How parents' microbiomes influence early brain development through the gut-brain connection

Pregnancy and lactation are accompanied by coordinated endocrine, immune, and metabolic adaptations that reshape the maternal microbiome across multiple body sites, including the gut, vagina, oral cavity, skin, and milk.20-22 These microbial ecosystems do not change uniformly. Rather, each niche responds differently to host physiology, environmental exposures, and clinical factors, with implications for maternal health, birth outcomes, and early microbial transfer to the infant.23^,24 Among these niches, the maternal gut microbiota shows the most extensively characterized remodeling during pregnancy, particularly in late gestation, when metabolic and inflammatory adaptations intensify.25^,26 However, the vaginal, oral, skin, and milk microbiomes are also relevant because they represent potential routes through which maternal physiology and perinatal exposures may influence early microbial inheritance.27-29 Importantly, this section focuses on how these maternal niches change across pregnancy and lactation and on the factors that modulate them. The neurodevelopmental relevance of specific microbial taxa and transmission pathways is examined in Section 3.

Pregnancy is characterized by tightly regulated hormonal, metabolic, and immune adaptations that support implantation, placentation, fetal growth, and preparation for parturition and lactation, while also shaping microbial ecology at maternal mucosal surfaces.22^,30 Human chorionic gonadotropin becomes detectable within days of fertilization and supports progesterone and estrogen production, both of which rise substantially across gestation and influence epithelial integrity, immune tone, and microbial composition.30^,31 These hormones also affect the gut–brain axis indirectly by modulating intestinal barrier function, mucosal immunity, and bacterial growth conditions.32 Maternal metabolism likewise shifts across gestation. Early pregnancy is relatively anabolic, favoring energy storage, whereas mid-to-late pregnancy becomes increasingly catabolic, with reduced insulin sensitivity and greater mobilization of glucose and lipids to support fetal growth.33^,34 Although these changes are physiological, they resemble some features of metabolic syndrome and provide an important context for understanding pregnancy-associated microbiome remodeling.33^,35

Immune regulation also changes over time. Early gestation is relatively pro-inflammatory to support implantation; mid-gestation shifts toward immune tolerance; and late gestation and parturition are again associated with inflammatory activation.36^,37 These stage-dependent immune shifts likely contribute to the restructuring of maternal microbial communities across body sites.38 After delivery, the sharp decline in progesterone and estrogen permits prolactin-driven milk synthesis, while oxytocin supports milk ejection in response to suckling.39^,40 Lactation also imposes major energetic demands and introduces a distinct mammary immune environment rich in secretory IgA and other host factors relevant to neonatal microbial colonization.41 Together, these physiological transitions provide the host context in which maternal microbiomes are remodeled during pregnancy and postpartum.

The maternal gut microbiota undergoes progressive, trimester-dependent remodeling during pregnancy, although the magnitude and direction of change vary across cohorts and study designs.25^,26 In healthy pregnancy, commonly reported taxa include Bifidobacterium, Blautia, Bacteroides, Akkermansia, Faecalibacterium, Ruminococcus, and members of the Lachnospiraceae, Ruminococcaceae, and Clostridiales.22 During the first trimester, gut microbial composition often resembles that of non-pregnant women, with relatively greater abundance of butyrate-producing taxa such as Faecalibacterium and Eubacterium and higher alpha diversity in some cohorts.25^,42 Between the first and second trimesters, compositional changes become more apparent, with alterations in beta diversity indicating that community structure is beginning to shift even when broad phylum-level patterns remain stable.43^,44 In a longitudinal U.S. cohort, gut microbial beta diversity differed between the first and second trimesters but not between the second and third, suggesting that part of this remodeling may stabilize by mid-pregnancy.43 Data from Chinese cohorts also indicate second-trimester enrichment of Firmicutes, Bacteroidetes, Actinobacteria, Tenericutes, and Proteobacteria, with increased representation of Bifidobacteriaceae and Enterobacteriaceae.45 The third trimester is the most frequently studied stage and is often characterized by reduced alpha diversity, increased inter-individual variation in community composition, and enrichment of taxa associated with inflammation or altered metabolic status, including Proteobacteria, Actinobacteria, Enterobacteriaceae, Streptococcus, and Collinsella.25^,46^,47 At the same time, some studies report increased abundance of Bifidobacterium and Blautia in late pregnancy, suggesting that late-gestation remodeling does not simply reflect loss of beneficial taxa but rather a complex ecological reorganization shaped by host physiology.48 Progesterone may contribute directly to this process, as experimental supplementation in non-pregnant mice increased Bifidobacterium abundance in vivo and in vitro.48 Hormonal effects may also act indirectly through immune and metabolic changes that alter the intestinal environment.26^,49 Overall, the maternal gut microbiota appears to shift across pregnancy toward a less diverse and more individualized late-gestation configuration, often with greater representation of lactic-acid-producing and inflammation-associated taxa.25^,47 However, interpretation should remain cautious. Findings vary across studies because of differences in sampling time, cohort characteristics, antibiotic exposure, dietary patterns, body composition, and sequencing approaches, and many studies remain underpowered or focused primarily on late pregnancy.23 This variability is important and should be acknowledged rather than treated as inconsistency to be ignored.

The vaginal microbiome plays a central role in reproductive health and is one of the best-defined maternal microbial niches relevant to pregnancy. In healthy reproductive-age women, vaginal communities are often dominated by Lactobacillus species, which promote a low pH through lactic acid production and thereby restrict pathogen growth.50^,51 During pregnancy, the vaginal microbiome generally becomes more stable and more likely to remain Lactobacillus-dominant than in the non-pregnant state.27^,51 Community state types are commonly classified according to dominant taxa, with four Lactobacillus-dominated states and a fifth enriched in anaerobes with lower lactic acid production.52 Pregnancy favors the former pattern. Longitudinal work has shown that pregnant women who deliver at term more often exhibit stable communities enriched in Lactobacillus crispatus, L. gasseri, L. jensenii, and related taxa, while bacterial-vaginosis-associated genera such as Prevotella, Sneathia, Gardnerella, Mobiluncus, and Parvimonas are less prevalent.27^,53 These shifts are thought to be influenced in part by rising estrogen levels, which promote glycogen availability and thereby support Lactobacillus metabolism and lactate production.53

Evidence also suggests that failure to maintain early-pregnancy vaginal stability is associated with adverse outcomes, particularly preterm birth. In one study, women who later delivered preterm showed significant reductions in richness, diversity, and evenness between the first and second trimesters, whereas community structure remained relatively stable in term pregnancies.54 Other cohorts similarly report that early gestation may be a critical window during which vaginal microbiome organization is linked to pregnancy outcome.55 At the same time, the vaginal microbiome is shaped by a range of biological and social factors, including age, reproductive history, sexual behavior, hygiene practices, and ancestry, which may contribute to between-cohort heterogeneity and should not be oversimplified as purely biological variation.56-58 Taken together, current evidence supports the view that pregnancy is generally associated with a stable, low-diversity, Lactobacillus-enriched vaginal microbiome, and that loss of this stability may mark vulnerability to adverse obstetric outcomes.27^,54 The neurodevelopmental implications of vaginally transferred taxa are considered later in the manuscript.

The oral cavity hosts one of the largest and most diverse microbial communities in the body, comprising more than 700 species across multiple oral habitats.59^,60 Pregnancy is associated with measurable changes in oral microbial load and community composition, likely driven by hormonal fluctuation, altered immune tone, and increased susceptibility to gingival inflammation.60 Clinical studies suggest that pregnancy, particularly the first and second trimesters, is associated with enrichment of periodontal-associated and opportunistic taxa, including Porphyromonas gingivalis, Aggregatibacter actinomycetemcomitans, Streptococcus, Staphylococcus, and Candida species.61 Elevated progesterone appears to increase susceptibility to plaque-associated gingival inflammation, and the abundance of some oral pathobionts has been positively correlated with circulating hormone levels during gestation.62 Additional taxa linked to periodontal dysbiosis, such as Prevotella intermedia, Campylobacter rectus, and Prevotella nigrescens, have also been associated with pregnancy-related hormonal changes.60 These oral shifts are clinically relevant because periodontal disease and oral dysbiosis during pregnancy have been associated with preterm birth, preeclampsia, and low birth weight, although causality remains difficult to establish and shared inflammatory pathways may contribute to these associations.63^,64 Importantly, oral microbial alterations appear at least partly reversible: postpartum, total bacterial load and some pathogenic taxa decline toward a non-pregnant baseline.65 Thus, current evidence supports the conclusion that the oral microbiome is a pregnancy-responsive niche whose dysregulation may reflect broader host inflammatory and hormonal changes.

Compared with the gut, vagina, and oral cavity, the maternal skin microbiome remains less well characterized during pregnancy. Available evidence nevertheless suggests that pregnancy is associated with structured reorganization of skin microbial communities, particularly in late gestation.29 In the first study to profile skin microbiota across trimesters, microbial composition differed across all pregnancy stages compared with non-pregnant controls, with the greatest divergence observed in the third trimester.29 Late pregnancy was associated with increased abundance of Pseudomonas and Janthinobacterium and reduced abundance of taxa such as Sphingomonas and Oscillospira, alongside evidence of altered network centrality for Corynebacterium simulans, a species associated with healthy skin microbial communities.29 These findings suggest that pregnancy may affect not only relative taxonomic abundance but also the ecological organization of the skin microbiome. However, this remains a relatively underdeveloped area. The current evidence base is small, often cross-sectional, and insufficient to determine whether observed changes are generalizable across populations or body sites. For that reason, the skin microbiome should be included in the review because of the manuscript’s multi-niche scope, but discussed proportionately and cautiously.

Human milk is a complex biological system that contains nutrients, immune mediators, bioactive molecules, and a dynamic microbial community that changes across lactation.66^,67 The major nutritional, bioactive, and microbial components of breast milk and their relevance to infant development are summarized in Figure 2. The origin of milk-associated microbes remains debated, with likely contributions from maternal skin, the infant oral cavity, environmental exposure, and possibly the maternal gut via an entero-mammary route.67^,68 Regardless of origin, milk represents an important postnatal microbial and biochemical interface between mother and infant. Milk microbial composition varies by lactation stage. Colostrum generally has the highest microbial diversity and may provide a broad early inoculum, with reported enrichment of Firmicutes and genera such as Staphylococcus, Lactobacillus, Acinetobacter, and Pseudomonas.69^,70 Strain-level work also suggests that early milk contains diverse Bifidobacterium populations relevant to infant gut colonization.68 As lactation progresses, community structure shifts. Transitional milk is associated with rapid remodeling, while mature milk shows changing relative abundance of Bifidobacterium, Lactobacillus, Pseudomonas, and Streptococcus, with some core genera remaining detectable throughout lactation.28^,69 Later lactation may increasingly reflect bidirectional mother–infant exchange, as oral-associated taxa such as Actinomyces, Veillonella, Rothia, and Prevotella become more abundant, consistent with retrograde transfer from the infant oral cavity during breastfeeding.28 At the same time, milk microbiome trajectories are not identical across populations. Studies from Irish, Chinese, and Thai-Myanmar cohorts suggest that geography, host characteristics, and environment influence lactational microbial succession.28^,69^,71 Preterm birth may also alter milk microbial organization, with enrichment of taxa such as Staphylococcus haemolyticus, Propionibacterium acnes, and gut-associated bacteria compared with term milk.71 Overall, human milk should be viewed not as a static fluid but as a dynamic microbial niche whose composition changes across lactation and may contribute to early-life microbial programming.

Multiple maternal exposures can remodel microbial communities during pregnancy and lactation. To reduce overlap with later mechanistic and intervention-focused sections, the emphasis here is on how these factors alter maternal microbiomes rather than on repeating downstream offspring outcomes in detail.

Among the taxa most consistently linked to healthy early-life programming are Bifidobacterium, Bacteroides, Lactobacillus, and several SCFA-producing anaerobes, including Faecalibacterium, Roseburia, Subdoligranulum, Anaerobutyricum hallii, and related Lachnospiraceae and Ruminococcaceae members.91^,101 These taxa are relevant because they occupy complementary ecological roles rather than acting in isolation. Bifidobacterium is a key early-life commensal because it is strongly enriched in breastfed infants, can be vertically transmitted from mother to infant, and is closely linked to human milk oligosaccharide utilization, acetate and lactate production, mucosal barrier support, and immune maturation.102 Experimental work further suggests that bifidobacteria and their metabolites can shape synapse formation, microglial function, and neurotrophin-related signaling, although these mechanistic data derive mainly from preclinical models.103^,104 Human observational studies are directionally consistent, linking higher early-life Bifidobacterium abundance with more favorable inflammatory and developmental profiles, but they remain largely associative.105

Bacteroides should also be established early as a core neurodevelopmentally relevant genus because it is central to fecal vertical transmission and infant gut ecological succession. Vaginally delivered infants are more likely to acquire maternal Bacteroides strains, whereas cesarean delivery is associated with reduced early Bacteroides abundance and delayed microbiome maturation.16^,106^,107 Functionally, Bacteroides contributes to complex glycan degradation, cross-feeding networks, immune education, and SCFA-related metabolism, thereby helping establish an intestinal environment that supports barrier integrity and downstream gut–brain signaling.11^,108 Although direct human proof that maternally transmitted Bacteroides improves neurodevelopment is still limited, its repeated association with healthier colonization trajectories makes it a foundational taxon in the developmental narrative.

Lactobacillus is particularly important in relation to the vaginal microbiome, delivery, and breast milk. During healthy pregnancy, Lactobacillus-dominated vaginal communities are associated with stability and protection from dysbiosis, and vaginal delivery provides an important route through which lactobacilli contribute to initial neonatal seeding.27^,55Lactobacillus also appears in milk and infant gut ecosystems and has recognized immunomodulatory and anti-inflammatory functions, including lactate production, pathogen exclusion, and support of epithelial homeostasis.68^,109 Some preclinical data further suggest that specific Lactobacillus species may influence offspring social behavior, vagal signaling, and stress-related pathways, but these findings remain strain-specific and should not be generalized to the entire genus.110^,111

Beyond these early colonizers, several strict anaerobic SCFA producers are likely to support neurodevelopment indirectly by generating butyrate, propionate, and acetate. Taxa such as Faecalibacterium prausnitzii, Roseburia hominis, Subdoligranulum, and Anaerobutyricum hallii contribute to anti-inflammatory signaling, epithelial barrier maintenance, and metabolic cross-feeding networks that sustain a mature and resilient gut ecosystem.112-114 Butyrate is especially relevant because it has been linked to histone deacetylase inhibition, neurotrophin regulation, microglial maturation, and synaptic plasticity in experimental systems.92^,115 However, in human pregnancy and infancy, the neurodevelopmental significance of these taxa is still inferred primarily from metabolite biology, ecological associations, and animal studies rather than from direct interventional evidence. Taken together, the most plausible model is that beneficial commensals support offspring neurodevelopment not because any single genus is uniquely protective, but because vertically transmitted maternal taxa help establish a metabolically cooperative early-life ecosystem enriched for SCFA production, glycan utilization, immune tolerance, and barrier stabilization. These processes are likely more biologically robust than taxon-by-taxon claims.

In contrast, maternal dysbiosis may increase offspring neurodevelopmental vulnerability by enriching taxa that promote inflammation, epithelial disruption, and aberrant immune signaling. The term pathobiont is used here to describe organisms that are not universally harmful but may become detrimental when ecological balance is disturbed or when host inflammatory conditions favor pathogenic behavior.116 Among the taxa most often implicated are Bilophila wadsworthia, Desulfovibrio, opportunistic Escherichia coli pathotypes, and other inflammation-associated Proteobacteria or sulfide-producing organisms.117-119 Their relevance lies less in simple presence than in the types of signals they amplify, including lipopolysaccharide, hydrogen sulfide, oxidative stress, impaired tight-junction integrity, and pro-inflammatory cytokine cascades. These mechanisms have been linked experimentally to increased gut permeability, altered BBB function, microglial activation, and impaired synaptic development.108^,120^,121 For example, expansion of Bilophila has been associated with inflammatory states and maternal obesity-related dysbiosis, while Desulfovibrio has been linked to sulfur metabolism, barrier dysfunction, and inflammatory neuroimmune signatures in disease-oriented studies.43^,117^,118 Similarly, vertically transmitted or perinatally acquired E. coli pathotypes may contribute to neonatal inflammatory burden through lipopolysaccharide and other virulence-associated products, particularly in vulnerable infants.122-124 However, evidence linking these taxa specifically to later neurodevelopment remains much stronger in mechanistic and animal studies than in human longitudinal cohorts. A more accurate interpretation is therefore that pathobiont-enriched maternal dysbiosis may create a pro-inflammatory developmental context that plausibly influences fetal and infant neurodevelopment, rather than that specific organisms directly cause neurodevelopmental disorders.

A third group includes taxa whose developmental significance is context dependent, meaning that their effects vary according to strain, maternal metabolic state, surrounding microbial ecology, and timing of exposure. This distinction is important because genus-level classification alone often obscures functional diversity. Akkermansia muciniphila illustrates this concept. In some contexts, it is associated with improved barrier function, metabolic health, and anti-inflammatory signaling, whereas in others excessive mucin degradation or strain-level variation may contribute to barrier fragility or inflammatory responses.68^,125 Similarly, genera such as Parabacteroides, Barnesiella, Odoribacter, Blautia, Eggerthella, and Ruminococcus include strains with divergent metabolic capacities, making broad functional generalizations potentially misleading.126^,127 This strain dependence extends to microbial metabolites. The same genus may support neurodevelopment under one ecological configuration by promoting SCFA production, vitamin synthesis, or anti-inflammatory signaling, yet behave differently in a dysbiotic environment characterized by succinate accumulation, inflammatory metabolites, or excessive mucin degradation. For this reason, functional output and ecological context are more informative than taxonomy alone.

The key message for the sections that follow is that neurodevelopmentally relevant microbial programming involves a recurring set of biological processes: establishment of early commensal-rich ecosystems, production of SCFAs and other neuroactive metabolites, maintenance of epithelial and BBB integrity, calibration of immune responses, and limitation of inflammatory spillover from dysbiotic states.11^,15^,91 The importance of specific maternal niches, including gut, vagina, milk, skin, and oral communities, lies in how they deliver or shape these functions across pregnancy, birth, and infancy. This framework also clarifies why Bacteroides, Bifidobacterium, and Lactobacillus should remain central throughout the review: they represent key anchors of fecal, milk-associated, and vaginal transmission pathways that converge on early immune and neurodevelopmental programming. Conversely, dysbiosis-associated enrichment of inflammatory pathobionts should be interpreted as a modifier of developmental risk rather than as deterministic proof of causation. The following sections therefore focus on routes of transfer and timing of exposure, while referring back to these core microbial mechanisms.

Current evidence does not support the presence of a consistent, viable placental microbiome. Early reports identifying bacterial DNA within placental tissues have largely been attributed to contamination and low-biomass artifacts, and subsequent metagenomic analyzes have failed to demonstrate reproducible colonization by live microbes.14 Instead, the placenta functions as a highly selective biological interface that transmits microbial metabolites, immune mediators, and host-derived signals from the maternal circulation to the developing fetus. This selective transfer is primarily mediated by the syncytiotrophoblast, a continuous epithelial layer that regulates molecular exchange through membrane transporters, receptor-mediated endocytosis, and transcytosis.128 Through this system, microbiota-derived metabolites can reach the fetal compartment without direct microbial translocation. For example, SCFAs, key products of maternal gut microbial fermentation, are detectable in cord blood and correlate with maternal circulating levels, indicating placental transfer.129 These metabolites have been implicated in fetal neurodevelopment, particularly in experimental models, through roles in microglial maturation, BBB integrity, and epigenetic regulation.92^,130 In parallel, placental tryptophan metabolism represents a critical interface between maternal microbiota and fetal brain development. The enzyme indoleamine-2,3-dioxygenase (IDO) converts maternal tryptophan into kynurenine-pathway metabolites that cross the placenta and influence neurodevelopmental processes.131 Although direct human evidence linking specific microbiota-derived tryptophan metabolites to neurodevelopment remains limited, disruptions in placental serotonin and tryptophan signaling have been associated with altered fetal brain development.132 Microbial indole derivatives, such as indole-3-propionic acid, may further contribute to placental homeostasis and fetal protection, although their precise role requires further clarification.133 A schematic overview of placental transfer of commensal- and dysbiosis-associated maternal microbial metabolites is shown in Figure 3.

Bile acids constitute another major class of microbiota-associated metabolites that traverse the placenta. Under physiological conditions, tightly regulated maternal–fetal gradients maintain controlled fetal exposure. However, in pathological states such as intrahepatic cholestasis of pregnancy, dysregulated bile acid transport leads to fetal accumulation and has been associated with altered neuronal differentiation and stress responses.134 Experimental models demonstrate that normalization of bile acid transport using ursodeoxycholic acid can mitigate adverse metabolic and neurodevelopmental outcomes in offspring,135 highlighting the functional significance of this pathway. In addition to metabolic signaling, maternal immune activation represents a critical mechanism linking the maternal microbiome to fetal brain development. Elevated maternal cytokines, particularly interleukin-6 and interleukin-17A, can signal across the placenta and disrupt cortical development, leading to long-term behavioral alterations in offspring in animal models.136^,137 These findings support a model in which maternal microbiome-driven immune responses influence fetal neurodevelopment indirectly through inflammatory signaling pathways. Anatomically, maternal blood carrying microbial metabolites and immune mediators enters the intervillous space, where it interfaces with the syncytiotrophoblast. Beneath this layer, fetal capillaries within the chorionic villi receive selectively transported molecules. Immune cells within the decidua, including macrophages and T cells, further modulate this environment by responding to microbial and inflammatory signals. This spatial organization enables differential transfer of molecular signals: commensal-derived metabolites such as SCFAs and indoles generally support neurodevelopmental processes, whereas pathobiont-associated molecules such as lipopolysaccharide and secondary bile acids promote inflammatory signaling that may disrupt fetal brain development. Collectively, the placenta functions not as a passive barrier but as an active regulatory interface that integrates maternal microbial, metabolic, and immune signals. Through selective transfer mechanisms, it shapes fetal exposure to neuroactive molecules, thereby establishing an early foundation for MGBA programming prior to birth.

Mode of delivery represents a critical postnatal gateway linking the maternal microbiome to early-life microbial colonization and neurodevelopment. During vaginal birth, the neonate is exposed to maternal vaginal and fecal microbiota, including key taxa such as Lactobacillus, Bacteroides, and Bifidobacterium, which initiate gut colonization and early immune programming.16^,100^,106^,138 In contrast, Cesarean delivery limits exposure to these maternal reservoirs and favors colonization by skin- and environmental-associated microbes, including Staphylococcus and Streptococcus.107 These differences are most pronounced during the first months of life, a period characterized by rapid synaptogenesis, immune maturation, and MGBA development.139^,140 Vaginally delivered infants typically acquire maternal strains that promote ecological succession and metabolic functionality of the gut microbiome, whereas cesarean-born infants often exhibit delayed colonization by key taxa such as Bacteroides and Bifidobacterium. These genera are important for SCFA production, tryptophan metabolism, and immune modulation, processes implicated in microglial maturation, neurotransmitter balance, and early neural circuit formation.11^,108

Epidemiological studies have associated cesarean delivery with increased risks of neurodevelopmental disorders, including autism spectrum disorder, attention-deficit/hyperactivity disorder, language delay, and emotional dysregulation.141 However, these associations should be interpreted cautiously, as they may reflect confounding factors such as maternal health status, antibiotic exposure, or obstetric complications rather than delivery mode alone. Thus, while altered microbial seeding is a plausible mechanism, causality remains unresolved. Experimental evidence supports a mechanistic role of delivery-associated signals. Natural birth has been linked to regulation of hippocampal mitochondrial function and neuronal differentiation,142 while early microbial exposure influences cytokine, metabolic, and vagal signaling pathways relevant to stress regulation and cognitive development.143 Importantly, emerging strategies aim to mitigate cesarean-associated dysbiosis. Vaginal microbiota transfer has been shown to partially restore infant gut microbial composition toward vaginal delivery profiles and may improve early developmental metrics, although current evidence remains preliminary.144 These approaches highlight a translational opportunity but require further validation regarding safety and long-term neurodevelopmental outcomes. Overall, vaginal delivery acts as a foundational microbial and neurodevelopmental event, although its long-term impact is modulated by subsequent exposures such as breastfeeding, environment, and antibiotic use.

Following birth, human milk represents a central route of continued maternal microbial and biochemical influence. This postnatal pathway, including microbial transfer, milk bioactives, and downstream effects on infant gut and brain development, is illustrated in Figure 4. Beyond nutrition, breast milk delivers microbes, human milk oligosaccharides (HMOs), immune factors, and neuroactive compounds that collectively shape infant gut colonization and neurodevelopment.41^,145^,146 The milk microbiome contains diverse taxa, including Staphylococcus, Streptococcus, Propionibacterium, Bacteroides, Blautia, Clostridium, Roseburia, and Ruminococcus, with evidence of strain-level overlap between maternal milk and infant gut microbiota.68^,99 This supports ongoing vertical microbial transmission during lactation, although distinguishing direct microbial transfer from substrate-driven selection remains challenging.

HMOs play a central role by selectively enriching Bifidobacterium longum subsp. infantis and related taxa, promoting gut barrier integrity and immune maturation.147 Additional components such as secretory IgA, lactoferrin, and antimicrobial peptides regulate microbial colonization, while fatty acids and neurotrophic factors contribute directly to brain development.148^,149 Neurodevelopmental associations are supported by both observational and mechanistic studies. HMOs such as 2′-fucosyllactose and N-acetylneuraminic acid have been linked to improved synaptogenesis, motor skills, and white matter development.146 Exclusive breastfeeding has also been associated with improved cognitive and behavioral outcomes, although these effects likely reflect combined biological and environmental influences.150 More direct microbiome-mediated evidence suggests that maternal milk microbial composition may influence infant neurodevelopment via modulation of the infant gut microbiome and SCFA production.151 This supports a model in which non-gut maternal microbiomes contribute indirectly to neurodevelopment by shaping the infant gut ecosystem. However, current evidence remains largely observational, and milk composition is influenced by multiple factors including maternal diet, metabolic status, delivery mode, and antibiotic exposure.67^,69 Therefore, causal interpretations should be made cautiously. Overall, the milk microbiome represents a sustained postnatal extension of maternal microbial programming, integrating microbial transfer, metabolic signaling, and immune regulation to shape early neurodevelopment.

Beyond delivery and breastfeeding, early-life environmental and tactile exposures provide additional pathways linking maternal microbiota and neurodevelopment. These overlapping tactile and close-contact pathways are summarized schematically in Figure 5. These include skin-to-skin contact, kangaroo care, affectionate touch, and environmental microbial exposure. Skin-to-skin contact facilitates exposure to maternal skin-associated microbiota and has been associated with changes in infant oral and gut microbial composition, including enrichment of taxa such as Gemella, Aggregatibacter, and members of the Lachnospiraceae family.152 However, whether these changes represent stable colonization or transient exposure remains unclear.

Kangaroo care, a structured form of prolonged skin-to-skin contact, has well-established neurodevelopmental benefits, including improved autonomic regulation, stress resilience, and behavioral organization in preterm infants.153^,154 Early-life stressors such as maternal deprivation have also been associated with long-term alterations in inhibitory interneuron number and morphology in limbic brain regions.155^,156 These effects are likely mediated primarily through neuroendocrine and autonomic pathways, with microbial contributions remaining secondary and less clearly defined. Affectionate caregiver touch, including holding and physical interaction, influences HPA axis activity, neural synchrony, and socioemotional development.157^,158 These interactions may also contribute to microbial exchange, although their primary impact appears neuroregulatory rather than microbiological. Environmental exposures further shape early microbial development. Infants raised in farm environments exhibit distinct gut microbiota enriched in taxa such as Clostridiaceae, Akkermansia, and Blautia, which are associated with SCFA production and immune conditioning.159 While these findings suggest broader ecological influences on neurodevelopment, direct mechanistic links remain limited. Overall, these routes act as modulatory pathways that reinforce or reshape microbial and neurodevelopmental trajectories established earlier, rather than serving as primary drivers.

Maternal microbial programming occurs through a sequence of interconnected transmission routes across developmental time. During pregnancy, the placenta mediates transfer of microbial metabolites and immune signals. At birth, vaginal delivery seeds the neonatal microbiome. During infancy, breast milk sustains microbial and metabolic signaling, while environmental and tactile exposures further modulate these processes. Together, these pathways form a temporally coordinated framework through which maternal multi-niche microbiomes shape the infant MGBA. Disruptions at different stages, including cesarean delivery, impaired breastfeeding, antibiotic exposure, or maternal dysbiosis, may therefore have distinct but overlapping consequences for neurodevelopment.

Dietary fiber is a central driver of maternal gut microbial metabolism. Fermentation of fiber by commensal bacteria generates SCFAs, including acetate, propionate, and butyrate, which act as key signaling molecules within the MGBA. These metabolites can cross the placenta and have been detected in fetal circulation, where they influence microglial maturation, synaptic development, and epigenetic regulation.162^,170-172 These effects extend to structural neuronal development, as microbial and metabolic perturbations have been shown to alter dendritic morphology and cortical circuit organization.173^,174 Clinical and preclinical studies consistently show that higher maternal fiber intake is associated with enrichment of SCFA-producing taxa such as Faecalibacterium, Roseburia, and Lachnospira, alongside reduced abundance of pro-inflammatory genera including Collinsella.175 In contrast, low-fiber diets promote dysbiosis and reduce circulating SCFAs, limiting fetal exposure to neuroactive metabolites. Experimental models further demonstrate that maternal fiber deficiency impairs offspring synaptic plasticity, alters hippocampal signaling pathways, and leads to behavioral deficits, which can be partially rescued by butyrate supplementation.170 Beyond gestation, lactation represents an additional window of microbiome-mediated programming. Maternal fiber intake influences milk composition and microbial transfer, shaping early gut colonization and immune maturation in the offspring.176 Collectively, these findings position dietary fiber as a key upstream regulator of SCFA-dependent neurodevelopmental pathways.

Polyphenols interact bidirectionally with the gut microbiota, acting both as substrates for microbial metabolism and as modulators of microbial community structure. Microbial conversion of polyphenols generates bioactive metabolites, including urolithins and phenolic acids, which exhibit anti-inflammatory and neuroprotective properties.177^,178 Maternal polyphenol intake has been associated with enrichment of beneficial taxa such as Akkermansia and Blautia, alongside reductions in lipopolysaccharide-associated bacteria.179^,180 These shifts promote a more anti-inflammatory microbial environment, which may indirectly support fetal brain development through reduced systemic inflammation and improved barrier integrity. Evidence from human studies indicates that microbial polyphenol metabolites can be transferred via breast milk, linking maternal diet to infant gut colonization. For example, urolithins derived from maternal intake have been detected in both breast milk and infant biological samples, accompanied by increased abundance of butyrate-producing taxa in the infant gut.181 While direct causal links to neurodevelopment remain limited, these findings support a microbiome-mediated pathway through which maternal polyphenol intake may influence early-life programming.

In contrast to fiber- and polyphenol-rich diets, maternal high-fat diet (HFD) induces microbial dysbiosis characterized by reduced diversity, depletion of SCFA-producing bacteria, and enrichment of pro-inflammatory taxa.182^,183 These microbial alterations are associated with increased intestinal permeability and elevated circulating lipopolysaccharide, promoting systemic inflammation. Maternal inflammation represents a key mechanistic link between HFD-induced dysbiosis and altered neurodevelopment. Experimental studies demonstrate that maternal HFD exposure disrupts fetal microglial maturation, alters glutamatergic signaling, and induces behavioral abnormalities in offspring, including anxiety-like behavior and cognitive deficits.184 These effects are partly mediated by altered microbial metabolite profiles, including reduced SCFAs and dysregulated tryptophan metabolism. Importantly, these microbiome alterations are vertically transmitted, with offspring of HFD-fed mothers exhibiting persistent dysbiosis despite postnatal dietary normalization.185^,186 Together, these findings highlight maternal HFD as a key disruptor of microbiome-dependent neurodevelopmental programming. The broader concept of early-life nutritional programming and its downstream metabolic consequences is illustrated in Figure 7.

Probiotic supplementation has emerged as a potential strategy to modulate the maternal microbiome and influence offspring neurodevelopment. Most evidence focuses on Bifidobacterium and Lactobacillus species, which are associated with SCFA production, immune regulation, and early-life gut colonization.111 Clinical studies indicate that maternal probiotic supplementation can increase beneficial taxa and reduce pro-inflammatory bacteria in both mother and infant.109 These microbial changes are associated with enhanced gut barrier function, reduced inflammation, and improved early microbial colonization patterns. In some studies, probiotic exposure has also been linked to improved neurobehavioral outcomes, although evidence remains limited and strain-specific.165 Mechanistically, probiotics may act through multiple pathways, including SCFA production, modulation of cytokine signaling, and vertical microbial transmission via breast milk. Notably, probiotic-induced changes in milk microbiota and metabolites have been associated with altered infant gut composition and early cognitive markers.187 However, heterogeneity across studies highlights the need for standardized interventions and mechanistic validation.

Maternal diet and microbiome-targeted interventions converge on shared biological pathways that regulate offspring neurodevelopment. Diets rich in fiber and polyphenols promote SCFA production, microbial diversity, and anti-inflammatory signaling, supporting neurodevelopmental resilience. In contrast, high-fat diets disrupt these pathways, promoting dysbiosis and neuroinflammatory risk. Probiotic interventions offer a targeted approach to partially restore microbial balance, although their effects depend on strain, timing, and host context. Overall, maternal nutrition shapes offspring neurodevelopment not only through direct nutrient supply but also through microbiome-mediated signaling networks. These findings reinforce the maternal microbiome as a central and modifiable interface linking environment, metabolism, and brain development across generations.

Paternal contributions to offspring development extend beyond genetic inheritance and increasingly include microbiome-mediated mechanisms. A schematic overview of paternal microbiome- and germline-mediated pathways relevant to offspring development is presented in Figure 8. Within the developmental origins of health and disease framework, the paternal microbiome, particularly the gut microbiota, acts as a regulator of germline signaling prior to conception.12^,188 Experimental evidence supports the existence of a gut–germline axis, whereby alterations in the paternal gut microbiome influence sperm molecular composition. Disruption of the paternal microbiota has been shown to modify sperm small non-coding RNA profiles, including piRNAs, which play a key role in early embryonic gene regulation.188 These microbiome-driven changes are associated with downstream effects in offspring, including altered metabolism, gut development, and behavior, suggesting that paternal microbial status may contribute to early-life programming. Importantly, these findings position the paternal microbiome as a mediator between environmental exposures, such as diet, stress, and antibiotics, and germline signaling, expanding the concept of intergenerational inheritance beyond maternal pathways.

In addition to gut-mediated effects, the seminal microbiome represents a direct route through which paternal microbial signals may influence early development. Contrary to earlier assumptions, semen is not sterile but contains a diverse microbial community, including commensal and opportunistic taxa that coexist with spermatozoa and bioactive molecules.12^,189 These seminal microbial communities are transferred to the female reproductive tract at conception, where they interact with maternal vaginal and uterine microbiota. This interaction may influence immune tolerance, inflammatory balance, and implantation processes, thereby indirectly shaping embryonic development. Conceptual models, such as the semino-vaginal microbiome framework, propose that microbial signals from both parents converge at the maternal–fetal interface to influence early developmental trajectories.12 Although the composition and function of the seminal microbiome remain incompletely characterized, emerging evidence suggests associations with sperm quality, oxidative stress, and reproductive outcomes.190 However, mechanistic links to offspring neurodevelopment remain largely indirect and require further investigation.

Epigenetic inheritance represents a key pathway through which paternal environmental and microbial signals may influence offspring development. The broader relationship between developmental epigenetic programming and transgenerational disease susceptibility is illustrated in Figure 9. Sperm carries multiple layers of epigenetic information, including DNA methylation, retained histone modifications, and small non-coding RNAs, all of which can regulate early embryonic gene expression.191^,192 Among these mechanisms, small non-coding RNAs are particularly sensitive to environmental and microbiome-related influences. Alterations in sperm RNA content have been shown to affect early embryonic transcriptional programs, including pathways related to metabolism, stress response, and neurodevelopment.188 However, the extent to which paternal epigenetic modifications are transmitted across generations remains a subject of ongoing debate. During early embryogenesis, extensive epigenetic reprogramming occurs, which erases most parental epigenetic marks. While certain regions, such as imprinted genes, escape this reprogramming, it remains unclear how consistently environmentally induced epigenetic changes persist and influence long-term outcomes.193 Similarly, evidence for histone-based inheritance is emerging but remains limited. For example, paternal obesity has been associated with altered histone modifications in sperm that may influence early embryonic gene expression, although causality and persistence are not fully established.194 Overall, while epigenetic mechanisms provide a plausible link between paternal microbiome status and offspring development, current evidence remains incomplete, and further research is required to resolve these uncertainties.

Rather than acting independently, paternal and maternal microbiomes likely function as an integrated system during early development. Microbial signals from both parents converge during critical windows, including fertilization, implantation, and early gestation, shaping the embryonic environment through combined metabolic, immune, and epigenetic influences.12^,195 Paternal contributions, mediated through sperm epigenetics and seminal microbiota, interact with maternal microbiome-derived signals that dominate during pregnancy and early infancy. This convergence may influence placental development, immune tolerance, and early microbial colonization, ultimately impacting neurodevelopmental trajectories. Although human evidence remains limited, this integrated parental framework provides a more comprehensive model of intergenerational programming and aligns with emerging systems-level approaches to microbiome research.

The paternal microbiome represents an emerging but still underexplored component of microbiome–gut–brain axis research. Evidence from experimental and observational studies suggests that paternal microbial status influences offspring development through interconnected pathways involving the gut microbiome, seminal microbiota, and epigenetic signaling. However, compared with maternal pathways, paternal mechanisms remain less well defined, and current evidence is often indirect or derived from animal models. Future studies should aim to clarify the relative contribution of paternal microbiome pathways, their interaction with maternal systems, and their relevance to human neurodevelopment.

Advances in multi-omics approaches have enabled a more integrated understanding of how the microbiome contributes to neurodevelopment through interconnected metabolic, immune, and epigenetic pathways. Rather than acting in isolation, the maternal and early-life microbiome interacts with host systems across multiple biological layers, including microbial composition (metagenomics), metabolite production (metabolomics), and host gene regulation (epigenomics).196^,197 In the context of the MGBA, these layers converge to influence key developmental processes such as microglial maturation, synaptic formation, and BBB integrity. Microbiota-derived metabolites, including SCFAs, tryptophan derivatives, and bile acids, act as central mediators linking gut microbial activity to brain development.92^,108 Integrating multi-omics data therefore provides a systems-level framework to understand how early-life microbial exposures shape neurodevelopmental trajectories.

Emerging multi-omics studies in pediatric populations demonstrate that combined microbiome–metabolome analyzes provide deeper insight into neurodevelopment than single-layer approaches. For example, integrative analyzes combining metagenomics and metabolomics have identified coordinated alterations in microbial taxa and neuroactive metabolites associated with neurodevelopmental disorders, including disruptions in SCFA pathways and neurotransmitter-related metabolism.198 Importantly, these studies highlight that microbiome-derived metabolites with BBB permeability may serve as functional mediators of gut–brain communication. For instance, alterations in microbial pathways involved in tryptophan metabolism and SCFA production have been linked to changes in brain connectivity, immune activation, and behavioral outcomes.166 These findings support a model in which microbial function, rather than taxonomy alone, is a key determinant of neurodevelopmental outcomes.

Integrating microbiome data with neurobiological readouts, including neuroimaging and behavioral assessments, represents a critical step toward mechanistic understanding. Studies combining microbial profiling with neurodevelopmental outcomes demonstrate associations between early-life microbiome composition and brain structure, connectivity, and cognitive performance.199 Machine learning approaches have further enabled the identification of microbiome-based signatures associated with neurodevelopmental phenotypes, although current models remain limited by cohort size and heterogeneity.200 Despite these limitations, such integrative frameworks support the concept that microbiome-derived signals contribute to neurodevelopment through coordinated effects on metabolism, immune signaling, and neural circuit formation.

Despite its potential, multi-omics integration in microbiome research faces several challenges. These include variability across cohorts, differences in sampling time points, and difficulty distinguishing causal relationships from associations. Additionally, the dynamic nature of the microbiome during pregnancy and early-life complicates longitudinal interpretation.200 Importantly, moving from descriptive associations to causal mechanisms will be essential for translating microbiome research into clinical applications targeting neurodevelopment. Future studies should prioritize longitudinal mother–infant cohort designs that capture dynamic microbiome changes across developmental windows, alongside integrative analyzes combining microbial, metabolomic, and neurodevelopmental data. Clear distinction between findings derived from human studies and animal models will be essential to improve translational relevance. In addition, functional validation of microbiome-derived metabolites is needed to establish causal mechanisms linking microbial activity to neurodevelopmental outcomes.

Current evidence supports a model in which early-life neurodevelopment is shaped by a dynamic parental microbial network acting across preconception, pregnancy, birth, and infancy. Within this framework, the maternal microbiome remains the dominant source of direct early microbial and metabolite exposure, but paternal contributions are increasingly recognized as biologically relevant modifiers of developmental programming. Across the maternal gut, vaginal, milk, oral, and skin niches, microbial communities influence offspring development through partially overlapping mechanisms that include metabolite transfer, immune modulation, vertical microbial transmission, and regulation of early gut colonization. These processes converge on the microbiome–gut–brain axis, where microbial products and host responses shape intestinal barrier maturation, microglial development, synaptic organization, neuroimmune tone, and, ultimately, behavioral and cognitive trajectories. A major strength of the current evidence base is that it supports a temporally organized model of transmission. During pregnancy, the placental interface appears to function primarily as a selective metabolic and immunological gatekeeper rather than a route for routine transfer of viable bacteria.14 Maternal microbiota-derived metabolites, including SCFAs, tryptophan-related metabolites, and bile-acid intermediates, can nevertheless reach the fetus and influence developmental pathways relevant to neurodevelopment.15^,92^,129^,131 At birth, vaginal delivery facilitates transfer of maternal vaginal and fecal taxa, especially taxa such as Bacteroides, Bifidobacterium, and Lactobacillus, that support early immune education and microbiome maturation.106^,144 During lactation, the milk microbiome and milk bioactives further shape infant gut colonization and may influence neurodevelopment through microbial, immunological, and metabolic signaling.91^,151 Early tactile and environmental exposures, including skin-to-skin contact, add an additional postnatal layer of microbial and neurobehavioral regulation.152^,157

At the mechanistic level, the literature increasingly suggests that the developmental relevance of the microbiome lies less in taxonomic presence alone than in microbial function. Recurrently implicated pathways include SCFA production, bile-acid transformation, tryptophan metabolism, inflammatory signaling, and modulation of epithelial and BBB integrity.92^,108 This is important because the same microbial species may exert beneficial or detrimental effects depending on strain identity, ecological context, host metabolic state, and timing of exposure. Accordingly, the relationship between parental microbiomes and offspring neurodevelopment should not be interpreted through overly simplified dichotomies of “beneficial” versus “harmful” taxa. Instead, the evidence favors a context-dependent developmental ecology in which maternal eubiosis tends to support immune and neurodevelopmental homeostasis, whereas maternal dysbiosis associated with obesity, metabolic dysfunction, stress, poor diet, or antibiotic exposure may shift metabolite and immune profiles toward inflammatory developmental risk.43^,78^,89^,201 The paternal microbiome adds a complementary, though still less well-defined, dimension to this model. Emerging evidence suggests that paternal gut and seminal microbial states may influence offspring development indirectly through sperm-associated epigenetic remodeling, small non-coding RNA cargo, and interactions with the maternal reproductive environment around conception.12^,13^,188 Although direct human evidence remains limited, this literature broadens the developmental framework from a maternal-only model to a dual-parent model of microbiome programming. Taken together, the available data support the view that parental microbiomes do not act as isolated compartments, but as coordinated biological systems whose signals intersect during sensitive windows of embryonic, fetal, and early postnatal development.

The translational relevance of this field lies in the fact that several microbiome-related influences on offspring development are potentially modifiable. Maternal diet, metabolic health, psychological stress, antibiotic exposure, mode of delivery, and breastfeeding practices all affect microbial transfer or microbial signaling during critical windows of neurodevelopment.82^,89^,91^,169^,175 This creates an opportunity to move from descriptive microbiome science toward developmental prevention strategies. However, the translational message must remain proportionate to the evidence. At present, the field supports cautious microbiome-informed optimization of perinatal health, but not deterministic prediction or routine clinical manipulation of the microbiome for neurodevelopmental benefit. Among candidate interventions, dietary modulation appears particularly promising because it acts upstream of microbial composition and function. Fiber-rich and polyphenol-rich dietary patterns consistently favor SCFA-producing and anti-inflammatory microbial profiles in both clinical and preclinical settings, whereas high-fat diets are more often associated with dysbiosis, endotoxemia, and altered offspring developmental outcomes.169^,179^,184 Probiotics also show potential, especially in relation to maternal metabolic health, infant gut colonization, and milk microbial composition, but their effects are strain-specific and not yet sufficiently standardized for broad neurodevelopmental recommendations.109^,165^,202 Similarly, growing evidence around cesarean-associated dysbiosis and microbial restoration strategies is encouraging, but current neurodevelopmental outcome data remain preliminary and do not justify oversimplified clinical claims.140

A second translational implication is conceptual rather than interventional: future maternal–fetal and early-life risk assessment should increasingly consider the microbiome as part of a broader developmental systems framework. Microbial signatures alone are unlikely to serve as sufficiently robust biomarkers, but integrated models combining microbial, metabolomic, inflammatory, and clinical variables may eventually improve stratification of pregnancies or infants at elevated neurodevelopmental risk. Importantly, this approach will require much stronger validation across populations and careful attention to confounding by socioeconomic, dietary, obstetric, and environmental variables. A third implication is that translational messaging must distinguish clearly between findings from human cohorts and mechanistic evidence from animal models. Animal studies have been invaluable for establishing causal links between microbial perturbation and offspring brain outcomes, but many pathways remain incompletely demonstrated in humans. Accordingly, preventive strategies should be framed around improving overall perinatal health and microbial resilience rather than promising direct prevention of specific neurodevelopmental disorders. This distinction is essential for both scientific rigor and ethical communication.

Despite rapid progress, several major gaps continue to limit interpretation and clinical translation. First, causality remains a central challenge. Many associations between parental microbiome features and offspring neurodevelopment are compelling, but they remain vulnerable to confounding and reverse interpretation. This is especially relevant for concepts such as “dysbiosis,” which are often used descriptively without sufficient mechanistic precision. Future work should more clearly distinguish correlation, mediation, and causation, and should avoid implying that microbiome alterations are necessarily primary drivers rather than markers or amplifiers of broader maternal or paternal physiological states. Second, the field still relies heavily on animal models for mechanistic depth. These models are indispensable, but human and animal evidence are not interchangeable. Human studies often provide ecological validity but limited causal resolution, whereas animal studies provide experimental control but may not fully recapitulate human developmental timing, microbial ecology, or social context. More explicit separation of human-derived and animal-derived conclusions throughout the literature will improve interpretability and prevent overstatement. Third, taxonomic description still exceeds functional understanding. Repeated identification of genera associated with favorable or adverse outcomes is useful, but insufficient. Strain-level resolution, metabolomics, and functional validation are now necessary to determine which microbial products actually mediate effects on the placenta, immune system, gut barrier, BBB, and developing brain. This is particularly important for taxa with context-dependent behavior and for niches such as human milk, where microbial identity alone may not capture developmental relevance. Fourth, paternal microbiome research remains at an early stage. Although the concept of paternal microbial programming is increasingly plausible, evidence is still sparse regarding seminal microbiome composition, its determinants, its interaction with the maternal reproductive tract, and its specific neurodevelopmental consequences in offspring. This area requires careful expansion, particularly in human studies, if the dual-parent framework is to move beyond conceptual novelty into a robust evidence base. Fifth, the field needs better integration across developmental windows and microbial niches. Most studies focus on a single niche, a single time point, or a single exposure. Yet the strongest emerging model is one of sequential and interacting influences across pregnancy, birth, lactation, and infancy. Future studies should therefore prioritize longitudinal mother–infant cohort designs, integration of microbial, metabolomic, and neurodevelopmental data, clear distinction between human and animal-derived evidence, and functional validation of microbiome-derived metabolites. Such designs will be crucial for identifying when parental microbial influences are most developmentally consequential and which interventions are most likely to be effective.

In conclusion, the evidence reviewed here supports a revised view of early-life neurodevelopment in which parental microbiomes contribute to developmental programming through coordinated metabolic, immunological, microbial, and epigenetic pathways. Maternal multi-niche microbial ecosystems remain the principal drivers of early-life exposure, while paternal microbiome-associated effects are emerging as important complementary influences. Across these parental contributions, the microbiome–gut–brain axis provides a biologically plausible framework linking microbial ecology to neurodevelopmental trajectories. At the same time, the field remains in a transitional phase, moving from association-rich description toward mechanism-based and clinically relevant understanding. The most important next step is not simply to catalog more taxa, but to define when, how, and under which conditions parental microbial signals shape the developing brain. Achieving that goal will be essential for transforming microbiome research into credible strategies for early-life neurodevelopmental risk reduction.