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REVIEW
Microbial Activities and Intestinal Homeostasis: A Delicate
Balance Between Health and Disease
Christina L. Ohland
1
and Christian Jobin
1,2
1
Department of Medicine and
2
Department of Infectious Diseases and Pathology, University of Florida, Gainesville, Florida
SUMMARY
This review discusses the equilibrium between host and
microbial community in the context of health and disease.
The focus is on bi-directional pressures between pro-
karyotes and eukaryotic cells, as well as inter-bacterial
interactions resulting in alterations to the microbiota.
The concept that the intestinal microbiota modulates
numerous physiologic processes, including immune devel-
opment and function, nutrition and metabolism, and path-
ogen exclusion, is relatively well established in the scientific
community. The molecular mechanisms driving these
various effects and the events leading to the establishment
of a “healthy” microbiome are slowly emerging. This review
brings into focus important aspects of microbial/host in-
teractions in the intestine and discusses key molecular
mechanisms controlling health and disease states. We
discuss the evidence of how microbes interact with the host
and one another and their impact on intestinal homeostasis.
(Cell Mol Gastroenterol Hepatol 2015;1:28–40; http://
dx.doi.org/10.1016/j.jcmgh.2014.11.004)
Keywords: Bacterial Communication; Bowel Disease; Host-
Microbe Interactions; Inflammatory; Microbiome.
A
ppearances can be deceiving. Despite what you see
in the mirror, humans are more prokaryotic than
eukaryotic, as the bacteria in and on our bodies outnumber
our own cells 10 to 1.
1
Microbes are embedded in our
biological system and are deeply integrated in our daily life,
and an emerging field of research has tackled the inter-
kingdom communication network present in the walking
mixed cultures we call people.
The gastrointestinal (GI) tract has the highest density and
variety of bacteria in the human body (approximately 100
trillion microbes made up of >1000 species) due to the ideal
growth conditions provided by this organ. In the colon, there
are up to 10
12
microbes per gram of luminal content which
accounts for 60% of fecal weight.
2,3
A healthy adult’s intestinal
microbiome is diverse, relatively stable over time, and domi-
nated by two phyla, Bacteroidetes and Firmicutes (w95%).
Nevertheless, there is considerable interindividual variability
at the species level due to genetic, environmental, and nutri-
tional factors.
4
Diet in particular has been shown to rapidly
shift this community,
5
resulting in geographic region-specific
microbial signatures as seen in rural African children eating a
fiber-rich diet compared to their European counterparts.
6
Although understanding the bacterial species present in
the gastrointestinal tract is important, recent work has shifted
the focus to the existence of a core enteric metabolome,
which has the potential to change the way we look at how our
gut functions.
7
Because bacterial genes have many over-
lapping and redundant functions, the end result of their
combined metabolism and catabolism can ultimately have a
tremendous impact on the intestinal environment and host
physiology. As we discuss later, these microbial-derived
products are a main component of the host-bacteria and
bacteria-bacteria communication network essential to intes-
tinal homeostasis.
External pressures, such as infection or antibiotics, cause
a disequilibrium in the microbial community, a phenomenon
designated as dysbiosis and often associated with pathol-
ogies including inflammatory bowel disease (IBD).
8,9
Alter-
natively, internal pressure resulting from defective host
genetics, such as innate and adaptive immune genes, results
in mismanagement of the microbiota, again leading to dys-
biosis and pathologic conditions seen in the airway,
10
the
skin,
11
and the gut.
12,13
IBD is a chronic, relapsing, and
remitting inflammatory disease that can be classified as
ulcerative colitis (UC) or Crohn’s disease (CD). Both forms
can be thought of as examples of disrupted communication
between the intestinal microbiota and the host. The nature
of this communication breakdown is not clear but involves
genetic susceptibility related to the epithelial barrier and
innate immunity, all of which are important components of
host-bacteria interaction.
14
This review will discuss the complex cross-talk between
intestinal cells and the microbiota as well as the antagonistic
and mutualistic interactions among enteric bacteria. This
multifaceted communication network is what shapes the
intestinal environment, drives homeostasis, and is thus
essential to understanding how to prevent and treat intes-
tinal disorders such as IBD.
Abbreviations used in this paper: AMP, antimicrobial peptides; CD,
Crohn’s disease; CDI, contact-dependent growth inhibition; GI,
gastrointestinal; HGT, horizontal gene transfer; IBD, inflammatory
bowel disease; MAMP, microbe-associated molecular pattern; QS,
quorum sensing; SCFA, short-chain fatty acids; SFB, segmented fila-
mentous bacteria; T6SS, type VI secretion system; UC, ulcerative
colitis.
©
2015 The Authors. Published by Elsevier Inc. on behalf of the AGA
Institute. This is an open access article under the CC BY -NC-ND
license (http://creativecommons.org/licenses/by-nc-nd/3.0/).
2352-345X
http://dx.doi.org/10.1016/j.jcmgh.2014.11.004
Host Effects on the Microbiota
Gastrointestinal Tract Environment
The intestinal microbiota is largely acquired during our
first few days of life, although recent studies have shown
that infants may not be bacteria free at birth.
15,16
Species
diversity and stability increase to an adultlike microbiota by
the age of 3 years as children are exposed to a new milieu
that includes solid food and individuals with different
microbiota.
17–19
The wide topologic and geographic differ-
ences that microorganisms encounter along the GI tract
dictate their environmental niche for growth and ultimately
shape the community as a whole (Figure 1).
The acidity of the stomach limits bacterial growth and
only a sparse microbiota (<10
1
bacteria/g of contents) is
present.
20
This community predominantly consists of Fir-
micutes and Actinobacteria, but Bacteroidetes, Proteobac-
teria, and Fusobacteria are also present.
21,22
Although they
are similar at the phylum level to the rest of the GI tract, the
relative quantities of each organism differ, indicating that
the gastric population is distinct.
23
When Helicobacter pylori
are present, the stomach microbiota is dominated by this
Proteobacterium, and diversity is severely reduced.
21,23,24
In the duodenum, stomach acid is neutralized, and bile
acids become the driving force of microbiota modulation in
the small intestine. For example, cholic acid has been shown
to directly increase the cecal Firmicutes/Bacteroidetes ratio
and decrease microbial diversity in vivo.
25
Here, diversity
and bacterial load (10
3
bacteria/g) are low, but both factors
Figure 1. Regional differences in the gastrointestinal tract affect microbial niche. In the stomach, high pH and oxygen
content restrict microbial colonization. The major phyla do not significantly differ from those found further along the GI tract,
but the predominant bacteria (Firmicutes and Actinobacteria) as well as the species are distinct. Diversity is thought to be
moderate, although this may be due to transient organisms. In the duodenum, the stomach acid is neutralized, bile is present,
oxygen is reduced by facultative anaerobes, and the host epithelium produces a mucous layer. Most starches have been
digested into monosaccharides and disaccharides, which are progressively absorbed throughout the small intestine. These
factors result in a microbiota dominated by Proteobacteria and Firmicutes such as Lactobacillales with low bacterial load and
diversity. Alternatively, host-indigestible polysaccharides promote the growth of Bacteroidetes and Firmicutes such as
Clostridiales in the colon where diversity and bacterial load are high. In addition to these factors, the intestinal barrier and
immune system affect which microbes can survive in the gut but do not appear to be region dependent.
January 2015 Microbial Activities and Homeostasis 29
increase along the length of the GI tract to the colon, which
has 10
12
bacteria/g.
20
The radial oxygen gradient with the gastrointestinal tract,
whereby oxygen diffuses inward from the epithelium into the
mucous layer, creates a microaerophilic zone in which
facultative anaerobes such as Proteobacteria thrive in an
anaerobic lumen.
26
Although nutrient absorption decreases
oxygenation of the mucosal layer by up to 40% due to
increased metabolic demands,
27
this is unlikely to substan-
tially affect the microbial community, as 4 days of hyperbaric
oxygen treatment are needed to alter the microbiota.
28
However, survival in an atmosphere with fluctuating oxy-
gen does require respiratory flexibility of commensal bacte-
ria. Some strict anaerobes, such as Bacteroides fragilis,
Clostridium acetobutylicum, Faecalibacterium prausnitzii,
have developed molecular switches and alternate respiratory
chains, including extracellular thiols and flavins, that allow
them to tolerate low levels of oxygen over the short term and
thereby achieve a selective growth advantage.
29–31
In disease states, including these accompanied by in-
testinal inflammation, diminished vascular perfusion and
heightened immune cell metabolic activity result in localized
hypoxia or even anoxia within the intestines.
32
It may
therefore be surprising that intestinal dysbiosis in IBD pa-
tients is characterized by an enrichment of aerobic bacteria
including Enterobacteriaceae, which is also seen in experi-
mental models of colitis (eg, Il10
/
, Tlr5
/
, TRUC).
33,34
This disparity is puzzling but may be explained by the
fitness advantage of Enterobacteriaceae, which can use ni-
trate generated during inflammation as an alternative ter-
minal electron acceptor.
35
Therefore, respiration has a
fundamental influence on the commensal bacteria that are
able to thrive in an altered gut milieu.
Dietary Components
Carbohydrates, proteins, and fats all have specific, pro-
found effects on the composition of the intestinal microbiota
and have been extensively reviewed elsewhere.
36–39
Notably, Bacteroidetes and Firmicutes such as Clostridiales
are able to use host-indigestible polysaccharides and thus
dominate in the colon, whereas Proteobacteria and Firmi-
cutes such as Lactobacillales are found in the small intestine
along with high levels of monosaccharides and di-
saccharides (Figure 1).
40
Moreover, dietary vitamins can
directly affect bacterial growth, as some microbes such as
Ruminococcus bicirculans cannot synthesize their own
essential factors.
41
Dietary vitamins can also modulate the
microbiota by promoting the fitness of Bacteroides species
(vitamins B
12
, C, and E) or by decreasing microbial numbers
(vitamin A, in particular for segmented filamentous
bacteria).
42–44
However, it is not entirely clear whether this
is a direct effect on the bacteria or occurs indirectly via the
host epithelium or immune system, as with vitamin D.
45
In
addition to host nutrient requirements, Suez et al
46
recently
demonstrated that indigestible artificial sweeteners directly
increase Bacteroidales and decrease Clostridiales in mice
and humans. This elegant study demonstrates that the
intricate relationship between our gut microbiota and what
we consume includes indigestible components and affects
whole body health.
Intestinal Immune System and Barrier Function
The gut also plays a very active role in shaping the mi-
crobial community to protect the host from the high antigenic
potential of bacterial and unwarranted immune stimulation.
The dynamic, responsive epithelial cells provide multiple
deterrents, including the formation of a mucous layer by
goblet cells, secretion of antimicrobial peptides (AMP) by
Paneth cells, intercellular tight junction complexes, and
microbe-associated molecular pattern (MAMP) recognition
systems.
47–49
Similarly, the underlying immune system is
very adept at tolerating nonharmful bacteria while recog-
nizing and responding to invading pathogens and opportu-
nistic commensal organisms. Luminal sampling by
tolerogenic immune cells in the lamina propria, secretory IgA
in the mucous layer, and the complement network operate
together to maintain intestinal homeostasis.
48–53
Computer-
based mathematical modeling of such a complex interaction
supports the theory that these defense systems, along with
host-derived nutrients, work together to shape the compo-
sition of the microbiota and maintain its stability.
54
Although
direct evidence of whether these systems impact microbial
species present in the intestine is lacking, host defense is a
critical factor in maintaining intestinal homeostasis.
Microbial Influences on the Host
Educating the Immune System
Tolerance of the normal gut microbiota is an absolutely
vital element of enteric homeostasis, requiring an extensive
network of regulatory immune cells including Tregs and
tolerogenic dendritic cells.
55,56
The intestinal architecture of
the uncolonized fetal or germ-free gut is immature, with
reduced epithelial turnover, thin muscle wall and mucous
layers, a decreased number of immune cells, and disorga-
nized gut-associated lymphoid tissue.
57–59
Microbial colo-
nization of mice enhances the intestinal barrier function via
MAMP signaling and educates the immune system, resulting
in maturation of the gut-associated lymphoid tissue into a
tolerant phenotype to prevent unregulated inflammation
(Figure 2).
2,60
However, there appears to be a window of
opportunity for this codevelopment, as colonization of adult
germ-free mice with healthy mouse microbiota does not
induce the same protective effects as when germ-free mice
are colonized as neonates.
61,62
Segmented filamentous bacteria (SFB) are able to traverse
the mucous layer and are found attached to the small intes-
tinal epithelium of many vertebrates, including humans.
63
Although they are only present in low numbers, SFB are
essential to the development of Th17 cells through epithelial
cytokine production and dendritic cell processing,
64–66
and
they are required for full immune system maturation in
mice.
67
This is an important discovery, as aberrant Th17
signaling has been documented in IBD, although evidence
that SFB have a similar function in humans is lacking.
Alternatively, Bacteroides fragilis express polysaccharide
A, which profoundly influences the development of enteric
30 Ohland and Jobin Cellular and Molecular Gastroenterology and Hepatology Vol. 1, No. 1
tolerance by converting proinflammatory CD4
þ
T cells into
Tregs during colonization
68,69
and mediates equilibrium
between T
H
1 and T
H
2 responses.
70
Infants born by cesarean
delivery have decreased microbial diversity, including
delayed colonization by the B fragilis (Bacteroidetes
phylum), which is associated with decreased T
H
1 activa-
tion.
71
Similarly, strains of Clostridium clusters IV and XIVa
(Firmicutes phylum) can promote differentiation, expansion,
and colonic homing of Treg cells through bacterial antigen
signaling and short-chain fatty acids (SCFA) stimulation of
epithelial transforming growth factor-
b
1 production.
72
Thus, the far-reaching influences of the microbiota indi-
cate the vital role of bacterial immunomodulation in main-
taining whole-body health.
Maintaining Homeostasis
Once an appropriately tolerant milieu is established,
maintenance of healthy host-microbial communication is
paramount for the host, as dysbiosis jeopardizes protective
microbial functions. A recent article by Zelante et al
73
estab-
lishes a role for microbial catabolism in balancing T-cell acti-
vation of the mucosal immune system. When converted from
sugar to tryptophan as the primary energy source, the popu-
lation of Lactobacilli expand and increase the production of
indole-3-aldehyde. This metabolite induces interleukin-22
expression through activation of aryl hydrocarbon receptors,
conferring both tolerance of the healthy microbiota and resis-
tance to the opportunistic fungal pathogen Candida albicans.
73
Figure 2. Microbial effects on the host. The microbiota induces host immune tolerance to commensal bacteria directly via a
microbe-associated molecular pattern (MAMP) and polysaccharide (PSA) signaling, indirectly through the production of short-
chain fatty acids (SCFA) and potentially through expression of epithelial intestinal alkaline phosphatase (IAP), which detoxifies
luminal lipopolysaccharides (LPS). Furthermore, segmented filamentous bacteria (SFB) promote immune development of Th17
cells through epithelial cytokine production and antigen presentation by dendritic cells (DC), and the community as a whole is
required for proper gut-associated lymphoid tissue (GALT) development. SCFA also induce IgA and mucus secretion into the
lumen, promote epithelial barrier integrity, and prevent pathogen colonization. The microbiota also participates in the formation
of the active, secondary forms of bile acids.
January 2015 Microbial Activities and Homeostasis 31
Beyond regulation of the host immune system, the
microbiota influences many other normal functions of a
healthy intestinal tract (Figure 2). For example, the micro-
biota convert bile acids into secondary forms in the lumen by
dehydroxylation, dehydrogenation, and deconjugation.
74,75
Studies in germ-free mice demonstrate that bacterial
signaling via G protein-coupled and nuclear receptors
(G protein-coupled bile acid receptor [TGR5] and farnesoid X
receptor [FXR], respectively) not only controls levels of sec-
ondary bile acids but also can modulate synthesis in the
liver.
76
Moreover, expression of intestinal alkaline phospha-
tase, an epithelial-bound enzyme that detoxifies luminal
lipopolysaccharide to alleviate inflammation and promote
tolerance,
77
is affected by diet and antibiotics. It is tempting to
speculate that such modulation could occur via changes in the
microbiota.
77,78
Maintaining symbiosis with our bacteria is
therefore key to preserving intestinal health and homeostasis.
The Extensive Effects of Fatty Acids
Fermentation, one of the key metabolic pathways
employed by the enteric microbiota, produces SCFA,
including acetate, propionate, and butyrate.
79
SCFA have
been shown to promote homeostatic mechanisms and pro-
tect against inflammation in multiple models.
80
This topic
has been thoroughly reviewed elsewhere.
60,75,81–83
Briefly,
SCFA stimulate protective mucus and IgA production, pro-
mote tolerance via Treg induction, inhibit the inflammatory
mediator nuclear factor kB, enhance epithelial barrier
integrity and repair, and promote competitive exclusion of
pathogens (Figure 2). However, butyrate has also been
shown to be both protective and deleterious in different
models of colorectal cancer, highlighting the complexity of
SCFA biology with a disease-specific effect.
80,84
Thus, even
predominantly beneficial molecules or microbes can
potentially have negative effects in complex environments
such as the GI tract.
Microbe-Microbe Interactions
In addition to their host-mediated effect on microbial
assembly, composition, and activities, microbial niches are
also under intense pressure from other surrounding bacte-
ria. Bacteria use sophisticated intercommunication systems
to help maintain their niches; consequently, this microbial
network is essential to host homeostasis. These microbial
relationships can be antagonistic or mutualistic, depending
on the nature of the species (Figure 3). Commensal bacteria
combat other microbes using AMP production and targeted
attacks by means of specialized secretion systems, and they
Figure 3. Bacteria use a complex communication network to thrive in an environment. Bacteria interact through
combative (A–C) and cooperative (D–F) methods. (A) Antimicrobial peptides (AMP) typically released after cell lysis either kill or
inhibit growth of surrounding microbes. (B) Contact-dependent growth inhibition (CDI) systems deliver the toxic C-terminal end
(CdiA) into the cytoplasm of target cells after contact. (C) The type 6 secretion system (T6SS) forcefully injects toxins into
attacking bacteria. Bacteria cooperate by increasing survival of similar microbes in their vicinity with (D) horizontal gene
transfer (HGT) and (E) the formation of a protective biofilm. (F) Quorum sensing (QS) allows bacteria to talk and coordinate
group behavior, and has been implicated in T6SS expression, production of AMP, and biofilm formation. However, several of
these mechanisms have not been observed in the healthy human intestinal tract. Red squares represent AMP; blue triangles
are T6SS toxin; and yellow stars are QS signaling molecules.
32 Ohland and Jobin Cellular and Molecular Gastroenterology and Hepatology Vol. 1, No. 1
compete for nutrients. Owing to their ruthless requirements
for survival, bacteria have also developed cooperative
mechanisms such as horizontal gene transfer, biofilm for-
mation, and quorum sensing to ensure the fitness of their
own community as a whole.
Combatting
Bacteria express highly potent bacteriocins, microcins,
and colicins that fend off other species or pathogens
invading their niche without causing collateral damage to
eukaryotic cells.
85
Bacteriocins are pore-forming AMP pro-
duced by Gram-positive bacteria; they directly relate to
the in vivo fitness and competitiveness of Lactobacillus
salivarius and Streptococcus pneumoniae in the gut and
nasopharynx, respectively.
86,87
Microcins (<10 kDa) and
colicins (30–80 kDa) are produced by Gram-negative bac-
teria, and they display a wider variety of antimicrobial
tactics than bacteriocins, including cell wall pore formation,
inhibition of RNA polymerase or tRNA synthetase, nuclease
activity, and interference with cell wall synthesis.
88,89
The degree to which the microbiota is affected by these
microbial products depends on the AMP employed. Some
have a minimal or subtle influence in various animal models,
but others have a profound impact, such as the broad-
spectrum lacticin 3147, which drastically reduces Bacter-
oidetes and Firmicutes and increases Proteobacteria.
90–92
As a similar microbial shift is also seen in IBD,
93,94
one
might speculate that bacteriocin overproduction could fos-
ter an IBD-like dysbiosis. Interestingly, mice colonized with
the bacteriocin-producing probiotic L salivarius UCC118
Bac(þ) displayed a relative increase in Bacteroidetes and
Proteobacteria compared with control mice, although no
sign of intestine inflammation was reported in these mice.
95
The importance of bacterial resistance to AMP for survival
in the gut is shown in certain pathogens such as Francisella
tularensis and H pylori. These pathogens rely on the phos-
phatase LpxF to catalyze the removal of the negatively
charged 4
0
-phosphate group from the lipid A backbone, a
feature that confers a high resistance level to various
AMP.
96,97
Whether a similar system is present in commensal
bacteria is currently unknown.
Bacterial-derived AMPs integrate environmental cues
and bacterial communication in order to modulate the
microbiota composition. Expression of colicin, for example,
modulates dynamics within a simple community of three
Escherichia coli species in vitro and depends on nutrient
availability, as the carbon-storage regulator A inhibits lysis-
mediated colicin release.
98
Moreover, the colicin produced
by the pathogen Salmonella Typhimurium is up-regulated
under iron-limiting and inflammatory conditions, allowing
this bacterium to outcompete other members of the Enter-
obacteriaceae family during infection.
99
However, AMP production is costly energywise, and it
often requires cell lysis for release. Therefore, bacteria have
evolved other methods for toxicity, such as contact-
dependent growth inhibition (CDI) systems or type VI
secretion systems (T6SS).
88
CDI systems are expressed by a
wide variety of Gram-negative and Gram-positive bacteria,
both pathogens and commensals.
100–102
Upon contact with
another bacterium, the toxic C-terminal end of the cell
surface CdiA protein is cleaved and translocated into the
target cell where most of these family members exert
nuclease activity.
103
Expression of cognate, but not heter-
ologous, CDI proteins can prevent growth inhibition in
related species by binding the toxin, thus leading to kin
selection.
100
This type of poison-antidote tactic has been
shown to be both cooperative and combative in mathe-
matical modeling, and it likely allows for localized regula-
tion of the dynamic microbiota.
104
Interestingly, the CDI
system of Burkholderia thailandensis E264 is required for
formation of cooperative biofilm communities in vitro but
acts independently of its antibacterial activity.
105,106
Conversely, T6SS systems are exclusively found in Gram-
negative bacteria and work as contractile nanomachines for
injecting toxins into target cells.
107
Remarkably, one group
demonstrated that Pseudomonas aeruginosa respond defen-
sively after being ambushed by another T6SS or a type IV
secretion system in what the investigators termed a tit-for-tat
assault, which allows them to distinguish between aggressive
and bystander T6SS-negative bacteria in vitro.
108,109
As T6SS
only target other Gram-negative bacteria or eukaryotic cells,
it follows that these injectors contribute to pathogenesis and
interbacterial competition.
110–113
However, only recently
have T6SS been shown to aid in colonization of mixed bac-
terial communities by conferring a competitive advantage to
Vibrio cholera (an intestinal pathogen) and Agrobacterium
tumefaciens (Proteobacteria that infect plants).
114,115
Similar
to CDI systems, T6SS have also been implicated in the for-
mation and maintenance of biofilms,
116,117
demonstrating
their versatility and potential influence on the intestinal
microbiota.
Alternatively, pathogens can use T6SS to cause virulence.
For example, Salmonella Typhimurium requires T6SS
expression for full intracellular replication and pathogenesis
in mice.
118,119
Similarly, a clinical isolate of the diarrheagenic
Aeromonas hydrophila requires functional T6SS for viru-
lence.
120
In contrast, the T6SS of enteroaggregative E coli,an
infectious diarrheal agent associated with IBD, does not
appear to contribute to its virulence in a mouse model.
116
Competing
Carbohydrate utilization is an essential colonization
factor and modulates the dynamics of the microbiota.
121
This is the fundamental concept behind nutrient niches in
the gut and is best demonstrated by the immediate (albeit
often transient) dysbiosis that inevitably follows antibiotic
therapy.
9
Antibiotics eliminate a group of bacteria and thus
their nutrient source becomes available. This can allow new
groups of potentially pathogenic bacteria to thrive on the
previously unavailable nutrient source and, potentially,
expand to dangerous levels. This was elegantly shown by Ng
et al
122
as the postantibiotic expansion of both Salmonella
Typhimurium and Clostridium difficile in vivo depended on
their ability to use sialic acid. This monosaccharide is
January 2015 Microbial Activities and Homeostasis 33
catabolized by the microbiota but is not normally found in
the feces, as it is quickly consumed by other bacteria. After
antibiotic treatment, there is a large spike in sialic acid
availability, which returns to baseline 3 days after treatment
as the microbiota is reestablished. These pathogens exploit
the vacant nutrient niche to establish themselves in the
intestinal tract and initiate inflammation.
122
Theoretically, a pathobiont could also take advantage of
increased sugar access to expand and cause pathology,
similar to how Bilophila wadsworthia blooms when supplied
with the bile acid taurocholic acid for sulfite reduction.
123
Inflammatory responses can further optimize the milieu
for invading species by providing an alternative method of
respiration, potentiating horizontal gene transfer of viru-
lence factors such as colicins and allowing the pathogen to
outcompete commensal bacteria.
35,99,124,125
Beyond fighting for sugars as their main carbon source,
intestinal microbes also exhibit fierce competition for nitro-
gen, phosphorus, trace elements, vitamins, and other essen-
tial cofactors.
126,127
For instance, bacteria encode a wide
variety of transporters for vitamin B
12
, which indicates the
necessity of these factors for survival.
43
Moreover, the
availability of iron, zinc, and selenium have each been shown
to modulate the microbiota in vivo, theoretically by allowing
the expansion of bacteria that are more efficient at competing
for those trace elements.
128–131
In fact, Salmonella Typhi-
murium infection causes up-regulation of intestinal epi-
thelial–derived lipocalin-2, an AMP that interferes with
bacterial iron uptake. Sensitive bacteria are thus out-
competed by the pathogen because Salmonella Typhimurium
is resistant to lipocalin-2 action.
132
Interestingly, the pro-
biotic E coli Nissle 1917 can reduce the Salmonella Typhi-
murium burden after chronic infection has been established,
as it has multiple lipocalin-2–resistant iron uptake systems
and can outcompete the pathogen for iron.
133
The ability of bacteria to metabolize host carbohydrates
and bile acids was recently shown to be critical during
mouse intestinal colonization, independent of the source of
the microbes.
134
Thus, nutrient competition is a key feature
of the microbial community dynamic and may play a role in
intestinal pathologies that exhibit nutrient deficiencies. For
example, IBD is associated with deficiencies in many
micronutrient levels, including zinc, vitamin A, and iron,
which could potentially influence the underlying dysbiosis
and microbial activities.
135,136
Cooperating and Communicating
Despite the cutthroat enteric battlefield, commensal
bacteria also share byproducts rather than competing with
their neighbors for the same food source. Intricate resource
networks have evolved within the microbiota employing
this waste not, want not attitude, and they form the most
basic method of bacterial communication via detection of
neighboring microbes’ substrates. These networks are
beyond the scope of this article, but they have been exten-
sively reviewed elsewhere.
40,137
Another method by which bacterial cooperation occurs is
horizontal gene transfer (HGT). Specifically, HGT of the
secretome is overrepresented in the intestinal microbiota, as
these molecules promote cooperation and social behavior
through the production of public goods.
138,139
One well-
established example where HGT promotes cooperation is in
the production of siderophores; iron chelators secreted to
scavenge this essential element.
140
Iron bound by side-
rophores can be taken up by any bacterium in the vicinity,
whether or not it expended the energy to create the chelator.
Thus, cheaters arise in these communities, who do not express
public goods but benefit from those who do, which hinders
cooperation.
141
In limiting conditions, HGT increases the
relatedness of cheaters and thus enhances microbiota stability
by preventing the fitness advantage of cheating.
142,143
Secretion of an extracellular matrix, or biofilm, binds
bacteria together and protects the bacteria from outside
attacks, such as antibiotics or host immunity, while also
smothering competing microbes.
144–146
Biofilms aid in the
fitness of a bacterial population as a whole by decreasing
the diffusion of public goods through the viscous medium
and thus preventing others from acquiring them.
147
This
function is important as biofilms are especially vulnerable to
cheaters, where any reduction in biofilm activity results in a
thinning of the biofilm matrix and increased susceptibility to
antimicrobials.
148
These structures are not regularly found
in the bowels of healthy humans, but are thick, dense, and
adherent in untreated IBD patients.
149
This could be related
to the dysbiosis that occurs with IBD and may also explain
why many patients are refractory to antibiotic treatment
despite the apparent microbial involvement in disease.
Tying many of these cooperative pathways together is
quorum sensing (QS), the primary method by which bacteria
communicate cell to cell and coordinate group behavior.
Bacterial signaling molecules are released into the envi-
ronment and initiate gene regulation once they reach a
threshold concentration (typically in the picomolar range),
thus providing a means of functionally measuring bacteria
density.
150
QS influences many survival mechanisms
important to intestinal bacteria, including T6SS expres-
sion,
151
antibiotic production,
126
and biofilm forma-
tion.
150,152
Cheaters exist within the QS world, and these
bacteria benefit from the protective signaling from other
members of the same species without expending the energy
to produce QS.
153
Similarly, some Gram-negative bacteria
eavesdrop by only expressing the QS response transcription
factor and not the signaling molecule, which could allow
commensal bacteria such as E coli to sense the presence of
invading pathogens.
154
Alternatively, some bacteria,
including multiple Proteobacteria species such as Klebsiella
pneumoniae and P aeruginosa, and even mammalian cells,
quench QS by degrading the signaling molecules to prevent
competitive colonization.
155,156
As most studies have examined pathogens, it is not
entirely clear whether human commensal bacteria use QS to
communicate despite intense speculation.
157
However, QS
signaling has been identified in the probiotics E coli Nissle
1917 and Lactobacillus species and may be involved in their
beneficial effects.
158–160
It is likely that bacterial communi-
cation is an important component of microbial community
assembly, composition, and activities. Further work is
34 Ohland and Jobin Cellular and Molecular Gastroenterology and Hepatology Vol. 1, No. 1
needed to establish the extent to which the various forms of
microbial communication are implicated in homeostasis and
diseases.
Conclusions and Perspective
The human gut is a dynamic environment where
eukaryotic and a multitude of prokaryotic cells establish a
complex network of communication that ultimately benefits
both parties. It has become clear that disrupting this pro-
ductive network has dire consequences for the host and
may contribute to intestinal pathologies, including IBD and
colorectal cancer, as well as extraintestinal disorders such
as diabetes and cardiovascular and liver diseases.
2
Although significant progress has been made in identi-
fying host factors implicated in the disruption of the intes-
tinal microbiota and associated pathologic consequences, a
paucity of information is available about the functional
consequences of commensal microbial communication. Ge-
netic manipulation of genes implicated in these processes
(eg, QS and biofilm formation in IBD) might allow dissection
of the roles of bacterial communication during health and
disease. Further advances will require the field of microbe-
microbe communication to move from the test tube and into
the animal, as many of the fascinating interactions in vitro
have not been examined in vivo. Thus, a large piece of the
health puzzle remains missing.
Although the overwhelming majority of genes (99.1%)
examined by metagenomic sequencing of the intestinal tract
are bacterial in origin,
1
the viruses, fungi, and archaea
present may influence specific host response and intestinal
homeostasis.
161,162
For example, susceptibility to enteric
viral infection is modulated by bacteria through enhanced
viral replication.
163
Bacteriophages in particular are an
intriguing area of research as they can enhance bacterial
fitness in vivo and alter its colonization.
164,165
Although there is value in defining which bacterial species
are present in the gut, the field is moving toward regarding
the enteric microbial community as an organ, rather than as
individual parts. For example, does a global “healthy micro-
biota” exist, and is it associated with a defined metabolomic
function? Because microbial metabolism is intrinsically
linked to the host, a holistic approach will be necessary to
dissect this complex relationship. Such an approach has been
successful in defining the relationship between diet, mi-
crobes, and cardiovascular diseases.
166
Although tremen-
dous progress has been made in the field of microbiome
research, especially regarding intestinal microbiome and
IBD, key elements of the dialogues are still missing, and this
hinders the generation of novel therapeutic modalities.
Replacing an altered microbiota has been validated as a
therapeutic alternative to recurrent cases of C difficile infec-
tion,
167
but it is less clear whether IBD would be a logical
candidate for this treatment.
168
In addition, because of the
role of host genetics in IBD, it is not clear how stable and
functional a transplanted microbe would be. Consequently, a
targeted manipulation of microbial activities may represent a
better approach to disease treatment and management.
Clearly, more research is needed to identify the microbial
activities implicated in health and disease and to harness
their full potential for therapeutic purposes.
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Received October 21, 2014. Accepted November 20, 2014.
Correspondence
Address correspondence to: Christian Jobin, PhD, Department of Medicine,
University of Florida, 2033 Mowry Road, Office 461, Gainesville, Florida
32610. e-mail: christian.jobin@medicine.ufl.edu; fax: (352) 392-3944.
Conflicts of interest
The authors disclose no conflicts.
Funding
This work was supported by the National Institutes of Health (RO1DK047700
and RO1DK073338 to C.J.).
40 Ohland and Jobin Cellular and Molecular Gastroenterology and Hepatology Vol. 1, No. 1
