Diet and the development of the human intestinal microbiome

Abstract

The important role of the gut microbiome in maintaining human health has necessitated a better understanding of the temporal dynamics of intestinal microbial communities as well as the host and environmental factors driving these dynamics. Genetics, mode of birth, infant feeding patterns, antibiotic usage, sanitary living conditions and long term dietary habits contribute to shaping the composition of the gut microbiome. This review focuses primarily on diet, as it is one of the most pivotal factors in the development of the human gut microbiome from infancy to the elderly. The infant gut microbiota is characterized by a high degree of instability, only reaching a state similar to that of adults by 2-3 years of age; consistent with the establishment of a varied solid food diet. The diet-related factors influencing the development of the infant gut microbiome include whether the child is breast or formula-fed as well as how and when solid foods are introduced. In contrast to the infant gut, the adult gut microbiome is resilient to large shifts in community structure. Several studies have shown that dietary changes induce transient fluctuations in the adult microbiome, sometimes in as little as 24 hours; however, the microbial community rapidly returns to its stable state. Current knowledge of how long-term dietary habits shape the gut microbiome is limited by the lack of long-term feeding studies coupled with temporal gut microbiota characterization. However, long-term weight loss studies have been shown to alter the ratio of the Bacteriodetes and Firmicutes, the two major bacterial phyla residing in the human gastrointestinal tract. With ageing, diet-related factors such as malnutrition are associated with microbiome shifts, although the cause and effect relationship between these factors has not been established. Increased pharmaceutical usage is also more prevalent in the elderly and can contribute to reduced gut microbiota stability and diversity. Foods con

Full text

REVIEW ARTICLE
published: 22 September 2014
doi: 10.3389/fmicb.2014.00494
Diet and the development of the human intestinal
microbiome
Noah Voreades, Anne Kozil and Tiffany L. Weir*
Department of Food Science and Human Nutrition, Colorado State University, Fort Collins, CO, USA
Edited by:
Anton G. Kutikhin, Research Institute
for Complex Issues of Cardiovascular
Diseases under the Siberian Branch of
the Russian Academy of Medical
Sciences, Russia
Reviewed by:
Carl James Yeoman, Montana State
University, USA
Franck Carbonero, University of
Arkansas, USA
*Correspondence:
Tiffany L. Weir, Department of Food
Science and Human Nutrition,
Colorado State University, 1571
Campus Delivery, 210 Gifford
Building, Fort Collins, CO 80523-1571,
USA
e-mail: tiffany.weir@colostate.edu
The important role of the gut microbiome in maintaining human health has necessitated a
better understanding of the temporal dynamics of intestinal microbial communities as well
as the host and environmental factors driving these dynamics. Genetics, mode of birth,
infant feeding patterns, antibiotic usage, sanitary living conditions and long term dietary
habits contribute to shaping the composition of the gut microbiome. This review focuses
primarily on diet, as it is one of the most pivotal factors in the development of the human
gut microbiome from infancy to the elderly. The infant gut microbiota is characterized by
a high degree of instability, only reaching a state similar to that of adults by 2–3 years
of age; consistent with the establishment of a varied solid food diet. The diet-related
factors influencing the development of the infant gut microbiome include whether the
child is breast or formula-fed as well as how and when solid foods are introduced. In
contrast to the infant gut, the adult gut microbiome is resilient to large shifts in community
structure. Several studies have shown that dietary changes induce transient fluctuations
in the adult microbiome, sometimes in as little as 24 h; however, the microbial community
rapidly returns to its stable state. Current knowledge of how long-term dietary habits
shape the gut microbiome is limited by the lack of long-term feeding studies coupled
with temporal gut microbiota characterization. However, long-term weight loss studies
have been shown to alter the ratio of the Bacteroidetes and Firmicutes, the two major
bacterial phyla residing in the human gastrointestinal tract. With aging, diet-related factors
such as malnutrition are associated with microbiome shifts, although the cause and effect
relationship between these factors has not been established. Increased pharmaceutical
usage is also more prevalent in the elderly and can contribute to reduced gut microbiota
stability and diversity. Foods containing prebiotic oligosaccharide components that nurture
beneficial commensals in the gut community and probiotic supplements are being explored
as interventions to manipulate the gut microbiome, potentially improving health status.
Keywords: enterotype, gut microbiome, aging, dietary patterns, colonization
IMPORTANCE OF THE GUT MICROBIOME
The consortium of single-celled organisms residing in our
intestines, the gut microbiome, is rapidly emerging as an impor-
tant determinant of health. Deterrents to proper bacterial col-
onization in early life are hypothesized to contribute to food
sensitivities, allergic reactions, Type I diabetes, and other autoim-
mune disorders (Kelly et al., 2007). Association of the microbiome
to autoimmune diseases has been explained by the “hygiene
hypothesis,” which suggests that the absence of a robust micro-
biome results in defects in development and regulation of the
immune system, resulting in a lack of immune tolerance (Okada
et al., 2010;Rook, 2012). Later in life, strong evidence supports an
important role for intestinal microbiota in weight regulation via
contributions to dietary energy harvest and appetite control (Tilg
and Kaser, 2011). The gut microbiome has also been implicated in
the pathology of several intestinal inflammatory diseases as well
as in the development of colorectal, gastric, and prostate cancers
and cardiometabolic disorders (Sekirov et al., 2010). Mechanisms
giving rise to these conditions include the production of geno-
toxins by bacterial pathogens, microbial metabolism of dietary
components to produce carcinogenic compounds, and inciting
local and systemic inflammatory cascades that result in chronic low
grade inflammation and damage to affected tissues and organs.
While a dysbiotic microbiota can cause disease, a healthymicro-
bial community is vital to assist the host in maintaining optimal
wellness. Thus, there is a need to understand the factors that shape
and alter the microbiome throughout the lifespan of an individ-
ual. Numerous elements, encompassing environmental exposures,
genetics, and other inherent host factors, contribute to the initial
colonization of the microbiome in infants and to the subtle shifts
that occur in adults, occasionally culminating in microbial decline
as observed in frail and unhealthy elderly individuals (Koenig et al.,
2011). However, none of these factors may be as important in the
development of the microbiome as diet. In this review we will
present evidence for the importance of diet in initial coloniza-
tion events and in determining the composition of a stable adult
microbiome. Factors such as malnutrition and pharmaceutical
interventions on the aging gut will also be reviewed. Finally, we
will discuss potential interventions, including dietary changes that
can be used to alter the intestinal microbial community.
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Voreades etal. Diet and the gut microbiome
EARLY MICROBIAL COLONIZATION AND ESTABLISHMENT
The infant gut is thought to be sterile at birth, although some
new research characterizing the placental microbiome challenges
that assumption (Aagaard et al., 2014). After birth initial colo-
nization and early establishment of the infant gut is influenced
by whether delivery was vaginal or caesarean, feeding patterns,
sanitary conditions, and antibiotic administration (Marques et al.,
2010). The relative importance of these factors on the long-term
structure of the intestinal microbial community and associated
health outcomes is still debated. It stands to reason that with con-
stant exposure between the microbiome and food components
that diet is one of the primary drivers shaping the changes that
occur during infancy and the structure of the adult microbiome
that eventually establishes. This section will focus on the diet’s role
in shaping the infant gut microbiome from birth to ∼3yearsof
age. Specifically, the following topics will be explored in detail: (1)
the influence of breast vs. formula-feeding in initial colonization,
(2) changes related to beginning of weaning and introduction of
solid foods, and (3) factors contributing to a stable gut microbiome
profile (Figure 1).
BREAST vs. FORMULA FEEDING
Following birth, the infant gut microbiome is characterized
by low-species diversity and high rates of bacterial flux until
∼2 or 3 years old (Bergström et al., 2014). Facultative anaerobic
bacteria including Staphylococcus, Streptococcus, Escherichia coli
and Enterobacteria are thought to be the first colonizers of the
gut. Their purpose is to consume oxygen and create an environ-
ment for obligate anaerobes to thrive (Palmer et al., 2007;Jost
et al., 2012). These are later replaced by facultative anaerobes that
dominate the gastrointestinal tract, primarily Actinobacteria and
Firmicutes (Turroni et al., 2012). This change in dominant taxa
representation can be attributed to the introduction of breast
or formula-feeding, signifying the first diet-related colonization
event in the infant gut microbiome (Harmsen et al., 2000;Jost
et al., 2012). In breast-fed infants, the dominant Actinobacteria
are represented by Bifidobacterium species, specifically,B.breve,
B. longum,B. dentium,B. infantis, and B. pseudocatenulatum
(Harmsen et al., 2000;Jost et al., 2012). The Firmicutes phylum
is represented principally by lactic acid bacteria such as Lacto-
bacillus and Enterococcus as well as Clostridium species (Turroni
et al., 2012;Bergström et al., 2014). More than 700 species of bac-
teria have now been identified in human colostrum and breast
milk, including multiple species of lactic acid bacteria as well as
species typically colonizing the oral cavity of infants (Cabrera-
Rubio et al., 2012). While this may contribute to the intestinal
community of breastfed infants, it is still unclear whether the com-
position of species in breast milk is driven by transfer from infant
to mother. The chemical composition of breast milk does influence
the gut microbiome through supplying unique oligosaccharides
that are selectively utilized by Bifidobacterium spp. (Turroni et al.,
2012).
There are conflicting reports regarding differences in the rel-
ative abundance of these bacteria between breast and formula
fed infants. Many studies have reported that formula-fed infants
display dominance of Bifidobacterium spp. similar to what has
been observed in breastfed infants (Harmsen et al., 2000;Fallani
et al., 2010,2011). However, another study reported approxi-
mately double the count of Bifidobacterium in breast fed infants
compared to those fed formula (Bezirtzoglou et al., 2011). For-
mula feeding was also associated with higher levels of Atopo-
bium (Bezirtzoglou et al., 2011); which corroborated reports by
Fallani et al. (2010),although they only noted Atopobium increases
in formula fed infants delivered by Cesearean section or whose
mother’s had been administered antibiotics. Higher numbers
of Bacteroides spp. as well as members of the Enterobacteri-
aceae have also been reported in formula-fed infants (Harmsen
et al., 2000;Fallani et al., 2010). Despite significant evidence
that Bifidobacterium is an important early colonizer in neonates,
Palmer et al. (2007) reported that Bifidobacterium was not present
in significant amounts in the infant gut (Palmer et al., 2007).
However, it is important to highlight that within their cohort,
there was a mixture of breast and formula-feeding, antibiotics
were provided to infants and a small subset required specialized
hospitalization.
The variability reported with regard to Bifidobacterium
abundance could be driven by differences in infant for-
mula composition. Formulas supplemented with the prebiotics
FIGURE 1 |Representation of the infant gut microbiome development from birth to 3 years of age. By 3 years old, toddler’s microbiomes are similar to
that in adults and long-term dietary patterns are beginning to establish.
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Voreades etal. Diet and the gut microbiome
galacto-oligosaccharide (GOS) and fructo-oligosaccharide (FOS)
may account for high levels of Bifidobacterium found in many
formula-fed infants (Marques et al., 2010;Oozeer et al., 2013). A
recent review discusses evidence supporting GOS and FOS sup-
plementation effects on the gut (Oozeer et al., 2013). Infant gut
microbial populations provided with either human breast milk
or prebiotic supplemented infant formula had similar levels of
Bifidobacterium; whereas gut microbial populations of infants
given traditional formula was reported to have about 20% fewer
Bifidobacterium (Knol et al., 2005). Additionally, the species com-
position of Bifidobacterium was similar between infants given
human breast milk and those on prebiotic supplemented for-
mula. However, traditional formula fed infants had markedly
different gut microbial communities and even the specific Bifi-
dobacterium species differed with higher relative abundances of
B. cantenulatum and B. adolescentis, which are typically repre-
sented in adult populations. Another potential explanation for
the variation in studies reporting bacterial abundances, partic-
ularly with regard to breast-feeding could be due to differences
in the maternal-diet (Cabrera-Rubio et al., 2012). Characteriza-
tion of the placental microbiome suggests that it is colonized
by the mother’s oral microbiome (Aagaard et al., 2014). Another
recent study showing that pre and post-natal maternal con-
sumption of a high fat diet, independent of obesity in the
mother, resulted in dysbiosis of the infant gut in a primate
model (Ma et al., 2014). Together, these studies suggest that
maternal diet may play a significant but previously unrecognized
role in determining early colonization and establishment of the
infant microbiome. Conduct of randomized trials in which the
maternal diet is controlled or large-scale cross-sectional studies
of pregnant mothers adhering to different diets (Western, veg-
etarian, gluten-free, etc) are necessary to further develop this
hypothesis.
WEANING AND THE SHIFT TOWARD AN ADULT MICROBIOME
Around the age of 1–2 years old, the infant gut microbiome
undergoes its second shift and the stable adult microbiome
begins to emerge, further supporting the significant role of
the diet in influencing the microbial community (De Fil-
ippo et al., 2010;Bergström et al., 2014). One study reported
that although there were differences in the microbiome pre-
and post-weaning, the impacts of earlier colonization events
(delivery mode, formula or breastfed, etc.) were still appar-
ent (Fallani et al., 2011). Another study comparing Italian vs.
African children’s gut microbiomes showed that after wean-
ing and solid foods were introduced there was a significant
diet-related shift in the gut microbiome profiles. Prior to the
introduction of their respective Western or African diets, the
children across both populations that were still breast-feeding
clustered together and had similar Bifidobacterium species domi-
nance. Only children who were already weaned reliably clustered
together into distinct geographic groupings. This study rein-
forced two important points related to dietary drivers of the
gut microbiome development in children. First, breast-feeding,
regardless of duration supports a specific bacterial state that
is unique and markedly different from that observed in indi-
viduals consuming solid foods. Second, once solid foods are
introduced, its role in shaping long-term gut microbiome pro-
files is so strong that individual’s cluster based on diet type over
other environmental and physiological factors (De Filippo et al.,
2010).
A similarly significant shift was reported by Bergström et al.
(2014) ina3yearDanish study with a cohort of 330 infants.
They reported that between 9 and 18 months, the infant gut bac-
terial abundances changed drastically with the introduction of
solid foods. Specifically, Bacteroidetes-related species increased.
Whereas Bifidobacterium and Lactobacillus species and Enter-
obacteriaceae declined, various species within Firmicutes phylum
were also reported to increase. This bacterial taxa shift is logi-
cal given that breast and/or formula-feeding has ceased, depleting
the primary fuel source for these bacteria. In addition, butyrate
producing bacteria such as Clostridium leptum group, E. halli, and
Roseburia species increased. Typically, butyrate producing bacteria
are responsible for the breakdown of otherwise indigestible com-
plex plant polysaccharides and resistant starches. Anecdotally, this
study found that the longer infants were breast and/or formula-fed,
the lower their levels of butyrate producing bacteria. Additionally,
more and different species begin to appear with introduction of
solid foods (Koenig et al., 2011;Bergström et al., 2014).
EMERGENCE OF A STABLE GUT PROFILE
From 18 to 36 months, the infant gut microbiome undergoes its
final significant shift to a more stable microbial profile composed
primarily of the bacterial phyla Bacteriodetes and Firmicutes.
This shift represents a temporal change that can be attributed
to the continued influence of a varied solid food diet (De Fil-
ippo et al., 2010;Koenig et al., 2011;Bergström et al., 2014).
The earlier that solid food is introduced into the diet, the more
quickly the gut microbiome begins to resemble a stable adult-
like microbiome (Bergström et al., 2014). The specific proportion
of Firmicutes and Bacteroidetes is strongly influenced by diet.
This was best demonstrated in the previously discussed work
by De Filippo et al. (2010) where the distinct microbial signa-
tures of the two groups of children were indicative of their
respective dietary habits. The most compelling evidence for this
was the dominance of Prevotella, capable of digesting complex
plant polysaccharides, in African children and its absence in Ital-
ian children. Similar diet-driven influences were reported in a
detailed temporal study of a single infant. This study demon-
strated that introduction of peas, formula, and other solid foods
led to an emerging co-dominance between Firmicutes and Bac-
teroidetes, with the increase in Bacteroidetes potentially resulting
from requirements for the breakdown of newly introduced plant
polysaccharides (Koenig et al., 2011). The previously mentioned
emergence of a stable gut microbiome can be substantially derailed
if the infant experiences either severe acute malnutrition or mod-
erate acute malnutrition. Emerging research is demonstrating
that either of these malnutrition states has the potential to sig-
nificantly alter the development of a healthy gut microbiome
profile, regardless of diet-based interventions (Subramanian et al.,
2014). These recent findings not only support a link between
diet and the development of a particular gut microbiota and
microbiome, but illustrate that nutrient quantity can impact
development too.
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Voreades etal. Diet and the gut microbiome
THE ADULT MICROBIOME
The typical adult intestinal microbiome is primarily comprised
of approximately six or seven different bacterial phyla, of which
Bacteroidetes and Firmicutes dominate (Eckburg et al., 2005).
Less abundant phyla can include Proteobacteria, Verrucomicro-
biota, Actinobacteria, and Euryarchaeota. A recent study followed
changes in the microbiome of 37 adults for up to 5 years and
reported that ∼60–70% of the bacterial strains present remained
unchanged over the course of the study and that the most sta-
ble members of the microbiome tended to be the most abundant
(Faith et al., 2013). They also observed that at the phyla level,
Bacteroidetes and Actinobacteria populations were less suscepti-
ble to perturbations whereas Firmicutes and Proteobacteria were
significantly less stable. These results are fairly consistent with find-
ings from an earlier study utilizing a microarray-based approach
to determine molecular taxonomy and which followed a smaller
cohort over a longer period of time (Rajilic-Stojanovic et al., 2013).
Both studies reported that the taxa present in an individual remain
fairly consistent over time, although the relative abundances of
these taxa were subject to change. However, data from Rajilic-
Stojanovic et al. (2013) suggests that larger fluctuations occur
between samples taken at longer intervals while Faith et al. (2013)
report the opposite trend, with larger fluctuations occurring in
samples taken over shorter periods of time compared to those
that are temporally farther apart. Despite this resilience, there is
evidence that the diet shapes the relative abundance of dominant
phyla and populations of specific bacterial groups are influenced
by the composition of macronutrients consumed.
DIET-DRIVEN ENTEROTYPES
There have been numerous attempts to identify a “core” micro-
biota, usually defined as bacterial taxa that are shared between
95% of individuals tested (Huse et al., 2012). Identification of a
core microbiome is important for defining a “normal” healthy
state from which major variations may indicate a dysbiotic system
that can result from or contribute to disease development. One
barrier to defining an intestinal core microbiome has been the
vast degree of variation between individuals. The microbial com-
munities identified in samples collected from an individual over
time are more similar to each other than microbial communi-
ties between two individuals, although related persons share more
bacterial strains than unrelated individuals (Palmer et al., 2007;
Yatsunenko et al., 2012;Faith et al., 2013). Although a consensus
for what constitutes a core gut microbiome has been elusive, one
report suggested that an international cohort of 39 individuals
could be assigned to one of three distinct clusters or “enterotypes”
based on metagenomic sequences (Arumugam et al., 2011). They
found that each cluster was dominated by a particular bacterial
genus (Bacteroides,Prevotella, and Ruminococcus) with positive
or negative associations with a number of other genera in the
community. They also reported that each cluster was enriched for
specific gene functions that reflected different microbial trophic
chains. Two of the three original enterotypes, Bacteroides, and Pre-
votella, were later confirmed and long term dietary patterns were
identified as the primary predictor of an individual’s enterotype
(Wu et al., 2011). The Bacteroides enterotype was associated with
a Western-type diet high in proteins and fat, while the Prevotella
enterotype was associated with plant fiber consumption. These
enterotypes appear to be extremely stable, and several studies
utilizing short-term interventions failed to result in a change in
the assigned enterotype of participants (David et al., 2014;Roager
et al., 2014).
The existence of enterotypes provided a convenient way of
classifying individuals based on their fecal microbiota (although
some argue a more appropriate term would be “faecotype”) and
speculation has begun as to whether enterotypes can be used
as a predictor of long term health risks. However, a microbial
survey of several body sites, including stool, conducted with
more than 200 individuals showed only minimal segregation
into the Bacteroides and Prevotella enterotypes rather than the
distinct and well separated clusters previously reported (Huse
et al., 2012). These discrepancies could be due to the fact that
the method for assigning enterotypes is not consistent across
studies. An analysis of archived 16S sequences also showed that
enterotype determination is sensitive to clustering methods and
distance metrics used and that there is a continuum of Bacteroides
abundances across samples rather than a bimodal distribution
(Koren et al., 2013). These studies suggest that the enterotype
concept is not be as clear cut as previously believed, and that
standard methods for defining enterotypes should be developed
and employed before they can be meaningfully tied with clinical
outcomes.
LONG TERM DIETARY PATTERNS AND THE MICROBIOME
Whether enterotypes truly exist or not, it is clear that diet is
an important factor in shaping the microbiome (Figure 2). In
addition to the divergence in microbial composition of Italian
children and those from Burkina Faso shortly after weaning (De
Filippo et al., 2010); other studies have shown microbiota seg-
regation of individuals from Malawi, Venezuela, and the United
States (Yatsunenko et al., 2012); children from Bangladesh and
the United States (Lin et al., 2013), and between rural Africans
and African Americans (Ou et al., 2013) that are at least partially
diet-driven. In the Yatsunenko etal. (2012) study, metagenomic
sequences revealed that enzyme classifications associated with
protein degradation and bile salt metabolism were enriched in
samples from the U.S. population where protein and fat consump-
tion is high. Conversely, glutamate synthase and starch degrading
enzymes were more abundant in the Amerindian and Malawian
samples; consistent with protein poor diets of corn and cassava.
This has been further demonstrated in a recent study of the diver-
sity and metabolism of the microbiome of a Tanzanian hunter
gatherer tribe, the Hadza. This study identified differences in
the microbiome between the sexes which were consistent with
their division of labor with regard to foraging (Schnorr et al.,
2014). They also have many bacterial species associated with fer-
mentation of plant-based fibers and are completely deficient in
Bifidobacterium, which was hypothesized to result from the lack of
meat and dairy in the diet; substrates that allow these bacteria to
continue to colonize Westerners into adulthood. Although com-
parative studies between populations with different diets has been
useful in identifying how dietary patterns shape the microbiome,
these studies have utilized international cohorts that introduce
confounding factors such as extreme differences in culture and
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Voreades etal. Diet and the gut microbiome
FIGURE 2 |The adult gut microbiome is characterized as existing in a steady state that requires a major disturbance to permanently alter that state.
Short-term diet interventions may transiently alter the gut microbiome community structure, but long-term diet changes are required to shift to a new
steady-state.
environment. Relatively few studies have been conducted that
examine the effects of diet on homogenous populations. One
study looked at correlations between specific dietary components
and microbial function and structure in the intestines of a human
cohort known for keeping meticulous diet logs (Muegge et al.,
2011). They found that there were significant correlations between
microbial gene function (Kegg orthologs) and protein intake,con-
firming the difference that was seen across multiple mammalian
species between carnivores and herbivores. They also reported
a correlation between insoluble fiber consumption and bacterial
community membership. A large-scale microbiome sequencing
effort called the American Gut Project is currently underway
and is attempting to address the effects of diet on the adult
microbiome capturing extremes within the American diet (i.e.,
vegan, paleo, etc) where cultural and environmental factors will
be minimized.
DIETARY INTERVENTIONS INTRODUCE TRANSIENT AND SUBTLE
CHANGES IN THE MICROBIOME
Short-term dietary interventions that include introducing novel
food components or altering macronutrient levels have also been
examined for their effects on intestinal microbial populations.
The first of these studies followed obese individuals partitioned
to restricted calorie diet groups that controlled for either fat or
carbohydrate intake (Ley et al., 2006). Regardless of the macronu-
trient composition of the diet, individuals that lost a significant
amount of body weight had a change in their ratio of Bacteroidetes
to Firmicutes, driven by increases in the Bacteroidetes. Weight-
loss driven changes in the microbiome was recently confirmed
in individuals consuming a calorie restricted liquid diet where
it was demonstrated that weight stability of an individual was a
better predictor of fecal microbiome stability than time between
sample collections (Faith et al., 2013). However, this and another
study (Duncan et al., 2008) noted changes in members of the
Firmicutes rather than an increase in Bacteroidetes when corre-
sponding weight loss occurred. Calorie restriction in obese and
overweight individuals has also been shown to increase micro-
bial gene richness, a parameter that was correlated to improved
metabolic parameters (Cotillard et al., 2013;Le Chatelier et al.,
2013).
Several studies have noted rapid but transient changes in fecal
microbial composition immediately following the start of a dietary
intervention study. Wu etal. (2011) conducted a controlled feed-
ing experiment in ten individuals randomized to high fat/low fiber
or high fiber/low fat diets and found that although there was no
increase in community similarity between individuals on the same
diet over a period of 10 days, the first 24 h period was considered an
outlier because transient dramatic shifts occurred in the fecal com-
munities of all individuals. Similarly, switching between animal
and plant-based diets produces similar results (David et al., 2014).
Another interesting finding of the David et al. (2014) study was
that foodborne microbes transiently colonized the gut, introduc-
ing the idea that food may not only select for commensal bacterial
species, but serve as a reservoir for new microbial introductions.
Intentional introduction of food-borne microorganisms (probi-
otics) as well as prebiotic food ingredients and foods high in fiber
can also be a means of subtly changing the relative abundance of
bacterial species in the gut (Preidis and Versalovic, 2009). Thus,
despite the inherent stability of the microbiome over time, changes
related to weight loss and diet composition continue to subtly alter
the composition and relative abundance of our commensal organ-
isms, driving the development of our gut microbiome throughout
adulthood.
THE AGING GUT
As a person ages, the stability and diversity of their gut micro-
biota declines with the state of their health. If health remains
intact however, microbiota composition often retains the stability
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Voreades etal. Diet and the gut microbiome
and compositional make-up of a healthy younger adult (Claesson
et al., 2012). The most prevalent age-related factors influenc-
ing the microbial population of the gut are: (1) physiological
changes, (2) dietary choices and malnutrition, (3) living situa-
tion (community-dwelling, hospitalized, or long-term care), and
(4) use of antibiotics (Bartosch et al., 2004;Woodmansey, 2007;
Claesson et al., 2012) and other prescription drugs (Qato et al.,
2008). This section will explore dietary alterations and antibiotic
usage as drivers of change in the elderly gut microbiome and dis-
cuss the use of probiotics and prebiotics as potential solutions for
the restoration of a healthy gut.
Diet is a major influence on the bacterial makeup of the aging
gut. Physiological changes, such as loss of taste and smell, difficulty
chewing or swallowing, impaired digestive function, and lack of
physical mobility can leave elderly individuals consuming a narrow
and nutritionally imbalanced diet, setting the stage for malnutri-
tion (Bartosch et al., 2004;Claesson et al., 2012). Relocation from
an in-home community setting to a long-term care facility can
change dietary intake as well. The move often contributes to a
greater consumption of fat and a decreased intake of fiber, fruits,
vegetables, and meat. These dietary alterations are associated with
a decrease in microbial diversity and increased frailty (Claesson
et al., 2012).
The use of antibiotics in elderly populations is especially preva-
lent in hospital and long-term care facilities. Antibiotics create an
environment of instability by diminishing the population of total
and commensal bacteria and opening the door for pathogenic
bacteria to overpopulate (Claesson et al., 2011). The use of
broad-spectrum antibiotics is associated with the overgrowth of
Clostridium difficile which flourishes in the antibiotic-weakened
gut, often resulting in a life threatening infection (Macfarlane,
2014). As health issues compound and antibiotic use increases,
elderly often see a decline in commensal anaerobes (Bacteroides,
Lactobacillus and Bifidobacterium) accompanied by a rise in pro-
teolytic and pathogenic bacteria (Fusobacteria,Propionibacteria,
Clostridia, and E. coli;Wu et al., 2011). Studies indicate that pro-
biotics may have potential as a therapeutic tool to replenish and
recolonize beneficial bacterial species like Bifidobacterium and Lac-
tobacillus, bringing the elderly gut back into balance (Likotrafiti
et al., 2014).
EFFECTS OF DIET AND MALNUTRITION ON THE ELDERLY MICROBIOME
A number of proposed factors contribute to alterations in the
elderly gut ecosystem and diet is a significant driver of change
(Claesson et al., 2012). Dietary intake can change for a number of
reasons with advanced age. Decline in physical mobility may limit
access to the grocery store or inhibit the ability to cook. Some
elderly lose the desire to eat due to loss of smell and taste or due
to slow digestion and prolonged satiety (Britton and McLaugh-
lin, 2013). Malnutrition is often an unintended consequence of
age-related physiological changes that can lead to changes in the
elderly gut microbiome. Furthermore, studies have shown that
compositional dietary changes can result in almost immediate
alterations in microbial populations. Wu et al. (2011) found that
changes in microbiome composition were detectable within 24 h
of dietary alteration and occurred even faster than transit time
of food through the gut. In an infant population, malnutrition
was shown to delay the maturation of the intestinal microbiota
(Subramanian et al., 2014), and it is likely to have consequences of
a similar magnitude in the elderly gut.
Dietary changes that come with age are also impacted by
living situation. Claesson et al. (2012) found distinct dietary
differences between elderly individuals living in a traditional com-
munity setting compared to those in long-term care facilities.
Community-dwellers may be healthier than their institutional-
ized counterparts for a number of reasons, but they broadly
stated that community-dwellers eat a healthier and more diverse
diet and have a distinct microbiota from those in long-term
care facilities (Claesson et al., 2012). The largest dietary differ-
ences were seen in consumption of fruits, vegetables, and meat.
Community-dwellers correlated 98% with a moderate fat/high
fiber diet and long-term care dwellers correlated 83% with high
fat/low fiber diet (Claesson et al., 2012). The gut microbiota of
community-dwellers was more diverse than long-stay subjects and
grouped more closely with healthy young adults, indicating that
age itself is not the driving factor of microbial change. Similar
to young adults, community-dwellers had a higher proportion
of phylum Firmicutes and unclassified bacteria, and abundant
populations of genera Coprococcus,Roseburia,Ruminococcus, and
Butyricoccus when compared to long-term stay individuals. Long-
stay subjects had a higher incidence of frailty accompanied by
a proportional increase in Bacteroidetes and an increased abun-
dance of Alistipes and Oscillibacter when compared to healthier
community-dwelling elderly (Claesson et al., 2012). Increasingly
frail individuals showed a significant 26-fold reduction in the
number of Lactobacillus and a significant sevenfold increase in
the number of Enterobacteriaceae compared to less frail subjects
(van Tongeren et al., 2005).
ANTIBIOTICS
The compounded effects of poor diet, ailing health, and prolonged
stays in a hospital or long-term care facility reduce the prevalence
of protective gut microbiota and give way to detrimental pop-
ulations (Bartosch et al., 2004;Wu et al., 2011). This leaves the
elderly individual vulnerable to infection and disease and a prime
candidate for antibiotic usage. Unfortunately, antibiotic therapies
only exacerbate the flux and instability of the already fragile gut
microbiome in unhealthy elderly. The use of antibiotics in elderly
populations is especially prevalent in hospital and long-term care
facilities and it is estimated that nearly 20% of elderly patients
in hospitals are receiving antibiotic treatment at any given time
(Bartosch et al., 2004).
Antibiotics cause significant disturbances in gut microbiota
resulting in the suppression of both beneficial and pathogenic
species, allowing the overgrowth of antibiotic-resistant strains. In
young, healthy volunteers administered two separate courses of
the antibiotic ciprofloxacin, a dramatic change in the microbiota
was noted, followed by the return to an alternative stable state of
undetermined consequences (Dethlefsen and Relman, 2011). Use
of broad-spectrum antibiotics is associated with the opportunistic
bacterium Clostridium difficile which flourishes in the antibiotic-
weakened gut and results in severe diarrhea (Macfarlane, 2014).
Elderly hospital patients and others with fragile immune systems
are especially susceptible to this life-threatening infection.
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Voreades etal. Diet and the gut microbiome
Most often, elderly individuals exposed to antibiotics see an
increased relative abundance of Bacteroidetes and a significant
increase in Bacteroidetes:Firmicutes ratio (Claesson et al., 2011).
Beneficial anaerobic species in the colon such as Bifidobacterium,
Lactobacillus, and Bacteroides can be drastically reduced or even
eradicated with the use of antibiotics (Bartosch et al., 2004). Bifi-
dobacterium and Lactobacillus are producers of short chain fatty
acids (SCFA’s), a nutrient vital to the proper function of intesti-
nal cells; the loss of these bacteria can be especially detrimental.
A study examining the differences in bacterial colonies between
healthy elderly, hospitalized patients, and hospitalized patients
receiving antibiotics, found that the hospitalized patients receiving
antibiotics saw a significant reduction in the numbers of Bifidobac-
terium spp. and an increased relative abundance of Enterococcus
faecalis compared to the other two groups. In some patients,
the antibiotic treatment eliminated certain bacterial communities
altogether (Bartosch et al., 2004).
Effects of antibiotic treatment on gut microbiota can differ sig-
nificantly with the type and dose of antibiotic administered. A
study by Bartosch et al. (2004) following elderly patients receiv-
ing antibiotics, found that the same antibiotic, clarithromycin,
had different effects on gut microbiota at different doses. A low
dose of the antibiotic decreased the proportion of Bacteroidetes
(Bacteroides and Parabacteroides) and increased Firmicutes (Alis-
tipes) and a high dose increased the proportion of Bacteroidetes
(Parabacteroides) and decreased the proportion of Firmicutes
(Alistipes;Claesson et al., 2011). Countless variables must be con-
sidered with the use of antibiotics in elderly individuals. What
seems like a lifesaving drug may have detrimental effects on the
aging microbiome and the health of the individual. Additional
research is needed to inform practitioners on the safest ways to
use antibiotics on the elderly while supporting their potentially
fragile gut microbiota.
PROBIOTICS AND PREBIOTICS
Probiotics and prebiotics, when taken together or individually,
may be particularly beneficial in restoring the proper microbial
balance to the elderly gut microbiota, helping to mitigate the detri-
mental effects of antibiotic usage and under nutrition. Probiotics
are live microbes that when administered in sufficient quantities
are beneficial to the host. Prebiotics are non-digestible food ingre-
dients such as inulin or various oligosaccharides, which have been
show to selectively stimulate growth of beneficial bacterial popula-
tions in the large intestine. Probiotic foods and supplements often
contain Bifidobacterium and/or Lactobacillus organisms, both of
which are extremely important to proper function of the intes-
tine (Duncan and Flint, 2013). Bifidobacterium and Lactobacillus
are often depleted in elderly individuals as health deteriorates.
Research shows that consumption of probiotics containing these
strains can result in a notable rise in their abundance along
with a reduction of more pathogenic microorganisms in the gut
(Toward et al., 2012). Prebiotics may support the Bifidobacterium
and Lactobacillus species delivered via probiotic supplementation
by providing a fermentable food source for these bacteria, allow-
ing them to flourish. More specifically, it has been reported that
prebiotics have the ability to exert a bifidogenic effect on human
subjects (O’Connor et al., 2014).
Arecentin vitro study showed promise that the elderly gut
microbiota can in fact be modulated with appropriate probiotics.
Species of Bifidobacterium and Lactobacillus along with two prebi-
otics were added to the fecal batch culture of elderly participants.
The addition of the beneficial bacteria significantly increased
the Bifidobacterium and decreased the Bacteroides count after
fermentation (Likotrafiti et al., 2014). Both probiotic/prebiotic
combinations added to the culture increased the Bifidobacterium
and Lactobacillus count in the vessel representing the distal colon.
These results represented a major shift in the gut microbiota
toward a healthier colon (Likotrafiti et al., 2014). However, pre-
biotics alone have also been shown to improve the health and
alter the gut microbial composition of elderly populations. A
study providing inulin supplementation to an elderly cohort
increased Bifidobacterium levels (Guigoz et al., 2002). Multiple
studies using either fructo or GOSs demonstrated both bifi-
dogenic effects and beneficial immune-related effects. Specific
immune related effects included reduction in pro-inflammatory
cytokines and an increase in the anti-inflammatory cytokine,
IL-10.
While probiotic supplementation has become a widely utilized
tool to positively impact health by assisting with digestion, bol-
stering intestinal barrier function and coordinating with the body
to regulate both the innate and specific immune responses, the
mechanisms by which they exert these beneficial effects is poorly
understood (Siciliano and Mazzeo, 2012). Proteomic-based probi-
otic research is beginning to inform both researchers and industry
that adaptation and adherence properties specific to probiotic
strains influence their ability to colonize the host (Siciliano and
Mazzeo, 2012;van de Guchte etal., 2012). Additionally, these
adaptation and adherence mechanisms have been reported to
potentially be strain specific, making it difficult to globally apply
these mechanisms to all probiotic bacterial strains (Siciliano and
Mazzeo, 2012).
Experimentation on the effects of probiotics and prebiotics of
the elderly gut microbiome is still limited, but results of the avail-
able research lends merit to the notion that beneficial bacteria
in the form of probiotics and the indigestible fibers of prebi-
otics has potential to help restore stability, increase diversity and
beneficially alter the immune system in the aging gut (Vulevic
et al., 2008). However, these beneficial effects must be placed in
perspective given the lack of a mutually agreed upon selection cri-
teria, evaluation methodologies and a clear mechanistic model.
With the reduced cost of sequencing and continued proteomic
research, hopefully researchers will be able to speak with increased
certainty as to the reasons probiotics can be beneficial to human
host.
CONCLUSION
The microbes that reside in our gastrointestinal tract comprise a
dynamic community that changes throughout the lifespan of an
individual. The early years of infancy and childhood are character-
ized by a microbial state that has been described as chaotic because
of the rapid and dramatic fluctuations observed. While the micro-
biota of small children begins to resemble that of adults at a very
early age, there is a paucity of studies examining temporal micro-
bial community shifts in children beyond infancy, so the stability
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Voreades etal. Diet and the gut microbiome
of their microbiota is not known. Once stable dietary patterns are
established, the microbiota of adults remains relatively unaltered;
however, significant weight changes have been associated with a
higher amount of microbial instability. Finally, factors related to
aging, including increased use of pharmaceuticals and changes in
diet likely play an important role in shaping the microbial com-
munities residing in the elderly. Changes in physical activity and
hormone levels may also be important determinants of the elderly
microbiome, but they have not yet been investigated with sufficient
depth. Some evidence suggests that the microbial communities of
healthy elderly individuals are similar to that of younger adults,
but whether the health of the individual contributes to microbial
stability or vice versa is not known. Current data suggest that diet
is an important driver in the development of the gut microbiome
and could serve as a means of therapeutic intervention for pre-
vention of diseases. Studies linking the composition and function
of the gut microbiome and disease development certainly high-
light the need for a better understanding of temporal microbiome
dynamics and their predictors.
ACKNOWLEDGMENTS
The authors would like to acknowledge support from NIH
R21CA161472, the Colorado Agricultural Experiment Station,
and Colorado State University Libraries Open Access Research
and Scholarship Fund.
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Conflict of Interest Statement: The authors declare that the research was conducted
in the absence of any commercial or financial relationships that could be construed
as a potential conflict of interest.
Received: 02 July 2014; accepted: 02 September 2014; published online: 22 September
2014.
Citation: Voreades N, Kozil A and Weir TL (2014) Diet and the development of the
human intestinal microbiome. Front. Microbiol. 5:494. doi: 10.3389/fmicb.2014.00494
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