A proposed framework for microbial inheritance in mammalian evolution: the apocrine-mammary-microbiota axis

1 Introduction

The evolution of complex animal life is traditionally interpreted through the inheritance of genetic information. Under this framework, anatomical structures and physiological processes arise through natural selection acting upon heritable genetic variation, and evolutionary success is determined by the transmission of host genomes across generations (Mayr, 1961; Kutschera and Niklas, 2004). Advances in microbiology, genomics, and microbial ecology, however, have revealed that animals exist in intimate association with diverse microbial communities that can contribute significantly to host fitness (Cho and Blaser, 2012; McFall-Ngai et al., 2013). These observations have motivated the holobiont concept, in which hosts and their associated microorganisms are considered integrated biological systems whose physiology emerges from interactions between host and microbiome (Zilber-Rosenberg and Rosenberg, 2008; Bosch and McFall-Ngai, 2011; Gilbert et al., 2012; Bordenstein and Theis, 2015). The extent to which such host–microbe associations constitute coherent evolutionary units, however, remains debated, particularly because microbial partners vary in their fidelity of transmission, persistence, and effects on host fitness. The present hypothesis does not require the holobiont to function universally as a unit of selection. It instead examines the narrower possibility that natural selection may favor host mechanisms that increase the reliable transmission of microbial partners when those associations confer fitness benefits.

The ubiquity of host-associated microorganisms raises a fundamental evolutionary question: if microbial communities contribute meaningfully to organismal fitness, how are beneficial host–microbe associations maintained across evolutionary timescales? Evidence consistent with vertical microbial inheritance has been identified throughout the animal kingdom, with microorganisms transferred through reproductive processes, parental care, and social interactions (Funkhouser and Bordenstein, 2013). These observations raise the possibility that microbial transmission constitutes a distinct layer of biological inheritance operating alongside host genes (Bordenstein and Theis, 2015). Throughout this manuscript, the term filial microorganism or filial microbial lineage refers to a microorganism or lineage for which a host lineage has evolved mechanisms that facilitate its transmission from parent to offspring. The term therefore describes an evolved relationship between a host and a microbial lineage rather than a distinct mode of microbial transmission. A filial microorganism may be transferred directly between parent and offspring or indirectly through host-mediated developmental interfaces, such as eggs, glandular secretions, milk, skin, or other parentally conditioned environments. Filial transmission may consequently overlap with conventional vertical transmission but does not require transmission to be obligate; the same microorganism may also be acquired horizontally or from environmental sources. In this sense, a microorganism is filial to a particular host lineage when host adaptations promote its intergenerational transmission.

While evidence for microbial inheritance is accumulating across diverse taxa, its evolutionary significance remains incompletely understood (Cho and Blaser, 2012; Funkhouser and Bordenstein, 2013). If beneficial microorganisms contribute substantially to host fitness, natural selection may favor mechanisms that increase the reliability of their transmission between generations. This possibility is particularly relevant in mammals, whose reproductive physiology places offspring in prolonged contact with maternal tissues and secretions throughout birth and early development (Funkhouser and Bordenstein, 2013). Mammalian reproductive and glandular systems therefore provide an opportunity to examine whether structures evolved for established functions such as nutrition, protection, communication, and reproduction may also have acquired secondary functions that increased the transmission fidelity of beneficial microorganisms.

The present framework builds upon the Acari Hypothesis, an evolutionary framework previously proposed and developed by the present author and a collaborator (Retzinger and Retzinger, 2020; Retzinger and Retzinger, 2021; Retzinger and Retzinger, 2022; Retzinger and Retzinger, 2024a; Retzinger and Retzinger, 2024b; Retzinger and Retzinger, 2024c; Retzinger and Retzinger, 2025; Retzinger, 2026). The hypothesis proposes that several distinctive features of mammalian biology, including glandular integument, microbial symbioses, mammary glands, and IgE-mediated immunity, were shaped, at least in part, by persistent evolutionary interactions with acarian ectoparasites and the pathogens they transmit. These arguments and their supporting evidence have been developed in detail in the preceding manuscripts of the Acari Hypothesis. These citations document the development of the framework rather than constituting independent validation of it, and the arguments are summarized here only insofar as they provide the evolutionary foundation for the present analysis.

Of particular relevance is the proposed functional relationship between mammalian glandular evolution and microbial symbiosis. Sebaceous and other cutaneous secretions create selective epithelial environments capable of supporting characteristic microbial communities, some members of which may contribute to defense against ectoparasites (Grice and Segre, 2011; Findley and Grice, 2014; Grice and Dawson, 2017; Sparber and LeibundGut-Landmann, 2017; Retzinger and Retzinger, 2024c). Mammary glands evolved from ancestral apocrine-like glandular systems, transforming glandular secretions into a sustained interface between mother and offspring. The previously proposed apocrine–mammary–microbiota axis extends this relationship to microbial inheritance: lactation and close maternal–offspring contact may have provided not only nutrition and protection but also increasingly reliable opportunities for transferring beneficial epithelial microorganisms to offspring (Oftedal, 2002a; Nagata et al., 2012; Zomorodian et al., 2021; Retzinger, 2026). Natural selection need not have favored mammary or other reproductive innovations primarily for microbial transmission. Rather, once such structures created recurrent maternal–offspring interfaces, microbial transmission could become an additional selectable function when host–microbe associations enhanced offspring or maternal fitness. Mammary evolution may therefore have progressively incorporated microbial transmission into mammalian reproductive biology, increasing the reliability with which beneficial host-associated microorganisms passed between generations.

This interpretation does not exclude established or competing explanations for the evolution of mammalian reproductive traits. Nutrition, offspring protection, developmental regulation, reproductive efficiency, and other selective pressures may independently or jointly account for their origins and diversification. The present hypothesis instead asks whether microbial transmission became an additional fitness-relevant function of these systems and whether selection subsequently modified them in ways that increased transmission fidelity. The present analysis therefore focuses on the narrower evolutionary proposition that mammalian glandular and reproductive biology may have evolved, in part, to preserve beneficial microbial partnerships across generations.

Building upon this framework, the present manuscript examines whether the evolution of mammalian reproductive and glandular systems progressively increased the fidelity of microbial transmission between generations. Potential transmission mechanisms and host–microbial associations are examined across monotremes, marsupials, and eutherian mammals through the lens of the apocrine–mammary–microbiota axis. The analysis is then extended to placental biology and contemporary medicine to generate experimentally testable predictions regarding the evolution, transmission, and ecological functions of mammalian microbial symbionts. Collectively, this framework explores the possibility that mammalian evolutionary success depends not only upon the inheritance of host genes but also, in part, upon the persistence of beneficial microbial partnerships and the biological systems that evolved to maintain them.

2 The apocrine–mammary–microbiota axis across mammalia

Modern mammals comprise three extant evolutionary lineages, Monotremata, Marsupialia, and Eutheria, that diverged from a common mammalian ancestor during the Mesozoic Era (Luo, 2007; Meredith et al., 2011; Flannery et al., 2022). Despite profound differences in reproductive biology, anatomy, and geographic distribution, all possess the defining mammalian characteristic of a diverse integumentary gland system including mammary glands (Renfree, 1995; Oftedal, 2002b; Meredith et al., 2011; Stannard et al., 2020; Flannery et al., 2022). Likewise, all extant mammals share conserved type 2 immune mechanisms, including mast cells and the IgE immunoglobulin isotype, which provide immune surveillance at epithelial and mucosal surfaces where host–microbe interactions are most intense (Gould and Sutton, 2008; Mukai et al., 2016; Hellman et al., 2017; Greene et al., 2025).

Mammary glands are widely regarded as specialized descendants of ancestral apocrine-like skin glands that presumably functioned in epithelial lubrication, antimicrobial defense, and maintenance of the cutaneous microenvironment (Goldman, 2002; Oftedal, 2002a; Oftedal, 2002b). Under the Acari Hypothesis, the evolution of mammary glands represents more than the origin of lactation. It reflects the progressive integration of glandular tissues into a coordinated epithelial system capable of regulating, supporting, and transmitting beneficial microbial communities during reproduction and early development (Retzinger, 2026).

The three living mammalian lineages preserve contrasting combinations of ancestral and derived reproductive traits that provide a comparative framework for examining how maternal microbial transmission may have become increasingly integrated with mammalian reproductive biology. Monotremes retain the most ancestral condition, in which mammary secretions are released directly onto mammary patches and associated hair follicles rather than through nipples. Consequently, both milk, and any microorganisms present within or acquired by it as it spreads across the mammary patch, are dispersed across the maternal integument before ingestion, potentially resulting in a comparatively less targeted mode of microbial transmission during early development (Renfree, 1995; Oftedal, 2002b; Stannard et al., 2020; Flannery et al., 2022). Marsupials elaborate this ancestral arrangement through specialized pouches that partition microbial conditioning between two epithelial compartments. Apocrine gland secretions within the pouch are proposed to establish microbial communities on the pouch-facing epidermis of the highly altricial neonate, whereas prolonged teat attachment continuously delivers mammary secretions that shape microbial colonization of the developing gastrointestinal tract (Renfree, 1995; Goldman, 2002; Stannard et al., 2020). Eutherian mammals exhibit a different and highly compartmentalized organization involving placentation, birth, prolonged lactation, and diverse integumentary exocrine glands (Goldman, 2002; Carter and Enders, 2016; Carter, 2018). Eutherians may therefore employ three complementary mechanisms of maternal microbial inheritance. Vaginal secretions together with apocrine secretions of the labial integument may condition and colonize the neonatal epidermis during birth, whereas lactation subsequently conditions and colonizes the developing gastrointestinal epithelium. The placenta may represent a third complementary mechanism by coordinating the establishment of maternally-derived microbial founder populations during the physiological transition from pregnancy to birth, a hypothesis developed in a later section. Passage through the birth canal, continued exposure to maternal epithelial secretions, and lactation would then reinforce, expand, and stabilize these founder populations throughout early postnatal development.

Across these lineages, maternal–offspring microbial interfaces differ substantially in their anatomical compartmentalization, spatial organization, and developmental timing. Despite profound differences in reproductive strategy, all three lineages rely upon sustained maternal glandular interactions during early development. These comparative patterns are consistent with the hypothesis that mammalian epithelial tissues became increasingly integrated with mechanisms regulating and transmitting beneficial microbial communities across generations.

2.1 Monotremata

Among living mammals, monotremes provide the clearest window into the evolutionary origins of maternal microbial transmission because they retain the most ancestral reproductive condition (Renfree, 1995; Oftedal, 2002b; Meredith et al., 2011; Stannard et al., 2020; Flannery et al., 2022). The short-beaked echidna (Tachyglossus aculeatus) is particularly informative, combining ancestral amniote traits, including oviparity and a cloaca, with derived mammalian features such as pilosebaceous units, mammary glands, and prolonged lactation (Morrow et al., 2009; Fenelon et al., 2025). During reproduction, females develop a temporary ventral brood pouch formed by folds of abdominal skin that receives the egg after oviposition and protects the developing hatchling throughout early lactation (Morrow et al., 2009; Fenelon et al., 2025). Within this pouch lie paired mammary patches, where milk is secreted directly onto specialized glandular skin rather than through nipples (Fenelon et al., 2025). As the hatchling repeatedly feeds while remaining in close contact with the mammary patches, it experiences prolonged exposure to maternal glandular secretions and associated microbiota. From oviposition through lactation, offspring encounter a succession of maternal epithelial interfaces, including the cloaca, brood pouch, and mammary patches, that provide repeated opportunities for exposure to maternal microorganisms and glandular secretions (Renfree, 1995; Oftedal, 2002a; Oftedal, 2002b; Stannard et al., 2020; Fenelon et al., 2025; Wilson et al., 2025).

The earliest opportunity for maternal microbial transfer occurs during oviposition. As the egg passes through the cloaca, it may encounter secretions and microorganisms originating from the gastrointestinal, urinary, and reproductive tracts before being deposited into the temporary brood pouch (Morrow et al., 2009; Fenelon et al., 2025). Although direct vertical transmission via the cloaca has not yet been demonstrated in T. aculeatus, this shared epithelial passage provides a plausible route by which maternal microorganisms may contact the egg before incubation (Morrow et al., 2009; Buthgamuwa et al., 2023; Fenelon et al., 2025). Immediately thereafter, the egg acquires a characteristic adhesive coating of uncertain origin that has been attributed to reproductive tract, cloacal, brood pouch, or other maternal epithelial secretions (Morrow et al., 2009; Fenelon et al., 2025). Regardless of its source, this coating forms a persistent maternal interface capable of retaining microorganisms together with antimicrobial and immunologically active glandular products throughout incubation. Thus, cloacal passage, brood pouch incubation, and the adhesive coating may together represent ancestral mechanisms of maternal microbial exposure that preceded the prolonged mammary-mediated transmission characteristic of therian mammals.

Following hatching, microbial exposure shifts from transient contact during oviposition to sustained interaction at the mammary patches within the brood pouch (Renfree, 1995; Stannard et al., 2020; Wilson et al., 2025). Milk secreted directly onto glandular skin contains not only nutrients but also antimicrobial proteins and, if present, microbial communities, although the presence of microbes in echidna milk has not yet been demonstrated (Goldman, 2002; Stannard et al., 2020; Wilson et al., 2025). Recent studies further demonstrate that the microbial communities of the lactating echidna pouch undergo marked remodeling during lactation, consistent with physiological regulation of the microbial environment encountered by developing offspring (Wilson et al., 2025). The evolution of mammary secretion therefore potentially transformed intermittent maternal microbial exposure into a prolonged epithelial association through which maternal microorganisms could be repeatedly transferred and ecologically supported during early development.

The reproductive biology of the short-beaked echidna also suggests a possible relationship between glandular secretions, microbial ecology, and chemical communication (Harris et al., 2012). During the breeding season, the cloacal region produces complex volatile secretions involved in reproductive signaling and mate recognition (Harris et al., 2012). In many therian mammals, comparable odor profiles arise through microbial biotransformation of apocrine and sebaceous gland secretions (Leclaire et al., 2014; Troccaz et al., 2015; Rojas et al., 2023; Carboni et al., 2025). Whether microorganisms similarly contribute to echidna reproductive odors remains unknown, but this prediction is readily testable. If confirmed, it would indicate that the monotreme cloaca functions not only in reproduction and oviposition but also as a specialized glandular ecosystem supporting both microbial regulation and chemical communication.

2.2 Marsupialia

Marsupials exhibit a more elaborate developmental system in which microbial regulation is integrated into offspring protection and postnatal development (Renfree, 1995; Chhour et al., 2010; Wang et al., 2011; Cheng and Belov, 2017; Sharp et al., 2017; Stannard et al., 2020; Weiss et al., 2021; Jayamanna Mohottige et al., 2025). The southern hairy-nosed wombat (Lasiorhinus latifrons) provides one of the best-characterized examples of a regulated marsupial pouch microbiome (Weiss et al., 2021). Like other marsupials, wombats give birth to highly altricial young that complete much of their development within the maternal pouch while attached to a teat (Renfree, 1995; Weiss et al., 2021).

Reproductively active wombat pouches undergo marked microbial restructuring (Weiss et al., 2021). Compared with non-reproductive pouches, they exhibit reduced microbial diversity and enrichment of an Actinomycetota-dominated community, including Corynebacterium, Brevibacterium, Dietzia, and members of the family Microbacteriaceae (Weiss et al., 2021). These findings indicate that the pouch microbiome is regulated by maternal reproductive physiology rather than reflecting adjacent skin or environmental contamination (Weiss et al., 2021). Several of these genera are common inhabitants of mammalian skin and gland-associated epithelia, suggesting that the pouch supports a specialized epithelial microbial community. To date their functional roles remain unknown; no study has yet demonstrated direct contributions to offspring development, host signaling, or long-term vertical microbial inheritance.

The tammar wallaby (Notamacropus eugenii, formerly Macropus eugenii) provides a complementary model because its pouch, milk, antimicrobial peptides, and pouch-young microbiota have been investigated in greater detail (Chhour et al., 2010; Wang et al., 2011; Cheng and Belov, 2017; Sharp et al., 2017; Jayamanna Mohottige et al., 2025). Following a short gestation, highly altricial young crawl to the pouch, attach to a teat, and remain there for many months while the immune system matures and milk composition changes with developmental stage (Cheng and Belov, 2017; Sharp et al., 2017; Jayamanna Mohottige et al., 2025). The pouch harbors a distinct microbiome dominated largely by Actinomycetota, while the gastrointestinal tract of pouch young acquires a complex microbial community during early teat attachment (Chhour et al., 2010). Around parturition, the pouch microbiome undergoes substantial restructuring accompanied by reduced bacterial diversity and increased expression of antimicrobial molecules, indicating coordinated regulation during the period of greatest neonatal vulnerability (Chhour et al., 2010; Cheng and Belov, 2017; Jayamanna Mohottige et al., 2025).

The tammar wallaby also demonstrates the functional diversity of marsupial glandular secretions. Pouch secretions exhibit pronounced antimicrobial activity around birth, while pouch and milk contain immune proteins, antimicrobial peptides, and other bioactive factors that likely protect immunologically immature young (Chhour et al., 2010; Sharp et al., 2017; Jayamanna Mohottige et al., 2025). Genomic studies have identified an expanded repertoire of cathelicidins, several of which are expressed in the mammary gland during early lactation and in pouch-young skin (Wang et al., 2011). These peptides exhibit broad antibacterial and antifungal activity in vitro, supporting the conclusion that marsupial glandular secretions actively regulate the microbial environment encountered by developing offspring (Wang et al., 2011; Cheng and Belov, 2017; Jayamanna Mohottige et al., 2025). Apocrine glands also contribute to chemical communication in the tammar wallaby. Specialized sternal glands located on the ventral thorax produce chemically complex secretions containing volatile and semi-volatile compounds implicated in social and reproductive signaling (Zabaras et al., 2005b; Zabaras et al., 2005a). Whether microorganisms associated with these glands contribute to the production or modification of these semiochemicals has not been established. The sternal gland therefore provides an additional example of functional specialization of marsupial apocrine secretions while identifying a testable question regarding possible gland–microbe interactions. Concurrent changes in milk composition further suggest that nutritional, immunological, and microbial regulation are coordinated throughout lactation.

Together, the wombat and tammar wallaby support a marsupial apocrine–mammary–microbiota axis in which the pouch functions as a regulated epithelial nursery integrating microbial filtering, antimicrobial defense, maternal nutrition, and immune protection. Within this framework, milk-borne microorganisms are well positioned to contribute to establishment of the neonatal digestive tract microbiome, whereas pouch-associated microbial communities and apocrine secretions may preferentially influence the developing epidermal environment through prolonged skin contact. Although direct evidence for tissue-specific microbial inheritance is lacking, this model provides a mechanistic framework for the coordinated regulation of pouch and mammary environments and predicts that mammary and pouch-associated microbiota should preferentially colonize distinct epithelial compartments. Compared with monotremes, marsupials may therefore exhibit greater compartmentalization of maternal microbial transmission between mammary and pouch-associated epithelial systems.

2.3 Eutheria

Eutherian mammals provide the most experimentally tractable systems for evaluating the proposed apocrine–mammary–microbiota axis because their mammary biology, microbial ecology, reproductive physiology, and maternal microbial transmission have been investigated in considerably greater detail than those of monotremes or marsupials. Among these, the domestic cow (Bos taurus) provides a useful non-human model for examining how maternal epithelial tissues structure microbial exposure during reproduction and early development (Falentin et al., 2016; Derakhshani et al., 2018; Yeoman et al., 2018; Derakhshani et al., 2020; Owens et al., 2021; Zhu et al., 2021; Messman and Lemley, 2023; Diddeniya et al., 2024). Importantly, however, demonstration of maternal transmission alone does not establish that a microorganism represents a coevolved filial lineage. Under the present framework, evidence of transmission must ultimately be distinguished from evidence that host adaptations facilitate the intergenerational persistence of a microbial lineage and that the resulting association contributes to host fitness.

Maternal microbial exposure in cattle begins during vaginal delivery rather than exclusively after nursing (Yeoman et al., 2018; Klein-Jöbstl et al., 2019; Owens et al., 2021; Zhu et al., 2021; Messman and Lemley, 2023; Diddeniya et al., 2024). Studies comparing maternal and neonatal microbial communities demonstrate that the maternal vaginal microbiota contributes substantially to early assembly of the calf gastrointestinal microbiome, with additional microorganisms subsequently acquired from colostrum, milk, maternal skin, and the surrounding environment (Yeoman et al., 2018; Klein-Jöbstl et al., 2019; Owens et al., 2021; Zhu et al., 2021; Messman and Lemley, 2023; Gomes et al., 2024). Longitudinal source-tracking further indicates that the relative contribution of these maternal reservoirs changes during early development: vaginal and colostral sources are most evident shortly after birth, whereas environmental and other sources contribute increasingly as the neonatal microbiome develops (Gomes et al., 2024). Maternal influence is not restricted to the gastrointestinal tract; similarities between the maternal vaginal microbiota and the neonatal upper respiratory microbiota suggest that parturition can seed microbial communities at multiple offspring epithelial sites (Lima et al., 2019). These observations indicate that early microbial assembly is a sequential and anatomically distributed process initiated during birth and reinforced throughout the neonatal period by repeated maternal contact.

This interpretation generates a readily testable prediction. If maternal apocrine glands contribute to regulation of the perineal microbiome (Blazquez et al., 1987a; Blazquez et al., 1987b), microorganisms associated with these gland-rich epithelial surfaces should contribute disproportionately to neonatal colonization immediately following vaginal delivery. Demonstrating such transmission would not, by itself, establish these organisms as filial microorganisms. Stronger evidence would require preferential maternal transmission, persistence or recurrence across host generations, evidence of host mechanisms that favor the association, and ultimately a fitness consequence for the host. Such studies could therefore distinguish microorganisms that are merely encountered during birth from microbial lineages whose transmission has become integrated into mammalian reproductive biology.

The bovine mammary gland provides a second interface through which maternal microbial exposure can continue after birth. It forms a continuous epithelial system extending from teat skin through the teat canal to the glandular lumen and milk (Falentin et al., 2016; Derakhshani et al., 2018; Derakhshani et al., 2020). These anatomical compartments harbor microbial communities whose composition varies by site and over time and is associated with susceptibility to intramammary infection (Falentin et al., 2016; Derakhshani et al., 2018; Derakhshani et al., 2020). Microorganisms inhabiting teat skin and the teat canal may influence epithelial ecology and colonization resistance, but their evolutionary relationships with the bovine host remain unresolved (Brooks and Barnum, 1984; Pankey et al., 1985; Hogan et al., 1988; Falentin et al., 2016; Carson et al., 2017; Derakhshani et al., 2018; Derakhshani et al., 2020; Porcellato et al., 2020). This distinction is important because several taxa commonly detected at these sites are also associated with mastitis.

Corynebacterium bovis illustrates this ambiguity. It commonly inhabits the bovine teat canal but has historically also been classified as a minor mastitis pathogen (Brooks and Barnum, 1984; Pankey et al., 1985; Hogan et al., 1988). Experimental studies have reported that mammary quarters colonized by C. bovis exhibit increased resistance to subsequent Staphylococcus aureus infection compared with bacteriologically negative quarters (Pankey et al., 1985; Hogan et al., 1988). Non-aureus staphylococci, including Staphylococcus chromogenes, present a similar problem: they commonly occur on teat skin, within the teat canal, and in milk, and some isolates produce bacteriocins or other inhibitory compounds capable of suppressing major mastitis pathogens, yet members of this group can themselves be associated with intramammary infection (Carson et al., 2017; Derakhshani et al., 2018; Derakhshani et al., 2020). These observations demonstrate that mammary-associated bacteria can exert context-dependent effects, but they do not establish that C. bovis, S. chromogenes, or other mastitis-associated taxa are coevolved filial microorganisms.

Their ambiguous status instead provides an opportunity to distinguish competing explanations. If these organisms are primarily environmental or opportunistic colonizers, their occurrence within the mammary ecosystem may reflect ecological filtering and repeated exposure without specialized host mechanisms promoting their intergenerational transmission. Conversely, if particular strains or lineages represent evolved maternal symbionts, the filial-microorganism hypothesis predicts evidence extending beyond their presence in the teat canal or milk: preferential association with healthy maternal epithelia, reproducible transmission from mother to offspring, persistence or recurrence across host generations, host traits that selectively facilitate their maintenance or transfer, and measurable benefits under the ecological conditions in which the association evolved. Strain-level resolution is particularly important because pathogenic and potentially beneficial phenotypes cannot necessarily be inferred from taxonomic identity alone. The bovine system therefore provides a means of testing, rather than assuming, whether particular mammary-associated microbial lineages satisfy the criteria for filial microorganisms.

Interpretation of these observations is additionally constrained by substantial biases in the mammalian systems that have been investigated. Studies of mammary-associated microbiota have disproportionately focused on domesticated species whose milk is collected for human consumption, particularly cattle, whereas the mammary-associated microbiota of most wild mammals remain poorly characterized. Conversely, studies of apocrine-associated microbiota have largely concentrated on species and anatomical sites in which apocrine secretions have recognized roles in chemical communication or intraspecies signaling. These research priorities have produced comparatively detailed but largely non-overlapping literatures on mammary and apocrine microbial ecology. Consequently, the comparative data required to determine whether microbial associations are conserved across apocrine-like, mammary, and reproductive epithelial systems remain limited. The apparent restriction of particular microbial associations to well-studied species or glandular sites may therefore reflect genuine biological specialization, but it may also reflect where investigators have looked. Systematic comparative sampling of homologous glandular and reproductive surfaces across monotremes, marsupials, eutherian mammals, and both domesticated and wild species will be necessary to distinguish these alternatives.

Within cattle, interpretation is further complicated by modern dairy hygiene and management. Pre- and post-milking teat preparation and disinfection, together with housing and environmental conditions such as bedding, can substantially alter microbial exposure and community composition at the teat surface and may influence the microbiota detected within the mammary gland (Gleeson et al., 2009; Metzger et al., 2018). Such practices are essential for controlling mastitis but may also modify microbial populations occupying these epithelial niches. Contemporary dairy cattle therefore represent a highly managed microbial ecosystem that may differ substantially from the conditions under which bovine mammary–microbial relationships evolved. This creates a bidirectional confounder for the present hypothesis. The absence, low abundance, or inconsistent detection of a candidate filial lineage could reflect either the absence of an evolved association or disruption of its maintenance or transmission under modern husbandry, whereas detection of a microorganism could reflect maternal transmission, environmental acquisition, or management-associated exposure. Comparisons among management systems, less intensively managed cattle populations, and, where feasible, related wild bovids, combined with longitudinal mother–offspring sampling and strain-resolved microbial tracking, could help distinguish these alternatives.

Whether healthy bovine milk itself contains a stable resident microbiome remains debated (Rainard, 2017; Derakhshani et al., 2018; Derakhshani et al., 2020; Porcellato et al., 2020), and interpretation is complicated by the low microbial biomass of milk, potential contamination from adjacent epithelial and environmental sources, and the influence of dairy-management practices. Bacterial DNA representing Corynebacterium, non-aureus Staphylococcus, members of the Clostridiales, and numerous additional taxa is routinely detected in milk, but some investigators attribute these findings to transfer from teat skin, the teat canal, environmental contamination, or phagocyte-associated transport rather than persistent intramammary colonization. Importantly, the present hypothesis does not depend upon the existence of a stable resident milk microbiome, nor does detection of a microorganism in milk establish filial status. Instead, it concerns the broader possibility that mammalian epithelial and reproductive systems evolved mechanisms that increase the probability that beneficial microbial lineages pass between generations. In cattle, distinguishing such lineages from transient environmental organisms, management-associated microorganisms, and opportunistic mastitis-associated taxa therefore represents a direct empirical test of the hypothesis rather than an assumption upon which it depends.

The giant panda (Ailuropoda melanoleuca) provides a complementary model in which prolonged lactation and intensive maternal care reinforce opportunities for maternal microbial transmission. Panda cubs are born altricial and remain milk dependent for an extended period while the biochemical composition of milk undergoes substantial remodeling (Zhang et al., 2015). This transition from colostrum to mature milk is accompanied by successive changes in the neonatal gut microbiome, including shifts in microbial diversity and the relative abundance of multiple bacterial taxa (Guo et al., 2023; Shu et al., 2025). Source-tracking studies further demonstrate that maternal vaginal, milk, and fecal microbiota collectively contribute to establishment of the neonatal intestinal microbiome (Guo et al., 2023). Unlike cattle, in which maternal microbial transfer is initiated during parturition and reinforced through nursing, giant panda cubs remain in prolonged physical contact with the mother for many months. This extended maternal association provides repeated opportunities for microbial exposure among maternal skin, mammary tissues, and the developing offspring, thereby complementing microbial transmission initiated during birth and sustained through lactation (Zhang et al., 2015; Guo et al., 2023; Shu et al., 2025).

Beyond the mammary gland, giant pandas possess specialized anogenital scent glands (AGS) in the perianal region whose secretions contribute to territorial marking, reproductive communication, and individual recognition (Zhang et al., 2008; Zhou et al., 2021). Although the glandular histology of the giant panda AGS has not been characterized sufficiently to establish its secretory classification directly, its anatomical location and scent-marking function are consistent with specialized perianal and anal-sac glandular systems found among other Carnivora, in which apocrine glands, often accompanied by sebaceous components, contribute to scent secretion (Zhou et al., 2019; Nývltová-Pírková et al., 2024). Accordingly, an apocrine contribution to panda AGS secretion is phylogenetically and anatomically likely, although confirmation will require species-specific histological characterization. If the panda AGS shares the glandular organization of related carnivoran scent-gland systems, histological examination should identify apocrine secretory units, potentially in association with sebaceous components.

Irrespective of its precise histological classification, the giant panda AGS provides a particularly informative example of functional integration between a specialized mammalian scent gland and its resident microbiota. AGS secretions contain a chemically diverse mixture of volatile and semi-volatile compounds involved in olfactory communication, and the gland supports a specialized microbial community distinct from the adjacent gastrointestinal microbiota (Zhang et al., 2008; Zhou et al., 2021). Metagenomic analyses identify microbial pathways capable of metabolizing host-derived glandular substrates and contributing to the production of volatile compounds associated with chemical signaling (Zhou et al., 2021). Among the bacterial genera implicated in these processes are Corynebacterium, Pseudomonas, and Psychrobacter, whose metabolic repertoires include pathways associated with lipid metabolism and the generation or modification of volatile aldehydes, ketones, and related odorants (Zhou et al., 2021). The microbial and chemical composition of AGS secretions also varies with reproductive state, further supporting a functional relationship among glandular physiology, resident microorganisms, and semiochemical signaling (Ma et al., 2022).

These findings provide evidence that gland-associated microorganisms can participate in a normal physiological function of a specialized mammalian exocrine system rather than merely colonizing its epithelial surface. In the giant panda, host glandular secretions provide both the anatomical environment and metabolic substrates upon which resident microorganisms can act, while microbial metabolism contributes to the chemical diversity of the resulting semiochemical signal. The AGS therefore illustrates a functional sequence of glandular secretion, microbial metabolism, and host chemical communication. This relationship is particularly relevant to the proposed apocrine–mammary–microbiota axis because it demonstrates the broader principle that mammalian glandular tissues can support specialized microbial communities whose metabolic activities contribute directly to host physiology, while comparative anatomy raises the possibility that apocrine secretion participates in establishing this ecological interface.

Importantly, however, functional integration of the AGS microbiota does not establish microbial inheritance. Whether Corynebacterium, Pseudomonas, Psychrobacter, or other functionally important members of the panda AGS community are preferentially transmitted from mother to offspring, persist or recur across host generations, or depend upon host adaptations that facilitate their intergenerational transmission has not been established. The giant panda therefore provides a particularly useful model for distinguishing gland–microbe functional integration from filial microbial inheritance. Strain-resolved comparison of maternal and offspring AGS communities across development could determine whether functionally important AGS microorganisms are acquired predominantly from the mother, from unrelated conspecifics, or from environmental reservoirs and whether particular microbial lineages exhibit the transmission fidelity predicted for filial microorganisms.

Together, the bovine and giant panda models illustrate complementary aspects of the proposed apocrine–mammary–microbiota axis. Cattle provide experimental evidence that neonatal microbial acquisition involves multiple maternal epithelial sources, including the reproductive tract, teat skin, mammary gland, and surrounding maternal environment. Giant pandas add evidence that a specialized exocrine gland can maintain a functionally differentiated microbial community whose metabolism contributes to host semiochemical signaling; comparative anatomy further suggests, but does not yet demonstrate, that an apocrine component participates in this glandular system. Prolonged maternal care and lactation provide additional opportunities for microbial exchange between mother and offspring throughout early development. Collectively, these observations support the broader proposition that eutherian glandular and reproductive tissues can function as interconnected epithelial environments regulating microbial ecology and maternal–offspring microbial transmission, while leaving open the critical question of whether functionally important microbial lineages are themselves targets of evolved intergenerational transmission.

Viewed in comparison with monotremes and marsupials, eutherians exhibit extensive compartmentalization of reproductive, glandular, and microbial interfaces. Despite substantial differences in reproductive anatomy, all three mammalian lineages employ glandular secretions that influence microbial ecology while repeatedly exposing offspring to maternally derived microorganisms. Mammalian exocrine glands may therefore function not merely as secretory organs but as specialized epithelial ecosystems capable of regulating microbial communities and, in some cases, supporting microbial metabolic functions that contribute directly to host physiology.

2.4 Humans

Humans provide one of the best-studied examples of mammalian maternal microbial transmission and illustrate how maternal epithelial surfaces contribute to the establishment of the neonatal microbiome (Dominguez-Bello et al., 2010; Rodríguez et al., 2015). During early life, maternal microorganisms are transmitted through several complementary routes, including exposure to the maternal birth canal during vaginal delivery, breastfeeding, and maternal skin contact, each of which contributes to the assembly and maturation of the infant microbiome (Dominguez-Bello et al., 2010; Bäckhed et al., 2015; Rodríguez et al., 2015; Bokulich et al., 2016; Pannaraj et al., 2017; Zimmermann and Curtis, 2020). Studies of mother–infant dyads have demonstrated that maternal microbial communities are major sources of early neonatal colonization and that bacteria present in human milk contribute directly to the establishment and development of the infant gastrointestinal microbiome (Dominguez-Bello et al., 2010; Bäckhed et al., 2015; Pannaraj et al., 2017). Importantly, strain-resolved metagenomic analyses provide evidence that this resemblance reflects direct transmission of maternal bacterial lineages rather than simply convergence at the species level (Yassour et al., 2018).

Like other eutherian mammals, humans possess mammary, sebaceous, apocrine, and eccrine glands that collectively comprise the major exocrine gland systems of the skin and breast (Saga, 2002; Wilke et al., 2007). Mammary glands have long been proposed to have evolved from specialized apocrine-like integumentary glands, consistent with their shared developmental, structural, and secretory characteristics, including the apocrine secretion of lipid droplets during lactation (Oftedal, 2002a; Hassiotou and Geddes, 2013). Classical apocrine glands are concentrated within the axillae, external auditory canal (ceruminous glands), eyelids (glands of Moll), and the anogenital region (Saga, 2002; Wilke et al., 2007). Together, these glandular tissues constitute epithelial interfaces with the external environment that support diverse physiological functions, including thermoregulation, lubrication, antimicrobial defense, chemical signaling, and lactation (Wilke et al., 2007; Belkaid and Segre, 2014).

During vaginal delivery, the infant is exposed to microorganisms originating from both the maternal birth canal and the adjacent vulvar and perineal skin, resulting in the transfer of maternal microbial communities to multiple neonatal body sites (Dominguez-Bello et al., 2010). In healthy reproductive-age women, the vaginal microbiota is commonly dominated by species of Lactobacillus, although several alternative community state types have been described (Ravel et al., 2011). The vulvar epithelium represents a distinct microbial niche at the interface of the vaginal mucosa and keratinized skin. Its microbial communities commonly include Lactobacillus, Staphylococcus, Corynebacterium, Cutibacterium, Prevotella, and other members of the Actinomycetota and Bacillota, reflecting contributions from adjacent vaginal, cutaneous, and intestinal microbial reservoirs (Grice et al., 2009; Grice and Segre, 2011; Byrd et al., 2018; Pagan et al., 2021). Although direct evidence that apocrine gland secretions contribute to neonatal microbial inoculation is presently lacking, the close anatomical association between apocrine-rich perineal skin and the birth canal suggests that these glands may represent an additional source of maternally derived microorganisms during parturition. This possibility remains hypothetical and has not yet been directly investigated.

Following birth, the mammary gland provides the most sustained route of maternal microbial transmission. Human milk contains microbial communities that commonly include Streptococcus, Staphylococcus, Cutibacterium, Bifidobacterium, and members of the family Lactobacillaceae, many of which have been detected in both milk and the infant gastrointestinal tract, consistent with maternal microbial transfer during lactation (Pannaraj et al., 2017; Zimmermann and Curtis, 2020). Human milk also contains abundant human milk oligosaccharides (HMOs), which are largely indigestible by the infant because human digestive enzymes cannot hydrolyze many of their glycosidic linkages (Bode, 2012). Instead, HMOs function as highly selective substrates for beneficial intestinal microorganisms, particularly Bifidobacterium species and selected Bacteroides, thereby promoting their establishment and persistence within the developing infant gut microbiome (Marcobal and Sonnenburg, 2012). Together, these findings indicate that the mammary gland simultaneously transmits microorganisms and provides human milk oligosaccharides that selectively promote the growth of beneficial members of the infant gut microbiota (Bode, 2012; Pannaraj et al., 2017). This complementary relationship suggests that lactation functions as an integrated system for microbial inheritance and microbial selection.

These maternally acquired microorganisms contribute to epithelial barrier maturation, immune development, colonization resistance, nutrient metabolism, and the production of bioactive microbial metabolites during early life (Hooper et al., 2012; Belkaid and Hand, 2014). Within the infant gastrointestinal tract, Bifidobacterium species efficiently metabolize human milk oligosaccharides (HMOs), producing acetate and other organic acids that promote intestinal epithelial health, enhance resistance to enteric pathogens, and contribute to the development of a stable gut microbial community (Fukuda et al., 2011; Bode, 2012; Marcobal and Sonnenburg, 2012). Other beneficial members of the developing infant gut microbiota, including selected members of the family Lactobacillaceae, further contribute to colonization resistance and immune maturation through interactions with the host mucosa and the production of antimicrobial metabolites (Hooper et al., 2012; Belkaid and Hand, 2014). On the skin, commensal bacteria including Staphylococcus epidermidis and Cutibacterium acnes contribute to cutaneous homeostasis by stimulating antimicrobial peptide production, modulating local immune responses, and reinforcing epithelial barrier function (Cogen et al., 2008; Naik et al., 2012; Byrd et al., 2018). Collectively, these findings indicate that maternally transmitted microorganisms are active participants in epithelial homeostasis and postnatal epithelial and immunological development rather than passive commensals.

Disruption of maternal microbial transmission is associated with measurable alterations in neonatal microbial assembly. Compared with vaginally delivered infants, infants born by cesarean section exhibit delayed acquisition of maternal vaginal and skin-associated microorganisms together with increased representation of environmental and hospital-associated taxa during early life (Dominguez-Bello et al., 2010; Bäckhed et al., 2015; Shao et al., 2019). Likewise, formula-fed infants develop intestinal microbiomes that differ from those of breastfed infants, including reduced abundance of Bifidobacterium species and altered patterns of microbial succession (Bäckhed et al., 2015; Bokulich et al., 2016; Pannaraj et al., 2017). Although the associations between cesarean delivery, reduced breastfeeding, and increased risks of allergic disease, asthma, obesity, type 1 diabetes, inflammatory bowel disease, and other immune-mediated disorders are likely multifactorial, accumulating evidence suggests that alterations in early microbial colonization contribute to these developmental trajectories (Milani et al., 2017; Stinson et al., 2018).

Viewed in the context of the preceding evidence, humans represent one of the best-characterized examples of maternal microbial transmission among mammals. Vaginal delivery, breastfeeding, and maternal skin contact together provide complementary routes through which maternal microorganisms are transmitted to the developing infant (Dominguez-Bello et al., 2010; Pannaraj et al., 2017; Ferretti et al., 2018). Collectively, these observations indicate that multiple maternal epithelial surfaces contribute to early microbial assembly while simultaneously providing environmental conditions and nutritional substrates that promote microbial establishment within appropriate host tissues. This perspective does not diminish the well-established nutritional, immunological, antimicrobial, or physiological functions of mammalian exocrine glands; rather, it raises the possibility that these functions may also facilitate the transmission, establishment, and long-term maintenance of beneficial microbial partners.

The principal maternal transmission pathways, observed microbial outcomes, and relative strength of evidence across the representative eutherian models discussed above are summarized in Table 1. Importantly, although maternal microbial transmission is well supported across cattle, giant pandas, and humans, evidence that particular microbial lineages satisfy the proposed criteria for filial microorganisms remains incomplete.

Table 1. Comparative evidence for maternal microbial transmission among eutherians.

2.5 Comparative evolutionary synthesis

Viewed comparatively, these eutherian models illustrate an evidentiary gradient rather than a simple progression in microbial inheritance. Maternal microbial transmission is well supported in cattle, giant pandas, and humans, whereas evidence for host-facilitated transmission, functional gland–microbe associations, and specific filial microbial lineages varies among models. Cattle demonstrate transmission from multiple maternal epithelial and glandular sources but remain complicated by environmental exposure and modern husbandry. Giant pandas combine maternal microbial transmission with direct evidence that a specialized exocrine gland supports a functionally integrated gland–microbe ecosystem, although intergenerational transmission of those gland-associated microorganisms has not been demonstrated. Humans provide extensive evidence for maternal microbial transmission together with host mechanisms that selectively promote microbial establishment, including lactational factors that shape the developing infant microbiome. None of these observations alone establishes that particular microorganisms are filial; rather, they identify complementary components of the evidence required to test that proposition.

Comparison across the three extant mammalian lineages reveals broader organizational similarities despite profound differences in reproductive anatomy and life history. Monotremes employ sequential maternal interfaces involving the cloaca, brood pouch or abdominal surface, and mammary patches; marsupials elaborate prolonged maternal–offspring contact through the pouch and lactation; and eutherians combine placentation, birth, diverse exocrine glands, lactation, and extended parental care. Across these lineages, glandular tissues influence the microbial environments encountered by developing offspring while simultaneously providing nutritional, immunological, antimicrobial, and other physiological functions.

Collectively, the evidence reviewed here supports three broad observations. First, mammalian exocrine glands can actively regulate epithelial microbial communities rather than functioning solely as secretory organs. Second, maternal epithelial tissues and glandular secretions contribute to microbial transmission during reproduction and early development. Third, maternal microbial transmission occurs across multiple anatomical interfaces rather than at a single site. These observations are consistent with the hypothesis that mammalian glandular and reproductive systems may form an integrated epithelial network linking reproduction, microbial ecology, and intergenerational microbial transmission.

Whether selection modified this system specifically to increase the transmission and spatial organization of beneficial microbial partners remains the central, experimentally testable proposition of this manuscript. Establishing filial status will therefore require evidence extending beyond maternal microbial transfer itself, including preferential transmission of particular lineages, recurrence or persistence across host generations, host mechanisms facilitating their transmission or establishment, and measurable consequences for host fitness.

In eutherian mammals, placentation introduced an additional and uniquely intimate interface between maternal and developing offspring tissues, raising the question of whether maternal microbial transmission might extend beyond the better-established pathways associated with birth, maternal contact, and lactation. The potential contribution of the eutherian placenta to maternal microbial transmission remains the subject of extensive investigation and ongoing debate, particularly regarding whether the healthy placenta harbors a resident microbiome or otherwise participates in vertical microbial transfer (Aagaard et al., 2014; Lauder et al., 2016; Perez-Muñoz et al., 2017; Walter and Hornef, 2021). The present framework does not require a persistent placental microbiome but instead considers the possibility that the placenta may participate transiently in maternal microbial transfer during a restricted developmental window. This possibility is examined in the following section.

3 The placenta as a potential organ of microbial inheritance

3.1 Evolutionary rationale

Comparison of monotremes, marsupials, and eutherians reveals lineage-specific elaborations of maternal–offspring interfaces that may influence maternal microbial transmission. Across these lineages, mammary secretions appear to represent an important route through which maternal microorganisms, including potential mutualists, are transmitted to developing offspring, while the birth canal, maternal skin, and other glandular epithelia likely reinforce this process. If the central premise of the Acari Hypothesis is correct, that mammalian glandular systems evolved in part to support the inheritance of beneficial microbial partners, then eutherian mammals may have functionally integrated the placenta into an older system of maternal microbial inheritance mediated primarily by epithelial and glandular interfaces. However, rather than functioning as a reservoir of microorganisms throughout gestation, the placenta may act as a highly regulated immunological interface through which microbial inheritance could be initiated during the transition from pregnancy to birth.

This hypothesis arises from a more fundamental evolutionary question than whether the placenta contains microorganisms. Importantly, mammalian epithelial microbiomes exhibit remarkable anatomical specificity (Grice et al., 2009; Byrd et al., 2018). Rather than being distributed randomly across the body, many microorganisms consistently occupy highly specialized epithelial environments whose physicochemical properties differ substantially from adjacent tissues. How maternal transmission, repeated environmental exposure, dispersal among body sites, and host ecological filtering interact to re-establish these communities across generations remains incompletely understood.

The human vagina provides one of the clearest examples of epithelial microbial specialization. In healthy reproductive-age women, the vaginal microbiota is commonly dominated by Lactobacillus crispatus, Lactobacillus gasseri, Lactobacillus jensenii, or Lactobacillus iners, species well adapted to the glycogen-rich, acidic environment of the human vaginal epithelium (Ravel et al., 2011; Petrova et al., 2015; France et al., 2020). Likewise, Staphylococcus auricularis is consistently enriched on the ceruminous (apocrine) gland-rich skin of the external auditory canal and adjacent auricular epithelium, despite the availability of numerous other cutaneous habitats throughout the body (Kloos and Schleifer, 1983; Frank et al., 2003). Similar anatomical specificity is observed across mammalian epithelia, where distinct microbial communities reproducibly associate with sebaceous skin, eccrine skin, apocrine skin, mammary glands, and the gastrointestinal mucosa (Costello et al., 2009; Grice and Segre, 2011; Human Microbiome Project Consortium, 2012; Byrd et al., 2018). Collectively, these highly reproducible, site-specific associations indicate that many host-associated microorganisms occupy narrowly defined epithelial niches and are repeatedly assembled within corresponding anatomical environments among individuals and across host generations.

Environmental exposure unquestionably contributes to microbial acquisition after birth, and host physiology plays a critical role in determining which microorganisms successfully colonize and persist within each epithelial niche. Ecological filtering and repeated environmental exposure explain much of this anatomical patterning, but it remains possible that maternal physiology also influences the identity or timing of the founder populations available for selection. The remarkable consistency with which anatomically distinct microbial communities are re-established in successive generations suggests the possibility that mammalian physiology may play a more active role in initiating these communities than has generally been recognized. Rather than functioning solely as a passive selector of environmentally acquired microorganisms, the host may also participate in establishing the founder populations upon which subsequent ecological succession and community maturation depend.

The present hypothesis proposes that maternal physiology may establish low-abundance microbial founder populations before postnatal ecological selection expands and refines mature microbial communities. This proposal concerns the transfer of viable microbial cells and is distinct from the better-established prenatal transfer of microbial metabolites, antigens, or other molecular signals. Importantly, this model does not require sustained fetal colonization during gestation or the existence of a resident placental microbiome. Instead, it proposes that selective maternal microbial transfer is initiated during the normal physiological transition from pregnancy to neonatal life.

This distinction addresses one of the principal objections to placental microbial inheritance: the successful production of axenic animals (Perez-Muñoz et al., 2017; Panzer et al., 2023). Germ-free mammals are routinely generated by aseptic hysterectomy or cesarean derivation, procedures that eliminate exposure to the maternal birth canal, maternal skin, and mammary secretions while simultaneously interrupting the normal physiological continuity of the maternal–placental–fetal interface through surgical separation of the fetus from the placenta and immediate clamping or transection of the umbilical cord (Perez-Muñoz et al., 2017). Successful germ-free derivation strongly argues against sustained prenatal colonization by viable microorganisms. It does not, however, specifically test whether a transient transfer event might occur during physiological labor, placental separation, or delayed umbilical-cord clamping. Direct experiments comparing these conditions would therefore be required.

Under this interpretation, the placenta functions not as a microbial reservoir but as a transient developmental interface through which maternal leukocytes carrying viable commensal microorganisms may traffic toward the neonate during birth. If such cellular transfer occurs, it would presumably depend on chemokine and adhesion pathways that regulate leukocyte passage across the maternal–fetal interface. The specific chemokines involved remain unknown, but identifying the chemokines, the tissues that produce them, and the responding leukocyte populations could identify the anatomical destinations of any transferred maternal cells. If correct, the same developmental pathways that guide immune-cell migration during late pregnancy may contribute to the tissue distribution of microbial founder populations, provided that transferred microorganisms remain viable and gain access to the relevant epithelial compartments.

Within this framework, placental trafficking would establish only microbial founder populations. Passage through the birth canal, maternal skin contact, lactation, and continued exposure to glandular secretions would presumably supplement, expand, stabilize, and refine these populations throughout early postnatal development. Accordingly, the placenta and mammary gland would represent complementary rather than competing interfaces of microbial inheritance: the former initiating the process during birth and the latter providing the principal mechanism by which inherited microbial communities are amplified and maintained during early life.

3.2 Clinical implications and testable predictions

If the placenta functions as a transient organ of microbial inheritance during the periparturient period, rather than throughout gestation, disruption of this tightly regulated process would be expected to produce recognizable pathological consequences. Although selective maternal microbial trafficking has not yet been directly demonstrated, several clinical observations are consistent with this possibility and generate experimentally testable predictions.

One observation consistent with this framework is the well-recognized susceptibility of retained products of conception to bacterial infection following delivery (Sellmyer et al., 2013; Bortoletto et al., 2022; Pek et al., 2022). Under physiological conditions, placental separation and expulsion mark completion of the placenta’s functional role. Failure to remove retained placental tissue substantially increases the risk of postpartum endometritis and maternal sepsis, findings conventionally attributed to persistence of devitalized tissue that provides a substrate for opportunistic bacterial proliferation (Sellmyer et al., 2013; Bortoletto et al., 2022; Pek et al., 2022). This explanation remains well supported. However, if the placenta also serves as a transient site of selective microbial trafficking during the periparturient period, retained placental tissue may also preserve maternal and fetal leukocytes carrying microbial cargo that would ordinarily be eliminated following placental separation. With cessation of placental perfusion, the mechanisms governing leukocyte trafficking, immune regulation, and microbial containment likewise cease. Under these conditions, microorganisms that were previously maintained under strict immunological control may expand within ischemic tissue or amplify local inflammatory responses in concert with ascending maternal flora. This model does not require the existence of a resident placental microbiome. Instead, it predicts that interruption of a tightly regulated, transient program of microbial trafficking contributes to the polymicrobial inflammatory environment characteristic of postpartum endometritis associated with retained products of conception.

A second observation consistent with this framework is the characteristic hypertension of preeclampsia and eclampsia. Despite decades of investigation, the initiating events underlying these syndromes remain incompletely understood (Redman and Sargent, 2005; Sibai et al., 2005; Staff, 2019). Preeclampsia is characterized by new-onset maternal hypertension accompanied by abnormal placentation, widespread endothelial dysfunction, exaggerated systemic inflammation, and dysregulated immune signaling at the maternal–fetal interface (Redman and Sargent, 2005; Sibai et al., 2005; Staff, 2019). Progression to eclampsia is marked by seizures reflecting severe multisystem vascular and neurological involvement. Although the initiating trigger remains uncertain, one of the most striking clinical features of both disorders is the frequent and often rapid resolution of maternal hypertension following placental delivery, strongly implicating the placenta as the central driver of disease (Redman and Sargent, 2005; Sibai et al., 2005; Staff, 2019). Within the framework proposed here, these syndromes may reflect dysregulation of the physiological immune-cell trafficking program that ordinarily coordinates selective maternal microbial inheritance during the periparturient period.

Late pregnancy and parturition are accompanied by extensive recruitment and trafficking of maternal and fetal leukocytes throughout the maternal–fetal interface, reflecting the dynamic immunological communication that coordinates placental separation, tissue remodeling, and birth (Collins et al., 2009; Mor and Cardenas, 2010; Nagamatsu and Schust, 2010; Moffett and Colucci, 2014; Mor et al., 2017). Within the framework proposed here, these migratory immune-cell populations constitute the cellular machinery through which highly selective maternal microbial founder populations would ordinarily be transmitted to the fetus during the periparturient period. However, it is conceivable that this developmental program may occasionally become dysregulated. Rather than transporting filial microbial founder populations, maternal leukocytes could inadvertently acquire non-filial microorganisms from dysbiotic epithelial surfaces and deliver them into this conserved trafficking pathway. Recognition of aberrant microbial cargo by cells at the maternal-fetal interface might then initiate an immune response, amplifying inflammatory signaling and contributing to the placental dysfunction that characterizes preeclampsia and eclampsia.

The precise mechanism of transfer remains unknown. One possibility is that maternal leukocytes carrying viable commensal microorganisms directly traverse the maternal–fetal interface and subsequently traffic to developing neonatal tissues, consistent with the well-established phenomenon of maternal microchimerism (Nelson, 2012). Alternatively, maternal leukocytes may transfer microbial cargo to fetal leukocytes at the maternal–fetal interface, which subsequently disseminate these founder populations throughout the developing fetus. Cytokine and chemokine signaling generated during these cellular interactions would simultaneously activate neighboring trophoblasts and placental endothelial cells, amplifying local inflammatory responses while guiding microbial founder populations toward developing epithelial tissues.

A defining feature of preeclampsia is the development of maternal hypertension, indicating that pathology at the maternal–fetal interface ultimately engages molecular pathways regulating systemic vascular tone (Redman and Sargent, 2005; Sibai et al., 2005; Staff, 2019). As discussed in a previous installment of the Acari Hypothesis, angiotensin-converting enzyme (ACE) occupies a unique position at the intersection of innate immunity and the modulation of vascular tone (Bernstein et al., 2012; Retzinger and Retzinger, 2025). Components of the renin–angiotensin system are widely expressed at the maternal–fetal interface. ACE1 is expressed in human decidual tissue and has been localized prominently to fetal placental vascular endothelium, while ACE2 and other RAS components exhibit broader distributions that include syncytiotrophoblasts, cytotrophoblasts, invasive trophoblasts, and decidual cells (Marques et al., 2011; Pringle et al., 2011). In addition to catalyzing the conversion of angiotensin I to the potent vasoconstrictor angiotensin II, ACE is upregulated on the surface of phagocytic leukocytes during bacterial infection, where its expression enhances antimicrobial activity and the oxidative response (Bernstein et al., 2012; Khan et al., 2017). As neutrophils and macrophages engulf microorganisms, they generate a respiratory burst characterized by the production of reactive oxygen species that are essential for intracellular microbial killing but also impose substantial oxidative stress on the phagocytes themselves (Nathan, 2006; Khan et al., 2017). Increased ACE expression appears to represent an adaptive response that enhances antimicrobial activity and may help sustain phagocyte function under these conditions of heightened oxidative stress. Maternal decidual macrophages and dendritic cells, together with fetal monocytes and macrophages, are among the principal professional phagocytes responsible for immune surveillance at the maternal–fetal interface (Collins et al., 2009; Mor and Cardenas, 2010; Nagamatsu and Schust, 2010; Moffett and Colucci, 2014; Mor et al., 2017). Although trophoblasts are not professional phagocytes, syncytiotrophoblasts and extravillous trophoblasts exhibit limited phagocytic and endocytic activity, express numerous pattern-recognition receptors, and actively participate in innate immune defense through cytokine and chemokine production (Abrahams, 2008; Koga et al., 2014).

Within the present model, the aberrant trafficking of non-filial microbial lineages could increase the effective microbial burden encountered by placental phagocytes, thereby activating the same physiological program of ACE upregulation that ordinarily accompanies antimicrobial defense. Activation of maternal and fetal phagocytes could, in turn, generate localized cytokine and chemokine signaling that propagates ACE induction to neighboring trophoblasts and placental endothelial cells, resulting in increased local production of angiotensin II. Although this coordinated response would initially function to augment innate immune defense, sustained or excessive activation could simultaneously promote vasoconstriction and ultimately produce the maternal hypertension characteristic of preeclampsia.

This interpretation also offers a potential explanation for one of the defining clinical characteristics of preeclampsia/eclampsia: the frequently rapid improvement in maternal hypertension following placental delivery (Redman and Sargent, 2005; Sibai et al., 2005; Staff, 2019). Within the present framework, delivery removes not only the placenta itself but also the principal site of aberrant immune activation, together with the trophoblast and endothelial cell populations sustaining ACE-mediated inflammatory and vasoactive signaling. The resulting resolution of maternal hypertension therefore reflects more than the termination of pregnancy; it represents removal of the organ in which a transient, tightly regulated program of maternal microbial inheritance has become pathologically dysregulated. If correct, this model predicts that the remarkable therapeutic efficacy of placental delivery in preeclampsia arises because it eliminates the anatomical and immunological focus of this aberrant host-defense response.

Importantly, this model predicts that highly selective transfer of low-abundance microbial founder populations occurs only during a narrow physiological window surrounding parturition. Consequently, failure to detect persistent microorganisms within healthy placental tissues would not be expected to exclude the proposed mechanism, because the hypothesis predicts a transient developmental process rather than the existence of a stable placental microbiome.

The proposed model generates several experimentally testable predictions. First, maternal decidual leukocytes isolated during the periparturient period should contain viable microorganisms that preferentially resemble highly adapted maternal epithelial symbionts. Second, pregnancies complicated by preeclampsia should demonstrate altered leukocyte trafficking together with reduced representation of filial microorganisms, increased representation of non-filial microorganisms, or both. Third, placentas from pregnancies complicated by preeclampsia should demonstrate increased ACE expression. Fourth, maternal and fetal leukocyte populations should localize along established developmental chemokine pathways linking reproductive tissues, the placenta, mammary glands, and developing neonatal epithelia. Identifying the chemokines responsible for this trafficking, together with the tissues that produce them and the leukocyte populations that respond to them, should reveal the intended anatomical destinations of maternally transmitted microbial founder populations. Finally, experimental interruption of the normal placental–umbilical transition through aseptic hysterectomy or germ-free derivation should abolish this trafficking pathway, whereas preservation of the physiological transition should favor successful maternal microbial inheritance.

Taken together, these predictions shift the focus of placental biology away from the controversial question of whether the healthy placenta contains a resident microbiome. Instead, they ask whether the placenta transiently coordinates highly selective communication between maternal and fetal immune systems to establish microbial founder populations during birth. Confirmation of this mechanism would establish the placenta as the earliest component of an integrated mammalian microbial inheritance system, with passage through the birth canal, lactation, maternal glandular secretions, and continued maternal contact subsequently expanding, selecting, and stabilizing these founder populations throughout early postnatal development.

4 Closing

This manuscript proposes that mammals evolved as specialized metaorganisms whose glandular systems function not only to nourish and protect offspring but also to increase the probability of transmitting selected beneficial microbial symbionts. Within this framework, mammalian evolution progressively refined mechanisms for the acquisition, selection, transmission, and spatial organization of microbial communities across generations. If this interpretation is correct, then many modern diseases may arise not solely from exposure to pathogens but from disruption of an ancient developmental program that evolved to ensure the reliable inheritance and establishment of beneficial microbial partners. Viewed in this context, host defense and microbial inheritance are not competing biological processes but complementary components of a single evolutionary strategy for maintaining mammalian health across generations.

Numerous modern medical and hygienic practices have the potential to alter the transmission of maternal microbial communities to offspring. Cesarean delivery, broad-spectrum antibiotic exposure, reduced maternal–infant contact, and formula feeding are known to modify early microbial assembly, while hygiene and early umbilical cord clamping may also influence transmission pathways proposed here (Dominguez-Bello et al., 2010; Bäckhed et al., 2015; Rodríguez et al., 2015; Bokulich et al., 2016; Milani et al., 2017; Pannaraj et al., 2017; Ferretti et al., 2018; Stinson et al., 2018; Zimmermann and Curtis, 2020). Many of these interventions have unquestionably conferred enormous medical benefits and have dramatically reduced maternal and infant morbidity and mortality from infectious diseases. However, within the proposed framework, they may also reduce the fidelity with which evolutionarily conserved microbial symbionts are transmitted across generations. If so, disruption of this developmental program could leave ecological niches within epithelial ecosystems only partially occupied, increasing susceptibility to colonization by opportunistic microorganisms and altering the long-term stability of host–microbial communities.

The concept of ecological vacancy provides a useful framework for understanding how disruption of microbial inheritance may contribute to disease (Hooper et al., 2012; Belkaid and Hand, 2014; Belkaid and Segre, 2014). Pathology may arise through two complementary mechanisms. First, loss of evolutionarily conserved filial microbial lineages may reduce microbial functions that contribute to immune regulation, colonization resistance, metabolic homeostasis, and tissue physiology. Second, the resulting ecological vacancies may permit colonization by non-filial microorganisms possessing different ecological properties, thereby altering host–microbial interactions and promoting inflammatory or metabolic dysfunction. Within this framework, disease reflects not merely the presence of pathogenic organisms but the failure to establish and maintain the evolutionarily conserved microbial functions and communities that contribute to normal mammalian physiology.

Several clinically relevant examples are consistent with this ecological framework. On mammalian skin and within the nasopharynx, Staphylococcus epidermidis frequently serves as a dominant commensal microorganism that produces antimicrobial compounds, competes for epithelial niches, and modulates host innate immunity (Otto, 2009; Naik et al., 2012; Nakatsuji et al., 2017). Experimental and clinical studies have demonstrated that particular strains of S. epidermidis can suppress colonization, biofilm formation, or virulence of S. aureus, an opportunistic pathogen responsible for a broad spectrum of skin and soft tissue infections (Nakatsuji et al., 2017). Loss or failure of establishment of protective S. epidermidis strains or functions may therefore diminish colonization resistance, creating ecological opportunities for S. aureus expansion and subsequent disease. Similarly, human milk sequencing studies have detected DNA assigned to members of the class Clostridia, including genera such as Blautia, Anaerostipes, Roseburia, Faecalibacterium, and Lachnoclostridium, and limited culture- and strain-resolved evidence suggests that viable maternal obligate anaerobes may sometimes reach infants through breastfeeding (Pannaraj et al., 2017; Zimmermann and Curtis, 2020; Edwards et al., 2022). If viable and successfully transmitted, these obligate anaerobes or their descendants could contribute to the later development of intestinal communities associated with metabolic and immunological homeostasis. Inadequate establishment of protective anaerobic communities could reduce colonization resistance against opportunistic enteric organisms, potentially including Clostridioides difficile (formerly Clostridium difficile), whose expansion commonly follows disruption of the intestinal microbiota after antibiotic exposure (Hooper et al., 2012; Buffie and Pamer, 2013; Belkaid and Hand, 2014). Likewise, breast milk frequently contains commensal streptococci, including Streptococcus salivarius, Streptococcus mitis, and Streptococcus parasanguinis, which are among the earliest colonizers of the infant oral cavity and tonsils (Wescombe et al., 2009; Di Pierro et al., 2013; Pannaraj et al., 2017; Zimmermann and Curtis, 2020). These pioneer organisms occupy epithelial niches, interact extensively with host immunity, and contribute to colonization resistance by limiting opportunities for subsequent pathogen establishment. Failure to establish these maternally derived streptococcal populations may reduce colonization resistance and potentially increase susceptibility to opportunistic pathogens, including Streptococcus pyogenes (Wescombe et al., 2009). In each example, disease could reflect not only exposure to a pathogen but also disruption of a microbial ecosystem in which protective commensals ordinarily constrain opportunistic competitors.

A particularly important implication of this framework is that microbial inheritance may exhibit cumulative effects across generations. Genetic inheritance operates through the transmission of relatively stable genetic information, but microbial inheritance depends upon the successful transfer of living microbial communities from parent to offspring. If beneficial microbial lineages are progressively lost from maternal reservoirs through repeated disruption of transmission pathways, each successive generation may inherit a less complete microbial ecosystem than the generation preceding it. Under this model, the consequences of antibiotics, cesarean delivery, formula feeding, and other factors need not be confined to a single individual. Instead, they may accumulate across generations through the progressive erosion of vertically transmitted microbial communities. The resulting loss of keystone filial species would be expected to increase the prevalence of ecological vacancies, reducing the resilience of host-associated ecosystems and creating opportunities for colonization by non-filial organisms. Such a process could contribute to the increasing prevalence of chronic inflammatory, metabolic, allergic, and infectious disorders observed in industrialized societies. This hypothesis therefore predicts that restoration of healthy microbial inheritance pathways may prove necessary not only to improve individual health but also to reverse the gradual intergenerational degradation of human microbial ecosystems.

This extension of the Acari Hypothesis generates numerous experimentally testable predictions across mammalian lineages. First, a subset of consistently vertically transmitted microbial lineages should show phylogenetic or functional evidence of long-term association and, in some cases, co-diversification with mammalian hosts. This prediction is consistent with the broader phenomenon of phylosymbiosis, in which similarities among host-associated microbial communities reflect host phylogenetic relationships. Comparative studies have demonstrated phylosymbiotic patterns across mammals and other vertebrates, indicating that host evolutionary history can contribute to microbiome structure (Youngblut et al., 2019; Mallott and Amato, 2020). However, phylosymbiosis alone does not establish vertical transmission or host–microbe co-diversification; the present hypothesis more specifically predicts that some of these phylogenetic associations will be attributable to persistent filial transmission across generations. Second, maternal glandular secretions should contain characteristic microbial communities that predict subsequent colonization of offspring epithelial surfaces. This prediction can be tested comparatively in the non-human mammalian systems discussed above. In the tammar wallaby, longitudinal strain-resolved sampling of maternal pouch, mammary, and offspring epithelial microbiota could determine whether these maternal reservoirs contribute reproducibly to distinct microbial communities in pouch young. In cattle, paired sampling of the maternal reproductive tract, perineal and teat skin, colostrum or milk, and calf microbiota from birth through weaning could distinguish persistent maternal transmission from environmental acquisition and determine whether candidate filial lineages traverse multiple maternal epithelial reservoirs. In the giant panda, longitudinal comparison of maternal and cub milk-, skin-, gastrointestinal-, and anogenital-gland-associated microorganisms could test whether prolonged maternal contact promotes persistent transmission of particular microbial lineages and whether functionally important gland-associated microorganisms are preferentially inherited. Third, epithelial diseases associated with dysbiosis should correlate with the absence of specific filial microbial lineages and the occupation of those ecological niches by non-filial organisms. Fourth, restoration of missing filial species should prove more effective than nonspecific microbial replacement strategies in preventing or treating such disorders. Finally, populations experiencing prolonged disruption of microbial inheritance pathways should exhibit evidence of progressive intergenerational loss of specific microbial lineages and corresponding increases in diseases associated with ecological vacancy.

Whether every aspect of the present hypothesis is ultimately supported by experimental evidence remains to be determined. Nevertheless, the distinct reproductive strategies represented by monotremes, marsupials, and eutherian mammals provide comparative systems in which the proposed mechanisms of microbial inheritance can be directly tested. The pouch and mammary environments of marsupials such as the tammar wallaby, the sequential reproductive and mammary transmission pathways observed in cattle, and the prolonged maternal association and specialized gland–microbe systems of the giant panda illustrate distinct anatomical and developmental routes through which the same underlying principle could operate: the acquisition, maintenance, and intergenerational transmission of beneficial microbial symbionts. Viewed in this comparative context, the emergence of mechanisms that promote microbial continuity across generations, together with the extraordinary diversification of mammalian glandular systems, raises the possibility that the inheritance of beneficial microbial symbionts represents a fundamental, yet underappreciated, principle of mammalian biology. If mammals are indeed specialized metaorganisms, then a complete understanding of health and disease will require consideration not only of the inherited genome but also of the inherited microbiome and of the evolutionary mechanisms that preserve its continuity across generations. Moreover, if microbial inheritance is cumulative over evolutionary time, safeguarding these systems may preserve more than individual health: it may help maintain long-standing biological partnerships that have shaped mammalian evolution and protect their continuity in future generations.

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Footnotes

Edited by: Ruiqi Li, University of Colorado Boulder, United States

Reviewed by: Marie Bunker, University of Puget Sound, United States

Chaoyuan Cheng, Hainan University, China