Running head: THE HUMAN GUT MICROBIOME AND IBD IN PEDIATRICS

The Human Gut Microbiome and Inflammatory Bowel Disease in Pediatric Patients

Caitlin J. Jacobsen

Colorado State University

FSHN 350 Honors Option Assignment

THE HUMAN GUT MICROBIOME AND IBS IN PEDIATRICS

Abstract

The human microbiome consists of a delicate balance of bacteria interacting with host

cells both inside and outside of the body. The presence, absence, and balance of these bacteria

depend on a variety of factors including diet, birth method, environment, and antibiotics. Infants

are especially susceptible to changes because of their rapidly developing microbiome. The

microbial community in the gut can play an important role in gastrointestinal health. One of the

most common diseases associated with gut microbiotic imbalances is Inflammatory Bowel

Disease. This literature review will discuss the pediatric gut microbiome, and its affect on the

development of Inflammatory Bowel Disease in young children.

THE HUMAN GUT MICROBIOME AND IBS IN PEDIATRICS

Introduction to the Human Gut Microbiome

The Human Gut Microbiome

The human body is composed of trillions of bacterial cells that are crucial to a variety of

processes. These bacterial cells are plentiful in the body, outnumbering human cells by a factor

of 10 (Johnson & Versalovic, 2012). In the gastrointestinal tract alone, there are 10-100 trillion

microbes that play important roles in digestion, absorption, and immune function (Kostic,

Xavier, & Gevers, 2014). In addition, some microbial species aid in the hydrolysis of otherwise

indigestible compounds (DArgenio & Salvatore, 2015). The human microbiome consists of

resident microbes that exist both inside and outside of the body (Johnson & Versalovic, 2012).

Major sites for microbial communities include the skin, mouth, gastrointestinal tract, female

genitalia, and mammary glands (Johnson & Versalovic, 2012). The majority of microbial

bacteria in the body reside in the gut (DArgenio & Salvatore, 2015). To allow for specificity and

diversity, different bacterial sites in the body are predominately colonized by different bacterial

phyla.

The human body is composed of several bacterial phyla. This review will discuss 4

major phyla in great detailFirmicutes, Bacteroidetes, Proteobacteria, and Actinobacteria

(Johnson & Versalovic, 2012). In the human gut alone, there are over 1,000 different species

within these 4 main phyla (DArgenio & Salvatore, 2015). This core microbiome plays a

crucial role in the synthesis of vitamins, immune function, fat storage, and digestion (DArgenio

& Salvatore, 2015). The gastrointestinal microbiome, which is the main focus of this review,

consists predominantly of Firmicutes and Bacteroidetes species (Reiff & Kelly, 2012).

Composition of the human microbiome varies between individuals, and depends on a variety of

factors such as location in or on the body, environment, diet, hospitalization, and exposure to
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antibiotics (Johnson & Versalovic, 2012). In addition, the human microbiome changes

dramatically throughout development, with the most profound changes occurring from infancy to

childhood (Johnson & Versalovic, 2012). In fact, most children reach a mature, adult-like

microbial composition by the age of three years old (DArgenio & Salvatore, 2015). In the first

few years of life, development of the microbiome is crucial to the future health of an individual.

The Infant Microbiome

The gut microbiome of infants is significantly different from that of adults. Infants are

born sterile and begin microbial colonization immediately following birth (DArgenio &

Salvatore, 2015). Within the first few days of life, the newborn acquires Escherichia Coli,

Alpha-hemolytic streptococci, enterococcus spp, and staphylococcus spp in their GI system

(Johnson & Versalovic, 2012). In the first few weeks of life, as bacteria begin to take in oxygen,

anaerobic conditions develop in the infant gut (Johnson & Versalovic, 2012). This leads to a

great shift in the microbial composition of the gut, with more anaerobic bacteria such as

bacteroides, bificobacterium, and clostridium spp being favored (Johnson & Versalovic, 2012).

Although this review focuses mainly on the gut microbiome, it is important to note that infants

have a uniform distribution of bacteria across body sites (Johnson & Versalovic, 2012). It takes

several weeks for bacteria to become site specific in the infant body (Jonson & Versalovic,

2012). Bacteria communities that develop in the infant gut directly after birth depend on a

variety of factors. From environmental factors to initial diet, the infant gut is highly vulnerable

to outside bacteria.

As early as birth, infants begin bacterial colonization in their gut. Infants who are

delivered vaginally show a different microbial colonization pattern than those who are born

through cesarean section (Johnson & Versalovic, 2012). Infants who are delivered vaginally
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acquire a microbiome that resembles the vaginal and intestinal microbiota of their mothers

(Johnson & Versalovic, 2012). Typically, this microbiotic community consists of Lactobacillus,

Prevotella, Escherichia, Bacteroides, Vifidobacterium, and Streptococcus spp (Johnson &

Versalovic, 2012). On the other hand, babies who are born by cesarean section have a

microbiome that coincides with the mothers skin microbiota (Johnson & Versalovic, 2012). In

most cases, these babies will show more staphylococcus spp bacterium, and less bifidobacterium

and bacteroides spp in the GI tract compared to infants who are born vaginally (Johnson &

Versalovic, 2012). Reduced diversity in the gut microbiome may reappear as disease later in

life.

Figure 1: Graphical representation of the vulnerability of the infant microbiome, as well as the major factors
that alter "microbiome complexity and stability" (Kostic, Xavier, & Geyers, 2014).
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Another major factor in the development of the gut microbiota in infants pertains to their

initial diet. For decades, individuals have debated the results of breast-feeding and formula

feeding infants. From a microbiotic standpoint, breast milk provides an infant with beneficial

imunoglobins, cytokines, growth factors, lysozymes, lactoferrin, and HMOs (Johnson &

Versalovic, 2012). There are over 200 carbohydrate components, or HMOs, in breast milk that

stimulate the growth of bifidobacterium spp (Johnson & Versalovic, 2012). These HMOs

contain a lactose core and act as a prebiotic in the body, encouraging diversity in the gut bacteria

(Johnson & Versalovic, 2012). Some HMOs help to protect infants from disease by preventing

pathogens from binding to epithelial cells (Johnson & Versalovic, 2012). In addition to

beneficial HMOs, babies who were vaginally delivered and breast fed show lower occurrence of

c difficile and e coli, with increase microbial colonization of bificobacterium spp (Johnson &

Versalovic, 2012). These beneficial bificobacterium help to protect the infant from allergies,

diarrhea, obesity, enterocolitis, and type 2 diabetes (Johnson & Versalovic, 2012). In contrast,

infants who are formula fed food show an increase in colonization by clostridium spp and c

difficile, which is associated with eczema and other skin disorders in infants (Johnson &

Versalovic, 2012). In addition to birth method, initial diet of an infant plays a crucial role in

microbiotic development.

As children mature, diet continues to play a crucial role in the development of gut

microbiota. Studies show that changes in the fiber, fat, and protein content in a childs diet, such

as in the switch from milk to solid foods, has a profound effect on gut bacteria (Johnson &

Versalovic, 2012). Children with a diet abundant in animal proteins and saturated fat have a

higher number of Bacteroides (Johnson & Versalovic, 2012). These Bacteroides are important in

the production of polysaccharide A and short chain fatty acids, which protect against colitis and
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aid in the maintenance of colonic epithelium, energy, and immunity (Johnson & Versalovic,

2012). Children with diets high in carbohydrates had higher levels of Prevotella, which has been

shown to increase fat and triglyceride storage in adipose tissue (Johnson & Versalovic, 2012).

Although the first few weeks of life are the most crucial for developing the gut microbiome, diet

affects the microbiome throughout childhood.

In the past decade, there has been an increase in awareness of the use of antibiotics in the

healthcare system. Antibiotics can have severe consequences in people of all ages, but especially

young children. General antibiotics can cause a dramatic and rapid decrease in microbial

diversity (Johnson & Versalovic, 2012). In infants younger than one year old, antibiotics can

cause significant reductions in bacteroides and bifidobacterium (Johnson & Versalovic, 2012).

In addition, use of antibiotics may lead to antibiotic-resistant bacterial strains, such as the

harmful c difficile (Johnson & Versalovic, 2012). Because of this, scientists are careful about

the use of antibiotic in the treatment of gastrointestinal disorders (Kostic, Xavier, & Geyers,

2014). Continuous exposure to a single antibiotic can significantly reduce bacteria diversity, and

increase the risk of dysbiosis and infections (Kostic, Xavier, & Geyers, 2014). While antibiotics

have been proven to be beneficial in the treatment of some diseases, it is apparent that the

repeated use of general antibiotics can have a profound affect on the human microbiome.

To fully understand the vulnerability of an infants gut microbiome, it is important to

consider the external environment on the development of the intestinal microbiota. Infants who

are born prematurely show similar intestinal bacterial patterns to other premature infants in their

first weeks of life (Johnson & Versalovic, 2012). This is because of cross transmission of

bacteria with other infants during hospitalization (Johnson & Versalovic, 2012). Furthermore,

infants with more hospital stays showed delays in the colonization and development of
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microbiota compared to infants with fewer hospitalizations (Johnson & Versalovic, 2012).

Babies held in hospitals for extended periods of time showed decreased bacterial diversity and

more c difficile than other infants, both of which can have severe consequences on the health of a

child (Johnson & Versalovic, 2012). These studies show that the infant microbiome is highly

influenced by the external environment, especially in the first few weeks of life.

The pediatric microbiome develops rapidly with the help of several environmental

factors. As the intestinal microbiome develops, it plays an important role in the infants ability

to digest substrates otherwise indigestible to humans, build a strong immune system, and fight

the growth of harmful microorganisms (Kostic, Xavier, & Geyers, 2014). The affect of the gut

microbiome on immunity is highlighted in patients with inflammatory bowel disease.

Inflammatory bowel disease is one of the most studied human conditions related to the

microbiome (Kostic, Xavier, & Geyers, 2014). Research on the pediatric gut microbiome and

inflammatory bowel disease has grown significantly in the past years. Development of

inflammatory bowel disease has significant connections to the human gut microbiome and its

maturation in the early years of life.

Inflammatory Bowel Disease

Introduction

Inflammatory bowel disease is a common ailment in individuals of all ages.

Inflammatory Bowel Disease, or IBD, can be sorted into three categories: Ulcerative Colitis

(UC), Crohns Disease (CD), and Indeterminate colitis (Pascarella et. al, 20009). Symptoms of

IBD include abdominal pain and diarrhea, bloody stool, and periods of relative remission with

random and recurring flare-ups of activity (Pascarella et al, 2009). Inflammatory bowel disease
THE HUMAN GUT MICROBIOME AND IBS IN PEDIATRICS

affects over 3.6 million individuals (Kostic, Xavier, & Geyers, 2012), with 1-1.5 million IBD

patients in the United States alone (Reiff & Kelly, 2012). In fact, North America and Northern

European countries have the highest rates of Inflammatory Bowel Disease in the world (Barclay

et al, 2009). 201 in 100,000 individuals in the United States suffer from Crohns Disease, and

238 in 100,000 individuals suffer from Ulcerative Colitis (Reiff & Kelly, 2012). Crohns

Disease generally affects the lower ileum and colon regions of the GI tract and is characterized

by inflammation and epitheloid granulomas (Reiff & Kelly, 2012). Ulcerative Colitis, on the

other hand, causes inflammation and ulcerations exclusively in the colon (Reiff & Kelly, 2012).

In several twin studies, concordance rate for inflammatory bowel disease in monozygotic twins

is less than 50% (Kostic, Xavier, Geyers, 2014). A low relationship of IBD in monozygotic

twins indicates factors other than genetics may play a role in the development of Inflammatory

Bowel Disease.

Inflammatory Bowel Disease and the human gut microbiota

In the past decade, research on the human gut microbiota has grown significantly. Within

the scope of the gut bacteria, Inflammatory Bowel Disease has become one of the most studied

human conditions (Kostic, Xavier, & Geyers, 2014). The underlying cause of Inflammatory

Bowel Disease may be an unfavorable immune response to the bacterial community in the

gastrointestinal tract (Johnson & Versalovic, 2012). To do this, intestinal epithelial cells target

general bacteria without differentiation between healthy and pathogenic bacteria (Reiff & Kelly,

2012). In patients with inflammatory bowel disease, studies have shown decreased levels of

faecalibacterium prausnitzii, and increased levels of Escherichia Coli bacterium (Kostic, Xavier,

& Geyers, 2014). In a quantitative sense, the gut bacteria of healthy individuals is composed of
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18.62% Faecalibacterium Prausnitzii whereas patients with active inflammatory bowel disease

showed less than 5-8% (Schwiertz et al, 2010). Faecalibacterium prausnitzii is a member of the

clostridium leptum group and plays an important role in colon health (Schwiertz et al, 2012). On

the other hand, Escherichia Coli has the ability to duplicate itself within the macrophages of

patients with active Crohns disease, posing an even greater problem (Reiff & Kelly, 2012).

Patients with IBD, specifically Crohns Disease, also exhibited less - diversity than healthy

patients in the control group (Kostic, Xavier, & Geyers, 2014). These changes may result in an

increase in gram negative bacteria, changes in metabolism, susceptibility to infection, secretion

of toxins, and a further increase in inflammation (Kostic, Xavier, & Geyers, 2014). This

microbial imbalance, or dysbiosis, causes many IBD patients to have symptoms of diarrhea and

constipation (Johnson & Versalovic, 2012). Dysbiosis also increases the vulnerability of mucosa

in the gut (Schwiertz et al, 2010). Altering the composition of the gut microbiome can have

serious affects on an individuals gastrointestinal health, as seen in adult patients with

inflammatory bowel disease. IBD is a serious condition in adults, but can be seen on an even

greater level in pediatric patients.

As previously noted, children develop their gastrointestinal microbiotic community

through a variety of environmental factors. In the early years of life, the microbiome is still

developing and has very little complexity and stability (Kostic, Xavier, & Geyers, 2014).

Approximately 15-25% of Crohns and Ulcerative Colitis cases are diagnosed at a young age

(Barclay et al, 2009). The microbiome is highly volatile in childhood, and can be affected by

birth route, changes in diet, illness, environment, and puberty (Kostic, Xavier, & Geyers, 2014).

Because of this, the peak age of Inflammatory Bowel Disease onset occurs between 15 and 30

years old, when the microbiome is still developing (Kostic, Xavier, & Geyers, 2014). Early
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onset IBD, which has become increasingly more common in the past decade, occurs before age

10 (Kostic, Xavier, & Geyers, 2014). Early onset IBD, especially Crohns disease, shows a

significant correlation with microbiotic changes in the gastrointestinal tract of children, similar to

adults (Schwiertz et al, 2010). Symptoms of Inflammatory Bowel Disease are more extensive in

children, with more severe flare-ups (Turner et al, 2007). A stool analysis in children ages 18

months to 18 years old with active IBD showed that children have an increase in C difficile, in

addition to a reduction in Faecalibacterium prausnitzii and an increase in Escherichia Coli

bacteria (Pascarella et al, 2009). C difficile is an anaerobic, spore forming bacteria that causes

symptoms of diarrhea, cramping, hematochezia, pseudo membrane formation, and intestinal

perforation (Pascarella et al, 2009). C difficile infection is higher in IBD patients treated with

broad-spectrum antibiotics, with extended hospital visits, and with a compromised immune

system (Pascarella et al, 2009). The gut microbiota plays a crucial role in the gastrointestinal

function of children. Dysbiosis, decreased faecalibacterium prausnitzii, and increased E. Coli and

C difficile are common precursors for Inflammatory Bowel Syndrome in children, which can

lead to unpleasant and sometimes painful gastrointestinal problems.

Treatment of Inflammatory Bowel Disorder in Children

There are several environmental factors that play a role in the development and

progression of Inflammatory Bowel Syndrome. By regulating these factors, symptoms of IBD

can be significantly reduced or even eliminated. As discussed, diet has a large affect on the

microbiotic development in young children (Kostic, Xavier, & Geyers, 2014). Infants who are

breast-fed are less likely to develop early-onset inflammatory bowel disease (Barclay et al,

2009). Breast-feeding encourages bacterial diversity and prevents the growth of c difficile and

E. Coli, both of which are common in children with IBD (Johnson & Versalovic, 2012). In
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addition to diet, probiotics have become increasingly popular in the treatment of gastrointestinal

disorders (Reiff & Kelly, 2012). The effectiveness of probiotics depends on the species, strain,

and environment of the bacteria (Reiff & Kelly, 2012). If used properly, probiotics can

repopulate the gut habitat with a healthy bacterial community and increase the microbial

diversity of the gut microbiome (Reiff & Kelly, 2012; Kostic, Xavier, & Geyers, 2014). This, in

turn, will decrease inflammation, increase immunity, and improve gastrointestinal health (Reiff

& Kelly, 2012). For example, mothers who consume probiotics during pregnancy increase the

amount of bificobacteria in their developing fetus (Reiff & Kelly, 2012). Probiotics and diet can

help to restore the bacterial community and decrease symptoms of Inflammatory Bowel Disease.
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