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Clinical Gastroenterology and Hepatology 2019;17:231–242
Influence of Early Life, Diet, and the Environment
on the Microbiome
,‡ ,‡,§
Tien S. Dong* and Arpana Gupta*
*Vatche and Tamar Manoukin Division of Digestive Diseases, University of California, Los Angeles, Los Angeles, California;
‡David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, California; and §G. Oppenheimer Center
for Neurobiology of Stress and Resilience, University of California, Los Angeles, Los Angeles, California
Advances in sequencing technology and bioinformatics disease models, such as obesity and irritable bowel syn-
have greatly enhanced our ability to understand the hu- drome (IBS), are discussed to highlight how environ-
man microbiome. Over the last decade, a growing body mental perturbations in the human microbiome
of literature has linked nutrition and the environment to contribute to disease.
the microbiome and is now thought to be an important
contributor to overall health. This paper reviews the Environmental Factors
literature from the past 10 years to highlight the influence
of environmental factors such as diet, early life adversity
and stress in shaping and modifying our microbiome to- The environment plays a critical part in the compo-
wards health and disease. The review shows that many sition of the human microbiome (Figure 1). A total of
factors such as the mode of delivery, breast milk, stress, 22%–36% of the interperson microbiome variability is
diet and medications can greatly influence the develop- associated with environmental factors and only 1.9%–
mentofourgutmicrobiomeandpotentially make us more 9%bygenetics.2 Environmental factors start in the early
prone to certain diseases. By incorporating environmental days of life and extend well into adulthood. Next we
factors into models that study the microbiome in the highlight how environmental factors, such as the mode of
setting of health and disease, may provide a better un-
derstanding of disease and potentially new areas of treat- delivery, breastfeeding, and introductions of foods, are
ment. To highlight this, we will additionally explore the critical steps in the development of a mature adult
role of the environment and the microbiome in the devel- microbiome. We later show how such environmental
opment of obesity and functional bowel disorders. factors as diet, smoking, home life, and stress can induce
shifts in the microbiome during the lifespan and make
Keywords: Gut Microbiome; Environment; Early Life Diet; humans more prone to certain diseases.
Stress; Obesity; Irritable Bowel Syndrome.
Early Life Events
n the last decade, advances in sequencing technol- Early life events are critical to the development of the
Iogyandbioinformaticshave enhanced the ability to humanmicrobiomebecausetheycanshapethesequence
understand the human microbiome, and how the envi- of microbial community establishment and ultimately the
ronment contributes to shifts in these complex systems final composition of the mature adult microbiome.6 This
over time.1,2 The human microbiome represents a mi- section summarizes how the microbiome matures during
crobial community that encompasses 10 times more cells the transition from inside the womb, which is a relatively
andapproximately 100 times more genes than contained sterile environment, into the external environment after
in the human body alone.3 Although the major function birth when ingestion of milk and solid food are intro-
of the gut microbiome is to aid in the fermentation and duced. Microbial community differences during each key
energy extraction of indigestible dietary fiber, multiple early life process are summarized in Table 1.
studies have linked the microbiome to energy homeo- Prenatal. Studies have suggested that the introduc-
stasis, immune function, and the development of certain tion of microbes can occur as early as during the prenatal
4
diseases. An increased understanding of the relation- period. Although certain intrauterine infections and
ship between humans, their microbes, and the environ- bacteria from such groups as Burkholderia,
ment can help better understand the maintenance of
health and the development of disease.5 This review
explores the recent literature related to the influence of Abbreviations used in this paper: C-section, cesarean section; IBS,
environmental factors, such as early life events, diet, irritable bowel syndrome; SCFA, short-chain fatty acid.
pathogens, social factors, and stress, on the complex Most current article
host-microbe interactions and how these interactions ©2019bythe AGA Institute
contribute to or are protective against disease. Example 1542-3565/$36.00
https://doi.org/10.1016/j.cgh.2018.08.067
232 Dong and Gupta Clinical Gastroenterology and Hepatology Vol. 17, No. 2
Figure 1. Environmental factors shape and change the microbiome over time and perturbations can lead to disease. Maternal
factors: vaginal infections and gut microbiome can lead to bacterial translocation into the uterus. Postnatal factors: mode of
delivery, breastfeeding versus formula feeding, introduction of solid food, and early life adversity and antibiotic exposure can
shape the developing microbiome in early childhood. Environmental factors across the lifespan: long-term diet and exposure
to animals can modify the microbiome throughout childhood and adulthood. Perturbations to the microbiome: medications,
suchasantibiotics, proton pump inhibitors, and metformin, and a variety of different diets can make individuals more prone to
disease, such as inflammatory bowel disease, IBS, and obesity. Stress can lead to changes in the microbiome that affects
intestinal permeability and SCFA production. Smoking can cause microbial shifts that change inflammatory signaling and
colonic mucin production, all of which can be mechanisms that lead to the development of disease.
Actinomycetales, and Alphaproteobacteria are associated abundant phyla isolated from first-pass meconium were
withpretermdelivery,ithasbeenshownthatavarietyof Firmicutes, Proteobacteria, and Bacteriodetes.10 All bac-
other microbes may be present in the placenta, umbilical teria isolated from the umbilical cord blood of healthy
cord, amniotic fluid, and meconium of normal preg- neonates belonged to the genus Enterococcus, Strepto-
7–9 11
nancy. Thematernal microbiome is likely translocated coccus, Staphylococcus,orPropionibacterium. In the
into the uterus via the bloodstream, an idea supported by placenta, the genus Bifidobacterium and Lactobacillus
the detection of labeled Enterococcus faecium in the were identified.8
meconium of inoculated pregnant mice.7 In a recent However, the role and function of these microbes in
population-based study, researchers found the most human health or disease during the prenatal period re-
mains unclear. Because of the possibility of maternal
contamination, it is difficult to definitively establish the
presence of a prenatal microbiome.12 Further studies are
Table 1.Microbial Communities Described by Type of Early required to confirm the existence of a viable
Life Environmental Factors
intrauterine-resident microbiota with the use of
Bacterial adequate controls (such as maternal blood or sampling
Environmental factors community References at a site nearby delivery) to determine if the existence of
Vaginal delivery vs [Lactobacillus 18,19 such a microbiome might affect the future development
cesarean section delivery [Prevotella of the newborn.
[Sneathia Delivery. Although the existence of a prenatal micro-
[Bifidobacterium biome may be controversial, many agree that the first
[Bacteroides major introduction of a microbial community to a
YStaphylococcus newborn is through delivery.6 As the newborn is passing
YPropionibacterium through the vaginal canal, it is ultimately introduced to
YCorynebacterium
Breastfeeding vs [Bifidobacteria 31,32 the commensal vaginal and fecal microbiome of the
formula feeding [Lactobacillus mother.13 This community of microbes seems to be
YClostridiales distinct from the community of nonpregnant women
YProteobacteria because the vaginal microbiome changes during preg-
Introduction of solid food [Lachnospiraceae 35,36 nancy.14 For example, healthy pregnant women, when
[Ruminococcaceae
[Bacteroidaceae compared with nonpregnant women, had lower vaginal
YLactobacillaceae bacterial diversity with higher levels of Lactobacillus,
YBifidobacterium Clostridiales, Bacteroidales, and Actinomycetales; these
YEnterococcaceae levels were associated with gestational age.15 Beyond
YEnterobacteriaceae the vaginal microbiome, there is also evidence that the
community of the maternal gut also changes during the
January 2019 The Environment Impacts the Microbiome 233
course of pregnancy. For example, a Finnish cohort of studies demonstrated that the direct mother-to-infant
91 healthy pregnant women demonstrated decreased transmission changes over time as different floras are
bacterial diversity as evidenced by increased levels of introduced through processes, such as skin contact and
high-energy-yielding fecal microbiota with increasing breastfeeding.23,24
gestational age.16 From the first to the third trimester, Breastfeeding and introduction of solid food. The
the proportion of Proteobacteria, including species of the other major early life events that affect the development
Enterobacteriaceae family and Streptococcus genus, and maturation of the newborn microbiome are breast-
decreased, whereas the proportion of Faecalibacterium feeding and the introduction of solid food. Breast milk
prausnitzii increased. These changes in the microbiome bacteria, such as Corynebacterium and Rothia, can seed
were independent of prepregnancy body weight, gesta- the infant gut and influence the bacteria that follows,
25
tional diabetes, diet, and antibiotic use, suggesting that affecting the communities even through adulthood.
they were caused by the changes of normal pregnancy. These early seeding events may be the mechanism by
These changes in the microbiome have a beneficial role which breast milk can protect children against autoim-
for the mother and neonate by protecting against certain mune diseases, such as asthma and type 1 diabetes.26
infections, such as Neisseria gonorrhea and bacterial Similar to the vaginal microbiome, it has been shown
vaginosis, and also by permitting greater efficiency for that the microbiome of breast milk also varies with
energy harvest to support the growth of the mother and increasing gestational age, and is related to maternal
fetus.16,17 health and mode of delivery.26,27 The breast milk mi-
With these specific pregnancy-related changes crobial community is dominated by Corynebacterium,
effecting the vaginal and fecal microbiome of the mother, Ralstonia, Staphylococcus, Streptococcus, Serratia, Pseu-
it is unsurprising that the mode of delivery also greatly domonas, Propionibacterium, Sphingomonas, and Bra-
affects how the newborn microbiome develops. The dif- dyrhizobiaceae.26 In a study of 107 healthy women who
ferences seen between cesarean section (C-section) and were breastfeeding their infants for the first 30 days of
vaginally delivered babies are drastic. Compared with life, the gut microbiome changed in a dose-dependent
vaginally born babies, those that are born by C-section manner with 27.7% of the mean bacteria being derived
without membrane rupture have no vaginal microbes, from breast milk and 10.3% from areola skin.26
such as Lactobacillus, Prevotella, and Sneathia. Instead, Breast milk also contains many important prebiotic
babies born by C-section are colonized with skin mi- compounds, such as human milk oligosaccharides. These
crobes, such as Staphylococcus, Propionibacterium, and sugar polymers are almost exclusively metabolized by
Corynebacterium.18 These babies have a delayed coloni- the gut microbiome28 and they can promote the growth
zation of intestinal microbes, such as Bacteroides and of key communities including Bifidobacterium spp.29
Bifidobacterium.19 Although the exact length of time Bifidobacteria has been shown to inhibit the growth of
these differences exist is unknown, microbial differences pathogenic organisms and improve barrier function in
between C-section and vaginally delivered babies have the infant gut.30 In a mouse model, human milk oligo-
been observed to as far out as 7 years of age.20 The saccharides were found to be protective in the develop-
deficits in the human microbiome associated with ment of autoimmune disease and obesity.31,32
C-section deliveries have been implicated in certain There are clear differences in the composition of the
childhood autoimmune disease, such as celiac disease, microbiome in infants who are breastfed versus those
asthma, and type I diabetes.21 These studies also suggest who are formula fed. Infants who are breastfed have a
that restoration of a more “normal” microbiome after higher proportion of Bifidobacterium and Lactobacillus
C-section deliveries may therefore be beneficial. “Vaginal spp, whereas infants who are formula-fed have a higher
seeding,” or the process by which vaginal fluids are proportion of Clostridiales and Proteobacteria.33,34
applied to a newborn child delivered by C-section, has Formula-fed infants also have lower diversity and rich-
been a method used to restore the human microbiome. ness even after the first year of life as compared with
Although a small pilot study of 4 babies demonstrated their breastfed counterparts.33 In a study of 30 preterm
the feasibility of restoring the early microbiome of babies infants, breastfeeding was found to be protective against
born by C-section,22 the long-term health consequence of gut immaturity and possibly necrotizing enterocolitis.35
such a procedure remains unknown and may even in- Several other epidemiologic studies have provided sup-
crease the risk of transmittable diseases to the newborn. port for the beneficial role of breastfeeding in the
Therefore, further prospective studies are needed to development of disease. Formula feeding has been
determine the safety and potential benefits, if any, of associated with various inflammatory and autoimmune
these methods used to restore the human microbiome. diseases.36 In contrast, breastfeeding, through its effects
Even though the mode of delivery is important to onthemicrobiome,hasbeenassociatedwithaprotective
microbial seeding, it may not be the only mode for ver- role against asthma, autism spectrum disorder, and type
tical transmission. Recent human studies have high- 1 diabetes.26,36
lighted maternal vertical transmission from multiple One of the last major events in early life affecting mi-
different sources, such as the skin, mouth, and gastro- crobial development is the introduction of solid food.
intestinal track.23,24 By examining strain-level data, these Although breast milk keeps the microbiome in a state that
234 Dong and Gupta Clinical Gastroenterology and Hepatology Vol. 17, No. 2
is characterized by low diversity and Bifidobacterium Diet
predominance, the introduction of solid food and the
cessation of breastfeeding increases adult-associated mi- During the early stages of life, breast milk and the
37
crobes, such as Lachnospiraceae and Ruminococcaceae. introduction of solid food are critical events in the
In a Danish study of 330 children between 9 and 36 development of the human microbiome. Therefore, it is
months of age, Lactobacillaceae, Bifidobacteriaceae, not surprising that the introduction of diet throughout
Enterococcaceae, and Enterobacteriaceae decreased, life has large effects on the human microbiome. The gut
whereas Lachnospiraceae, Ruminococcaceae, and Bacter- microbiota can change within days of a new diet, but to
oidaceae increased during the period when solid foods what extent these changes are permanent once the new
38 48
was being introduced. Another study of 531 children diet has terminated remains uncertain. In this section,
born in 5 different countries showed similar results in- we review the current literature, focusing on popular
dependentoflocation, use of antibiotics, mode of delivery, diets and how the microbiome is connected (summarized
or milk feeding practices, suggesting that these changes in Table 2).
were typical of the normal developing microbiome as Westerndiet. The Western diet or standard American
39 diet is a diet characterized by high fat, high sugar, high
solid foods are being introduced. This transition is
necessary and beneficial. It allows for a microbial com- level of red and processed meat, high levels of refined
munity that is better equipped to extract energy and grains, and a lower level of fiber.48 Many studies have
process a diet that is no longer dependent on milk to a linked the Western diet to inflammation, diabetes, car-
diet that is higher in fiber and protein, similar to the diet diovascular risks, obesity, and metabolic syndrome.48,49
of a mature adult. Although a Western diet affects many different cell
Early life adversity. Recently, researchers are discov- types, such as adipocytes, immune cells, and endocrine
ering that early life adverse events can manipulate the cells, there is also a strong link that connects the dele-
microbial community in significant ways. In rats, limited terious effects of a Western diet to shifts in the micro-
nesting stress during postnatal days 2–10 led to a biome.48 Compared with other indigenous diets, the
delayed maturation of the hypothalamic-pituitary- microbiome on a Western diet is characterized by a
adrenal axis that was associated with decreased micro- significantly lower microbial diversity and species rich-
bial diversity, an increase of gram-positive cocci, and a ness.50 The Western diet microbial composition is clas-
reduction of fiber-degrading bacteria.40 Similar findings sically characterized by an overabundance of the phyla
were demonstrated in mice and rhesus monkeys when Firmicutes and a decrease in Bacteroidetes.51 On a genus
exposed to stress at an early age.41,42 Finally, in patients level, a Western diet shows a decrease in Bifidobacterium
with IBS, those that had a microbiome profile distinct and Lactobacillus, whereas being high in Enterobacter.52
from healthy control subjects were more likely to have a Consequently, the Western diet has been linked to an
history of early adverse events and trauma than those increase in endotoxemia, a state characterized by
with a microbiome that was more similar to healthy decreasedintestinal barrier function and increased levels
control subjects.43 Although these studies are predomi- of bacterial lipopolysaccharides and inflammatory
nantly associations, exploring how adverse events and signaling.53,54 Furthermore, a Western diet can possibly
early gut dysbiosis can cause such diseases as IBS is an lead to permanent microbiome changes that may be
active research area. responsible for postdieting weight regain or the common
Antibiotic use can also play a significant role during concept of yo-yo dieting, which has been linked to higher
early life. The average U.S. child receives about 1–3 long-term weight gain, increased obesity-related risk
antibiotic courses by the age of 2 years.44 Several studies 55
factors, and increased difficulty reducing weight.
have highlighted how antibiotic exposure in children can Mediterranean diet. In contrast to a Western diet, a
beassociated with an increased risk for obesity, diabetes, Mediterranean diet is considered a healthier diet. It is
allergies, asthma, IBS, and inflammatory bowel dis- characterized by a beneficial fatty acid profile; higher
ease.33,45 Children exposed to antibiotics have delayed intake of fiber, vegetables, and fruits; and with lower
maturation of their microbiome as compared with their intake of sugar and red meat.56 A recent study demon-
respective control subjects, but whether this is the exact strated that out of 153 participants, those who were
mechanism by which early antibiotics predisposes chil- more adherent to a Mediterranean diet had an increased
dren to disease is still unclear.33 In animal models, per- level of short-chain fatty acids (SCFA), Prevotella, and
ipartum antibiotic exposure in the mother can lead to certain Firmicutes, which have all been associated with
persistent gut dysbiosis in the offspring and colitis in decreased cardiovascular events.57 Additionally, they
susceptible individuals.46,47 Although these studies do also showed that low adherence to the Mediterranean
not provide an exact mechanistic explanation of the ef- diet led to decreases in urinary trimethylamine oxide
fect of antibiotic use on microbiome development or on levels, which is associated with higher cardiovascular
disease susceptibility, they do highlight that early anti- risk.57,58 Several studies have shown that consumption of
biotic exposure is linked in some way to the normal foods encompassing the typical Mediterranean diet
development of microbial community and to disease improved obesity, inflammation, and lipid profile and
development. were associated with increases in Lactobacillus,
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