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. Author manuscript; available in PMC: 2022 Jan 14.
Published in final edited form as: Birth Defects Res. 2018 Dec 1;110(20):1494–1503. doi: 10.1002/bdr2.1436

Inherited Nongenetic Influences on the Gut Microbiome and Immune System

Kathryn A Knoop 1, Lori R Holtz 2, Rodney D Newberry 1
PMCID: PMC8759455  NIHMSID: NIHMS1768705  PMID: 30576093

Abstract

The gut microbiome and the immune system co-develop around the time of birth, well after genetic information has been passed from the parents to the offspring. Each of these “organ systems” displays plasticity. The immune system can mount highly specific adaptive responses to newly encountered antigens, and the gut microbiota is affected by changes in the environment. Despite this plasticity, there is a growing appreciation that these organ systems, once established, are remarkably stable. In health, the immune system rapidly mounts responses to infections, and once cleared, resolves inflammatory responses to return to homeostasis. However, a skewed immune system, such as seen in allergy, does not easily return to homeostasis. Allergic responses are often seen to multiple antigens. Likewise, a dysbiotic gut microbiota is seen in multiple diseases. Attempts to reset the gut microbiota as a therapy for disease have met with varied success. Therefore, how these co-developing “organ systems” become established is a central question relevant to our overall health. Recent observations suggest that maternal factors encountered both in utero and after birth can directly or indirectly impact the development of the offspring’s gut microbiome and immune system. Here we discuss how these nongenetic maternal influences can have long term effects on the progeny’s health.

Introduction:

Our intestinal tract is home to trillions of organisms comprising a diverse community termed the gut microbiota (Human Microbiome Project, 2012). The microbes comprising the gut microbiota are not merely passengers, but actively contribute to our health in a symbiotic relationship that has existed on an evolutionary timescale (Moeller et al., 2016). An imbalance in this community, or dysbiosis, increases our risk of multiple diseases including obesity, malnutrition, allergy, inflammatory bowel disease, and diabetes (Cho et al., 2012; Gilbert et al., 2016; Gill et al., 2006; Halfvarson et al., 2017; Jostins et al., 2012; Subramanian et al., 2014; Tsabouri, Priftis, Chaliasos, & Siamopoulou, 2014). The gut microbiota begins assembly at or around the time of birth. Once established, this complex microbial community remains remarkably stable over time (Faith et al., 2013), emphasizing that the proper assemblage of this community is a critical component of our long-term health. The gut microbiota affects and is affected by the intestinal immune system. These organ systems co-develop in early life to establish a stable relationship, which is necessary to prevent inflammation and dysbiosis. There is growing evidence of maternal influences on the assemblage of the gut microbiota and the development of the intestinal immune system. We thus inherit these organ systems in a manner that is at least partially independent of genetics. Alterations in this inheritance by extension can have long-standing impacts on health.

How and when the gut microbiota is acquired

Trillions of microbes reside in our intestine. Their impact on health includes positive and negative effects on metabolic, immune, and endocrine functions. In the healthy state, symbiotic mutualism characterizes our relationship with our gut microbiota. An imbalance in this community, or dysbiosis, increases our risk of multiple diseases including obesity, malnutrition, allergy, inflammatory bowel disease, and diabetes (Gilbert et al., 2016). Once established, this complex microbial community remains remarkably stable over time (Faith et al., 2013), emphasizing that the proper assemblage of this community is a critical component of our long-term health. Thus, how our gut microbiota develops is a fundamental question.

The current understanding is that at the time of birth our gastrointestinal tract is sterile, or contains few microbes, and quickly becomes colonized by microbes encountered in the environment. The functional maturation of the human gut microbiota is relatively conserved between individuals in markedly different environments and concludes around three years of life (Yatsunenko et al., 2012), suggesting that development of this community is not solely dependent upon serendipitous encounters with microbes. While individuals have unique gut microbial communities, their gut microbiota most resembles those of other members of their family (Schloss, Iverson, Petrosino, & Schloss, 2014). This raises the possibility of a parental contribution to the development of the gut microbiota and by extension a non-genetic inherited contribution to our long term health. Indeed, transplant of fetuses into genetically disparate mice revealed the offspring’s microbiota was most similar to the birth mother (Friswell et al., 2010), indicating a strong role for nongenetic factors in the development of the mammalian gut microbiota.

How and when the microbes comprising the gut microbiota are acquired and how this community becomes assembled are not well understood. At the time of delivery, babies become exposed to a plethora of microbes. The microbes encountered are at least partially dependent upon delivery mode, with vaginally delivered babies having microbial communities similar to their mother’s vaginal microbiota and caesarian section delivered babies having microbial communities similar to those of their mother’s skin (Backhed et al., 2015; Dominguez-Bello et al., 2010). While this suggests that delivery mode influences the offspring’s gut microbiota, this has not been universally observed across studies (Bokulich et al., 2016; Chu et al., 2017; Korpela et al., 2018), raising the possibility that other sources of microbes are also important for the developing microbiota. In addition to birth, the developing gut microbiota undergoes substantial changes at the time of the introduction of solid foods (Bokulich et al., 2016; Koenig et al., 2011; Palmer, Bik, DiGiulio, Relman, & Brown, 2007), and accordingly it is not surprising that early life feeding practices have been observed to effect the developing gut microbiota (Azad et al., 2016; Bokulich et al., 2016; Gregory et al., 2016). Human milk oligosaccharides (HMOs) are abundant in breastmilk where they can serve as a prebiotic supporting the growth of specific beneficial bacterial species (Underwood et al., 2017; Underwood et al., 2014) and in part underlies differences seen in the gut microbiota of breastfed and formula fed children (Bokulich et al., 2016; Gregory et al., 2016).

Breastmilk may contribute to the offspring’s developing gut microbiota beyond providing a nutrient source for microbes. Breastmilk has been found to have its own microbiome (Fernandez et al., 2013; Latuga, Stuebe, & Seed, 2014; Martin, Heilig, Zoetendal, Smidt, & Rodriguez, 2007), raising the possibility that breastmilk could directly seed microbes in the offspring’s gastrointestinal tract. Interestingly, the breastmilk microbiome is comprised of bacteria commonly seen on the skin and within the gastrointestinal tract (Cabrera-Rubio et al., 2012; Gueimonde, Laitinen, Salminen, & Isolauri, 2007; Heikkila & Saris, 2003; Hunt et al., 2011; Thompson, Pickler, Munro, & Shotwell, 1997; Tyson, Edwards, Rosenfeld, & Beer, 1982). Traditionally the bacteria seen in breastmilk were have been thought to be contaminants, but they persist even after collecting breastmilk using aseptic techniques (Thompson et al., 1997). Skin microbes might inoculate the breast during nursing, but how the gut-associated microbes could enter breastmilk is less clear. Enteromammary trafficking of gut bacteria during lactation has been observed in mice, and the peripheral blood and breastmilk from healthy mothers were observed to contain bacteria and bacterial DNA suggesting a gut origin (Perez et al., 2007). Moreover, some of these bacterial DNA signatures were found in the offspring’s feces (Perez et al., 2007), which suggests the seeding of live microbes from the gut microbiota of mothers to their offspring via breastmilk. How enteromammary trafficking of live bacteria occurs, how this process is restricted to a period during lactation, and whether this is a significant and important contributor to the offspring’s developing gut microbiota remain interesting questions whose answers may underlie inherited nongenetic contributions of the gut microbiota to our long-term health.

Whether the healthy human fetus is sterile, and if not, the origins of the microbes in the fetus, are issues of increasing debate(Funkhouser & Bordenstein, 2013; Perez-Munoz, Arrieta, Ramer-Tait, & Walter, 2017; Willyard, 2018). Decades of research using traditional culture based methods have suggested that the fetus develops in a sterile environment. However, modern molecular and sequencing-based techniques challenge this dogma. Not surprisingly, only a few studies have evaluated the presence of live bacteria in the healthy human fetus. Live bacteria have been cultured from the amniotic fluid and cord blood of term pregnancies undergoing cesarean section (Bearfield, Davenport, Sivapathasundaram, & Allaker, 2002; Jimenez et al., 2005). Moreover, studies using culture-independent methods have identified the presence of an array of bacteria associated with the fetus in the absence of preterm labor. These microbes may originate from the mother’s vagina, oral cavity, or gut (Bearfield et al., 2002; S. Rautava, Collado, Salminen, & Isolauri, 2012; Steel et al., 2005). In addition, meconium, the intestinal contents of fetuses and newborns, contains its own microbiota (Gosalbes et al., 2013; Jimenez et al., 2008). However, other studies have found that the bacterial microbiota of term placentas and amniotic fluid resemble that of negative controls (Lauder et al., 2016; Lim, Rodriguez, & Holtz, 2018; Rehbinder et al., 2018). Thus, while there is evidence that the human fetus is not necessarily sterile and is exposed to maternally derived microbes prior to birth, the concept that the healthy human fetus is exposed to microbes prior to rupture of the fetal membranes remains controversial.

Whether this transfer of microbes to the fetus represents normal physiology remains to be proven. If the fetus is exposed in utero, potential sources could be the vaginal, gut, and oral microbiomes. Bacteria are assumed to ascend the vaginal canal to colonize the fetus and fetal membranes. Indeed, bacterial vaginosis has been associated with the presence of bacteria in utero and preterm delivery (Gravett, Hummel, Eschenbach, & Holmes, 1986; Hillier et al., 1995). Bacteria originating from the oral cavity and gut may disseminate and colonize the fetus as bacteremia occurs following oral procedures, teeth brushing, minor manipulations of the lower gastrointestinal tract, and potentially even bowel movements (Hoffman, Kobasa, & Kaye, 1978; Lockhart et al., 2008; Maharaj, Coovadia, & Vayej, 2012; Slavin & Goldwyn, 1979; Tandberg & Reed, 1978). While these sporadic events might be sufficient to expose the fetus to microbes, this alone is insufficient to explain why pregnancy is associated with increased incidence of bacteremia (Perez et al., 2007). Bacteremia during pregnancy might be a physiologic event, potentially related to immune suppression during pregnancy.

From an evolutionary perspective, a regulated mechanism for the maternal-fetal transmission of microbes would ensure the transfer of components crucial to multiple aspects of health. Indeed, the maternal-fetal transfer of microbes is seen across the animal kingdom (Funkhouser & Bordenstein, 2013). A prime example is the obligate endosymbiotic relationship between the pea aphid and the bacteria Buchnera aphidicola. The pea aphid acquired the bacterium hundreds of millions of years ago. Their genomes have co-evolved such that the pea aphid depends upon Buchnera for digestion and Buchnera cannot survive outside of the pea aphid. Buchnera is transferred to the ovaries or developing embryo in the pea aphid to ensure survival of both species (Baumann, 2005; Koga, Meng, Tsuchida, & Fukatsu, 2012). That a similar relationship exists between humans and their gut microbiota and that essential components of the gut microbiota might have a mechanism of enforced vertical transmission in utero are intriguing concepts. However, this is at odds with the ability to generate germ-free humans (Barnes, Fairweather, Reynolds, Tuffrey, & Holliday, 1968) and might suggest that if there is enforced vertical transmission of gut microbes in utero in humans these microbes are transient inhabitants.

A time-dependent nature to the benefit of the gut microbiota on health

While the transfer of microbes in utero remains debatable, the transfer of microbes from mothers to children during breastfeeding and touching to colonize and develop the gut microbiota is well supported. Moreover, evidence is mounting that there is a critical period in the proper assemblage of the gut microbiota for some aspects of health. Perturbations of the microbiota during this developmental window can have long-term consequences. Multiple studies have found that increased hygienic practices increase the risk for immune-mediated diseases such as asthma, allergy, and inflammatory bowel disease (Lopez-Serrano et al., 2010; Strachan, 1989; von Mutius, 2007). These practices are associated with changes in the gut microbiota in individuals from developed countries (Yatsunenko et al., 2012) providing a link between dysbiosis and immune-mediated diseases. Attempts to restore the normal gut microbiota, however, have had varied therapeutic success (Malikowski, Khanna, & Pardi, 2017; Moayyedi et al., 2015; Rossen et al., 2015). The inability of fecal microbial transfer as a therapy could be due to inappropriate donor microbiota, inefficient colonization, or the presence of a critical window of benefit from the normal gut microbiota, which cannot be reset once it has passed. Several observations suggest that this window is in early life. Disruption of the gut microbiota by antibiotic use in children in the first year of life is associated with an increased risk of allergic disorders and inflammatory bowel disease (Han, Forno, Badellino, & Celedon, 2017; Love et al., 2016; Mitre et al., 2018; Pitter et al., 2016; Shaw, Blanchard, & Bernstein, 2010; Yamamoto-Hanada, Yang, Narita, Saito, & Ohya, 2017; Yoshida, Ide, Takeuchi, & Kawakami, 2018). This effect is also seen in animal models of allergy. In mice, antibiotic exposure before, but not after weaning increases allergic outcomes (Russell et al., 2012; Russell et al., 2013). Moreover, colonization of germ-free mice with a normal gut microbiota before but not after weaning offers protection from colitis and allergy (Olszak et al., 2012). This is a strong implication that the effects of antibiotic use on the risk for allergic disorders and inflammatory bowel disease is largely mediated by a time limited changes in the gut microbiota pre-weaning.

A reduction in T regulatory (Treg) cells, which suppresses inflammatory responses, is seen in allergic disorders (Stelmaszczyk-Emmel, Zawadzka-Krajewska, Szypowska, Kulus, & Demkow, 2013) and inflammatory bowel disease (Eastaff-Leung, Mabarrack, Barbour, Cummins, & Barry, 2010) suggesting that the basis for benefit of exposure to the gut microbiota on decreasing the risk of allergic disorders and inflammatory bowel disease may lie in the development of Tregs. Studies in mice identified a population of Tregs that develop in early life in response to gut bacteria. This Treg population is particularly adept at suppressing allergic responses and colitis (Ohnmacht et al., 2015; Sefik et al., 2015). Further supporting this concept, the induction of a Treg cell population during a distinct pre-weaning interval produces antigen-specific tolerance to gut commensal bacteria in mice (Knoop, Gustafsson, et al., 2017). The timing of this interval is proposed to be under maternal control via temporal changes in breastmilk (Al Nabhani & Eberl, 2017; Knoop, Gustafsson, et al., 2017). Thus, maternal breast milk may provide both the microbes and the cues to develop this unique population of Tregs resulting a reduction in the risk of allergic diseases and colitis. Combined with observations that a significant proportion of the microbes constituting our gut microbiota in the first year of life are of maternal origin, this suggests that the gut microbiota and its effects on the developing immune system are an inherited trait affecting our long term health.

Nongenetic inherited influences directly on the immune system

The gut microbiota and intestinal immune system co-develop in early life with each affecting the other. Environmental influences on the gut microbiota in early life will thus affect the immune system. As noted above, some of these effects may be long lived and not easily reset. Beyond this, there is evidence supporting nongenetic influences directly affecting the development of the immune system resulting in life long alterations. Salient examples of this are maternal influences on the development of secondary lymphoid organs (SLOs) and the effects of maternal microchimerism (MMc) on the offspring’s immune system.

Secondary lymphoid organs, which include lymph nodes and Peyer’s Patches, are tissues integral for the initiation of adaptive immune responses whose development is imprinted in utero (Newberry & Lorenz, 2005; Randall, Carragher, & Rangel-Moreno, 2008). New SLOs cannot be formed after the window for SLO development has passed. Thus, the number of SLOs becomes fixed after birth and alterations in SLO development occurring in utero will have lifelong effects. A subset of type 3 innate lymphoid cells (ILC3) or lymphoid tissue inducer (LTi) cells initiates the development of SLOs (Newberry & Lorenz, 2005; Randall et al., 2008). Retinoids from the maternal diet control the development of LTi cells in the fetus, and by extension control the development of secondary lymphoid tissues in the offspring (van de Pavert et al., 2014). Accordingly, disrupting the signals delivered by retinoids in the maternal diet during gestation results in life long alterations in secondary lymphoid organs and immune deficits (van de Pavert et al., 2014). In addition to this role, retinoids are important for other functions of the immune system, including gut-homing specificity of plasma cells and T cells, the development of T regulatory cells (Tregs), and the prevention of allergic responses (Coombes et al., 2007; Kang, Lim, Andrisani, Broxmeyer, & Kim, 2007; Mora et al., 2006; Sun et al., 2007; Yokota-Nakatsuma et al., 2014). Whether these functions extend to the retinoids derived from the maternal diet and the developing fetus and whether alterations in retinoid signals in utero have durable impacts on these aspects of the offspring’s immune system remain to be explored.

Maternal microchimerism (MMc) is an incompletely understood phenomenon that refers to the presence of cells of maternal origin within the offspring (Adams & Nelson, 2004). The acquisition of maternal cells occurs in utero and during nursing. The transferred cells persist into adulthood (Dutta et al., 2009; Vernochet, Caucheteux, & Kanellopoulos-Langevin, 2007). MMc occurring in utero vs. during nursing seem to have slightly different effects, with the exposure to maternal antigens during nursing being more efficient at inducing tolerance to maternal antigens and facilitating the long term persistence of MMc (Dutta et al., 2009). The cells transferred during MMc are largely of hematopoietic origin and include mature lymphocytes, antigen presenting cells, and stem cells (Dutta & Burlingham, 2010; Nijagal et al., 2011; Stelzer, Thiele, & Solano, 2015). MMc has been observed in a wide variety of organs in the offspring including the gut (Stelzer et al., 2015). The maternal cells are functional in the offspring and have been observed to have various effects on the offspring’s immune system including contributing to protective responses such as antibody production, induction of tolerance to maternal antigens and potentially tolerance to other non-self environmental antigens acquired by antigen presenting cells within the mother, or conversely contributing to autoimmunity in the offspring (Stelzer et al., 2015). The effects of MMc are most apparent in studies of transplants and autoimmunity demonstrating that recipients of maternal tissue had a reduced rate of rejection when compared with recipients of paternal tissue and that autoimmune disorders are associated with higher levels of MMc (Artlett, Miller, Rider, & Childhood Myositis Heterogeneity Collaborative Study, 2001; Joo et al., 2013; van Rood et al., 2002; Vanzyl et al., 2010; Ye, Vives-Pi, & Gillespie, 2014). This suggests that MMc shapes the offspring’s immune system to promote tolerance toward maternal antigens and maternally acquired environmental antigens, but maternal cells also respond to antigens in the offspring to promote autoimmunity.

There are other examples of maternal influences on the developing immune system occurring in utero or through breast milk. Whether these influences have durable effects on the offspring’s immune system, similar to MMc and effects on SLO development, are less clear. Some of these maternal contributions are to protect the fetus and infant during a time when the offspring’s immune system is underdeveloped and unable to properly combat infection, while others help guide the tone of immune responses, especially intestinal immune responses, to promote tolerance toward microbial and dietary antigens. Microbial products from the maternal intestine encountered in utero directly affect innate immunity in the fetus by increasing the population of ILC3s and mononuclear cells and increasing the expression of genes involved in innate defense of the intestine (Gomez de Agüero et al., 2016). The effects of exposure to microbial products from the maternal gut in utero persists for some time after birth, providing the offspring enhanced protection from infection (Gomez de Agüero et al., 2016). Following birth, maternal cues continue to promote the development of the offspring’s immune system. Breastmilk provides nutrition, but also shapes the developing immune system. Breastmilk is rich in immunoglobulins (Ig), including the well-appreciated microbial-specific IgA necessary to prevent pathogen infection in the offspring’s intestinal lumen (Brandtzaeg, 2003). The impact of maternal Ig extends beyond the gut. IgG from breast milk can be transcytosed across the offspring’s intestinal epithelium via the neonatal-Fc-receptor (Roopenian & Akilesh, 2007). Once internalized, maternal Ig containing bound proteins efficiently support the induction of oral tolerance. Complexes of allergens and maternal IgG were superior at inducing allergen-specific Foxp3+CD25+ Tregs in the nursing offspring, compared to oral introduction of allergen alone (Bernard et al., 2014; Mosconi et al., 2010; Nakata et al., 2010; Ohsaki et al., 2018). Additionally, maternal T-independent IgG antibodies limit the exposure of the offspring’s immune system to commensal microbial antigens from the developing gut microbiome, thus preventing the development of inflammatory adaptive responses toward the microbiome and dysbiosis (Koch et al., 2016). Biologically active proteins in breast milk, such as cytokines and growth factors, also direct the offspring’s immune system away from inflammation and toward tolerogenic responses (Järvinen, Suárez-Fariñas, Savilahti, Sampson, & Berin, 2015). Maternal TGF-β can inhibit IL-1β-driven inflammation in the offspring (Samuli Rautava et al., 2011). Maternal IL-6 promotes the development of IgA responses in the offspring (Saito, Maruyama, Kato, Moriyama, & Ichijo, 1991), which is essential for maintaining homeostasis with the microbiome. Breast milk derived epidermal growth factor promotes tolerance by inhibiting TLR4-driven inflammation (Good et al., 2015) and regulates the exposure of offspring to microbial antigens (Knoop, McDonald, et al., 2017). Interestingly, living conditions influence the composition of such cytokines and proteins in the breastmilk. One study reported concentrations of cytokines and growth factors decreased at different rates in women in England, Italy, and Russia (Munblit et al., 2016). Another study found Estonian women had increased IL-10, IFN-g, and SIgA when compared with Swedish women living in more affluent conditions, who had increased IL-13 within colostrum. (Tomičić et al., 2010) These differences were correlated to environmental endotoxin concentrations in Swedish women suggesting decreased microbial exposure in mothers could result in increased IL-13 in breastmilk and promote the development of allergies in offspring. Environmental exposures of mothers during lactation could hence greatly influence the offspring’s immune system, potentially recapitulating the “hygiene hypothesis” whereby increased hygiene and reduced microbial exposure contributes to the development of allergic disorders.

The metabolites found in breastmilk can also influence the offspring’s immune system. As previously discussed, human milk oligosaccharides, the composition of which may be subject to environmental factors and diet (Davis et al., 2017), support the development of the offspring’s microbiome (Marcobal & Sonnenburg, 2012), which in turn drives the development of the immune system (Maynard, Elson, Hatton, & Weaver, 2012). Milk fat globule membrane from lactation contains biologically active fatty acids (Lindquist & Hernell, 2010) that can drive differentiation of intestinal secretory cells and protect against inflammation (Bhinder et al., 2017). The composition of the mother’s dietary fats affects the fatty acid composition of her breastmilk. Diets rich in unsaturated fats might thus be protective, and diets rich in saturated fats may promote inflammation and TLR4 signaling (Caplan et al., 2001; Lu, Jilling, Li, & Caplan, 2007; Robinson & Caplan, 2014). These non-inherited maternal contributions once again show how the mother’s environment and diet can influence the offspring’s immune system via breastmilk.

While it remains to be seen how a maternal deficiency in any of the above contributions may influence the offspring, infants without access to breastmilk clearly fare worse in multiple disease outcomes during early life (Lamberti et al., 2013; Turin & Ochoa, 2014). The World Health Organization Global Breastfeeding Collective current initiative is to promote breastfeeding within an hour of a child’s birth and exclusive breastfeeding for the first six months of life (Grummer-Strawn et al., 2017; Khan, Vesel, Bahl, & Martines, 2015). Since this is not always possible for multiple reasons, physiological and emotional, use of donor milk through milk banks, have become a popular diet choice compared to infant formula (Chen, 2018; Parra-Llorca et al., 2018). Though the biologically active proteins reviewed above can be destroyed during the pasteurization process (Untalan, Keeney, Palkowetz, Rivera, & Goldman, 2009) (Reeves, Johnson, Vasquez, Maheshwari, & Blanco, 2013), increasingly neonatal intensive care units have begun providing donor milk in an effort to provide complete nutrition and protection to premature infants (Adhisivam et al., 2017). Preterm infants fed donor milk had gut microbiomes that more closely resembled infants fed their mother’s own milk compared with formula fed infants (Parra-Llorca et al., 2018). Additionally, some groups have tested the viability of “spiking” donor milk with infants’ own mothers milk to inoculate the infants with a personalized microbiome (Cacho et al., 2017), a concept similar to a recent push to include probiotics in infant formula (Mugambi, Musekiwa, Lombard, Young, & Blaauw, 2012; S. Rautava et al., 2012) (Aceti et al., 2016) (Villamor-Martínez et al., 2017) (Cavallaro, Villamor-Martínez, Filippi, Mosca, & Villamor, 2017). These interventions showcase the importance of breastfeeding, or in lieu of breastfeeding, a diet reflecting the myriad of components maternally transferred that support the development of the offspring’s immune system and shape gut homeostasis during early life.

Conclusion

The immune system and the gut microbiota develop jointly around the time of birth. Although both display some degree of plasticity, once established these “organ systems” are remarkably stable. There is a growing appreciation of the many influences that our parents, and particularly our mothers, have on the development of the gut microbiota and immune system through events occurring in utero and after birth. Our parents give us much more than genes.

Figure 1.

Figure 1.

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Inherited influences on the gut microbiome and immune system

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