protection primarily through direct modulation of maternal immune tolerance, such as via regulatory T-cell induction, or indirectly by suppressing pathobiont expansion and reducing ascending intrauterine infection remains to be fully elucidated [138]. Together, these findings indicate that PTB is associated with disruption of maternal gut microbial balance, characterized by reduced protective taxa and enrichment of pro-inflammatory species. Such dysbiosis likely contributes to premature initiation of labor by impairing immune tolerance, enhancing inflammatory signaling, and increasing susceptibility to infection-driven triggers.

Across pregnancy-related complications, gut microbiota dysbiosis appears to arise from a combination of intrinsic factors, including hormonal fluctuations, immune adaptation, and metabolic stress, as well as extrinsic influences such as diet, antibiotic exposure, infection, and environmental factors. Although these drivers may induce overlapping microbial disruptions, the resulting clinical outcomes depend on which host pathways are predominantly affected. For example, dysbiosis that amplifies inflammatory and insulin-resistant signaling is more closely linked to gestational diabetes mellitus, whereas alterations that impair vascular regulation and endothelial function are more relevant to preeclampsia. Similarly, disruption of bile acid–microbiota interactions contributes to intrahepatic cholestasis of pregnancy, while loss of immune tolerance and barrier integrity increases susceptibility to preterm birth and sepsis. Figure 2 integrates microbiome alterations across pregnancy-related complications, highlighting shared dysbiotic patterns and inflammatory pathways that may represent convergent mechanisms underlying distinct clinical phenotypes.

Fig. 2.

Microbiome dysbiosis and associated functional changes in pregnancy complications. The figure integrates evidence from metagenomic and 16 S rRNA studies showing microbial and metabolic alterations in gestational diabetes, pre-eclampsia, intrahepatic cholestasis, preterm birth, and sepsis

Factors influencing maternal microbiome

Antibiotics

Antibiotics are among the most commonly prescribed medications during pregnancy, representing nearly 80% of all prescriptions, with approximately 20–25% of pregnant women receiving them [139]. Extensive epidemiological and experimental studies demonstrate that prenatal antibiotic exposure profoundly reduces maternal bacterial load and alters gut microbial beta diversity [140]. Such disruptions are associated with multiple adverse outcomes in offspring. These include elevated systolic blood pressure, altered metabolic signatures, abnormal weight trajectories, and increased risks of atopic diseases [141]. Furthermore, impaired immune development has been reported, with offspring exhibiting greater infection-related mortality and heightened susceptibility to IBD and colitis [142]. Animal models show mechanistic insight. In interleukin-10 knockout (IL-10 KO) mice, perinatal antibiotic treatment caused long-term dysbiosis, abnormal immune programming, and increased vulnerability to both spontaneous and chemically induced colitis [143]. Additionally, reduced levels of short-chain fatty acids (SCFAs) following antibiotic exposure are positively linked to higher asthma risk in children [144]. Collectively, these findings emphasize that prenatal antibiotic exposure disrupts the maternal microbiota, which may have lasting intergenerational effects on immune function, metabolism, and disease susceptibility. Figure 3 illustrates major environmental, metabolic, and lifestyle factors that converge to reshape the maternal microbiome, emphasizing modifiable exposures with potential translational relevance.

Fig. 3.

Key factors influencing the maternal microbiome. This figure highlights various environmental and lifestyle elements that impact the function and diversity of the maternal microbiome, with potential implications for both maternal and fetal health

Obesity

Obesity represents the most common metabolic disorder in pregnancy and is closely linked to unfavorable maternal and fetal outcomes, such as placental hypoxia [145]. Pregnant women with obesity typically exhibit an elevated level of the Firmicutes-to-Bacteroidetes ratio and a marked decrease in overall gut microbial diversity, particularly in the later gestation period [146]. Maternal diet–induced obesity has also been linked to diminished intestinal levels of short-chain fatty acid (SCFA)-producing Lachnospiraceae, reduced concentrations of butyric acid, and reduced expression of SCFA receptors [147]. Moreover, beneficial taxa such as Lactobacillus and Bifidobacterium are significantly reduced, while potentially harmful bacteria—including Escherichia coli, Enterobacteriaceae, and Staphylococcus aureus are preferentially enriched within the gut microbial community of obese pregnant women [148].

Similarly, the effects of maternal obesity extend to the offspring. Infants born to overweight mothers are more likely to develop obesity, potentially due to vertical transmission of specific metabolites and microbes [149]. Fecal microbiota analyses of these infants reveal decreased abundances of Eubacterium, Ruminococcus, and Blautia, alongside increased prevalence of Oscillibacter and Parabacteroides. Such shifts are thought to predispose offspring to metabolic dysfunction and higher lifetime risk of obesity and related disorders [150]. In summary, maternal obesity is closely tied to dysbiosis, systemic inflammation, and altered microbial transmission, with risks for both the mother and the child’s metabolic trajectory.

Nicotine exposure

Maternal smoking during pregnancy has been identified as a major contributor to adverse health outcomes in both mothers and newborns, such as preterm birth, low infant weight, and spontaneous miscarriage [151]. Nicotine, the principal toxic compound in tobacco, enters the body via inhalation, dermal absorption, or ingestion. Offspring of mothers who smoke during pregnancy face elevated risks of sudden infant death syndrome, impaired respiratory function, obesity, and cardiovascular disease later in life [152]. One proposed mechanism underlying these risks is nicotine-induced disruption of the maternal gut microbiota. Nicotine exposure has been shown to reduce beneficial bacteria such as Lactobacillus and Bifidobacterium, while promoting the overgrowth of pathogenic taxa, including E. coli and Klebsiella pneumoniae [153]. Prenatal nicotine exposure also alters the diversity of major microbial phyla such as Bacteroidetes, Firmicutes, Actinobacteria and Proteobacteria, and cuts down short-chain fatty acid (SCFA) concentrations in both maternal blood and amniotic fluid [154]. Additionally, at the molecular level, nicotine has been shown to downregulate key genes in the proximal colon of pregnant women. These include FFAR2 (free fatty acid receptor 2), responsible for SCFA signaling, as well as propionate and acetate transporters, and TPH2 (tryptophan hydroxylase 2), the rate-limiting enzyme in serotonin biosynthesis. Such changes impair microbial signaling pathways and may disrupt maternal-fetal immune and metabolic regulation [155]. Overall, this evidence suggests nicotine exposure during gestation disrupts the composition of the gut microbiota. It interferes with microbial metabolite signaling, ultimately compromising fetal development and the long-term health of the offspring.

Diet and lifestyle

Maternal diet and lifestyle play crucial roles in shaping maternal and neonatal health, significantly influencing the composition of both maternal and infant microbiomes [156]. Dietary habits in pregnancy are strongly linked with shifts in the infant gut microbiota. For instance, a high-fat maternal diet has been linked to alterations in the neonatal microbiome, partly through the vertical transfer of mobile genetic elements carrying diet-related adaptive genes [157]. Similarly, western dietary patterns, consisted of high fats and refined carbohydrates, are interlinked with reduced “ancestral” microbial diversity and increased dysbiosis, which may negatively impact maternal and infant health [158]. Carbohydrate intake has also been correlated with microbiota structure: high carbohydrate consumption increases Proteobacteria and Bacteroides while decreasing Firmicutes members such as Ruminococcaceae, Ruminococcus, and Roseburia. Conversely, low-carbohydrate diets are linked with elevated Lachnospira [159]. Protein intake further modulates microbiota composition. Diets high in animal protein reduce Actinobacteria and Proteobacteria while enriching methanogens, which contribute to hydrogen removal and improved nutrient energy harvest. Similarly, sugar-rich diets decrease the indole (microbial metabolite), whereas protein-rich diets increase it. Since indole is crucial for glucose regulation and lipid metabolism, the Mediterranean diet, which naturally supports higher indole levels, may act as a protective dietary pattern [160].

High-fat diets also increase Akkermansia (a mucin-degrading genus) while reducing Lachnospira and Ruminococcus (butyrate-producing bacteria). These alterations can damage gut barrier integrity and improve IL-17 A production, potentially influencing placental vascular development and fetal gut maturation [161]. Similarly, micronutrient intake such as vitamin-D supplementation has been positively linked to increased abundance of Proteobacteria and Actinobacteria, while higher maternal vitamin E consumption is linked to decreased abundance of Proteobacteria and Sutterella, taxa that are typically elevated in infants presenting with autism spectrum disorder and gastrointestinal dysfunction [162, 163]. However, imbalanced folic acid and choline intake during pregnancy can trigger dysbiosis and increase offspring obesity risk [164]. Collectively, these findings emphasize that maternal dietary choices during pregnancy exert lasting effects on both maternal and neonatal microbiome, with consequences for immune maturation, metabolism, and long-term health outcomes.

Microplastics (MPs)

Microplastics (MPs) are growing environmental pollutants that have raised considerable concern due to their potential effects on human health, particularly during pregnancy [165]. Ingested MPs can induce microbial dysbiosis, intestinal inflammation, and functional impairments of the gut barrier. Such alterations can lead to broader health problems, such as diabetes, metabolic disorders, and mental health conditions [166].

Maternal exposure to MPs during pregnancy has been linked with an increased risk of gestational diabetes mellitus, likely mediated through microbiota disruption [167]. Experimental evidence further indicates that MPs derived from disposable paper cups exert dose-dependent harmful effects on murine fetal development and maternal physiology [168]. Similarly, maternal dysbiosis induced by MPs in animal models has been shown to result in fetal resorption, impaired placental development, and altered vascularization—pathological features that closely resemble those observed in preeclampsia [169].

Human studies have confirmed MP presence in placental tissue and fetal meconium, underscoring prenatal exposure. For example, a study in Shanghai identified 16 types of MPs in samples from mother-infant pairs and reported inverse correlations between MP levels and specific microbial genera in both placenta and meconium, suggesting that MPs can alter microbial composition even before birth [170]. Long-term effects may also extend across generations. Research in maternal mice demonstrated that polystyrene MP exposure during gestation and lactation disrupted gut microbial and metabolic balance, while offspring displayed persistent dysregulation of hepatic lipid metabolism [171]. Taken together, these findings highlight MPs as a novel risk factor in maternal-fetal health, with the ability to reshape microbiota, impair placental function, and exert intergenerational effects. Despite growing experimental evidence linking microplastic exposure to microbial dysbiosis and adverse pregnancy-related outcomes, the current body of data is largely derived from animal models and observational human studies. Important limitations include variability in exposure assessment, particle composition, and dose relevance to real-world human exposure. Consequently, while microplastics represent a plausible emerging risk factor, their causal role and clinical significance during pregnancy remain to be definitively established.

Establishment of the infant gut microbiota in the first 1000 days

The first 1,000 days of life, spanning from conception to around three years of age, constitute a crucial period for gut microbiota establishment, which is fundamental to immune maturation, metabolic regulation, and lifelong health outcomes [172]. This period is marked by rapid microbial shifts in response to environmental influence and dietary transitions. Perturbations during this stage can predispose individuals to chronic conditions, including inflammatory, autoimmune, metabolic, and neurological disorders [173].

Neo-natal period

The neonatal period, encompassing the first days of life, marks the beginning of this colonization process in what was previously a sterile gastrointestinal tract. Vaginal delivery encourages exposure to the mother’s vaginal and intestinal microbes, such as Lactobacillus, Sneathia, and Prevotella, whereas cesarean section is associated with colonization by skin and environmental microbes [174]. These early colonizers initiate essential microbial–immune interactions that calibrate neonatal immunity and promote tolerance to commensals. Early gut colonization is initially dominated by facultative anaerobes such as Enterobacteriaceae and Staphylococcus, which are progressively replaced by obligate anaerobes, including Bifidobacterium and lactic acid bacteria, within the first few weeks of life [175].

Infancy (0–12 months)

During infancy, microbial composition remains highly dynamic and is shaped primarily by diet. Breastfed infants are enriched in Bifidobacterium and Lactobacillus, sustained by human milk oligosaccharides (HMOs) [176]. Similarly, in contrast, formula-fed infants show greater microbial diversity with increased Clostridium and Enterobacteriaceae, but reduced Bifidobacterium dominance [177]. At nearly six months, the shifts to solid foods promote diversification, with increasing abundance of Bacteroides and Firmicutes, initiating the transition toward adult-like communities [178]. During the weaning period, dietary diversification continues to drive compositional changes, gradually reducing the dominance of Bifidobacterium and supporting the establishment of more complex microbial networks [179].

Toddlerhood (12–36 months)

As dietary complexity expands further in toddlerhood, additional diversification and stabilization of the microbiota occur. Fiber-degrading taxa such as Ruminococcus and Faecalibacterium increase in abundance while Bifidobacterium continues to decline [180]. By around three years, the gut microbiota closely mirrors the composition observed in adults, characterized by functional specialization and ecological stability [181]. Environmental exposures, including siblings, pets, and urban versus rural living, further shape microbiota development during this period. These dynamics highlight the plasticity of the early microbiome and underscore how colonization during the first three years establishes long-term foundations for immune and metabolic health. These developmental stages are summarized in Fig. 4, which illustrates the temporal progression of gut colonization from birth through the toddler years, integrating the effects of delivery mode, feeding practices, dietary diversification, and environmental influences.

Fig. 4.

Infant gut-microbiota development during the first 1000 days. Gut colonization begins at birth and is shaped by delivery mode, feeding (breastmilk vs. formula), and early antibiotics. Infancy favors Bifidobacterium and Lactobacillus, while the introduction of solids increases Bacteroides and Firmicutes. By toddlerhood, diet and environment drive diversification, resulting in an adult-like microbiota dominated by Bacteroides, Ruminococcus, and Faecalibacterium

Maternal to infant microbial transmission

The inheritance of maternal microbes helps shape the infant’s intestinal microbiota and supports immune system development. This transfer can occur during pregnancy, delivery, and breastfeeding, with each stage transferring distinct microbial communities to the neonate [149]. Although debated, some studies suggests that microbial colonization starts in utero, with the maternal–placental–fetal axis providing an early foundation for microbiome development. As pregnancy progresses, maternal microbiota adapts to support fetal growth and prepare for microbial transmission at birth [182]. As discussed earlier, delivery mode is a critical determinant of neonatal microbial seeding. Vaginal birth allows infants to come in contact with maternal vaginal microbiota [175], whereas cesarean is associated with delayed colonization and reduced transmission of taxa such as Bacteroides, sometimes persisting for up to 18 months [183].

Breastfeeding represents the most important route of vertical microbial transfer after birth. Beyond nutrition, breast milk carries diverse microbial communities, with approximately 22–23% derived from the maternal gut via the entero-mammary pathway. It is estimated that around one-quarter of the infant gut microbiota arises from breast milk [184]. In addition to live bacteria, breast milk also provides human milk oligosaccharides (HMOs), which selectively enrich Bifidobacterium and act as key prebiotics. It also supplies immunological mediators, including secretory IgA, IgG, and cytokines such as TGF-β, which regulate microbial composition, promote immune tolerance, and protect against pathogen overgrowth. Notably, genera including Faecalibacterium, Blautia, Lachnoclostridium, Streptococcus salivarius, Bifidobacterium longum, and Lactobacillus gasseri have been shown to transfer directly from mother to infant through this continuum [185, 186].

Transmission also occurs through multiple additional pathways. Skin-to-skin contact during early bonding, vaginal seeding, and horizontal transfer from siblings, caregivers, and household pets all contribute to the infant microbiome. Maternal factors such as obesity, metabolic disease, and physical activity, as well as environmental contexts ranging from industrialized to traditional populations, further modulate the process [149]. Microbial seeding is site-specific, with contributions from the mother’s oral, gut, and vagina, while feeding practices (exclusive breastfeeding, formula feeding, or expressed breast milk) refine the colonization trajectory [187]. Collectively, these factors highlight the dynamic interplay between maternal and infant microbiomes across gestational and postnatal stages, with transfer occurring through multiple pathways. This process is critical for immune system priming and can influence lifelong health trajectories. Figure 5 synthesizes maternal, environmental, and lifestyle determinants of maternal–infant microbial transmission, highlighting the complexity and redundancy of microbial seeding pathways.

Fig. 5.

Maternal, environmental, and lifestyle determinants of maternal–infant microbial transmission. Microbes are transferred from maternal sources (gut, vagina, skin, oral cavity, breast milk) and shaped by maternal health, population context, feeding practices, antibiotics, and household contacts, highlighting complex early-life microbial interplay

Microbial–Immune interactions in the first days after birth

The immediate postnatal period is a significant window for microbial–immune interactions that shape the infant’s immune trajectory and influence long-term health. Immediately after birth, microbes begin to colonize the neonatal intestine and other body surfaces, initiating a dialogue with the immature immune system that is essential for tolerance to commensals and the development of protective immunity [149]. As outlined in Fig. 5, the sequence of colonization from birth through the toddler years is tightly linked with these immune programming events, underscoring the importance of timing in microbial–immune crosstalk. Microbial cues are central to immune maturation. Colonizing taxa stimulate gut-associated lymphoid tissue (GALT) and engage pattern recognition receptors (PRRs), such as Toll-like receptors (TLRs), to calibrate the balance between tolerance and pathogen defense [188]. Similarly, it also contributes to the maturation of both innate and adaptive immunity, while innate immunity is largely established prenatally, adaptive immunity undergoes extensive development after birth, strongly influenced by these early microbial signals [189].

Animal models demonstrate the consequences of impaired microbial exposure. Germ-free mice exhibit abnormal Peyer’s patches, reduced CD4 + T cells, diminished IgA-producing cells, and skewed Th2 responses during early life [190]. Similarly, vaginally delivered mice exposed to lipopolysaccharide (LPS) display epithelial activation, a response absent in TLR4-deficient animals [191]. Early-life disruptions such as cesarean delivery or antibiotics alter this dialogue, delaying colonization by commensals and impairing immune calibration [187]. Perturbations of microbial–immune crosstalk during this early critical period have been linked with an exaggerated risk of allergy, autoimmunity, and metabolic disease later in life [192]. These findings emphasize that microbial sensing through pattern recognition pathways is essential for appropriate immune calibration.

In humans, the early neonatal period is marked by systemic innate immune activation, characterized by increased monocytes and elevated cytokines such as IL-1 and IFNγ, balanced by regulatory factors including IL-1Ra [37, 193]. Breast milk reinforces these processes by providing immunological mediators: secretory IgA and IgG coat microbial taxa, TGF-β promotes Treg differentiation, and HMOs act as prebiotics that modulate barrier function and immune pathways [194]. Collectively, these insights highlight the first days after birth as a ‘window of opportunity’ in which microbial colonization and immune system maturation are tightly intertwined, laying the foundation for long-term immune homeostasis and disease resilience.

Interventions in infancy and early childhood

Infancy and early childhood are crucial developmental stages during which the gut microbiome and immune system are particularly malleable. Targeted interventions during this stage can optimize microbial colonization, strengthen immunity, and decrease the risk of later diseases [195]. Probiotics, live microorganisms administered in appropriate amounts, have demonstrated benefits in reducing inflammation and supporting gut health. Clinical studies and meta-analyses show that supplementation with Bifidobacterium and Lactobacillus strains can ameliorate conditions such as allergic rhinitis, antibiotic-associated diarrhea, and inflammatory bowel disease [196]. Similarly, Prebiotics, non-digestible dietary components, such as fibers and complex carbohydrates, selectively stimulate beneficial microbes [197]. Clinical trials suggest that prebiotic supplementation in infants can lower the risk of atopic dermatitis by nearly 50%, underscoring their protective role in immune development [198].

Furthermore, Fecal microbiota transplantation (FMT) has tested for efficacy in restoring gut microbial balance in cases of recurrent Clostridioides difficile infection, and is also being used in IBD and obesity [199]. Although its direct use in infants remains experimental, FMT highlights the therapeutic potential of microbiome restoration [200]. Similarly, breastfeeding, beyond providing nutrition, serves as a primary source of beneficial microbes and immune-modulating compounds. It supports colonization with Bifidobacterium and Lactobacillus, while delivering immunoglobulins, growth factors, and cytokines which guide immune maturation [201]. In addition, associations have been documented between microbiome composition and digestive disorders, including celiac disease, gastritis, Helicobacter pylori infection, and systemic autoimmune diseases, emphasizing the potential for early interventions to reduce long-term risks [202]. Overall, interventions targeting the microbiome in infancy and early childhood, whether through diet, microbial supplementation, or breastfeeding, represent promising strategies to optimize health outcomes during this critical window of development.

Emerging interventions for managing dysbiosis in early childhood

Emerging technologies offer innovative approaches to address dysbiosis during infancy and early childhood, with several experimental strategies showing promise for clinical application. Figure 6 summarizes emerging microbiome-targeted interventions, distinguishing established approaches from experimental strategies and emphasizing current translational limitations.

Fig. 6.

Promising interventions for mitigating early-life dysbiosis

Prebiotic- and probiotic-enriched hydrogels

Hydrogels are 3D polymer structures capable of absorbing and retaining substantial quantities of water, making them suitable delivery vehicles for probiotics and prebiotics [203]. Encapsulation of probiotics within hydrogels can protect bacterial viability against harsh gastric conditions and improve storage stability. Studies indicate that such systems enhance probiotic survival during gastrointestinal passage and heat stress, thereby amplifying their therapeutic potential [204]. However, issues related to safety, biocompatibility, and scalability must be addressed before clinical application.

Gut microbiota transplantation (GMT)

Gut microbiota transplantation, a variant of fecal microbiota transplantation (FMT), has been proposed as a strategy to optimize maternal and infant microbiota during pregnancy [172]. Although FMT is an established therapy for recurrent Clostridioides difficile infections in adults, its safety in pregnancy remains uncertain [199]. Current international guidelines recommend that FMT be reserved only for severe, treatment-resistant cases in pregnant women. Further studies are required to assess the long-term effects of GMT on both mother and infant health before it can be considered a routine intervention.

Microbial ecosystem therapeutics (MET)

Microbial ecosystem transplantation (MET) represents a more refined alternative to FMT, involving the isolation, cultivation, and reintroduction of defined microbial consortia [205]. Age-specific MET formulations tailored to the needs of infants during the first 1,000 days of life may promote healthy microbial development and reduce the risk of dysbiosis-related disorders [172]. While promising, rigorous evaluation of efficacy, safety and long-term outcomes are required before MET can be translated into clinical practice.

CRISPR-Based microbiota therapies

The advent of gene-editing approaches, including CRISPR/Cas9, enables precise targeting of detrimental bacteria within the gut microbiome while sparing beneficial taxa [206]. Such precision-based approaches hold potential for mitigating microbiome-associated disorders, including metabolic and immune-related diseases. However, significant challenges remain, including targeted delivery, specificity, and the prevention of off-target effects [207]. Consequently, further research is necessary before CRISPR-based microbiome editing can advance from experimental models to clinical application.

Although these emerging microbiome-targeted strategies offer conceptual promise, most remain at an early experimental or preclinical stage. Significant challenges, including safety, ethical considerations, regulatory oversight, and long-term efficacy, must be addressed before clinical implementation, particularly in pregnant women and infants. At present, these approaches should be viewed as future research directions rather than near-term therapeutic options.

Conclusion

The maternal microbiota is increasingly recognized as an important regulator of pregnancy outcomes and early-life health. Dynamics shifts in gut, vaginal, oral, and controversially placental microbial communities during gestation influence fetal development, immune programming, and the risk of pregnancy-related complications. These microbial alterations are shaped not only by intrinsic factors such as hormonal changes but also by extrinsic influences, including antibiotics, maternal obesity, smoking, diet, and environmental pollutants such as microplastics.

Similarly, microbial transmission from mother to infant via the intrauterine environment, mode of delivery, and breast milk plays a fundamental role in seeding the infant gut microbiota. This early colonization sets the foundation for immune maturation and metabolic regulation during the first 1,000 days of life. Disruptions to this process may increase long-term susceptibility to chronic diseases. Looking forward, microbiome-targeted strategies—including prebiotics, probiotics, postbiotics, microbial ecosystem therapeutics, and next-generation CRISPR-based interventions offer promising avenues for improving maternal and neonatal outcomes. However, their safety, efficacy, and long-term impacts must be thoroughly evaluated before clinical implementation. Ultimately, deepening our understanding of microbiota–hormone–immune crosstalk during pregnancy and early life will be critical for informing the development of personalized, precision-based interventions to enhance maternal health and optimize infant outcomes.

Abbreviations

hCG

Human chorionic gonadotropin

NKc

Natural Killer Cells

HLAs

Human leukocyte antigens

Treg

Regulatory T cells

LPS

lipopolysaccharide

PCOS

Polycystic ovary syndrome

TPOAb

Thyroid peroxidase antibody

SCH

Subclinical Hypothyroidism

CST-IV

Community State Type IV

BVAB-I

Bacterial vaginosis-associated bacterium

IBD

Inflammatory bowel disease

NET

Neutrophil extracellular trap

HMOs

Human milk oligosaccharides

BSH

Bile salt hydrolase

BV

Bacterial Vaginosis

Erβ

Estrogen receptor-β

MET

Microbial ecosystem therapeutics

T3

Triiodothyronine

T4

Thyroxine

Author contributions

Muhammad Junaid conceived the review topic and wrote the original manuscript. Zeming Hu and Aftab Ahmad contributed to the literature review, data interpretation, and manuscript editing. Mengyao Xu, Xinyi Shi, Na Qu, and Tianyu Du assisted in data collection and reference organization. Yabin Zhu and Huiqing Ding supervised the study, provided critical revisions, and served as the corresponding authors. All authors approved the submitted manuscript.

Funding

The authors acknowledge the financial support from the Major Project of 2035 Sci &Tech Innovation of Ningbo (2024Z034, 2024Z204). This work was also sponsored by the K.C. Wang Magna/Education Fund of Ningbo University.

Data availability

No new data were generated. All information is derived from previously published studies cited in this article.

Declarations

Ethical approval

Not applicable.

Use of generative AI and AI-assisted tools in the writing process

ChatGPT was used to assist with language editing and improve sentence flow. The authors have reviewed and edited all AI-assisted content and take full responsibility for the final manuscript.

Competing interests

The authors have not conflicted of interest to declare.