medicina

Review
Breastfeeding-Related Health Benefits in Children and Mothers:
Vital Organs Perspective
Julio César Muro-Valdez 1 , Alejandra Meza-Rios 1 , Blanca Rosa Aguilar-Uscanga 2 ,
Rocio Ivette Lopez-Roa 3 , Eunice Medina-Díaz 4 , Esmeralda Marisol Franco-Torres 3
and Adelaida Sara Minia Zepeda-Morales 1, *

1 Laboratorio de Análisis Clínicos y Bacteriológicos (Vinculación), Departamento de Farmacobiología, CUCEI,

Universidad de Guadalajara, Boulevard Marcelino García Barragán, No. 1421, Guadalajara 44430, Mexico;
julio.muro@alumnos.udg.mx (J.C.M.-V.); alejandra.mezarios@academicos.udg.mx (A.M.-R.)
2 Laboratorio de Microbiología Industrial, Departamento de Farmacobiología, CUCEI,
Universidad de Guadalajara, Boulevard Marcelino García Barragán, No. 1421, Guadalajara 44430, Mexico
3 Laboratorio de Investigación y Desarrollo Farmacéutico, Departamento de Farmacobiología, CUCEI,
Universidad de Guadalajara, Boulevard Marcelino García Barragán, No. 1421, Guadalajara 44430, Mexico
4 Instituto Transdisciplinar de Investigación y Servicios, CUCEI, Universidad de Guadalajara,
Av. José Parres Arias 5, Rinconada de la Azalea, Industrial Belenes, Zapopan 45150, Mexico
* Correspondence: adelaida.zepeda@academicos.udg.mx; Tel.: +52-3323845364

Abstract: Breast milk (BM) is a constantly changing fluid that represents the primary source of
nutrition for newborns. It is widely recognized that breastfeeding provides benefits for both the
child and the mother, including a lower risk of ovarian and breast cancer, type 2 diabetes mellitus,
decreased blood pressure, and more. In infants, breastfeeding has been correlated with a lower risk of
infectious diseases, obesity, lower blood pressure, and decreased incidence of respiratory infections,
diabetes, and asthma. Various factors, such as the baby’s sex, the health status of the mother and
child, the mother’s diet, and the mode of delivery, can affect the composition of breast milk. This
review focuses on the biological impact of the nutrients in BM on the development and functionality
of vital organs to promote the benefit of health.
Citation: Muro-Valdez, J.C.;
Keywords: breast milk; lactation; breastfeeding; human health
Meza-Rios, A.; Aguilar-Uscanga, B.R.;
Lopez-Roa, R.I.; Medina-Díaz, E.;
Franco-Torres, E.M.; Zepeda-Morales,
A.S.M. Breastfeeding-Related Health
Benefits in Children and Mothers: 1. Introduction
Vital Organs Perspective. Medicina BM is widely recognized as the benchmark for nourishing newborns. The World
2023, 59, 1535. https://doi.org/ Health Organization (WHO) and the United Nations Children’s Fund (UNICEF) advocate
10.3390/medicina59091535 for exclusive breastfeeding during the initial 6 months of an infant’s life, with the exception
Academic Editor: Simone Ferrero of water, and introducing complementary foods up to the age of 2 years [1,2]. Other WHO
recommendations for breastfeeding management include initiating breastfeeding within
Received: 9 July 2023 the first hour after birth and feeding the baby on demand [3]. However, according to
Revised: 30 July 2023
the Infant Feeding Area Graphs Interpretation Guide published by UNICEF, exclusive
Accepted: 16 August 2023
breastfeeding rates were reported to be only 44 percent globally in 2021 [1]. BM is a biofluid
Published: 25 August 2023
known to contain a diverse array of macro- and micro-nutrients, including proteins, carbo-
hydrates, lipids, vitamins, and minerals. Furthermore, it includes bioactive compounds
such as hormones, growth factors, digestive enzymes, transporters, and antimicrobial
Copyright: © 2023 by the authors.
agents, as well as maternal cells, including leukocytes and stem cells [4]. Based on its rich
Licensee MDPI, Basel, Switzerland. composition, BM is presumed to fulfill the nutritional requirements of infants, facilitating
This article is an open access article optimal development, growth, and cognitive function [5]. The composition of BM behaves
distributed under the terms and dynamically, constantly changing and adjusting to the infant’s needs over time. Several
conditions of the Creative Commons factors influence BM composition, including the duration of lactation, maternal health
Attribution (CC BY) license (https:// conditions, genetic factors, and dietary choices, among others [6].
creativecommons.org/licenses/by/ Research has demonstrated that the consumption of BM offers a multitude of health
4.0/). benefits. These include the modulation of the gut microbiota, protection against pathogenic

Medicina 2023, 59, 1535. https://doi.org/10.3390/medicina59091535 https://www.mdpi.com/journal/medicina

Medicina 2023, 59, 1535 2 of 14

bacteria in the gut, and potential protective effects against diseases such as diabetes and
obesity [7–9]. Additionally, BM has been shown to possess antiviral properties [10,11]. This
article is a scoping review that provides specific benefits of BM for the brain, lungs, liver,
kidneys, and heart, as well as its effect on the intestinal microbiota and the health benefits
to the breastfeeding mother, based on studies registered in public databases as well as in
specialized engines. The evidence discussed here is based on clinical trials and comes from
a search that goes back to ten years before the publication date except for information or
classic documents necessary for the basis of the review.

2. Breastfeeding Effects on Brain Health and Development

The correct diet in early life plays a decisive role in ensuring the proper functional
and structural development of the central nervous system [12]. Numerous studies have
investigated the impact of BM on brain development, with a particular focus on the
effects of 20 -fucosyllactose (20 -FL). Recently, a study demonstrated that sialic acid derived
from sialyllactose present in the milk freely crosses the blood–brain barrier, with higher
concentrations observed in gangliosides and glycoproteins within the gray matter [13].
In this context, Vázquez et al. evaluated the effect of 20 -FL on synaptic plasticity and
cognitive function in an animal model using C67BL/6 mice and Sprague–Dawley rats. The
results revealed that animals treated with 20 -FL exhibited improved scores in cognitive
tests, along with increased expression levels of molecules associated with short-term
memory [14]. In 2020, Berger and colleagues demonstrated through the Bayley scale
(which evaluates cognitive, motor, and linguistic abilities at 24 months of life) that the
frequency of lactation in the first month of life is a key factor in the cognitive development
of infants, associated with higher exposure to 20 -FL [15], suggesting the importance of
early exposure to 20 -FL, especially within the window of the first 6 months when the
brain mass reaches half of its adult size [15,16]. Tarr et al. evaluated the properties of
human milk oligosaccharides (HMOs) on brain tissue by administering 30 Sialyllactose and
60 Sialyllactose to C57BL/6 mice for two weeks. The HMOs protected the mice from the
deleterious effects of stressor factors, regulated the gut microbiota, and maintained the
normal number of neurons in the brain convolutions; these results showed the pivotal role
of BM in the gut-brain axis [17].
A publication from 2015 investigated the impact of the duration of BM consumption,
revealing that infants who were breastfed for a minimum of 12 months exhibited an average
increase of 3.76 IQ points in adulthood compared to infants who were breastfed for only
1 month [18]. While it is widely acknowledged that BM consumption offers short-term
benefits, it is important to emphasize that breastfeeding can also yield long-term advantages
for the infant.
In another study using magnetic resonance imaging, brain white matter volume
was compared in infants who were breastfed for a minimum of 3 months, finding that
infants who were breastfed had greater white matter development in brain regions linked
to language, emotion, and cognition [19]. These results are consistent with the results
obtained in a study where BM consumption was associated with increased white matter
and greater cognitive development [20].
The phospholipids present in BM have also demonstrated beneficial effects on brain
development. The precursors of choline sphingomyelin and phosphatidylcholine are a
factor in normal memory and cognitive function, as well as brain and neurological devel-
opment [21]. Comparative studies between BM and formula milk have shown that BM
significantly increases the levels of sphingomyelin and choline in the brain [22]. Several
components of BM, such as cholesterol, long-chain polyunsaturated fatty acids, and docosa-
hexaenoic acid, among others, can provide benefits to the less-developed brains of preterm
infants and enhance neurodevelopment [23]. In this context, Zhang et al. conducted a
study to evaluate the effect of breastfeeding on early brain development in premature
babies. Their observations revealed that BM increased regional gray matter volume in
comparison to formula-fed babies, specifically in various brain regions, including the right
Medicina 2023, 59, 1535 3 of 14

temporal lobe, left caudate nucleus, and bilateral frontal lobe. Furthermore, BM was found
to enhance brain activation in the superior temporal gyrus [24].
In a study aimed at investigating the target sites of cells present in BM, a BALB/c mice
model was utilized, and fluorescently labeled cells were employed along with real-time
PCR and immunohistochemistry techniques. Stem cells were found in the blood and
brain, which were derived from BM; furthermore, these cells demonstrated the ability to
differentiate into neuronal and glial cells. Based on these results, it has been postulated
that breast milk stem cells might play a role in brain maturation and provide support to
host cells through the secretion of growth factors [25].
One of the functions related to brain development is speech ability. Results of a meta-
analysis conducted by Abida et al. show the effect of breastfeeding on speech development
in children. The results of the analysis of cohort studies indicate that breastfeeding increases
language development by 1.19 times compared to children who did not receive this type
of feeding; the effect observed in cross-sectional studies was 1.54 times greater language
development in breastfed children compared to those who did not [26]. The results are con-
sistent with what was published by Rosidi and collaborators, who suggest that exclusively
breastfed children acquire sufficient energy to favor this improvement in speech [27].
Recently, interventional clinical trials have used BM as a nutritional intervention for
some specific conditions to enhance newborn brain development. Some of these clinical
trials are summarized in Table 1 [14 March 2023 from: https://clinicaltrials.gov/].

Table 1. Clinical trials using breast milk to enhance newborn brain development.

Status Title Intervention Country Identifier

Targeting breast milk fortification
Individually targeted
Recruiting to improve preterm infant growth USA NCT03977259
fortification
and brain development
Supplemental choline and brain Phosphatidylcholine
Completed USA NCT00678925
development in humans Corn oil placebo
Pasteurized donor human BM
Completed OptiMoM kindergarten study Canada NCT02759809
Preterm formula
Renoir: a randomized,
double-blind, controlled trial to France, Germany,
Test product
Active, not recruiting evaluate the effects of a new breast The Netherlands, and the NCT03315221
Control product
milk fortifier on growth and United Kingdom
tolerance in preterm infants.
BM, breast milk.

3. Breastfeeding Benefits Kidney Performance

The current information on this subject is limited; however, the existing studies in
this area are summarized below. Boutrid et al. conducted a systemic review to explore the
association between breastfeeding and renal prognosis. The review revealed several notable
findings. (a) New thresholds for calciuria were determined according to different child
feeding, (b) lactation during the first 4 months of life was correlated with a lower estimated
glomerular filtration rate (eGFR) and increased combined kidney volume (p < 0.05) (based
on the analysis of over 5000 children) [28], (c) higher protein content in formula milk
led to increased kidney size (42.6 cm3 ) in 6-month-old infants compared to infants who
were breastfed and had a normal kidney size (19.1 cm3 ); however, the long-term effect of
consuming high-protein formulas needs to be studied [28,29]. This suggests a possible
negative impact of excessive protein consumption in the early stages of infancy. The author
concluded that BM may have favorable renal effects during infancy [28]. There is a direct
association between the amount of protein consumed and the growth and function of the
kidneys, where the amount of protein consumed in the first months of life may promote
different patterns of kidney tissue growth and, thus, affect the long-term function of these
organs [29]. In this context, Miliku et al. explored the associations between breastfeeding
duration and kidney outcomes during school age; the study included a total of 5043 children
Medicina 2023, 59, 1535 4 of 14

from the Netherlands and found that breastfed children versus never breastfed had smaller
kidneys and presented lower eGFRs. In addition, shorter durations of breastfeeding were
associated with smaller kidney volumes and a lower risk of microalbuminuria. Based
on their findings, the authors concluded that breastfeeding is associated with subclinical
changes in kidney outcomes during childhood [30].
The development of kidney stones has been associated with the type of diet, the type
of fluids consumed, and micronutrients such as vitamin D and calcium. Urolithiasis in
children has also been related to hereditary genetic factors and metabolic disorders [31,32].
Shajari et al. investigated the correlation between the type of milk consumed and the risk
of developing kidney stones. The study involved 30 children below the age of two who
had been diagnosed with kidney stones and 125 children without stones as a control
group. The results showed a significant difference in the duration of breastfeeding between
children with kidney stones and those without, concluding that breastfeeding may serve
as a nutritional factor to prevent and protect against the development of kidney stones
in children [31]. Recently Bozkurt et al. evaluated the potential impact of breastfeeding
duration on the clinical progression and therapy of kidney stones detected in infancy. The
study included 48 children with renal stones, and the duration of lactation was evaluated,
taking into account the characteristics of the stones at the time of the diagnosis. The find-
ings demonstrated that the duration of breastfeeding was longer in patients who did not
experience disease progression and in infants with a smaller size and/or fewer stones. Fur-
thermore, according to this study, children who exclusively breastfed for the first six months
of life required less treatment and exhibited lower rates of growth retardation [32].

4. Breastfeeding and the Lung Function

The influence of exclusive breastfeeding on lung function in a later stage of life is still
a topic of controversy. Several studies have explored the potential correlations between
breastfeeding and lung function in children who were exclusively breastfed for an extended
duration [33]. Furthermore, investigations into the lung microbiome have revealed insights
into the relationship between respiratory diseases and lung microbiota, highlighting the
favorable effects of prolonged exclusive breastfeeding on the function of smaller airways
throughout childhood. Observational studies have also suggested that breastfeeding miti-
gates the lung consequences of respiratory infections, leading to improved lung function
during school age, particularly among children with atopic backgrounds. Moreover, re-
search has indicated that breastfeeding can help protect lung function in individuals who
are exposed to high levels of air pollution [34], including passive smoking [35]. These
findings suggest that breastfeeding might mitigate the negative impacts of environmental
factors on the developing lungs [36].
The protective influences of breastfeeding on lung function may be attributed to a
decrease in respiratory infections [37] and the association with increased height in breastfed
children [38]. Moreover, the positive impact of longer breastfeeding duration on lung
capacity, as measured at 10 years old, persists until 18 years of age [37]. This is of particular
significance considering that asthma, the highest prevalent chronic non-communicable
childhood disease, affects approximately 14% of children worldwide [39], leading to fre-
quent emergency room visits and school absenteeism, often resulting in lifelong impair-
ments in lung health [40]. Several investigations have demonstrated that certain HMOs
have the ability to directly modulate the immune response by mitigating viral pathogens
and modulating the behavior of immune cells within the host [41]. These findings highlight
the potential immunomodulatory properties of HMOs concerning respiratory health.
Furthermore, there is an additional potential mechanism through which HMOs pro-
vide protection against asthma. Around 1% of HMOs are absorbed into the bloodstream
and eventually reach target organs, including the lungs [42]. HMOs can influence the
turnover of airway epithelial cells, the formation of glycocalyx mucus, and interact with
immune cells and pathogens, thereby offering protection against asthma [43]. Many factors
could contribute to the effect of breastfeeding on lung function outcomes. Breastfeeding
Medicina 2023, 59, 1535 5 of 14

plays a role in preventing respiratory tract infections, which, in turn, promotes optimal
lung growth. Additionally, the reduced accumulation of body fat in breastfed infants may
contribute to enhanced lung performance [38].
Several studies have reported conflicting results. In a research study conducted on
healthy children with minimal risk of asthma, the duration of breastfeeding was not found
to be associated with lung function outcomes at 6 years of age [38,44]. These divergent
findings may be attributed to variations in the size of the sample, the focus of determinants,
participant age, confounding factors, and study methodologies. On the other hand, the
literature also mentions a non-immunological effect of BM. For instance, Castellote et al.
highlighted that colostrum contains abundant growth factors such as TGF-β, and the
concentration of these molecules gradually decreases in BM during the initial months of
life [45]. These growth factors have the potential to promote positive lung development by
enhancing elastin activity in fibroblasts [37,46].

5. Breastfeeding Effects on the Liver Tissue and Hepatic Functions

The liver plays a vital role as the primary organ responsible for biochemical metabolism
within the human body (energy metabolism and the maintenance of metabolic homeostasis).
It metabolizes various compounds, both beneficial and harmful, as well as endogenous
and exogenous molecules. Compounds absorbed by the intestine, including drugs and
nutrients, first pass across the liver, resulting in the formation of smaller products and the
regulation of their blood levels [47,48]. The shift from being a fetus to becoming a newborn
represents the most intricate adaptation that takes place in the human journey [49]. The
liver of a newborn must swiftly adjust and develop to meet the demands presented by
life outside the uterus. This maturation process involves various molecular, cellular, and
environmental factors, as identified previously by Chen et al. [50]. The consumption of milk
and, later, the introduction of solid foods provides a greater abundance of nutrients and
requires the neonate to take charge of its metabolic requirements, consequently influencing
postnatal hepatic metabolism [51–53]. A pioneering study focused on breast milk’s impact
on liver development was conducted by Kohno et al. They researched the influence
of BM on DNA synthesis in rat neonatal hepatocytes to assess its physiological role in
liver growth. The results demonstrated that BM increased DNA synthesis; also, the BM
presented a mitogenic activity in vitro, suggesting its potential importance for the growth
and development of the infant liver [54].
Carvalho et al. studied the impact of postnatal diet (BM versus formula milk) on liver
mitochondrial bioenergetics phenotypes in male piglets. The researchers explored how
this “programming” of physiological systems could have potential metabolic consequences
in childhood and adulthood. The piglets fed with milk formula exhibited higher ADP-
linked respirations, suggesting increased ATP turnover in the liver, which in turn drove an
elevation in oxygen consumption [55]. In this context, Pena–Leon et al. investigated the
impact of breastfeeding on the infant’s reprogramming of energy balance during childhood
and adulthood. They utilized a rat model where prolonged breastfeeding or suckling was
followed by feeding the rats either a chow diet or a high-fat diet until adulthood. The results
revealed that extended breastfeeding could mitigate the consequences of diet-induced obe-
sity by serving as a persistent physiological stimulus for thermogenesis in brown adipose
tissue. The activation of this program stimulated energy expenditure, leading to reductions
in adiposity, dyslipidemia, and weight gain. The proposed mechanism that underlies
this protective effect involves the liver, specifically by promoting elevated expression and
secretion of hepatic FGF21. This molecule is able to access the central nervous system,
where it regulates systemic effects and reprograms hypothalamic circuitries, rendering the
descendants additionally resistant to diet-induced obesity later in life [56]. On the other
hand, a comparison of serum biochemistry between breastfed children and formula-fed
children revealed significant differences in molecules directly related to liver metabolism.
The breastfed group exhibited higher levels of cholesterol, triglycerides, alanine amino-
transferase, aspartate aminotransferase, gamma-glutamyl transferase, total bilirubin, and
Medicina 2023, 59, 1535 6 of 14

direct bilirubin compared to the formula-fed infants. These findings indicate that different
sources of nutrition may cause distinct metabolic responses [57].
Conversely, Gart et al. investigated the hepatoprotective properties of HMO (20 -FL)
in an animal model of non-alcoholic liver disease (NAFLD). The results showed that
supplementation with 20 -FL acted as a hepatoprotective molecule in the liver, effectively
suppressing the accumulation of lipids or microvesicular steatosis, which is associated
with obesity. The treatment also improved lipid handling, demonstrated by functional
transcriptome analysis. In addition, 20 -FL was found to reduce specific bioactive lipids in
the liver, such as diacylglycerol, which is known to affect insulin signaling and play a role
in ER stress. Diacylglycerol is also a significant factor in the dysmetabolic state that leads to
insulin resistance [58].

6. Breastfeeding Effects on Cardiovascular Tissue

The heart is one of the vital organs responsible for blood distribution across the
body. Currently, it is well known that breastfeeding has protective effects against childhood
obesity [59,60] and cardiovascular disease risk factors [61]. Some studies have demonstrated
that BM led to a small reduction in adult blood pressure levels, reduced total cholesterol and
LDL cholesterol levels, and modified adult body mass index (BMI) [62]. BM has antibodies,
stem cells, hormones, HMOs, growth factors, and enzymes which have the potential to
enhance cardiovascular tissue development during the neonatal and infant stages [63].
Based on the BM’s composition, the potential mechanisms that could reduce long-
term cardiovascular risk focus on molecules, including vascular endothelial growth factor
(VEGF) and adiponectin [63]. Animal model systems have demonstrated that VEGF partic-
ipates in many different aspects of cardiovascular development, including endothelial cell
differentiation, survival, and migration, including heart formation and hematopoiesis [64].
Adiponectin is a major component of BM and has demonstrated direct effects on the vascu-
lature and the heart. It also helps mitigate oxidative stress in endothelial cells, promotes the
mobilization and function of endothelial progenitor cells, and inhibits apoptosis, oxidative
stress, and inflammation in cardiomyocytes [63]. In addition, stem cells found in BM have
demonstrated the ability to differentiate into cardiomyocytes and integrate into different
tissues, contributing to normal development [63,65]. As described, HMOs play a role in
maintaining hemodynamics and supporting the proper development of heart tissue and
the vascular system [63,66].
Furthermore, Umer et al. evaluated the correlation between childhood cardiovascular
disease (CVD) risk factors and breastfeeding in 10,457 children in fifth grade with a mean
age of 11.0 ± 0.5 years. The outcome variables in the study included blood pressure and
lipid profile. The results showed that children who were fed with BM had significantly
smaller mean triglyceride amounts when compared to individuals who were not breastfed.
Biological samples and participant data were collected at an average age of 11 years [67].
In contrast, the long-term cardiovascular consequences of premature birth include
reduced bi-ventricular volume, reduced systolic and diastolic function, disproportionate
growth of muscle mass, higher probability of heart disease, and lower exercise tolerance,
among others. BM might exhibit protective effects by reducing these pathophysiological
alterations and preventing the onset of CVD in adulthood [63]. Exclusively breast milk-fed
preterm infants present a reduction in cardiac structural parameters as adults compared
with those who received formula milk, indicating a protective effect of BM on long-term
cardiac phenotype [68].
Finally, interventional clinical trials that are recruiting, enrolling by invitation, active,
unknown, not recruiting, or completed using breast milk as a treatment for cardiovascular
diseases are summarized in Table 2 [14 March 2023 from: https://clinicaltrials.gov/].
Medicina 2023, 59, 1535 7 of 14

Table 2. Clinical trials using breast milk as a strategy for cardiovascular diseases.

Status Title Intervention Country Identifier

Intestinal function in neonates
NPO
Completed with complex congenital heart USA NCT01475357
Fresh BM
disease
Exclusive breast milk feeding in
BM Derived Fortifier
Active, not recruiting infants with single ventricular USA NCT02860702
Human/Bovine Milk
physiology
Internasal breast milk for
Active, not recruiting BM Canada NCT04225286
intraventricular hemorrhage
Effect of breastfeeding Breastfeeding
Unknown optimization on early vascular optimization Indonesia NCT01566812
development Usual care
Lower protein intake and
Modified infant formula
Active, not recruiting long-term risk of obesity and London NCT03456934
Standard infant formula
cardiovascular disease
NPO, nothing by mouth; BM, breast milk.

7. Comparison between Breastfeeding and Non-Breastfeeding in Gut Microbiota

Health and Outcomes
The term microbiota refers to the collection of microorganisms that reside in a partic-
ular environment and share a common habitat [69]. The human microbiota is formed by
different types of microorganisms, including bacteria, fungi, viruses, and other unicellular
organisms living in diverse anatomical zones [69,70]. About 80% of the microbiota found
in healthy adults consists of Bacteroidetes and Firmicutes phyla, together with others like
Proteobacteria, Fusobacteria, Actinobacteria, and Verrucomicrobia [69,71]. The factors
that can affect microbiota composition in childhood and adult life include the method
of delivery (cesarean section or vaginal), BM or formula milk feeding, diet, exposure to
drugs/antibiotics, presence of siblings in the household, presence of furry pets in the
household, geographical location, and others [72].
Victora et al. conducted meta-analyses based on 28 systematic reviews to investigate
the connections between breastfeeding and outcomes in children or mothers. The results
indicated that breastfeeding provides protection against childhood infections, reduces the
risk of dental malocclusions, enhances intelligence, lowers the risk of overweight and
diabetes, and, overall, reduces infectious morbidity and mortality [73]. It is well known
that healthy gastrointestinal flora is responsible for the complete health of the host [74]. In
addition, breastfeeding has important effects on microbiota composition. Infants fed with
BM have a dynamic gut microbiome and present lower incidences of certain diseases [75].
BM serves as a rich source of bacterial species, harbors its microbiome, and plays a crucial
role in introducing beneficial bacteria to the infant’s gastrointestinal tract after birth. It is
throughout the first thousand days of life that a child’s gut microbiota is established, and
any disturbances or altered colonization during this neonatal period can potentially impact
health outcomes later in life [75,76]. Some of the microbiota mechanisms of action in the
gut are the production of antimicrobial molecules, enhancing intestinal mucin production,
and preventing the adhesion of pathogenic bacteria [75,77].
On the first day of life, the gut microbiota of newborns delivered vaginally closely
resembles that of the maternal vagina and intestinal tract, in contrast to those born via
cesarean section; their microbiota is like maternal skin. The gut microbiota at birth is
characterized by its low variety. By 1–2 years of age, the microbiota is more complex than
the gut microbiota of adults; therefore, the initial year of life plays a crucial role in the
establishment of microbiota, with BM being the primary influencing factor in terms of
composition and its long-term impact on health [72]. BM is a bioactive substance that
acts as a prebiotic and probiotic due to its oligosaccharides and bacteria that are not yet
Medicina 2023, 59, 1535 8 of 14

mimicked in formula milk [5]. Lactation influences health-promoting microorganisms

mediated by factors like antibacterial peptides, components of the innate immune system,
and polymeric IgA. BM also improves the mucosal defenses and barrier integrity of the
intestinal tissue [72,78,79]. Ma et al. compared gut microbiota from 91 healthy children
that were totally fed with BM or different types of formula milk for more than four months.
The findings indicated that breastfed groups exhibited lower alpha diversity compared
to formula-fed groups at 40 days of age, but this diversity increased significantly by the
time the infants reached 6 months of age. The predominant genera were Bifidobacterium
and Enterobacteriaceae in babies with 40 days of life, Bacteroides and Bifidobacterium were
higher in the breastfed group, and Streptococcus, Lachnospiraceae, Veillonella, Clostridioides,
and Enterococcus were lower compared to the formula-fed group [72]. Bifidobacteria has a
major role in the development of the immune system, preventing infections in children.
In contrast, Bifidobacterium has multiple health benefits, including vitamin production,
modulation of the immune system, reduction in the prevalence of atopic dermatitis and
rotavirus infections, and lower lactose intolerance in children and adults [72,80]. In addition,
Bifidobacteria abundance indicates a better immune response to vaccination and is correlated
with a reduced risk of obesity and allergic diseases [72,81,82]. Bacteroides is another bacteria
that, in the earlier neonatal phase, participates in the growth of the mucosal immune system.
These mechanisms may confer lifelong protection against health disorders in the human
body. This beneficial bacteria is also linked with increased diversity and faster maturation
of the gut tissue [72]. Among the bacteria with lower abundances in children fed with BM
is Streptococcus sp. Some studies have shown that higher levels of this genus are seen in
patients with type 1 diabetes [72,83].
The gut microbiota and brain develop together during the first year of life. Gut micro-
biota is recognized as a modulator of behavior, including cognition and social skills [84].
In addition, several researchers have demonstrated that the gut microbiota also impacts
neurodevelopment in the first year of age, reducing the risk of acquiring neurodevelop-
mental and neuropsychiatric diseases [5,85]. Research has indicated that an increased
abundance of Bacteroides and a decreased abundance of Shigella/Escherichia and Bifidobac-
terium are negatively associated with fine motor skills in children. Similarly, elevated levels
of certain taxa from Lachnospiraceae and Clostridiales and reduced levels of Bacteroides are
negatively correlated with communication and social skills in children at the age of 3 [86].
Carlson et al. published results from a pilot study in infants exclusively breastfeeding until
1 month of life whose microbiota composition showed an association with non-social fear
behavior [87].

8. Lactation Benefits in Mother’s Health

Longer lactation has been correlated with long-term health; mothers can experience
various benefits, including a reduced risk of heart disease (high blood pressure), some
types of cancer (endometrial, ovarian, and breast cancer), metabolic syndrome, NAFLD,
hypercholesterolemia, and type 2 diabetes mellitus [73,88–90]. The short-term benefits of
lactation in women’s health include reductions in infectious symptoms, stress responsivity,
blood pressure, weight loss, better positive moods, and fertility control; all of them related
to parasympathetic activation, endocrine factors, and oxytocinergic mechanisms present in
the breastfeeding period [89].
Studies showed a correlation between breastfeeding and a reduced relative risk of
breast cancer in parous women. Specifically, for every 12 months of breastfeeding, the
relative risk of breast cancer decreases by 4.3%. Additionally, parous women who have
breastfed at any point in their lives have a 14% lower risk of developing breast cancer
compared to those who have never breastfed. The protective effect of breastfeeding is
more pronounced in women who have breastfed for a cumulative duration of 12 months or
longer, with a 28% lower risk of breast cancer [90]. Based on the meta-analysis conducted
by Victora et al. published in 2016, which included 50,000 patients with cancer, for every
additional 12 months of breastfeeding over a woman’s lifetime, there was a 4.3% decrease
Medicina 2023, 59, 1535 9 of 14

in the occurrence of invasive breast cancer [73]. The authors estimated the potential effect
of lactation on breast cancer mortality. In their estimation, the current global rates of
breastfeeding prevent 19 breast cancer deaths annually, compared to a scenario where
no women breastfeed. To summarize, the current global rates of breastfeeding prevent
approximately 20,000 deaths from breast cancer each year [73]. However, Lambertini et al.
reported that breastfeeding was significantly associated with lower odds of developing
luminal and triple-negative breast cancer subtypes but with no difference in the human
epidermal growth factor receptor (2HER2) breast cancer subtype [91].
Alternatively, Victora et al.’s meta-analysis included 41 studies for ovarian cancer.
They reported a 30% decrease correlated with prolonged periods of breastfeeding [73].
In 2020, Babic et al. published the results of a pooled analysis of 13 case-control studies
involving parous women with ovarian cancer and controls with the objective of determining
the association between lactation and this type of cancer. The analysis included a total of
9973 women with ovarian cancer and 13,843 controls; the results indicated that women who
had ever breastfed had a decreased risk of developing all types of invasive ovarian cancers,
with a particularly notable reduction in the risk of endometrioid and high-grade serous
subtypes (which are the most lethal types of ovarian cancer). Women who breastfed for 1
to 3 months were related with 18% lower risk, and lactation for ≥12 months was correlated
with a 34% lower risk. This reduction in risk persists for decades. The author concluded
that the findings indicate that breastfeeding could be a factor that can be modified and has
the potential to reduce the risk of ovarian cancer [92].
For diabetes mellitus type 2, six cohort studies showed an odds ratio of 0.68 [73,93].
In addition, an association analysis between overweight and breastfeeding that included
740,000 British women with long-term follow-up revealed that mean BMI was 1% less for
every 6 months of lactation [73,94]. Other meta-analyses showed that the longest period
of lactation was correlated with a 32% decreased relative risk of type 2 diabetes versus
the shortest period of lactation [95]. On the other hand, Pinho–Gomes et al. conducted a
systemic review and meta-analysis research to evaluate the correlation between lactation
and maternal risk of type 2 diabetes. Longer-term studies have revealed a consistent and
gradual protective association between lactation and the risk of type 2 diabetes. The risk
reduction appears to be more pronounced in mothers with gestational diabetes compared
to those without. Breastfeeding versus never breastfeeding was correlated with a 27%
lower risk of this pathology, and each additional month of breastfeeding was found to be
associated with a 1% decrease in the risk of developing type 2 diabetes [96]. In 2018, Gun-
derson et al. published results from the 30-year Coronary Artery Risk Development study,
aiming to address the key question, “Is there a biochemical evidence basis supporting the
protective association between lactation duration and progression to gestational diabetes?”.
The study enrolled 1238 women, and the association analysis revealed a robust and graded
inverse relationship between the incidence of diabetes and lactation duration. The findings
indicated an increased risk of developing diabetes among women who did not engage in
lactation compared to those who lactated for 12 months or more [97].
Tschiderer et al. published a systemic review and meta-analysis of eight studies and
more than 1 million parous women, and they found that lactation prevents future stroke,
coronary heart disease, and fatal CVD. The authors also found a progressive reduction in
cardiovascular risk with breastfeeding durations of up to 12 months throughout life [98].
In accordance, researchers have shown that breastfeeding was correlated with lower odds
of hypertension and a lifetime lactation duration of >6 months was significantly associated
with this outcome [95]. Furthermore, non-breastfeeding women have a higher risk of
vascular changes associated with future cardiovascular diseases like calcified atherosclerotic
plaques and higher carotid adventitial diameter. Evidence showed that mothers who never
breastfed had larger adventitial diameters and carotid artery lumen versus mothers who
breastfed. These characteristics are indicative of poorer cardiovascular health status [95,99].
A study with middle-aged and elderly women with a lifetime lactation duration longer
than 12 months presented a reduced risk of incident myocardial infarction versus parous
Medicina 2023, 59, 1535 10 of 14

women who never breastfed. In addition, breastfeeding appeared to reduce mortality from
ischemic heart disease. Women aged over 65 years who have never breastfed have an
approximately threefold higher risk of CVD mortality over a 15-year period compared to
women who have breastfed for more than 24 months in their lifetime [95,100,101].
In contrast, a study conducted by Veeral et al. demonstrated that breastfeeding for
a longer duration, specifically more than 6 months, is associated with a reduced risk of
non-alcoholic fatty liver disease (NAFLD) in mid-life. The study followed 844 women over
a period of 25 years, with 32% reporting a breastfeeding duration of 0 to 1 month, 25%
breastfeeding for 1 to 6 months, and 43% breastfeeding for more than 6 months. The results
revealed an inverse relationship between longer lactation and the development of NAFLD
in mid-life, particularly breastfeeding for more than 6 months. This finding suggests that
breastfeeding duration may serve as a modifiable risk factor for NAFLD. The authors propose
that the mechanism underlying this association could be attributed to the long-lasting effects
on body fat distribution, insulin sensitivity, and circulating lipid levels [88].

9. Conclusions
Breastfeeding has beneficial effects on infant and maternal health, as breast milk is
the main source of newborn nutrition. The current evidence obtained from observational
studies points out the strong role between breastfeeding and improvement in long-term
vital organ outcomes. Breastfeeding is the best choice of diet for a newborn. Promotion of
breastfeeding during the perinatal period may represent an exceptional chance to reduce
the risk prevalence of health problems until adulthood. However, it is necessary to clarify
the metabolic pathways that lead to the benefit of breast milk consumption from birth.

Author Contributions: Conceptualization, A.S.M.Z.-M., A.M.-R. and E.M.F.-T.; investigation, J.C.M.-V.,

A.M.-R. and E.M.-D.; writing—original draft preparation, J.C.M.-V., A.M.-R. and E.M.-D.; writing—
review and editing, A.M.-R., B.R.A.-U. and R.I.L.-R.; visualization, R.I.L.-R. and E.M.F.-T.; supervision,
A.S.M.Z.-M. All authors have read and agreed to the published version of the manuscript.
Funding: This research was funded by Universidad de Guadalajara.
Institutional Review Board Statement: Not applicable.
Informed Consent Statement: Not applicable.
Data Availability Statement: Not applicable.
Conflicts of Interest: The authors declare no conflict of interest.

References
1. UNICEF Infant Feeding Area Graphs Interpretation Guide for Infant and Young Child Feeding at 0 5 Months—PDF Free
Download. Available online: https://docplayer.net/229259300-Infant-feeding-area-graphs-interpretation-guide-for-infant-and-
young-child-feeding-at-0-5-months.html (accessed on 22 May 2023).
2. WHO Breastfeeding. Available online: https://www.who.int/health-topics/breastfeeding (accessed on 22 May 2023).
3. WHO Infant and Young Child Feeding. Available online: https://www.who.int/news-room/fact-sheets/detail/infant-and-
young-child-feeding (accessed on 27 July 2023).
4. Chiurazzi, M.; Cozzolino, M.; Reinelt, T.; Nguyen, T.D.; Elke Chie, S.; Natalucci, G.; Miletta, M.C. Human Milk and Brain
Development in Infants. Reprod. Med. 2021, 2, 107–117. [CrossRef]
5. Charton, E.; Bourgeois, A.; Bellanger, A.; Le-Gouar, Y.; Dahirel, P.; Romé, V.; Randuineau, G.; Cahu, A.; Moughan, P.J.;
Montoya, C.A.; et al. Infant Nutrition Affects the Microbiota-Gut-Brain Axis: Comparison of Human Milk vs. Infant Formula
Feeding in the Piglet Model. Front. Nutr. 2022, 9, 976042. [CrossRef]
6. Mosca, F.; Giannì, M.L. Human Milk: Composition and Health Benefits. Pediatr. Med. Chir. 2017, 39, 155. [CrossRef]
7. Gopalakrishna, K.P.; Hand, T.W. Influence of Maternal Milk on the Neonatal Intestinal Microbiome. Nutrients 2020, 12, 823.
[CrossRef]
8. Moore, R.E.; Xu, L.L.; Townsend, S.D. Prospecting Human Milk Oligosaccharides as a Defense Against Viral Infections. ACS
Infect. Dis. 2021, 7, 254–263. [CrossRef]
9. Xiao, L.; van’t Land, B.; Engen, P.A.; Naqib, A.; Green, S.J.; Nato, A.; Leusink-Muis, T.; Garssen, J.; Keshavarzian, A.; Stahl, B.; et al.
Human Milk Oligosaccharides Protect against the Development of Autoimmune Diabetes in NOD-Mice. Sci. Rep. 2018, 8, 3829.
[CrossRef]
Medicina 2023, 59, 1535 11 of 14

10. Morozov, V.; Hansman, G.; Hanisch, F.-G.; Schroten, H.; Kunz, C. Human Milk Oligosaccharides as Promising Antivirals. Mol.
Nutr. Food Res. 2018, 62, 1700679. [CrossRef]
11. Triantis, V.; Bode, L.; van Neerven, R.J.J. Immunological Effects of Human Milk Oligosaccharides. Front. Pediatr. 2018, 6, 190.
[CrossRef]
12. Ottolini, K.M.; Andescavage, N.; Keller, S.; Limperopoulos, C. Nutrition and the Developing Brain: The Road to Optimizing Early
Neurodevelopment: A Systematic Review. Pediatr. Res. 2020, 87, 194–201. [CrossRef]
13. Schnaar, R.L.; Gerardy-Schahn, R.; Hildebrandt, H. Sialic Acids in the Brain: Gangliosides and Polysialic Acid in Nervous System
Development, Stability, Disease, and Regeneration. Physiol. Rev. 2014, 94, 461–518. [CrossRef]
14. Vázquez, E.; Barranco, A.; Ramírez, M.; Gruart, A.; Delgado-García, J.M.; Martínez-Lara, E.; Blanco, S.; Martín, M.J.; Castanys, E.;
Buck, R.; et al. Effects of a Human Milk Oligosaccharide, 20 -Fucosyllactose, on Hippocampal Long-Term Potentiation and
Learning Capabilities in Rodents. J. Nutr. Biochem. 2015, 26, 455–465. [CrossRef]
15. Berger, P.K.; Plows, J.F.; Jones, R.B.; Alderete, T.L.; Yonemitsu, C.; Poulsen, M.; Ryoo, J.H.; Peterson, B.S.; Bode, L.; Goran, M.I.
Human Milk Oligosaccharide 20 -Fucosyllactose Links Feedings at 1 Month to Cognitive Development at 24 Months in Infants of
Normal and Overweight Mothers. PLoS ONE 2020, 15, e0228323. [CrossRef]
16. Bobiński, R.; Bobińska, J. Fatty Acids of Human Milk—A Review. Int. J. Vitam. Nutr. Res. 2022, 92, 280–291. [CrossRef]
17. Tarr, A.J.; Galley, J.D.; Fisher, S.E.; Chichlowski, M.; Berg, B.M.; Bailey, M.T. The Prebiotics 30 Sialyllactose and 60 Sialyllactose
Diminish Stressor-Induced Anxiety-like Behavior and Colonic Microbiota Alterations: Evidence for Effects on the Gut–Brain Axis.
Brain. Behav. Immun. 2015, 50, 166–177. [CrossRef]
18. Victora, C.G.; Horta, B.L.; de Mola, C.L.; Quevedo, L.; Pinheiro, R.T.; Gigante, D.P.; Gonçalves, H.; Barros, F.C. Association
between Breastfeeding and Intelligence, Educational Attainment, and Income at 30 Years of Age: A Prospective Birth Cohort
Study from Brazil. Lancet Glob. Health 2015, 3, e199–e205. [CrossRef]
19. Deoni, S.C.L.; Dean, D.C.; Piryatinsky, I.; O’Muircheartaigh, J.; Waskiewicz, N.; Lehman, K.; Han, M.; Dirks, H. Breastfeeding and
Early White Matter Development: A Cross-Sectional Study. NeuroImage 2013, 82, 77–86. [CrossRef]
20. Isaacs, E.B.; Fischl, B.R.; Quinn, B.T.; Chong, W.K.; Gadian, D.G.; Lucas, A. Impact of Breast Milk on Intelligence Quotient, Brain
Size, and White Matter Development. BRAIN Dev. 2010, 67, 357–362. [CrossRef] [PubMed]
21. EFSA Scientific Opinion on the Substantiation of Health Claims Related to Choline and Contribution to Normal Lipid Metabolism
(ID 3186), Maintenance of Normal Liver Function (ID 1501), Contribution to Normal Homocysteine Metabolism (ID 3090),
Maintenance of Normal Neurological Function (ID 1502), Contribution to Normal Cognitive Function (ID 1502), and Brain and
Neurological Development (ID 1503) Pursuant to Article 13(1) of Regulation (EC) No 1924/2006. EFSA J. 2011, 9, 2056. [CrossRef]
22. Su, M.; Subbaraj, A.K.; Fraser, K.; Qi, X.; Jia, H.; Chen, W.; Gomes Reis, M.; Agnew, M.; Day, L.; Roy, N.C.; et al. Lipidomics of
Brain Tissues in Rats Fed Human Milk from Chinese Mothers or Commercial Infant Formula. Metabolites 2019, 9, 253. [CrossRef]
[PubMed]
23. Tudehope, D.I. Human Milk and the Nutritional Needs of Preterm Infants. J. Pediatr. 2013, 162, S17–S25. [CrossRef] [PubMed]
24. Zhang, Y.; Deng, Q.; Wang, J.; Wang, H.; Li, Q.; Zhu, B.; Ji, C.; Xu, X.; Johnston, L. The Impact of Breast Milk Feeding on Early
Brain Development in Preterm Infants in China: An Observational Study. PLoS ONE 2022, 17, e0272125. [CrossRef]
25. Aydın, M.Ş.; Yiğit, E.N.; Vatandaşlar, E.; Erdoğan, E.; Öztürk, G. Transfer and Integration of Breast Milk Stem Cells to the Brain of
Suckling Pups. Sci. Rep. 2018, 8, 14289. [CrossRef] [PubMed]
26. Abida, L.L.; Murti, B.; Prasetya, H. Meta-Analysis: The Effect of Breast Milk on Child Language. J. Matern. Child Health 2020, 05,
579–589.
27. Rosidi, A.; Bening, S.; Sulistyowati, E.; Hunandar, C.; Sunarto; Wijaningsih, W. Withdrawal Notice: Inadequate Energy Intake as a
Risk Factor to Developmental Delay of Pre-School Aged Children. Curr. Nutr. Food Sci. 2018, 15, 1. [CrossRef]
28. Boutrid, N.; Rahmoune, H.; Bioud, B.; Abdelmalek, D.; Amrane, M. Breastfeeding Impact on Kidney Functions: A Systematic
Review. Am. Heart J. 2022, 254, 258. [CrossRef]
29. Escribano, J.; Luque, V.; Ferre, N.; Zaragoza-Jordana, M.; Grote, V.; Koletzko, B.; Gruszfeld, D.; Socha, P.; Dain, E.; Van Hees, J.-N.; et al.
Increased Protein Intake Augments Kidney Volume and Function in Healthy Infants. Kidney Int. 2011, 79, 783–790. [CrossRef]
30. Miliku, K.; Voortman, T.; Bakker, H.; Hofman, A.; Franco, O.H.; Jaddoe, V.W.V. Infant Breastfeeding and Kidney Function in
School-Aged Children. Am. J. Kidney Dis. 2015, 66, 421–428. [CrossRef]
31. Shajari, H.; Shajari, A.; Golshan Tafti, M.; Samaninejad, R. The Relationship between the Type of Milk Consumed and the Risk of
Kidney Stones in Children Under Two Years of Age. J. Iran. Med. Counc. 2021, 3, 205–210. [CrossRef]
32. Bozkurt, H.B.; Çetin, T.; Sarıca, K. The Possible Beneficial Effect of Breastfeeding on the Clinical Course of Urolithiasis Detected
During Infancy. Breastfeed. Med. 2020, 15, 84–89. [CrossRef] [PubMed]
33. Tsanidou, E.; Gougoula, V.; Tselebonis, A.; Kontogiorgis, C.; Constantinidis, T.C.; Nena, E. Socio-Demographic Factors Affecting
Initiation and Duration of Breastfeeding in a Culturally Diverse Area of North Eastern Greece. Folia Med. 2019, 61, 566–571.
[CrossRef]
34. Zhang, C.; Guo, Y.; Xiao, X.; Bloom, M.S.; Qian, Z.; Rolling, C.A.; Xian, H.; Lin, S.; Li, S.; Chen, G.; et al. Association of
Breastfeeding and Air Pollution Exposure with Lung Function in Chinese Children. JAMA Netw. Open 2019, 2, e194186.
[CrossRef]
35. Moshammer, H.; Hutter, H.-P. Breast-Feeding Protects Children from Adverse Effects of Environmental Tobacco Smoke. Int. J.
Environ. Res. Public Health 2019, 16, 304. [CrossRef]
Medicina 2023, 59, 1535 12 of 14

36. Perikleous, E.P.; Fouzas, S.; Michailidou, M.; Patsourou, A.; Tsalkidis, D.; Steiropoulos, P.; Nena, E.; Chatzimichael, A.;
Paraskakis, E. Association between History of Prolonged Exclusive Breast-Feeding and the Lung Function Indices in Childhood.
Children 2022, 9, 1708. [CrossRef]
37. Di Filippo, P.; Lizzi, M.; Raso, M.; Di Pillo, S.; Chiarelli, F.; Attanasi, M. The Role of Breastfeeding on Respiratory Outcomes Later
in Childhood. Front. Pediatr. 2022, 10, 829414. [CrossRef]
38. Waidyatillake, N.T.; Allen, K.J.; Lodge, C.J.; Dharmage, S.C.; Abramson, M.J.; Simpson, J.A.; Lowe, A.J. The Impact of Breastfeeding
on Lung Development and Function: A Systematic Review. Expert Rev. Clin. Immunol. 2013, 9, 1253–1265. [CrossRef]
39. Dai, D.L.Y.; Petersen, C.; Hoskinson, C.; Del Bel, K.L.; Becker, A.B.; Moraes, T.J.; Mandhane, P.J.; Finlay, B.B.; Simons, E.;
Kozyrskyj, A.L.; et al. Breastfeeding Enrichment of B. Longum Subsp. Infantis Mitigates the Effect of Antibiotics on the Microbiota
and Childhood Asthma Risk. Med 2023, 4, 92–112.e5. [CrossRef]
40. Dharmage, S.C.; Perret, J.L.; Custovic, A. Epidemiology of Asthma in Children and Adults. Front. Pediatr. 2019, 7, 246. [CrossRef]
41. Chen, C.-N.; Lin, Y.-C.; Ho, S.-R.; Fu, C.-M.; Chou, A.-K.; Yang, Y.-H. Association of Exclusive Breastfeeding with Asthma Risk
among Preschool Children: An Analysis of National Health and Nutrition Examination Survey Data, 1999 to 2014. Nutrients 2022,
14, 4250. [CrossRef] [PubMed]
42. Bode, L. The Functional Biology of Human Milk Oligosaccharides. Early Hum. Dev. 2015, 91, 619–622. [CrossRef] [PubMed]
43. Orczyk-Pawiłowicz, M.; Lis-Kuberka, J. The Impact of Dietary Fucosylated Oligosaccharides and Glycoproteins of Human Milk
on Infant Well-Being. Nutrients 2020, 12, 1105. [CrossRef] [PubMed]
44. Gorlanova, O.; Appenzeller, R.; Mahmoud, Y.S.; Ramsey, K.A.; Usemann, J.; Decrue, F.; Kuehni, C.E.; Röösli, M.; Latzin, P.;
Fuchs, O.; et al. Effect of Breastfeeding Duration on Lung Function, Respiratory Symptoms and Allergic Diseases in School-Age
Children. Pediatr. Pulmonol. 2020, 55, 1448–1455. [CrossRef]
45. Castellote, C.; Casillas, R.; Ramírez-Santana, C.; Pérez-Cano, F.J.; Castell, M.; Moretones, M.G.; López-Sabater, M.C.; Franch, Í.
Premature Delivery Influences the Immunological Composition of Colostrum and Transitional and Mature Human Milk123.
J. Nutr. 2011, 141, 1181–1187. [CrossRef]
46. Burri, P.H. Structural Aspects of Postnatal Lung Development—Alveolar Formation and Growth. Biol. Neonate 2006, 89, 313–322.
[CrossRef] [PubMed]
47. Liu, X.; Wang, H.; Liang, X.; Roberts, M.S. Hepatic Metabolism in Liver Health and Disease. In Liver Pathophysiology; Elsevier:
Amsterdam, The Netherlands, 2017; pp. 391–400. ISBN 978-0-12-804274-8.
48. Monroy-Ramirez, H.C.; Galicia-Moreno, M.; Sandoval-Rodriguez, A.; Meza-Rios, A.; Santos, A.; Armendariz-Borunda, J. PPARs
as Metabolic Sensors and Therapeutic Targets in Liver Diseases. Int. J. Mol. Sci. 2021, 22, 8298. [CrossRef] [PubMed]
49. Hillman, N.H.; Kallapur, S.G.; Jobe, A.H. Physiology of Transition from Intrauterine to Extrauterine Life. Clin. Perinatol. 2012,
39, 769–783. [CrossRef] [PubMed]
50. Chen, C.; Soto-Gutierrez, A.; Baptista, P.M.; Spee, B. Biotechnology Challenges to In Vitro Maturation of Hepatic Stem Cells.
Gastroenterology 2018, 154, 1258–1272. [CrossRef]
51. Marsac, C.; Saudubray, J.M.; Moncion, A.; Leroux, J.P. Development of Gluconeogenic Enzymes in the Liver of Human Newborns.
Biol. Neonat. 2009, 28, 317–325. [CrossRef]
52. Pégorier, J.-P.; Chatelain, F.; Thumelin, S.; Girard, J. Role of Long-Chain Fatty Acids in the Postnatal Induction of Genes Coding
for Liver Mitochondrial β-Oxidative Enzymes. Biochem. Soc. Trans. 1998, 26, 113–120. [CrossRef] [PubMed]
53. Bougneres, P.F.; Lemmel, C.; Ferré, P.; Bier, D.M. Ketone Body Transport in the Human Neonate and Infant. J. Clin. Investig. 1986,
77, 42–48. [CrossRef]
54. Kohno, Y.; Shiraki, K.; Mura, T. The Effect of Human Milk on DNA Synthesis of Neonatal Rat Hepatocytes in Primary Culture.
Pediatr. Res. 1991, 29, 251–255. [CrossRef]
55. Carvalho, E.; Adams, S.H.; Børsheim, E.; Blackburn, M.L.; Ono-Moore, K.D.; Cotter, M.; Bowlin, A.K.; Yeruva, L. Neonatal Diet
Impacts Liver Mitochondrial Bioenergetics in Piglets Fed Formula or Human Milk. BMC Nutr. 2020, 6, 13. [CrossRef] [PubMed]
56. Pena-Leon, V.; Folgueira, C.; Barja-Fernández, S.; Pérez-Lois, R.; Da Silva Lima, N.; Martin, M.; Heras, V.; Martinez-Martinez, S.;
Valero, P.; Iglesias, C.; et al. Prolonged Breastfeeding Protects from Obesity by Hypothalamic Action of Hepatic FGF21. Nat.
Metab. 2022, 4, 901–917. [CrossRef] [PubMed]
57. Wu, T.-C.; Huang, F.I.; Chen, Y.-C.; Chen, P.-H.; Yang, L.-Y. Differences in Serum Biochemistry between Breast-Fed and Formula-
Fed Infants. J. Chin. Med. Assoc. 2011, 74, 511–515. [CrossRef] [PubMed]
58. Gart, E.; Salic, K.; Morrison, M.C.; Giera, M.; Attema, J.; de Ruiter, C.; Caspers, M.; Schuren, F.; Bobeldijk-Pastorova, I.;
Heer, M.; et al. The Human Milk Oligosaccharide 20 -Fucosyllactose Alleviates Liver Steatosis, ER Stress and Insulin Resistance by
Reducing Hepatic Diacylglycerols and Improved Gut Permeability in Obese Ldlr-/-.Leiden Mice. Front. Nutr. 2022, 9, 904740.
[CrossRef] [PubMed]
59. Umer, A.; Hamilton, C.; Britton, C.M.; Mullett, M.D.; John, C.; Neal, W.; Lilly, C.L. Association between Breastfeeding and
Childhood Obesity: Analysis of a Linked Longitudinal Study of Rural Appalachian Fifth-Grade Children. Child. Obes. 2015,
11, 449–455. [CrossRef]
60. Weng, S.F.; Redsell, S.A.; Swift, J.A.; Yang, M.; Glazebrook, C.P. Systematic Review and Meta-Analyses of Risk Factors for
Childhood Overweight Identifiable during Infancy. Arch. Dis. Child. 2012, 97, 1019–1026. [CrossRef]
61. Plagemann, A.; Harder, T. Breast Feeding and the Risk of Obesity and Related Metabolic Diseases in the Child. Metab. Syndr.
Relat. Disord. 2005, 3, 222–232. [CrossRef]
Medicina 2023, 59, 1535 13 of 14

62. Parikh, N.I.; Hwang, S.-J.; Ingelsson, E.; Benjamin, E.J.; Fox, C.S.; Vasan, R.S.; Murabito, J.M. Breastfeeding in Infancy and Adult
Cardiovascular Disease Risk Factors. Am. J. Med. 2009, 122, 656–663.e1. [CrossRef]
63. EL-Khuffash, A.; Jain, A.; Lewandowski, A.J.; Levy, P.T. Preventing Disease in the 21st Century: Early Breast Milk Exposure and
Later Cardiovascular Health in Premature Infants. Pediatr. Res. 2020, 87, 385–390. [CrossRef]
64. Haigh, J.J. Role of VEGF in Organogenesis. Organogenesis 2008, 4, 247–256. [CrossRef]
65. Hassiotou, F.; Hartmann, P.E. At the Dawn of a New Discovery: The Potential of Breast Milk Stem Cells. Adv. Nutr. 2014, 5,
770–778. [CrossRef]
66. Varadharaj, S.; Helal, M.; Duska-McEwen, G.O.; Boslett, J.; Pereira, S.L.; Buck, R.H.; Ahmed, N.; Zweier, J.L. The Human Milk
Oligosaccharide 3–Fucosyllactose Facilitates Preservation of Nitric Oxide-Induced Vasodilation in Aortic Vessels In Vitro. FASEB J.
2017, 31, lb808.
67. Umer, A.; Hamilton, C.; Edwards, R.A.; Cottrell, L.; Giacobbi, P.; Innes, K.; John, C.; Kelley, G.A.; Neal, W.; Lilly, C. Association
Between Breastfeeding and Childhood Cardiovascular Disease Risk Factors. Matern. Child Health J. 2019, 23, 228–239. [CrossRef]
[PubMed]
68. Lewandowski, A.J.; Lamata, P.; Francis, J.M.; Piechnik, S.K.; Ferreira, V.M.; Boardman, H.; Neubauer, S.; Singhal, A.; Leeson, P.;
Lucas, A. Breast Milk Consumption in Preterm Neonates and Cardiac Shape in Adulthood. Pediatrics 2016, 138, e20160050.
[CrossRef]
69. Gutiérrez-Cuevas, J.; Sandoval-Rodriguez, A.; Meza-Rios, A.; Monroy-Ramírez, H.C.; Galicia-Moreno, M.; García-Bañuelos, J.;
Santos, A.; Armendariz-Borunda, J. Molecular Mechanisms of Obesity-Linked Cardiac Dysfunction: An Up-Date on Current
Knowledge. Cells 2021, 10, 629. [CrossRef]
70. Marchesi, J.R.; Ravel, J. The Vocabulary of Microbiome Research: A Proposal. Microbiome 2015, 3, 31. [CrossRef] [PubMed]
71. Marzullo, P.; Di Renzo, L.; Pugliese, G.; De Siena, M.; Barrea, L.; Muscogiuri, G.; Colao, A.; Savastano, S.; on behalf of
Obesity Programs of nutrition, Education, Research and Assessment (OPERA) Group. From Obesity through Gut Microbiota to
Cardiovascular Diseases: A Dangerous Journey. Int. J. Obes. Suppl. 2020, 10, 35–49. [CrossRef] [PubMed]
72. Ma, J.; Li, Z.; Zhang, W.; Zhang, C.; Zhang, Y.; Mei, H.; Zhuo, N.; Wang, H.; Wang, L.; Wu, D. Comparison of Gut Microbiota in
Exclusively Breast-Fed and Formula-Fed Babies: A Study of 91 Term Infants. Sci. Rep. 2020, 10, 15792. [CrossRef] [PubMed]
73. Victora, C.G.; Bahl, R.; Barros, A.J.D.; França, G.V.A.; Horton, S.; Krasevec, J.; Murch, S.; Sankar, M.J.; Walker, N.; Rollins, N.C.
Breastfeeding in the 21st Century: Epidemiology, Mechanisms, and Lifelong Effect. Lancet 2016, 387, 475–490. [CrossRef]
74. Jandhyala, S.M. Role of the Normal Gut Microbiota. World J. Gastroenterol. 2015, 21, 8787. [CrossRef]
75. Lyons, K.E.; Ryan, C.A.; Dempsey, E.M.; Ross, R.P.; Stanton, C. Breast Milk, a Source of Beneficial Microbes and Associated
Benefits for Infant Health. Nutrients 2020, 12, 1039. [CrossRef] [PubMed]
76. Boudry, G.; Charton, E.; Le Huerou-Luron, I.; Ferret-Bernard, S.; Le Gall, S.; Even, S.; Blat, S. The Relationship Between Breast
Milk Components and the Infant Gut Microbiota. Front. Nutr. 2021, 8, 629740. [CrossRef] [PubMed]
77. Riaz Rajoka, M.S.; Mehwish, H.M.; Siddiq, M.; Haobin, Z.; Zhu, J.; Yan, L.; Shao, D.; Xu, X.; Shi, J. Identification, Characterization,
and Probiotic Potential of Lactobacillus Rhamnosus Isolated from Human Milk. LWT 2017, 84, 271–280. [CrossRef]
78. Stewart, C.J.; Ajami, N.J.; O’Brien, J.L.; Hutchinson, D.S.; Smith, D.P.; Wong, M.C.; Ross, M.C.; Lloyd, R.E.; Doddapaneni, H.;
Metcalf, G.A.; et al. Temporal Development of the Gut Microbiome in Early Childhood from the TEDDY Study. Nature 2018, 562,
583–588. [CrossRef]
79. Walker, W.A.; Iyengar, R.S. Breast Milk, Microbiota, and Intestinal Immune Homeostasis. Pediatr. Res. 2015, 77, 220–228.
[CrossRef]
80. Lewis, Z.T.; Sidamonidze, K.; Tsaturyan, V.; Tsereteli, D.; Khachidze, N.; Pepoyan, A.; Zhgenti, E.; Tevzadze, L.; Manvelyan, A.;
Balayan, M.; et al. The Fecal Microbial Community of Breast-Fed Infants from Armenia and Georgia. Sci. Rep. 2017, 7, 40932.
[CrossRef]
81. Björkstén, B.; Sepp, E.; Julge, K.; Voor, T.; Mikelsaar, M. Allergy Development and the Intestinal Microflora during the First Year
of Life. J. Allergy Clin. Immunol. 2001, 108, 516–520. [CrossRef]
82. Huda, M.N.; Lewis, Z.; Kalanetra, K.M.; Rashid, M.; Ahmad, S.M.; Raqib, R.; Qadri, F.; Underwood, M.A.; Mills, D.A.; Stephensen,
C.B. Stool Microbiota and Vaccine Responses of Infants. Pediatrics 2014, 134, e362–e372. [CrossRef]
83. Levin, A.M.; Sitarik, A.R.; Havstad, S.L.; Fujimura, K.E.; Wegienka, G.; Cassidy-Bushrow, A.E.; Kim, H.; Zoratti, E.M.;
Lukacs, N.W.; Boushey, H.A.; et al. Joint Effects of Pregnancy, Sociocultural, and Environmental Factors on Early Life Gut
Microbiome Structure and Diversity. Sci. Rep. 2016, 6, 31775. [CrossRef]
84. Vaher, K.; Bogaert, D.; Richardson, H.; Boardman, J.P. Microbiome-Gut-Brain Axis in Brain Development, Cognition and Behavior
during Infancy and Early Childhood. Dev. Rev. 2022, 66, 101038. [CrossRef]
85. Jiang, H.; Ling, Z.; Zhang, Y.; Mao, H.; Ma, Z.; Yin, Y.; Wang, W.; Tang, W.; Tan, Z.; Shi, J.; et al. Altered Fecal Microbiota
Composition in Patients with Major Depressive Disorder. Brain Behav. Immun. 2015, 48, 186–194. [CrossRef] [PubMed]
86. Sordillo, J.E.; Korrick, S.; Laranjo, N.; Carey, V.; Weinstock, G.M.; Gold, D.R.; O’Connor, G.; Sandel, M.; Bacharier, L.B.;
Beigelman, A.; et al. Association of the Infant Gut Microbiome With Early Childhood Neurodevelopmental Outcomes: An
Ancillary Study to the VDAART Randomized Clinical Trial. JAMA Netw. Open 2019, 2, e190905. [CrossRef] [PubMed]
87. Carlson, A.L.; Xia, K.; Azcarate-Peril, M.A.; Rosin, S.P.; Fine, J.P.; Mu, W.; Zopp, J.B.; Kimmel, M.C.; Styner, M.A.;
Thompson, A.L.; et al. Infant Gut Microbiome Composition Is Associated with Non-Social Fear Behavior in a Pilot Study. Nat.
Commun. 2021, 12, 3294. [CrossRef] [PubMed]
Medicina 2023, 59, 1535 14 of 14

88. Ajmera, V.H.; Terrault, N.A.; VanWagner, L.B.; Sarkar, M.; Lewis, C.E.; Carr, J.J.; Gunderson, E.P. Longer Lactation Duration Is
Associated with Decreased Prevalence of Non-Alcoholic Fatty Liver Disease in Women. J. Hepatol. 2019, 70, 126–132. [CrossRef]
[PubMed]
89. Groer, M.W.; Jevitt, C.M.; Sahebzamani, F.; Beckstead, J.W.; Keefe, D.L. Breastfeeding Status and Maternal Cardiovascular
Variables Across the Postpartum. J. Womens Health 2013, 22, 453–459. [CrossRef]
90. Anstey, E.H.; Shoemaker, M.L.; Barrera, C.M.; O’Neil, M.E.; Verma, A.B.; Holman, D.M. Breastfeeding and Breast Cancer Risk
Reduction: Implications for Black Mothers. Am. J. Prev. Med. 2017, 53, S40–S46. [CrossRef]
91. Lambertini, M.; Santoro, L.; Del Mastro, L.; Nguyen, B.; Livraghi, L.; Ugolini, D.; Peccatori, F.A.; Azim, H.A. Reproductive
Behaviors and Risk of Developing Breast Cancer According to Tumor Subtype: A Systematic Review and Meta-Analysis of
Epidemiological Studies. Cancer Treat. Rev. 2016, 49, 65–76. [CrossRef]
92. Babic, A.; Sasamoto, N.; Rosner, B.A.; Tworoger, S.S.; Jordan, S.J.; Risch, H.A.; Harris, H.R.; Rossing, M.A.; Doherty, J.A.;
Fortner, R.T.; et al. Association Between Breastfeeding and Ovarian Cancer Risk. JAMA Oncol. 2020, 6, e200421. [CrossRef]
93. Aune, D.; Norat, T.; Romundstad, P.; Vatten, L.J. Breastfeeding and the Maternal Risk of Type 2 Diabetes: A Systematic Review
and Dose–Response Meta-Analysis of Cohort Studies. Nutr. Metab. Cardiovasc. Dis. 2014, 24, 107–115. [CrossRef]
94. Bobrow, K.L.; Quigley, M.A.; Green, J.; Reeves, G.K.; Beral, V. for the Million Women Study Collaborators. Persistent Effects of
Women’s Parity and Breastfeeding Patterns on Their Body Mass Index: Results from the Million Women Study. Int. J. Obes. 2013,
37, 712–717. [CrossRef]
95. Nguyen, B.; Jin, K.; Ding, D. Breastfeeding and Maternal Cardiovascular Risk Factors and Outcomes: A Systematic Review. PLoS
ONE 2017, 12, e0187923. [CrossRef] [PubMed]
96. Pinho-Gomes, A.; Morelli, G.; Jones, A.; Woodward, M. Association of Lactation with Maternal Risk of Type 2 Diabetes: A
Systematic Review and Meta-analysis of Observational Studies. Diabetes Obes. Metab. 2021, 23, 1902–1916. [CrossRef] [PubMed]
97. Gunderson, E.P.; Lewis, C.E.; Lin, Y.; Sorel, M.; Gross, M.; Sidney, S.; Jacobs, D.R.; Shikany, J.M.; Quesenberry, C.P. Lactation
Duration and Progression to Diabetes in Women Across the Childbearing Years: The 30-Year CARDIA Study. JAMA Intern. Med.
2018, 178, 328. [CrossRef] [PubMed]
98. Tschiderer, L.; Seekircher, L.; Kunutsor, S.K.; Peters, S.A.E.; O’Keeffe, L.M.; Willeit, P. Breastfeeding Is Associated With a Reduced
Maternal Cardiovascular Risk: Systematic Review and Meta-Analysis Involving Data From 8 Studies and 1 192 700 Parous
Women. J. Am. Heart Assoc. 2022, 11, e022746. [CrossRef]
99. McClure, C.K.; Catov, J.M.; Ness, R.B.; Schwarz, E.B. Lactation and Maternal Subclinical Cardiovascular Disease among
Premenopausal Women. Am. J. Obstet. Gynecol. 2012, 207, 46.e1–46.e8. [CrossRef]
100. Stuebe, A.M.; Michels, K.B.; Willett, W.C.; Manson, J.E.; Rexrode, K.; Rich-Edwards, J.W. Duration of Lactation and Incidence of
Myocardial Infarction in Middle to Late Adulthood. Am. J. Obstet. Gynecol. 2009, 200, 138.e1–138.e8. [CrossRef]
101. Natland Fagerhaug, T.; Forsmo, S.; Jacobsen, G.W.; Midthjell, K.; Andersen, L.F.; Ivar Lund Nilsen, T. A Prospective Population-
Based Cohort Study of Lactation and Cardiovascular Disease Mortality: The HUNT Study. BMC Public Health 2013, 13, 1070.
[CrossRef]

Disclaimer/Publisher’s Note: The statements, opinions and data contained in all publications are solely those of the individual
author(s) and contributor(s) and not of MDPI and/or the editor(s). MDPI and/or the editor(s) disclaim responsibility for any injury to
people or property resulting from any ideas, methods, instructions or products referred to in the content.