J. Dairy Sci.

107:7504–7519
https://doi.org/10.3168/jds.2024-24835
Crown Copyright © 2024. Published by Elsevier B.V. on behalf of the American Dairy Science Association®.
This is an open access article under the Open Government Licence (https://www.nationalarchives.gov.uk/doc/
open-government-licence/version/3/).

Invited review: Impact of maternal health and nutrition

on the microbiome and immune development of neonatal calves
Gayathri Diddeniya,1* Morteza Hosseini Ghaffari,2 Emma Hernandez-Sanabria,3 Le Luo Guan,4
and Nilusha Malmuthuge5†
1
Faculty of Agriculture, University of Peradeniya, Kandy 20400, Sri Lanka
2
Institute of Animal Science, Physiology Unit, University of Bonn, 53115 Bonn, Germany
3
Department of Microbiology and Immunology, Laboratory of Molecular Bacteriology, Rega Institute, KU Leuven, Leuven 3000, Belgium
4
Faculty of Land and Food Systems, University of British Columbia, Vancouver, BC V6T 1Z4, Canada
5
Lethbridge Research and Development Center, Agriculture and Agri-Food Canada, Lethbridge, AB T1J 4B1, Canada

ABSTRACT Nonetheless, calf microbiome research lacks links to

early development of the immune system. An in-depth
This comprehensive review highlights the intricate understanding of the influence of maternal factors on mi-
interplay between maternal factors and the co-develop- crobiomes and immunity will improve the management
ment of the microbiome and immune system in neonatal of pregnant cows to raise immune-fit neonatal calves. It
calves. Based on human and mouse studies, multiple is essential to investigate the diverse effects of maternal
prenatal and postnatal factors influence this process by health conditions and nutrition during pregnancy on the
altering the host-associated microbiomes (gut, respira- gut microbiome and immunity of neonatal calves through
tory tract, skin), microbial colonization trajectories, and collaboration among researchers from diverse fields such
priming of the immune systems (mucosal and systemic). as microbiology, immunology, nutrition, veterinary sci-
This review emphasizes the importance of early-life ence, and epidemiology.
exposure, highlighting postnatal factors that work in Key words: neonatal calf, co-development, microbiome,
synergy with maternal factors in further fine-tuning the immunity, maternal factors
co-development of the neonatal microbiome and immu-
nity. In cattle, there is a general lack of research to iden-
INTRODUCTION
tify the maternal effect on the early colonization process
of neonatal calves (gut, respiratory tract) and its impact The neonatal period represents a crucial window of
on the priming of the immune system. Past studies have time during which the microbiota and host immunity co-
primarily investigated maternal effects on the passive develop in a complex manner, a process that is strongly
transfer of immunity at birth. The co-development pro- influenced by several perinatal factors. Prenatal factors
cess of the microbiome and immune system is vital for (Figure 1) are the maternal factors, such as diet and nutri-
lifelong health and production in cattle. Therefore, com- tion, health or stress, interventions (antimicrobials, pre-
prehensive research beyond the traditional focus on pas- and probiotics), and exposure (hygiene, chemicals) that
sive immunity is an essential step in this endeavor. Calf alter fetal developmental programs, maternal microbiota,
microbiome research reports the colonization of diverse and metabolites that fetuses and newborns are exposed
bacterial communities in newborns, which is affected by to during the birthing process (Jeong, 2022). Postnatally
the colostrum feeding method immediately after birth. In (Figure 1), the neonatal microbiome is further refined
contrast to human studies reporting a strong link between by diet (breast milk vs. formula), exposure (pets, green
maternal and infant bacterial communities, there is a lack space, mother, siblings), interventions (antimicrobials,
of evidence to clearly define cow-to-calf transmission in pre- or probiotics), activity (exercise), and stress (Arrieta
cattle. Maternal exposure has been shown to promote the et al., 2014; Renz et al., 2017; Jeong, 2022). In addition,
colonization of beneficial bacteria in neonatal calves. the birth process itself is a crucial factor in modulating
microbial transmission. The acquisition of microbiota
Received February 27, 2024. and colonization trajectories are also modulated by the
Accepted May 1, 2024. birth mode (Arrieta et al., 2014), labor duration (Rai,
*Current address: Faculty of Veterinary Medicine, University of
Calgary, Calgary, AB T2N 1N4, Canada. 2018), and intrapartum antibiotics (Chen et al., 2021b).
†Corresponding author: nilusha.malmuthuge@​agr​.gc​.ca These factors, together, contribute to a spectrum of disor-
The list of standard abbreviations for JDS is available at adsa.org/jds-abbreviations-24. Nonstandard abbreviations are available in the Notes.

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Figure 1. Prenatal and postnatal factors affecting the gut microbial colonization process in neonates. Prenatally, maternal diet and nutrition,
health and stress, exposure, and interventions affect the gut microbial community composition and colonization trajectories in neonates. Postnatally,
neonatal diet, exposure, interventions, activity, and stress level alter the gut microbial community composition. These factors have been studied
mainly in human and laboratory rodent models.

ders that are known as microbiome-linked pathologies by and the role of early-life exposure in modulating the co-
affecting the co-development of the microbiomes (gut, development process using the knowledge generated by
respiratory, skin) and immune systems (mucosal and sys- human and mouse research. Then, we will evaluate the
temic). These microbiome-linked pathologies consist of roles of maternal factors such as maternal microbiota,
intestinal and extra-intestinal disorders and diseases such exposure and contact, diet and nutrition, and health and
as obesity, necrotizing enterocolitis, inflammatory bowel stress in modulating microbiomes and the overall im-
disease, allergies, asthma, eczema, diabetes, diarrhea, munity of neonates. Simultaneously, we aim to critically
colorectal cancers, and autism spectrum disorder (de Vos evaluate the existing research in neonatal calves to high-
et al., 2022). Recent advanced research on early-life gut light the future need for microbiome and immunology
microbiomes has greatly expanded our knowledge of the research in cattle to improve the management of cows to
microbial influence on mucosal and systemic immune sys- raise healthy offspring.
tems (Al Nabhani and Eberl, 2020; Henrick et al., 2021)
and microbiome-linked pathologies (de Vos et al., 2022). CRITICAL WINDOWS OF OPPORTUNITY:
In addition, studies in laboratory animals have shed light MICROBIAL PRIMING OF IMMUNITY
on the mechanisms of host-microbe interactions during
early immune development. Along with being a major Neonatal Period
mucosal immune site, the gastrointestinal tract harbors
most host-associated commensal microbiota. Therefore, Diverse microbial communities colonize newborn ani-
the primary focus of human and livestock research is mals (in and out of the body) during and after the birth
the gut microbial community and its influence on host process, which will present a wide array of molecular
health and immunity. However, other host-associated mi- patterns to the immune system (Ganal-Vonarburg et al.,
crobial communities (respiratory, skin) also play equally 2020). Microbial priming at critical windows of develop-
important roles in priming local and systemic immune re- ment ensures that the host is equipped with long-term
sponses, which are vital for overall host health (Belkaid defense mechanisms. Recent studies suggest that the
and Hand 2014). Therefore, an in-depth understanding neonatal period is the most critical window of oppor-
of the neonatal microbiome and its role in priming host tunity for microbial priming of the immune system, in
immunity is vital in the process of evaluating the role of which interventions can be implemented to promote
maternal factors on these interconnected elements. This well-balanced immunity (Robertson et al., 2019). Archer
review will first evaluate the importance of neonatal mi- et al. (2023) used a well-designed mouse model to assess
crobiome in priming immunity (co-development process) the importance of the timing of gut microbial coloniza-
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tion in priming the immune systems. They examined the composition and colonization trajectories are influenced
systemic and mucosal immune cell populations of mouse by various factors (Figure 1) that determine the extent
pups born to germ-free and conventional dams in the first of exposure during the neonatal period. Differential lev-
56 d of life. Pups from germ-free dams were colonized els of exposure can lead to altered priming of immune
either at birth (early colonizers) or after 4 wk of delay responses during early life. For example, the hygiene
(delayed colonizers) by oral gavage. The study found hypothesis explains that exposure to an environment rich
that early colonizers had significantly fewer CD8+ T cells in microbiota leads to well-balanced immunity character-
and NKp46+ natural killer cells in the spleen and fewer ized by a balance between inflammatory and protective
dendritic cells in the mesenteric lymph node compared immune responses (Renz et al., 2006, 2017). In contrast,
with conventionally born pups. However, all other im- a sterile or hygienic environment primes skewed im-
mune cell populations in the spleen, mesenteric lymph munity, resulting in less activation of protective immune
node, and blood circulation were similar between these 2 responses (Renz et al., 2006, 2017).
groups. Delayed colonizers, in contrast, had fewer CD4+ A recent Canadian child cohort study found that expo-
and CD8+ T cells in the spleen than conventional pups sure to natural green spaces promotes protection against
and early colonizers. They also had an increase in CD19+ allergies by altering the microbial community in the gut
B cells, dendritic cells, and macrophages in the spleen of infants (Buchholz et al., 2023). The authors observed
compared with conventional pups. Interestingly, the dif- a 72% lower likelihood of developing an allergy to 2 or
ferences in immune cell populations between convention- more allergens in 3-yr-old children living closer to natu-
al pups and early colonizers accounted for only 2.36% of ral green spaces (within 500 m) compared with those who
the variation in immunophenotype. In contrast, the varia- had no exposure to green spaces. This effect was mediat-
tion between delayed colonizers and conventional pups ed by the higher bacterial diversity and higher abundance
was 12 times higher (29%) than the difference between of Actinobacteria in their gut at 4 mo of age (Buchholz et
early colonizers and conventional pups. These results al., 2023). Desensitization to allergens indicates activa-
suggest that the pioneer microbiota, which colonizes the tion of oral tolerance by the commensal gut microbiota
gut of newborns immediately after birth, plays an essen- via priming protective immune responses (Belkaid and
tial role in priming the neonatal immune system, whereas Hand, 2014). Additionally, a study in Finland reported
exposure to the maternal microbiota plays a smaller role that exposure to a natural environment alters the skin and
in immune cell differentiation and proliferation. This gut microbiota composition and systemic immune re-
confirmed that early-life exposure to microbiota is the sponses (cytokine levels, Treg cells) in children (Roslund
most important determinant of a host immune phenotype et al., 2020). Children exposed to a natural environment
and the neonatal period is the most critical window of op- showed increased diversity in the bacterial class Gamma-
portunity in animals. Therefore, knowledge of neonatal proteobacteria on their skin and the family Ruminococ-
microbiomes and immune systems, as well as the factors caceae in the gut. When the systemic cytokine responses
that influence them is vital to improve animal health. were measured, the ratio of IL10 to IL17A was higher
Previous studies (Barrington and Parish, 2001; Chase et in children exposed to a natural environment compared
al., 2008) have reported well-developed mucosal (in the with those placed in a standard urban daycare setting
gut) and systemic immune systems in newborn calves. (Roslund et al., 2020). The secretion of IL10 and IL17A,
Additionally, recent microbiome studies have revealed which mediate protective immune responses is primed by
the colonization of active, diverse, and dense microbial the commensal microbiota colonizing the gut (Belkaid
communities along the gastrointestinal tract of newborn and Hand, 2014). The neonatal gut microbiota initiates
calves (Song et al., 2018; Malmuthuge et al., 2019a,b) long-term immune memory during the co-development
and their rapid establishment with a single feeding of process (Al Nabhani and Eberl, 2020). Using germ-free
colostrum (Malmuthuge et al., 2015; Ma et al., 2019; mouse models, researchers demonstrated that gut micro-
Song et al., 2019, 2022). However, our understanding of bial priming for a lifelong immune memory can only be
early-life priming of the immune system (mucosal and initiated during the neonatal period. For example, mi-
systemic) by the pioneer commensal microbiota that rap- crobial colonization of neonatal germ-free mice reduced
idly colonizes neonatal calves is still limited. the number of invariant natural killer T cells (iNKT) in
the colon and lungs, but not when they were colonized
Exposure During the Neonatal Period as adult mice (Olszak et al., 2012). As iNKT cells are
tissue-resident lymphocytes playing protective immune
Although the neonatal microbiome plays an important roles (Crosby and Kronenberg, 2018), microbial prim-
role in the long-term health of animals by promoting ing of well-balanced immune responses (inflammatory:
gut maturation (Sanidad and Zeng, 2020) and the gut- protective responses) during the neonatal period is ir-
associated immune system (Arshad et al., 2021), its replaceable. Together, these studies suggest that early-
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life exposure modulates protective immune responses immune system to generate lifelong immune memory.
by influencing the composition of neonatal microbiota Understanding the factors influencing early-life exposure
and the co-development of the microbiomes and immune of neonatal calves is critical for modulating the microbial
systems. colonization trajectories and immune system priming,
Facilitating the colonization of beneficial microbiota which can have significant implications for calf health
that promotes a balance between protective and inflam- and disease resistance.
matory responses is vital in raising immune-fit calves.
Therefore, it is important to evaluate the effects of Fetal Stage
various early-life management strategies on neonatal
microbiome and immunity. The extent of early-life expo- Although the effect could be less than the neonatal pe-
sure of neonatal calves is influenced by various factors riod, the fetal stage is another critical window in which
such as housing strategies, bedding materials, feeding microbial priming of the immune system could occur via
methods, and extent of contact with the dam or other the maternal microbiota. Exposure to the maternal gut
calves. These different exposures can lead to different microbiota or metabolites plays a vital role in priming
patterns of microbial colonization in the gut and respira- the offspring’s immune system (Gomez de Agüero et al.,
tory tract and immune system development in calves. A 2016). Transient colonization of pregnant dams during
study comparing the bacterial composition in the feces of gestation has shown that the maternal gut microbiota
healthy calves (1–30 d old) from different farms revealed can prime the gut-associated innate immune system of
significant differences in the relative abundance of bac- mice pups differently than in germ-free status (Gomez de
terial taxa particularly between grouped and individu- Agüero et al., 2016). The authors exposed pregnant mice
ally housed animals (Gomez et al., 2017). Group-housed (from the placental attachment to the logarithmic growth
animals showed a higher abundance of Fusobacteria and phase) to a genetically engineered bacterial strain that
a lower abundance of Proteobacteria in the feces com- could not colonize the gut permanently. As a result, both
pared with those in individual housing (Gomez et al., the dams and the pups were germ-free at birth. When
2017). In addition, the abundance of Actinobacteria was the gut-associated mucosal immune systems of mouse
lower in group-housed diarrheic calves compared with pups were examined at 2 wk of age, the proportion of
healthy calves. However, no differences in the relative small intestinal lymphoid cells (NKp46+ RORγt+ ILC3)
abundance of bacterial taxa were found between healthy was higher in pups born to transiently colonized dams
and diarrheic calves from individual housing. Age is than in those born to germ-free dams. In addition, regu-
a major determinant of the gut bacterial community latory and protective immune responses were activated
composition of neonatal calves, which is a confounding in the small intestinal transcriptome of the pups born to
factor in this study. The authors identified that housing transiently colonized dams compared with those born to
conditions also can influence the composition of the gut germ-free dams (Gomez de Agüero et al., 2016). Both
microbial community of neonatal calves. However, there these studies (Gomez de Agüero et al., 2016; Archer et
is a general lack of studies evaluating different housing al., 2023) showed that exposure to gut microbiota (or
methods (individual vs. social housing) on microbial microbial metabolites) during the fetal and neonatal pe-
colonization trajectories, transmission of pathogens, or riods together modulates the development of the immune
early priming of the immune system of dairy calves. systems (mucosal and systemic) in neonates. Pregnant
The immune system of calves that begins to develop cows undergo a nutritional regimen tailored to their
in the early fetal stage (Barrington and Parish, 2001; need for maintenance, fetal growth, and future lactation,
Chase et al., 2008) becomes fully capable of eliciting which directly affects the gut microbiome and microbial
immune responses upon induction. The use of in utero metabolites that are presented to the fetus. However, our
vaccines in ruminants has demonstrated that the fetal understanding of maternal effects on the priming of the
immune system can generate antibody and cell-mediated calf immune system at the molecular and cellular levels is
immune responses following induction (Gerdts et al., limited. Tröscher-Mußotter et al. (2021) investigated the
2000). Moreover, priming of the fetal immune system fecal microbiota of pregnant multiparous cows from late
with an in utero vaccine has been shown to induce long- gestation to early lactation (last 42 d of gestation + 126 d
term immune memory detectable at birth (Gerdts et al., after calving). In general, the authors grouped cows into
2002). This suggests that newborn ruminants possess 3 clusters (Bifidobacterium cluster, Clostridiales cluster,
a well-developed immune system that undergoes rapid and Spirochaetaceae cluster) based on the fecal bacterial
priming and induction immediately, particularly follow- community composition during late gestation and lac-
ing exposure to microbiota. Therefore, early exposure of tation regardless of a dietary supplement (l-carnitine),
newborn calves (that modulate microbial colonization calving, or postcalving lipopolysaccharide challenge.
trajectories) plays a vital role in priming the developing The authors observed bacterial cluster-dependent varia-
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tions in fecal metabolites, health outcomes, and body the neonatal gut play a crucial role in both metabolic and
weight of cows. Cows belonging to the Bifidobacterium immunological programming. Therefore, any perturba-
cluster had a higher total fecal metabolite concentration tion (birth mode, antibiotics, feeding method, and ma-
than the cows in the Spirochaetaceae cluster. These re- ternal factors) in the initial colonization process can lead
sults suggest that maternal metabolites vary depending to long-term altered metabolic and immune functions. A
on the gut microbial community composition. It would recent study examining the maternal and infant micro-
be interesting to understand how these variations in the biota (colonizing various body sites) in the first month
maternal microbiome play a role in the early gut micro- after birth found that maternal sources contribute on
bial colonization and priming of the immune system. average to 58.5% of the composition of the infant micro-
In-depth reviews have presented the importance of biota (Bogaert et al., 2023). The largest contribution was
early life on the co-development of the gut microbiome made by the maternal microbiota associated with breast
and immune system (mucosal and systemic) of mammals milk (31.6%), followed by skin, saliva, nasopharynx,
using human and mouse research (Al Nabhani and Eberl, feces, and vagina. However, the contribution of maternal
2020; Renz and Skevaki, 2021; Di Simone et al., 2023; sources to infant microbiota varied according to birth
Torow et al., 2023). The significance of neonatal gut mode, breastfeeding status, and infant body site (Bogaert
and respiratory microbiota is now gaining recognition et al., 2023). For example, the contribution of the vaginal
in livestock, particularly in cattle (Osman et al., 2018; microbiota to the infant nasopharyngeal microbiota was
O’Hara et al., 2020; Osorio, 2020; Amin and Seifert, higher in vaginally delivered (VD) babies than those
2021). Despite increasing understanding of maternal delivered by cesarean section (CS). In CS infants, the
effects on offspring microbiome and immunity, current contribution of the maternal vaginal microbiota was
livestock management practices for pregnant dams focus higher in secondary CS (CS after labor) than in elective
more on maternal performance than on the health and CS (CS without labor), indicating that the contribution
immunity of their offspring. This gap highlights the of a maternal source is highly dependent on the level of
need for improved maternal management strategies that exposure. In addition, the contribution of the maternal
increase offspring resilience and influence early immune fecal microbiota to infant fecal microbiota was higher in
development. VD babies than in those delivered by CS. In general, this
study suggests that the influence of the maternal micro-
MATERNAL CONTRIBUTION TO THE DEVELOPING biota on the establishment of infant microbiota depends
MICROBIOME AND IMMUNE SYSTEM on other external factors that determine the extent of
exposure.
The pioneer gut microbiota and their priming of the In contrast to studies in humans, microbiome research
neonatal immune system have been linked to maternal in cattle has not fully elucidated the contribution of
factors during and after pregnancy. In humans, an exten- the maternal microbiota to the microbiota of neonatal
sive body of knowledge exists on the effects of maternal calves. In our previous studies (Malmuthuge, 2016),
microbiota, diet and nutrition, health, and exposure dur- we compared the bacterial profiles (small intestinal tis-
ing pregnancy on the microbiome and health of infants. sue and contents, skin, nose, mouth) of newborn dairy
In cattle, studies have mainly focused on the effects of calves with those of their dams (vagina and rectum) to
maternal nutrition on neonatal calf health, especially identify the inoculum of the small intestinal microbiota.
on the transfer of passive immunity. This section will When comparing bacterial profiles generated using 16S
critically discuss the effects of maternal factors on the rRNA gene sequencing (amplicon sequencing), we found
microbiome (mainly gut microbiome) and immunity of significant differences between the small intestinal
neonates, highlighting their relevance to neonatal calves bacterial communities of newborn calves (digesta- and
(Table 1). An in-depth understanding of the effects of ma- tissue-associated) and their dams’ vaginal and rectal bac-
ternal factors on the neonatal microbiome and immunity terial communities (Table 2, ANOSIM R = 0.9, P < 0.01).
(the most critical window of opportunity) will facilitate Additionally, the bacterial communities from the body
the management of pregnant cows to raise healthy calves habitats of the calves (skin, mouth, nose) differed signifi-
in the future. cantly from the bacterial communities of dams (Table 2,
ANOSIM R = 0.7, P < 0.01). However, calf body habitat
Maternal Microbiota: Inoculum bacterial communities were very similar to those of the
of the Neonatal Microbiota? calving pen floor (Table 2, ANOSIM R = 0.06, P < 0.29).
During calving, the behavior of the dams (frequently ly-
In humans, an increasing number of studies have in- ing on the stall floor, even after rupture of the amniotic
vestigated the maternal contribution to the establishment membranes) could increase the exposure of calf body
of infant microbiota. The pioneer microbes that colonize habitats (especially the skin) to the bacteria on the stall
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Table 1. Effects of maternal factors on microbiome and immunity of neonates

Effect on offspring

Maternal factor Microbiome Immunity Animal model

Gut microbiome Main inoculum Human
No strong link Cattle
Exposure Breastfeeding; increases the colonization Breastfeeding; decreases atopy, allergies, eczema Human
of beneficial bacteria
Full and partial contact; Full and partial contact; Cattle
increases Lactobacillus reduces health score;
increases antibiotic treatment
Fiber-rich diet Increases Akkermansia colonization; Decreases TNFα, IL-22 (proinflammatory Mice
decreases Bacteroides caccae, cytokines);
Desulfovibrio piger, Clostridium increases IL-17F (protective cytokine);
symbiosum increases innate lymphoid cells and Th17 cells in
the colon lamina propria
High-fat diet Decreases Bacteroides Human
n-3 PUFA Decreases allergies Human
DHA Reduces CD4+, CD8+, CD25+, CD28+ T cells in Mice
spleen
ARA Increases TNFα, IFNγ, IL-1β (proinflammatory
cytokines) production from T cells after bacterial
challenge
Vitamin and minerals Increase rumen bacterial diversity Cattle
Fish oil and linseed Increase colostral IgG, IgA Cattle
Concentrate supplement Reduces enteric infections
Energy and protein Increases the positive seroconversion rate against Cattle
supplement respiratory pathogens
High-energy diet Decreases colostral IgG Cattle
Undernutrition Reduces antibody responses to vaccines Human, cattle
Reduces the expression of genes modulating viral Cattle
infections, NK cell activity
Stress Increases Lachnospiraceae, Mice
Ruminococcaceae
Obesity Increases Firmicutes Increases expression of tnf gene Mice
Psychological stress Decreases fecal bacterial diversity; Human
decreases Proteobacteria
Metabolic stress Increases oxidative status; Cattle
increases inflammation
Heat stress Decreases serum IgG; Cattle
increases epithelial cell apoptosis in the jejunum

floor. Initially, we attributed the observed differences detailed study to assess the influence of maternal micro-
between calf small intestinal and dam rectal bacteria to biota on microbial colonization trajectories of neonatal
gut-regional differences, as the bacterial communities calves by profiling bacteria across the gastrointestinal
in the small intestine were significantly different from tract. Similar to Klein-Jöbstl et al. (2019), this study
those colonizing the hindgut (Malmuthuge et al., 2014). also reported the presence of some maternal bacteria
However, similar results were reported in recent studies (operational taxonomic units, OTU) along the calf gut.
that compared calf and dam fecal bacterial communities. Profiling of the bacteria along the gastrointestinal tract
Klein-Jöbstl et al. (2019) found that the fecal bacterial of calves revealed that shared OTU varied depending on
profiles of newborn calves were distinct from those of the gut region (Yeoman et al., 2018). Although calves
cows during the first 48 h of life. Only the bacterial were reared separately from dams, udder skin microbiota
profiles generated from colostrum were clustered closely shared the highest number of OTU with that of calves,
with the fecal bacterial profiles generated from calves followed by the colostral and vaginal microbiota. How-
within 6 h of calving. This suggests that the similarity ever, most OTU identified in this study were not shared
between the maternal and calf microbiota varies depend- between calves and cows. Additionally, the β-diversity
ing on the duration after calving as microbial succession analysis comparing the bacterial profiles generated from
progresses. The calf oral bacterial community was simi- cows and calves revealed lower similarity (confirmed by
lar to the vaginal bacteria of cows, confirming that the the ANOSIM R-value that compares the mean of ranked
contribution of the different maternal sources depends on dissimilarities between groups), confirming that calf
the body site of calves. Yeoman et al. (2018) executed a gut microbial communities were different from those of

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Table 2. Comparison of bacterial community profiles generated from newborn calves, dams, and calving pen
environment bacterial communities1

Bacterial profile comparison ANOSIM R P-value

Calf small intestine vs. dam (vagina + rectum) 0.88 <0.01
Calf small intestine vs. dam vagina 0.90 <0.01
Calf small intestine vs. dam rectum 0.91 <0.01
Calf small intestine contents vs. dam vagina 0.72 <0.01
Calf small intestine contents vs. dam rectum 0.68 <0.01
Calf small intestine tissue vs. dam vagina 0.76 <0.01
Calf small intestine tissue vs. dam rectum 0.61 <0.01
Calf small intestine vs. body habitats (skin, nose, mouth) 0.71 <0.01
Calf small intestine vs. floor 0.79 <0.01
Calf small intestine contents vs. tissue 0.26 <0.01
Body habitats vs. floor 0.06 0.29
Body habitats vs. dam 0.66 <0.01
Floor vs. dam 0.10 0.24
Floor vs. dam rectum 0.07 0.50
Floor vs. dam vagina 0.40 0.04
1
Adapted from Malmuthuge, 2016, PhD thesis.

dams (Yeoman et al., 2018). These studies together sug- born through elective CS surgery who lack exposure to
gest that when comparing calf gut bacterial communities maternal gut and birth canal microbiota (Tun et al., 2018;
with those of cows, there is a lack of shared bacterial Reyman et al., 2019; Morais et al., 2020). Moreover, the
taxa between them. Dairy calves are separated from their duration of labor has also been shown to alter neonatal
dams immediately after birth, without contact between gut microbial communities (Rai, 2018). A longer dura-
cow-calf pairs, whereas beef calves remain with their tion of labor (both first and second stages) has been as-
dams until weaning at 6 to 7 mo of age. When Barden sociated with a lower abundance of bifidobacteria in the
et al. (2020) examined the microbiota (cows: fecal, birth gut of 3-mo-old infants. Bifidobacteria are considered
canal, udder, colostrum, milk; calves: fecal and oral) of beneficial pioneer bacteria that prime the developing
cow-calf pairs of beef and dairy cattle, they found no mucosal immune system (Turroni et al., 2020). Diffi-
evidence of cow-to-calf transmission in beef cattle. No culty in calving due to significantly prolonged labor in
clustering of calf and dam fecal bacterial profiles at birth cows, namely dystocia, is a major problem in the dairy
was found. In contrast, at 4 wk after calving, bacterial and beef industries. Dystocia also leads to either assisted
profiles generated from calves were clustered apart from calving or CS, exposing calves to antibiotics. However,
cows. The authors did not find significant differences in the effects of dystocia on gut microbiota and immunity in
the oral and fecal bacterial communities between dairy neonatal calves remain understudied.
and beef calves at 4 wk of age, despite the variations in
the level of maternal contact. Compared with microbi- Maternal Exposure and Contact: Impact on the Gut
ome studies in calves, research in infants and children Microbial Community and Health
currently relies on cohort studies in which mother-infant
pairs are followed over a period to assess the dynamics Although the precise mechanisms of microbial
of the gut and other host-associated microbiomes. This transmission from cows to calves remain to be fully
approach provides sufficient power to conduct modeling- elucidated, the exposure of newborn calves to cows in
based source tracking of bacteria taxa between moms and early life could significantly affect the composition of
infants. However, identifying maternal influence on the neonatal calf gut microbiota. A recent study by Beaver
microbiome of newborn calves remains challenging due et al. (2021) reported differences in the fecal bacterial
to the limited sample sizes in cattle studies. Our under- communities of 4-wk-old calves raised conventionally
standing of the transmission of the microbiota from cow (separated from cows at birth) versus exposed to mater-
to calf can be improved by conducting similar large-scale nal contact (at least 24-h physical contact but no suck-
(multi-institutional and multi-geographic) longitudinal ling). Calves with maternal contact had a higher relative
studies to profile the microbial communities of both the abundance of the genus Lactobacillus compared with the
cow and the calf after calving. conventionally reared calves at 4 wk of age. Similarly,
Exposure to the maternal microbiota at birth plays a Wenker et al. (2022) observed changes in the composi-
critical role in the subsequent immune system priming tion of the fecal bacterial communities of neonatal calves
and development. Studies in infants have clearly shown exposed to different levels of maternal contact during the
an increase in microbiome-linked pathologies in infants preweaning period (no contact; partial contact: physi-

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 Diddeniya et al.: INVITED REVIEW: DAM ROLE IN NEONATE MICROBIOTA AND IMMUNITY 7511
cal contact without suckling; or full contact: suckling + ment. Furthermore, it is equally important to evaluate the
physical contact). The relative abundance of Lactobacil- lifelong health and production of animals when exposed
lus was higher in 1-wk-old and 4-wk-old calves that were to different maternal or adult contact in their early life.
exposed to full maternal contact compared with those This knowledge will inform decision-making processes
with no or partial maternal contact. Lactobacillus, a pio- to aim at gut microbiota enrichment of neonatal calves
neer beneficial bacterium in neonatal calves (Schwaiger in early life.
et al., 2020), has been linked to priming the developing
immune system. Moreover, the abundance of Lactobacil- Maternal Diet and Nutrition: Impact
lus in feces was lower in calves with diarrhea than in on the Co-Development of the Neonatal
healthy calves (Schwaiger et al., 2022). Taken together, Gut Microbiota and Immune System
these results suggest that maternal contact during early
life may promote the colonization of beneficial bacteria Diet or nutrition is pivotal in regulating host-microbe
in the gut of neonatal calves. interactions in the gut, influencing animal immunity and
When calves were exposed to full maternal contact health (Zmora et al., 2019; Fontaine et al., 2023). Mater-
during the preweaning period, there was an increase in nal diet and nutrition stand out as critical factors shaping
antibiotic treatments compared with those without con- the gut microbial community and immunity of the neo-
tact (Wenker et al., 2022). In addition, hematological nate. Maternal diet or nutrition initiates metabolic and
parameters such as counts of erythrocytes, hepatocytes, immunological programs in the developing fetus, laying
and leukocytes and hemoglobin levels were higher in the foundation for offspring health. For example, studies
calves with full contact compared with those without in humans have demonstrated that maternal undernutri-
contact. This suggests that despite the observed changes tion exerts significant effects on offspring immunity by
in beneficial gut bacteria colonization, exposing neonatal attenuating immune responses to vaccines in early child-
ruminants to adult animals longer (in the same pen or hood (Obanewa and Newell, 2017). Beyond effects on
a separate pen) could expose them to adult pathogens. immunity, maternal diet or nutrition can directly influ-
Interestingly, Beaver et al. (2021) observed an increase ence the colonization of the neonatal gut microbiota. A
in Lactobacillus colonization in calves only when they recent study exploring the effects of maternal dietary fiber
were exposed to cows for a shorter period during the intake showed that mouse pups born to dams fed a high-
first 24 h of life, suggesting that maternal contact im- fiber diet were colonized by Akkermansia muciniphila
mediately after birth for a shorter duration is sufficient earlier than pups born to dams on a fiber-free diet (Grant
to promote the colonization of beneficial bacteria in the et al., 2023). Furthermore, the presence of dietary fiber in
gut. Although Beaver et al. (2021) lacked health data, the maternal diet during pregnancy affected the relative
Wenker et al. (2022) could not distinguish between in- abundance of several other fecal bacterial species, includ-
fectious and nutritional diarrhea. Further investigation is ing Bacteroides caccae, Bacteroides ovatus, Bacteroides
needed to determine the optimal duration and intensity of uniformis, Desulfovibrio piger, and Clostridium symbio-
maternal contact to promote beneficial bacteria coloniza- sum in offspring. Colonization of B. caccae, D. piger,
tion while minimizing pathogen exposure and neonatal and C. symbiosum was higher in mouse pups of dams fed
enteric infections. a fiber-free diet than those of dams on a fiber-rich diet.
A study on goats reported that the presence of adult The absence of fiber in the maternal diet led to altered
companions can alter the rumen microbial composition priming of the mucosal immune responses, as evidenced
of goat kids (Palma-Hidalgo et al., 2021). Goat kids by the differential expression of transcripts. Various im-
reared with a nonlactating adult companion exhibited mune pathways, such as epithelial barrier development
different bacterial and archaeal communities compared and cell-cell adhesion, peptide cross-linking, apoptosis
with conventionally reared goat kids. This study suggests associated with cell detachments from epithelial tissue,
that early-life exposure to adult animals can influence oxidative stress-induced intrinsic apoptotic signaling
microbial colonization trajectories in neonatal ruminants. pathways, and response to IFNβ, were enriched in mouse
Overall, there is a lack of information to determine the pups born to dams on a fiber-free diet compared with
benefits of short-term versus long-term exposure to dams those born to dams on a fiber-rich diet. The expression of
or other adults for gut microbiota establishment and calf proinflammatory cytokines (TNFα and IL-22) was higher
health. In addition, the effects of these microbial changes in pups born to dams on a fiber-free diet compared with
on calf immune system development and long-term those born to dams on a fiber-rich diet. In contrast, the
production performance require further investigation. expression of IL-17F, which initiates protective immune
It is essential to evaluate both microbiome and immune responses during gut homeostasis (Mills, 2023), was
parameters when assessing the benefits of exposure or lower in pups born to dams on a fiber-free diet compared
contact for calf microbiota and immunity co-develop- with those born to dams on a fiber-rich diet (Grant et al.,
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2023). When the authors examined the population of im- system of mouse pups (Patel et al., 2023). Supplementing
mune cells in the lamina propria of the colon, they found dams with DHA and ARA affects T cell populations in
that the fiber-rich maternal diet increased the number of the spleen of 3-wk-old mouse pups. For example, pups
innate lymphoid cells and Th17 T cells in the mice pups from dams receiving DHA and ARA had lower numbers
compared with a fiber-free maternal diet. These results of CD4+, CD8+, CD25+, and CD28+ T cells in the spleen
together suggest that the absence of fiber in the maternal than those born to dams receiving a control diet (Patel et
diet alters the gut microbial community and priming of al., 2023). Despite the lower proportion, T cells isolated
the mucosal immune system of offspring. from pups born to DHA- and ARA-supplemented dams
Similarly, high-fat diets during the third trimester of produced high levels of proinflammatory cytokines (IL-
pregnancy have been shown to alter infant gut microbial 1β, IFNγ, TNFα) in response to a bacterial challenge.
communities at birth (Chu et al., 2016). However, the These results together suggest that maternal supplemen-
effect of high maternal fat intake on the bacterial com- tation can alter immune cell differentiation and priming
munity was subtle in 6-wk-old infants, suggesting that of immune responses in offspring.
other early factors (feeding method, other exposures) Human studies have suggested links between maternal
may exert a more pronounced influence than maternal diet and nutrition and the gut microbiota and immunity
diet alone. Moreover, high fat intake during pregnancy of the offspring (Sausenthaler et al., 2007; Chu et al.,
decreased the colonization of Bacteroides in the gut of 2016; Obenewa and Newell, 2017; Lundgren et al.,
infants. Another study investigating the effects of ma- 2018). Grant et al. (2023) used a well-designed animal
ternal dietary habits in late-mid pregnancy (24–28 wk) trial to illustrate the effects of maternal diet (or fiber
showed a birth mode-dependent effect of maternal diet intake during pregnancy) on the co-development of the
on the gut microbiota of 6-wk-old infants (Lundgren et gut microbiota and mucosal immune system. Therefore,
al., 2018). The study identified distinct clusters distin- animal models are sounder and safer to establish causal
guishing infants based on the abundance of bacterial taxa effects of maternal diet and nutrition on the microbiota
in the feces, with maternal dietary habits showing cor- and immunity of the offspring. In cattle, there is a lack of
relations with microbial cluster membership. The likeli- understanding of how maternal diet affects the gut micro-
hood of belonging to cluster 2 (which was dominated by biota of neonatal calves. Recently, Luecke et al. (2023)
Streptococcus and Clostridium) increased 2.73-fold in conducted a study to investigate the effect of maternal
VD infants with each additional maternal fruit serving vitamin and mineral (VTM) supplementation during
per day. This study did not control for maternal dietary pregnancy on the microbial colonization of 8 different
intake but examined the relationship between maternal microbial communities in neonatal calves. The authors
feeding habits and infant gut bacterial community using reported that VTM treatment contributed to 27% (PER-
data from a cohort study. MANOVA R2 = 0.27) of the observed variation in the
A German cohort study (Sausenthaler et al., 2007), rumen bacterial communities of VTM and control calves.
investigating the influence of lifestyle-related factors Additionally, bacterial diversity (Shannon index and in-
on the immune system and the development of aller- verse Simpson’s index) was higher in the rumen of VTM
gies in childhood, established a link between maternal calves compared with control calves. At the genus level,
dietary habits during the third trimester and infant health the relative abundance of Escherichia-Shigella was lower
outcomes in the first 2 yr of life. The prevalence of ec- in VTM calves compared with control calves (Luecke et
zema at 2 yr of age increased with increasing maternal al., 2023). Furthermore, maternal diet has been shown
consumption of margarine, vegetable oils, and seeds. Al- to alter the microbiota of bovine milk, the primary diet
lergic sensitization (the production of immunoglobulin of neonatal calves during the preweaning period. When
E to antigens that are ingested, absorbed, or inhaled) to cows were fed a high-starch and low-fiber diet, an in-
food allergens increased in babies with high consumption crease in mastitis-associated bacteria in milk was found,
of celery and citrus fruits during pregnancy. Maternal compared with cows fed a low-starch and high-fiber diet
intake of n-3 PUFA is another highly investigated area (Coates et al., 2022). This suggests a possible change
to understand its effects on offspring health. A meta- in milk microbiota, a major contributor (31.6%) of off-
analysis (Gunaratne et al., 2015) conducted using data spring microbiota (Bogaert et al., 2023), that calves may
from 8 different studies found that n-3 PUFA intake be exposed to in their early life. In general, the effects
during pregnancy, breastfeeding, or both, reduces aller- of dam diet and nutrition on calf microbiomes (composi-
gies in children aged 12 to 36 mo. However, no effect tion, diversity, colonization trajectories) are limited.
of maternal n-3 PUFA was found beyond 36 mo of age. Previous studies in cattle have primarily investigated
Supplementing pregnant mice with docosahexaenoic acid the effects of maternal nutrition on calf health (passive
(DHA) and arachidonic acid (ARA) throughout gestation transfer of immunity at birth), particularly concerning
and lactation has been shown to modulate the immune over- and undernutrition. Although the effects of mater-
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nal nutrition on calf health have been studied primarily pared with cows fed grass silage (McGee et al., 2006),
in beef cattle, few studies in dairy cattle have examined indicating a potential reduction in passive transfer of
colostrum quality (primarily colostral IgG) to understand immunity to newborn calves when cows are undernour-
the effects of maternal nutrition on the passive transfer ished. A recent study found an increasing trend in IgG
of immunity. Most of these studies have focused on concentration in calves when cows were given a protein
maternal nutrition during the last trimester of gestation supplement during the dry period on pasture (Silva et
when fetal growth is progressing rapidly. However, the al., 2022). These studies suggest that even short-term
development of the immune system begins in the early malnutrition can influence the passive transfer of immu-
stages of fetal development and continues throughout nity to newborn calves. Short-term energy restriction in
the neonatal period (Chase et al., 2008). Feeding a high beef cows during late gestation may affect calf immune
energy-density diet (150% of energy requirements) dur- priming beyond the passive transfer of immunity. Moriel
ing the last trimester of pregnancy reduced colostral IgG et al. (2016) conducted a 70% energy restriction during
levels compared with cows fed a control diet (100% of the last 40 d of gestation in multiparous cows to inves-
energy requirements; Mann et al., 2016). However, the tigate the effects of dietary restriction on calf immunity.
study lacked information on the serum IgG levels of the There was no effect of energy restriction on the serum
offspring. Therefore, it is unclear whether a high-energy IgG levels of calves at birth. However, maternal energy
maternal diet influenced the passive transfer of immu- restriction reduced the priming of antibody responses to
nity. Interestingly, cows in both groups had colostral vaccines in weaned calves. Specifically, calves born to
IgG concentrations above the recommended levels (>50 energy-restricted cows had lower systemic antibody ti-
g IgG/L colostrum), suggesting successful transfer of ters (serum titers) for bovine viral diarrhea virus (BVDV-
passive immunity if the calves received sufficient colos- 1) than those born to control cows (100% daily NEm re-
trum at birth. Another study (Dunn et al., 2017) reported quirement). Another study (Moriel et al., 2020) reported
that feeding grass silage with or without concentrate that both energy and protein supplementation during
supplementation during the dry period (the last 2 mo of late gestation increased the positive seroconversion rate
gestation) did not affect colostral IgG or serum IgG of against respiratory pathogens (bovine viral diarrhea virus
the calves. However, calves from cows fed concentrates and parainfluenza-3) in beef calves after vaccination. A
had fewer enteric infections than the control group. It is study examining the blood transcriptome profile of beef
possible that concentrate supplementation during the dry calves showed that the expression of genes modulating
period altered the priming of the immune system or the responses to viral infections and natural killer cell ac-
establishment of gut microbiota differently in neonatal tivity was downregulated by maternal energy restriction
calves, which needs to be explored in the future. In addi- (70%) during late gestation (Sanglard et al., 2018). These
tion to nutrition, supplementation of pregnant cows with studies suggest that maternal nutritional restriction dur-
fish oil and linseed during late gestation has been shown ing late gestation may affect calf immunity at different
to increase fat, protein, IgG, IgA, DHA, and conjugated stages of life (at birth, before and after weaning) by
linoleic acids in colostrum (Grodkowska et al., 2023), altering the expression of immune-related genes and
suggesting that they may influence the passive transfer antibody responses to vaccines. This affects the ability
of immunity to newborn calves. Omega-3 fatty acids, to raise healthy offspring in the cattle industry. Current
including DHA, have long been tested as dietary supple- nutritional standards for cows are mainly based on cow
ments for pregnant dairy cows. However, the effects performance, and information on offspring health is lack-
of DHA or other n-3 fatty acids on the immune system ing, particularly on the effects of maternal nutrition on
of newborn calves are limited. Mee (2023) provides a early-life immune development. Immune development in
comprehensive review of the effects of maternal diet early life shapes lifelong memory. Therefore, an in-depth
and nutrition on calf health. These studies mainly focus understanding of calf immune priming in early life is es-
on colostrum IgG, passive transfer of immunity, health sential to improve the nutrition of pregnant cows to raise
data, growth, or different blood markers (haptoglobin) healthy offspring.
to evaluate calf health. In general, knowledge is lacking
on the effects of maternal diet and nutrition on the devel- Maternal Health and Stress: Impacts on Calf Gut
opment of the immune system (systemic, mucosal) and Microbiome and Immunity
the priming of immune responses (antibody responses,
cellular responses) in neonatal calves. Mild inflammation in the mucosal membranes (e.g.,
In beef cattle, the effect of maternal malnutrition on the gut-associated immune system) is typical during
calf health is one of the major research focuses. Feeding pregnancy. However, maternal conditions such as obesi-
straw in the last 15 d of gestation resulted in lower total ty, diabetes, stress, and leaky gut syndrome can increase
IgG1 levels in the colostrum of multiparous cows com- inflammation during pregnancy and alter the gut micro-
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biome (Edwards et al., 2017). For example, maternal cows are considered metabolic stresses (Lucy, 2019).
stress during early pregnancy has been shown to reduce Lack of animal-to-animal and animal-to-human interac-
fecal bacterial diversity and alter taxa composition in tions, infections, and calving can also lead to stress in
pregnant mice (Jašarević et al., 2017). When pregnant pregnant cows (Lucy, 2019). The effects of stress during
mice were exposed to stress during early gestation, the pregnancy have been studied mainly in terms of lacta-
colonization of Lachnospiraceae and Ruminococcaceae tion performance, reproduction, and cow and calf health.
in the gut increased during late gestation compared with Calves from cows with higher metabolic stress had lower
nonstressed dams. These microbial changes may then body weight and higher reactive oxygen and nitrogen
lead to an altered gut microbiome and immunity in the species, haptoglobin, and TNFα in the blood than calves
offspring due to the altered microbial composition in the from cows with lower metabolic stress (Ling et al., 2018).
first inoculum of neonates or due to altered metabolite This suggests that maternal stress alters the systemic im-
profiles. A study conducted by Soderborg et al. (2018) mune responses of calves during the preweaning period.
showed that colonization of germ-free mice with the A limited number of studies have evaluated the effects
gut microbiota of infants born to obese mothers alters of stress on the maternal and neonatal gut microbiome
inflammatory responses and increases the risk of devel- of livestock species. Chen et al. (2018) reported that
oping obesity and nonalcoholic fatty liver disease. The heat stress decreased the abundance of Firmicutes and
authors colonized 8- to 10-wk-old germ-free mice with increased the abundance of Bacteroidetes in the feces of
the stool of 2-wk-old infants born to either obese or lean lactating dairy cows compared with those without heat
mothers. Mice colonized with stool from infants born to stress (Chen et al., 2018). A study in pigs has shown that
obese mothers had a higher abundance of Firmicutes in heat stress in pregnant sows can alter the composition of
the gut than those colonized with stool from infants born the gut bacterial community in piglets (He et al., 2020).
to lean mothers (Soderborg et al., 2018), which is a clas- When sows were exposed to heat stress during late ges-
sic observation in the gut microbiome of obese humans. tation, the abundance of Firmicutes decreased and the
In addition, mice colonized with obese gut microbiota abundance of Proteobacteria increased in the piglets (He
showed higher intestinal permeability than those colo- et al., 2020). Due to global warming, pregnant cows are
nized with lean microbiota. When liver inflammation now exposed to more heat stress than in the past. Howev-
was assessed, expression of the tnf gene and the number er, there is limited understanding regarding the effects on
of resident macrophages were higher in the liver of obese the microbiome of dams and newborn calves or the early
microbiota-colonized mice than in those colonized with development of the mucosal and systemic immune sys-
lean microbiota. Similarly, gestational diabetes mellitus tems. Maternal heat stress has also been shown to affect
has been shown to affect infant gut microbiota (Soder- calf health (Tao et al., 2012; Ahmed et al., 2021). Heat
borg et al., 2020; Chen et al., 2021a) and health (Singh stress during the last 45 d of gestation decreased both
et al., 2023), indicating that maternal health affects the birth and weaning weights of calves (Tao et al., 2012).
microbiome and immunity of offspring. Both human and Ahmed et al. (2021) reported that heat stress during the
mouse models have shown that maternal stress affects last 45 d of gestation decreased calf birth weight, thymus
the colonization of offspring’s gut in early life. Severe and spleen weights at birth, and serum IgG during the
maternal psychological stress during the first 16 wk of first 28 d of life, but increased apoptosis of epithelial
pregnancy reduced the fecal bacterial diversity in 5- to cells in the jejunum (Ahmed et al., 2021). These studies
6-mo-old infants (Galley et al., 2023). In contrast, severe suggest that heat stress during late gestation negatively
maternal stress during the third trimester of pregnancy affects calf growth and health.
has been associated with increased fecal bacterial diver- Maternal vaccination represents a cost-effective ap-
sity in newborns (Weiss and Hamidi, 2023). In addition, proach to enhance the passive transfer of immunity to
maternal depression has been shown to reduce coloniza- newborn calves. Cows can be vaccinated either before
tion of Proteobacteria (family Enterobacteriaceae) in breeding with modified live vaccines (MLV) or during
the gut of 3- to 4-mo-old infants (Rodriguez et al., 2021), pregnancy with killed vaccines (KV). Most studies have
Proteobacteria being a pioneer bacterial taxon that plays focused on the effect of using respiratory vaccines in
a vital role in creating the environment for the anaerobic cows on calf immunity. The use of KV in pregnant cows
gut residents. increased the pathogen-specific IgG in colostrum (Smith
Pregnant cows are exposed to various stress factors, et al., 2015) and in calf serum 24 h after birth (Reppert et
including metabolic, heat and cold, and transportation al., 2019) compared with unvaccinated cows, suggesting
stress (Lucy, 2019; Ghaffari, 2022). Inadequate adapta- a successful increase in passive transfer of pathogen-
tion to the increased nutritional requirements during specific immunity. Despite the superior production of
pregnancy can lead to metabolic stress in cows. There- pathogen-specific antibodies by MLV compared with KV
fore, malnutrition and overfeeding of protein in pregnant (Dubovi et al., 2000), the influence on passive transfer of
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 Diddeniya et al.: INVITED REVIEW: DAM ROLE IN NEONATE MICROBIOTA AND IMMUNITY 7515
immunity remains poorly understood. Future research is the neonatal gut and modulates its composition. How-
needed to elucidate the differential effects of MLV and ever, such understanding is limited in neonatal calves,
KV on the passive transfer of immunity. In addition to despite maternal vaccination practices targeting various
enhancing the passive transfer of immunity, maternal pathogens before breeding and or during gestation.
antibodies may also play a role in modulating the neo-
natal gut microbiome (Sanidad et al., 2022). Research CONCLUSIONS AND FUTURE DIRECTIONS
in mice has shown that the neonatal Fc receptor (FcRN)
in the gut facilitates the transfer of maternal IgG from This comprehensive review highlights the need for
the mother to the fetus, influencing the colonization of a deeper understanding of the maternal factors shap-
gut microbiota in offspring (Sanidad et al., 2022). The ing the gut microbiome and immune development and
authors compared the ability to inhibit the colonization maturation of neonatal calves (Figure 2). We highlight
of enteric pathogen Citrobacter rodentium in the gut of the existing knowledge gap, particularly during the
mice pups from wild-type and FcRN knockout dams. gestational period, and the relative paucity of studies in
The pups born to wild-type dams exhibited a decrease in cattle compared with extensively studied species such
pathogen load 7 d following infection, whereas the pups as humans and mice. Future research in cattle needs to
of FcRN knockout dams showed sustained pathogen den- adopt a holistic and longitudinal approach while explor-
sity (Sanidad et al., 2022). This suggests that maternal ing a broad range of maternal factors that alter maternal
IgG neutralizes the microbiota or pathogen colonizing microbiomes and metabolites. Longitudinal studies are

Figure 2. Influence of maternal factors on the co-development of the microbiome and immunity of neonatal calves. During gestation, pregnant
cows undergo various stresses and dietary changes that can modulate the maternal microbiota, metabolites, colostrum and milk composition, and
fetal developmental programs. At calving, newborn calf exposure can be varied due to dystocia, leading to prolonged and assisted calving as well as
potential antibiotics use. Postnatally, neonatal calves are exposed to various management conditions (nutrients, housing, treatments). The effects of
postnatal factors on gut microbial community composition are a major research focus. The role of maternal factors on calf health has been mainly
studied in terms of passive transfer of immunity. SFCA = short-chain fatty acids. The figure was created using BioRender (https:​/​/​app​.biorender​
.com).

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NOTES ota during infancy. mSystems 8:e0119022. https:​/​/​doi​.org/​10​.1128/​
msystems​.01190​-22.
This review received no external funding. Because no Chase, C. C. L., D. J. Hurley, and A. J. Reber. 2008. Neonatal immune
development in the calf and its impact on vaccine response. Vet.
human or animal subjects were used, this analysis did not Clin. North Am. Food Anim. Pract. 24:87–104. https:​/​/​doi​.org/​10​
require approval by an Institutional Animal Care and Use .1016/​j​.cvfa​.2007​.11​.001.
Committee or Institutional Review Board. The authors Chen, S., J. Wang, D. Peng, G. Li, J. Chen, and X. Gu. 2018. Exposure to
heat-stress environment affects the physiology, circulation levels of
have not stated any conflicts of interest. cytokines, and microbiome in dairy cows. Sci. Rep. 8:14606. https:​/​
/​doi​.org/​10​.1038/​s41598​-018​-32886​-1.
Nonstandard abbreviations used: ARA = arachidon- Chen, T., Y. Qin, M. Chen, Y. Zhang, X. Wang, T. Dong, G. Chen, X.
Sun, T. Lu, R. A. White 3rd, P. Ye, H. M. Tun, and Y. Xia. 2021a.
ic acid; CS = cesarean section; DHA = docosahexaenoic Gestational diabetes mellitus is associated with the neonatal gut
acid; FcRN = neonatal Fc receptor; KV = killed vaccine; microbiota and metabolome. BMC Med. 19:120. https:​/​/​doi​.org/​10​
MLV = modified live vaccine; OTU = operational taxo- .1186/​s12916​-021​-01991​-w.
Chen, Y. Y., X. Zhao, W. Moeder, H. M. Tun, E. Simons, P. J. Mand-
nomic units; VD = vaginally delivered; VTM = vitamins hane, T. J. Moraes, S. E. Turvey, P. Subbarao, J. A. Scott, and A.
and minerals. L. Kozyrskyj. 2021b. Impact of maternal antibiotics and caesarean
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Journal of Dairy Science Vol. 107 No. 10, 2024