Review Article

https://doi.org/10.1038/s41564-018-0278-4

The role of the microbiota in infectious diseases

Josie Libertucci1 and Vincent B. Young   1,2*

The human body is colonized by a diverse community of microorganisms collectively referred to as the microbiota. Here, we
describe how the human microbiota influences susceptibility to infectious diseases using examples from the respiratory, gas-
trointestinal and female reproductive tract. We will discuss how interactions between the host, the indigenous microbiota and
non-native microorganisms, including bacteria, viruses and fungi, can alter the outcome of infections. This Review Article will
highlight the complex mechanisms by which the microbiota mediates colonization resistance, both directly and indirectly,
against infectious agents. Strategies for the therapeutic modulation of the microbiota to prevent or treat infectious diseases
will be discussed, and we will review potential therapies that directly target the microbiota, including prebiotics, probiotics,
synbiotics and faecal microbiota transplantation.

F
ollowing birth, and possibly before, the human body becomes
colonized with a diverse community of archaea, bacteria, fungi,
viruses and microeukaryotes1–4. This diverse community of
microorganisms and the environment that they occupy is referred
to as the microbiome (see Box 1 for definitions). Colonization by
microorganisms during the first year of life is influenced by mul-
tiple factors, and influences human health throughout the life of the
host5. The microbial communities that inhabit the human body pro-
vide essential functions for the host, including immunomodulation,
breakdown of complex carbohydrates required for complete nutri-
tion, and metabolism of drugs and other xenobiotics6–8.
In addition to the aforementioned roles for the microbiota in
maintaining homoeostasis, we will focus on an additional func-
tion of the microbiota: the ability to influence susceptibility to and
outcomes of infectious diseases. The microbiota plays a key role in
colonization resistance, which is the prevention of growth, persis-
tence and subsequent infection by non-native microorganisms9.
Classically, the study of infectious diseases has focused primarily on
non-indigenous microorganisms, commonly referred to as ‘patho-
gens’, as central to the aetiopathogenesis of infectious diseases10.
Under this schema for infectious diseases as originally postulated
by Koch, infection occurs in a linear progression; a non-indigenous
microorganism enters the host, colonizes and causes disease10. For
over a century, research has focused on the mechanisms by which
a pathogen can overcome host defences and establish infection11. In
this Review Article, we will expand from a focus on the host–patho-
gen interaction and discuss how the indigenous microbiota is an
additional element that plays a critical role in determining suscepti-
bility to, and outcomes of, infectious diseases.
Interactions among host, microbiota and pathogen
Health and disease reflects the overall balance between host
responses, the indigenous microbiota and potential pathogens (see
Box  1 for a definition of ‘indigenous microorganism’)12. This bal-
ance is maintained through mechanisms of colonization resistance,
which can be both directly and indirectly mediated by the microbi-
ota13. The microbiota can indirectly mediate colonization resistance
by stimulating host mucosal immune defences to prevent inva-
sion of non-indigenous microorganisms and subsequent infection.
Normal development and function of the mucosal immune system
and its responses are influenced by the presence of the indigenous
microbiota14. Conversely, the indigenous microbiota may directly
inhibit non-native microorganisms through various mechanisms.
Disruptions in the established community structure and subsequent
function change the overall balance between the microbiota and
host to result in altered infection susceptibility.
The microbiota mediates colonization resistance to prevent
infections. Invading non-native microorganisms have to overcome
barriers created by the microbiota that work to limit the persistence
and colonization of pathogens15. The availability of a niche, whether
in terms of nutritional or functional space, is essential for coloni-
zation. Factors that perturb the microbial community structure
and function, such as antibiotics, allow for potential pathogens to
colonize, grow and persist. Growth and persistence of these micro-
organisms provides an opportunity for them to come into close con-
tact with the host through direct contact with the epithelium or via
secreted products.
Community ecology principles can be applied to the micro-
biota to better understand how the community protects the host
from invading microorganisms16. Three factors can be attributed
to the growth rate and ultimate survival of an invading species in
an established community: the availability of resources, presence of
natural enemies and physical environment17. Persistence of invad-
ing microorganisms is dependent on resource availability, or niche
opportunity. This concept was characterized in a study that assessed
invasion ecology of an indigenous bacterial species of the human
intestinal tract18. The authors administered live bacteria—the pro-
biotic Bifidobacterium longum strain AH1206—to participants, and
found that long-term establishment, or persistence, of AH1206
was directly dependent on under-representation of an indigenous
B. longum species and functional genes related to carbohydrate uti-
lization, resulting in higher resource availability, or a niche opportu-
nity for AH1206. Consequently, B. longum was able to persist in the
gut due to an available niche.
One prominent example of the importance of niche availability
in the pathogenesis of infectious disease is Clostridium difficile.
C. difficile—a Gram-positive anaerobic spore-forming bacterium
that can cause C. difficile infection (CDI)—is able to exploit host
nutrient availability to establish colonization in individuals that
have been administered antibiotics. A prevailing hypothesis for
the cause of CDI is that antibiotic therapy disrupts the indigenous

Department of Internal Medicine, Infectious Diseases Division, University of Michigan Medical School, Ann Arbor, MI, USA. 2Department of Microbiology
1

and Immunology, University of Michigan Medical School, Ann Arbor, MI, USA. *e-mail: youngvi@med.umich.edu

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Review Article
Box 1 | Glossary
Indigenous microorganism. A microorganism that resides with-
in or on a host.
Colonization resistance. The ability of the host and the
indigenous microbiota to prevent growth and persistence of
foreign microorganisms.
Microbiome. A community of microorganisms (bacteria, archaea,
microeukaryotes and viruses), and the environment (including
the specific environmental conditions) that they occupy. For
example, the vaginal microbiome would include not only the
microorganisms that occupy that site, but also all aspects of the
host, including (but not limited to) vaginal epithelial cells, mucus,
immune cells and immune cytokines. This is consistent with
the earliest uses of the term and the root word ‘biome’, meaning
environment161.
Microbiota. A community of microorganisms that occupy a
specific site or habitat. Often, the terms microbiota and microbiome
are used interchangeably. Here, we use microbiota when referring
only to the microorganisms, and reserve microbiome for when we
bring in all elements of a given microbial environment.
Metagenome. The collective genomes of a microbial community
in a given community or sample.
Metabolome. The collection of metabolites produced by a
community of microorganisms. For a given environment or site,
this would include the metabolites produced by the community of
microorganisms present, but also those produced from the host.
gut microbiota, rendering the community susceptible to the veg-
etative growth of C. difficile spores19. Murine models and human
studies show that antibiotic administration can alter the com-
position of the gut microbiota by diminishing a large portion of
bacterial taxa, predisposing individuals to CDI20,21 as a result of
vacant nutrient niches, which was highlighted in a recent study22.
Using a murine model, different classes of antibiotics were admin-
istered via drinking water, or in the case of clindamycin given
by intraperitoneal injection, to disrupt the caecal microbiome to
evaluate C. difficile gene expression and metabolic profile. The
authors found that C. difficile is a bacterial generalist—a bacte-
rial species that is able to adapt to a variety of nutrient niches and
hosts, making it well suited to expand into niches cleared by a
range of antibiotics. Mathematical modelling predicted that indig-
enous Lachnospiraceae are required for colonization resistance,
and murine models have shown a reduction of these bacteria
following antibiotic treatment23.
Antibiotics also aid the creation of a niche by altering bile acid
metabolism. C. difficile is transmitted as a spore, which requires
specific bile acid signals for maximum germination into active
vegetative cells. Studies have shown that antibiotics cause a
decrease in microorganisms that have 7α​-dehydroxylase activity,
which in turn reduces secondary bile acids such as deoxycholate.
This reduction in deoxycholate causes an increase in the pri-
mary bile acid taurocholate. This disruption is important because
deoxycholate can inhibit the growth of C. difficile, whereas tauro-
cholate promotes the germination of spores. Therefore, antibiot-
ics that alter the concentration of deoxycholate prevent C. difficile
from germinating19,24–26.
The mucosal immune system, which includes the physical and
chemical barrier of the gut epithelium, secreted antimicrobial pep-
tides (AMPs) and dynamic and adaptive production of targeted
immunoglobulins, forms a robust system for regulating the compo-
sition of the indigenous microbiota and responding to pathogenic
challenges. When these mechanisms are deficient, the host is more
susceptible to infection. However, the indigenous microbiota itself
36 Nature Microbiology | VOL 4 | JANUARY 2019 | 35–45 | www.nature.com/naturemicrobiology
NATuRe MicRoBiology
Homoeostasis. For the purposes of this Review Article, this
refers to a stable state between host immune responses and the
indigenous microbiota.
Infection. A disruption of homoeostasis that results in lower
colonization resistance from either an indigenous or non-
indigenous microorganism(s).
Community structure. The composition of the microbiota, which
encompasses both the range of unique species and their relative
abundance.
Community function. The sum of the total activity of the
microbiota (for example, production of metabolites or metabolism
of environmental compounds) at a given time and in a specific
environment.
Prebiotic. Non-digestible complex polysaccharide food
compounds meant to stimulate the growth and/or activity of one
or more taxonomic groups of bacteria to provide a benefit to the
health of the host.
Probiotic. Live bacteria in the form of supplements or within a
food product, which when ingested in adequate amounts, provide
health benefits to the host.
Synbiotic. A product that contains both prebiotics and probiotics.
FMT. The delivery of a faecal suspension from a healthy donor to a
recipient, administered to modulate the structure and/or function
of the microbiota with therapeutic intent.
plays an essential role in excluding pathogenic expansion through
modulation of host responses to maintain homoeostasis (see Fig. 1
for examples of how the microbiota modulates host responses).
Indigenous and invading non-indigenous microorganisms are
physically separated from epithelial cells by an overlying layer of
mucus, which forms the outermost physical barrier of mucosal sur-
faces. The major components of the mucus layer are glycoproteins
called mucins, which are differentially expressed within the gastro-
intestinal tract, respiratory tract and female reproductive tract27–30.
Mucins are secreted from the apical side of the epithelium into the
lumen, with expression being either constitutive or regulated31.
The importance of mucus in creating a physical barrier for muco-
sal defence is clear in mice deficient in the major intestinal mucin,
muc2. These muc2−/− animals have a diminished mucus layer, allow-
ing the microbiota to come into close contact with the epithelium,
leading to inflammation and the onset of colitis32.
Mucin production is influenced by the presence and composi-
tion of the indigenous microbiota, as germ-free mice show a reduc-
tion in MUC2 production and the mucous layer is protected by
species belonging to the genera Bifidobacterium in SPF (specific-
pathogen-free) mice33. This notion is supported by recent research
that used human intestinal organoids (HIOs) as a model system to
understand the relationship between colonization of Escherichia coli
(another early colonizer of the gut) and intestinal development34.
The research showed that E. coli promotes the production of intes-
tinal epithelial mucins. In addition to indigenous microbiota influ-
encing mucin production, pathogens can alter the presence and
composition of the mucous layer. MUC2 production is reduced
when C. difficile is injected into HIOs, and patients with CDI have
decreased MUC2 production35. Altering the composition of the
microbiota (for example, through modifying dietary components)
can exacerbate mucin degradation during infection. For example,
in mice that are deprived of dietary fibre during Citrobacter roden-
tium infection, the composition of the microbiota is enriched with
bacterial species that can degrade host mucins, resulting in greater
epithelial access and, in this case, lethal colitis36. Thus, mucin
NATuRe MicRoBiology Review Article
Invading non-indigenous
microorganisms

Inhibition Infection

SCFAs
Dietary fibre
Antibiotics High-fat diet

Salmonella C. difficile
AMPs

E. coli GPR43 IgA Paracellular permeability ?

Bifidobacterium Mucin
production

IL-22

B cells
DC and
macrophages

Fig. 1 | Disruptions to the microbiota alter mechanisms of colonization resistance and affect infection outcomes. Dietary fibre can alter the community
structure of the microbiota and subsequent function via the production of SCFAs, such as acetate, propionate and butyrate62. SCFAs can bind to the
G-protein-coupled receptor GPR43 and can stimulate AMPs, including REGIIIγ​ and β​-defensins55. SCFAs can inhibit the growth of Salmonella, as it can
diffuse through the membrane, acidify the cytoplasm and inhibit growth58. Microorganisms, such as E. coli, can influence the production of mucins, thereby
limiting the access of indigenous and non-indigenous microorganisms to the epithelium33. Alterations to the microbiota (for example, as a result of
antibiotic treatment) can result in lowered B-cell-modulated production of IgA68, and a high-fat diet may result in increased paracellular permeability as
this dietary alteration results in claudin switching in murine models47, both of which can result in susceptibility to infection. DC, dendritic cell.

production is regulated by interactions between the indigenous
microbiota, pathogens and host.
The passage of dietary antigens, ions and microbial products
from the lumen into the laminal propria is controlled by epithelial
cells and can occur via transcellular or paracellular pathways37. The
paracellular pathway is controlled by tight–junction–protein com-
plexes that connect adjacent epithelial cells at their apical border.
These are composed of occludin proteins, claudins and junctional
adhesion molecules, where occludin and claudins interact with
zonulae occludentes that link to the actin cytoskeleton to control
paracellular permeability and maintain cellular polarity38. The
assembly/disassembly of tight junctions is a dynamic process, so
that when this process or its components are impaired, paracellular
permeability is altered and this can result in inflammation—a com-
mon occurrence in inflammatory bowel disease39.
Tight junctions are an important component of host defences
used to mitigate infections. In vitro studies have documented how
certain bacteria can alter the function of tight junctions40. For exam-
ple, C. difficile is able to disrupt tight junctions via the expression of
toxins41. The C. difficile toxins TcdA and TcdB are able to increase
paracellular permeability by disrupting the link between zonula
occludens-1 and the actin cytoskeleton. More recently, the disrup-
tion of tight junctions via C. difficile toxins has also been shown
using a HIO system42. This has been observed for other pathogens,
such as Yersina enterocolitica, which can disrupt the assembly of
tight junction proteins to impair barrier function43. Barrier damage
by pathogens is not restricted to the gut, nor are bacteria the only
pathogen able to cause epithelial damage. Influenza A can disrupt
tight junctions of the pulmonary alveolus, resulting in an influx of
fluid into the lung44. Disruption is associated with the loss of a tight
junction protein called claudin-4. Thus, careful regulation of epi-
thelial barrier permeability in the presence of invading microorgan-
isms is essential for the maintenance of homoeostasis and inhibition
of infection.
Alterations to the microbiota resulting from dietary composi-
tion (for example, a high-fat diet) could also affect paracellular
permeability, and thus infection susceptibility. In mice, a high-fat
diet is associated with changes to the microbiota45,46 and reduced
expression of tight junction proteins, resulting in impaired bar-
rier function46. More recent studies have demonstrated that mice
fed a high-fat diet exhibit remodelling and claudin switching
affecting paracellular permeability47. Given the established rela-
tionship between microbiota composition and diet, and new evi-
dence that points to barrier function abnormalities resulting from
dietary composition, this may be an under-appreciated mecha-
nism driven by the microbiota, which contributes to increased
infection susceptibility.
AMPs are essential components of innate immune defences,
and work to limit pathogen interaction with the epithelium. They
are produced by host epithelial cells, neutrophils, paneth cells,
mast cells and adipocytes. These molecules can either be cationic
or anionic, due to a high concentration of either hydrophobic or
hydrophilic amino acids, and work by binding to negatively or
positively charged bacterial membranes to disrupt bacterial mem-
brane integrity48–50. AMPs are secreted at all mucosal surfaces
and their expression can be enhanced by the presence of specific

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Review Article NATuRe MicRoBiology

Table 1 | Examples of microbiota associated with altered mucosal immunity and increased infectious disease susceptibility
Site Infectious disease/condition
Gastrointestinal tract Entamoeba histolytica,
Giardia,
Cryptosporidium,
Blastocystis hominis
Simian immunodeficiency virus
HIV
Respiratory tract Fungal or viral pneumonia
Female reproductive tract Bacterial vaginosis
(clinical condition associated with
susceptibility to infection)
HIV
Community structure Immune component References
↑​ Prevotellaceae Augmented Th17-mediated 150–155
↑​ Prevotella copri response
↑​ Proteobacteria ↑​IL-23, IL-1, IL-6, IL-8
↓​ Firmicutes
↑​ Pasteurellaceae, Aggregatibacter, ↓​Expression of TLR4, TLR8
Actinobacillus, Mycoplasma
↑​ Proteobacteria, Prevotella ↑​Activated T cells and
↓​ Firmicutes myeloid dendritic cells
↑​ Prevotella, Veillonella ↑​ Th17 cells, IL-1α​, IL-1β​, IL-7 114, 156,157
↑​ Diversity ↑​ IL-1β​, IL-12p70 158–160
↓​ Lactobacillus ↓​IP-10, elafin
↑​ Gardnerella vaginalis, A. vaginae,
↑​ Diversity ↑​Activated CD4+ T cells,
↓​ Lactobacillus IL-23, IL-1β​, IL-17
↑​ Gardnerella vaginalis, A. vaginae,
Prevotella bivia

microorganisms and the composition of the microbiota51,52.
Within the gut, Bacteroides thetaiotaomicron and Bifidobacterium
breve upregulate the expression of the peptidoglycan-binding
C-type lectin regenerating islet-derived protein IIIγ​ (REGIIIγ​),
which is known to target and inhibit Gram-positive bacteria53.
Short-chain fatty acids (SCFAs) are products of bacterial fer-
mentation from non-digestible carbohydrates that act as an energy
source for colonocytes, and have been shown to alter the produc-
tion of AMPs. The most abundant SCFAs in the colon are acetate,
propionate and butyrate54, and the composition of the indigenous
microbiota alters their production. Recently, it has been shown that
SCFAs can induce intestinal epithelial cell production of AMPs
by binding to the G-protein-coupled receptor GPR43 to stimulate
REGIIIγ​ and β​-defensins55. Additionally, the production of SCFAs
in the colon can reduce the fitness of pathogens. For example,
Salmonella can use propionate as a carbon source at low concen-
trations, but high concentrations inhibit its growth56,57. A suggested
mechanism by which propionate can limit the growth of Salmonella
typhimurium is through disruption of intracellular pH homoeosta-
sis58. Propionate diffuses across the membrane of Gram-negative
bacteria, including S. typhimurium, and dissociates into a proton
and propionate anion that acidifies the cytoplasm, resulting in a
prolonged lag phase and reduced growth rate58,59. Propionate lev-
els are influenced by the composition of the indigenous microbiota
(for example, species belonging to the genus Bacteroides), again
providing evidence of how the indigenous microbiota can limit
the growth, colonization and persistence of pathogens. Moreover,
Salmonella expression of virulence genes can also be regulated via
butyrate and propionate60,61. For example, HilD—a transcriptional
regulator found within Salmonella pathogenicity island 1 (essen-
tial for invasion of Salmonella into the intestinal epithelium)—is
post-translationally modified by propionyl-CoA—a product of
propionate metabolism60. Other pathogens, such as C. difficile, are
also limited by the production of SCFAs, as diets that encourage
the development of propionate and butyrate are associated with
decreased bacterial fitness, resulting in a reduction of C. difficile-
mediated inflammation in murine models62.
Another host factor influenced by the composition of the micro-
biota, immunoglobulin A (IgA), is constitutively secreted at muco-
sal surfaces to contain the indigenous microbiota but also to defend
the host from invading microorganisms. Studies in germ-free mice
demonstrate that secretion of IgA in the intestine is dependent
on the presence of the indigenous microbiota and plays a role in
shaping the community structure63–65. In mice, segmented fila-
mentous bacteria closely associated with the intestinal epithelium
can enhance B-cell production of IgA, and interleukin-17 (IL-17)-
producing CD4+ T cells, to promote barrier function66. The muco-
sal immune system keeps the expansion of segmented filamentous
bacteria in check through neutrophil recruitment to the ileum via
the production of IL-17A, and chemokine (C–X–C motif) ligands 1
and 2 (ref. 67). Microbiota-mediated IgA production is associated
with reduced infection risk, since antimicrobial treatment results in
deficient pulmonary IgA production and, consequently, a greater
risk of Pseudomonas aeruginosa pneumonia in intensive care unit
patients and murine models68.
Relationship between microbial community structure, altered
immune responses and infection susceptibility. In chronic
inflammatory diseases, such as inflammatory bowel disease, celiac
disease and metabolic disorders, alterations to the microbiota have
been associated with an altered immune response69–71. Before clini-
cal presentation of these diseases, alterations to the microbiota may
result in host immune changes and subsequent chronic low-grade
inflammation72,73. Recent clinical data have shown that there are
associations between chronic low-grade inflammation and suscep-
tibility to certain infections. This was highlighted by a 2016 study
that investigated the relationship between C-reactive protein (CRP)
and the risk of infection74. CRP is an acute-phase protein that plays
a key role in the amplification of both local and systemic inflamma-
tion. The synthesis of this molecule is regulated by the proinflam-
matory cytokines IL-1 and IL-6 secreted at the site of inflammation
or infection, and it is used as a marker of active inflammation in
Crohn’s disease and many other inflammatory conditions. Chronic
low-level increases in CRP are associated with an increase in Gram-
negative bacterial infections, such as Gram-negative pneumonia.
More recent data demonstrate that the indigenous microbiota
may play a role in altering host responses to produce low levels of
inflammation, resulting in greater risk for infection. Table 1 shows
examples of infectious diseases that are associated with low-grade
inflammation and specific microbiota community structure.
An example of the relationship between the resident micro-
bial community and altered host immune responses that result in
altered infectious disease susceptibility can be seen in the vaginal
microbiota (described in Fig. 2). The community structure of the
vaginal microbiota can be described as either having low diver-
sity, consisting of mostly Lactobacillus species, or high diversity

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NATuRe MicRoBiology Review Article
Non-inflamed Inflamed

HIV
Lactic acid
O

AMPs H3C Decreased

O– AMPs
OH
Low Lactobacillus
High-diversity community

Lactobacillus
Low-diversity community

Dendritic cell
DC

CD4+ T cell Macrophage

IL-6, TNF, IL-8

IL-1RA IL-6, TNF, IL-8 IL-1RA

Fig. 2 | Example of how the indigenous microbiota influences infectious disease susceptibility in the female genital tract. Vaginal microbiota with high
diversity and low Lactobacillus species prevalence are associated with inflammation and increased HIV-1 infection82,85,158,159. In the absence of Lactobacillus
species, there is decreased production of the AMP α​-defensin97, which can bind to the gp120 receptor on HIV and stop entry into CD4+ T cells98.
Protonated lactic acid produced by Lactobacillus species results in decreased inflammatory mediators, including IL-6, IL-8 and TNFα​99. TNFα​ exacerbates
epithelial damage, which can result in greater access of HIV to the host mucosal immune system92. Anti-inflammatory cytokines and responses, including
IL-1RA, are reduced in the presence of a high-diversity vaginal microbiota92.

(diversity being defined as species richness and evenness)75–79. This
has been shown to be highly associated with ethnicity80–82. The
high-diversity vaginal microbiota subset is defined by a reduction
of Lactobacillus species and an increase in strict anaerobes, includ-
ing taxa belonging to the genera Prevotella, Dialister, Atopobium,
Gardnerella, Megasphaera and Sneathia75,83–89. This high-diversity
subset is associated with the clinical condition bacterial vagino-
sis, and increased risk of acquiring sexually transmitted infections
such as human immunodeficiency virus, Neisseria gonorrhoeae,
Chlamydia trachomatis and human papilloma virus85. The specific
association between bacterial vaginosis and the acquisition of HIV
is poorly understood. Previously, it has been reported that bacterial
vaginosis is associated with female genital tract inflammation90,91.
Secretion of an inflammatory cytokine profile consisting of IL-1β​
and IL-12p70 has been linked to a particular microbial composition
(specifically, microbial communities with Prevotella, Atopobium
vaginae, Fusobacterium and Gardnerella) that is postulated to
place women at higher risk of acquiring HIV. Anti-inflammatory
cytokines and responses, including interleukin-1 receptor agonist
(IL-1RA), are reduced in the presence of a high-diversity vaginal
microbiota92. In a 2018 study, Lennard and colleagues were able to
identify microbial taxa that were associated with persistent bacterial
vaginosis and a high inflammatory profile93. The use of a bead-based
multiplex assay—a system able to profile the concentrations of host
cytokines, chemokines and growth factors—enabled the identifi-
cation of two distinct profiles: high and low inflammation94. The
high inflammatory profile was associated with taxa that have been
classically associated with bacterial vaginosis, such as Megashaera
and Gardnerella vaginalis. In comparison, low inflammation was
associated with a high abundance of Lactobacillus species, includ-
ing Lactobacillus iners and Lactobacillus crispatus, and this is consis-
tent with previous work where Lactobacillus was found to decrease
the risk of acquiring HIV95. In another recent study, women who
acquired HIV displayed greater vaginal microbiota diversity and
an increased risk of acquiring HIV if Parvimonas species types I
and II, Gemella asaccharolytica, Mycoplasma hominis, Leptotrichia,
Eggerthella and Megasphaera were present96.
It is hypothesized that the diminished abundance of Lactobacillus
species contributes to an increased risk of acquiring HIV because
many defence mechanisms are repressed (Fig.  2). For example, a
decrease in Lactobacillus species results in decreased production
of the AMP α​-defensin97. α​-Defensins bind to the gp120 receptor
on HIV and stop entry into CD4+ T cells98. This means that in an
environment where Lactobacillus species are reduced and HIV is
present, HIV may have greater access to CD4+ T cells. Additionally,
Lactobacillus species are able to produce lactic acid. A recent study
has shown that protonated lactic acid results in decreased inflam-
matory mediators, including IL-6, IL-8 and tumour necrosis factor
α​ (TNFα​)99. TNFα​exacerbates epithelial damage, so in the absence
of lactic acid, the increase in TNFα​can result in greater access of
HIV to the host mucosal immune system92.
The relationship between microbiota structure and altered
immune response has also been seen in the lung. Our understand-
ing of the relationship between the structure and function of the
lung microbiota and health is in its infancy, partly due to the fact
that until relatively recently the lower respiratory tract (LRT) was

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Review Article
considered to be sterile in healthy individuals100. Culture protocols
within the clinical microbiology laboratory were developed to iden-
tify specific bacterial species that cause acute respiratory infections
using selective media101, rather than as a means to survey the lung
microbiota, which requires an extensive suite of culture condi-
tions102. The invasive nature of sampling the LRT via bronchoalveo-
lar lavage103 also meant that samples were not readily available. As a
result, the Human Microbiome Project did not include the lungs in
its original surveys of the human microbiome104.
In many healthy individuals, the structure of the lung microbial
community comprises microorganisms that are found in the oro-
pharyngeal community105–109. In 2015, Bassis and colleagues char-
acterized the oral, nasal, lung and gastric communities, and found
that membership was significantly shared between the lungs and
oral cavity109, including Prevotella, Streptococcus, Pasteurellaceae,
Fusobacterium and Streptococcus. From this analysis, they postu-
lated that the oral community seeds the LRT. Other studies have
supported this hypothesis and identified the mechanism as sub-
clinical microaspiration in healthy individuals110. Dickson and col-
leagues propose that their findings support the notion of the adapted
island model, where the distal lung bacterial community displays
reduced richness and evenness, and reduced taxa similarity to the
upper respiratory tract106,111. In healthy individuals, the lung micro-
biome can be viewed as a balance between microbial immigration
due to microaspiration and the elimination of bacteria (coughing
and mucocilliary clearance)112.
There is evidence to suggest that high microbial diversity of
the lung microbiota is associated with infection113. Particularly,
enrichment of microbial community members within the lung,
seeded from the oral community and including anaerobes such
as Prevotella and Veillonella, is associated with a distinct meta-
bolic and inflammatory profile. In a 2016 study, the authors found
that enrichment of Prevotella and Veillonella was associated with
increased numbers of Th17 cells and secretion of Th17 chemoat-
tractant cytokines (for example, IL-1α​and IL-1β​)114. This elevated
inflammatory state may allow for increased infection suscepti-
bility resulting from an altered immune response. Although the
Th17 response is associated with pathogen clearance, in some
cases, there is also evidence to suggest that this response is associ-
ated with impaired pathogen clearance. Aspergillus fumigatus is a
fungal pathogen that can result in pneumonia in immunocompro-
mised patients. In an IL-17-deficient mouse model, clearance of
A. fumigatus conidia was enhanced, while the presence of IL-17
was associated with driving a T-helper 2 (Th2)-mediated inflamma-
tory response characterized by eosinophilia115.
Alterations to microbiota community structure change the
overall dynamics between the microbiota and host to result in
altered infection susceptibility. Additionally, the composition of
the microbiota may cause some individuals to be at a greater risk
of acquiring infection. These examples suggest that there may
be other pathogens that interact with the host and microbiota to
generate low levels of inflammation, which leads to reduced colo-
nization resistance. By understanding the relationships between
the microbiota, host responses and non-native microorganisms,
we can propose treatments that act to prevent the invasion of
pathogenic microorganisms.
Therapies targeted to modulate the microbiota
Therapies that target the modulation of the microbiota aim to pre-
vent colonization by pathogens or promote the clearance of patho-
gens. These therapies include prebiotics, probiotics and faecal
microbiota transplantation (FMT; refer to Box 1 for definitions of
these therapies)116,117. Although these therapies have shown success
in the clinical setting, the mechanisms of action are varied and, in
many cases, unclear. In this section, we discuss the proposed mech-
anisms underlying these therapies (outlined in Fig. 3).
40 Nature Microbiology | VOL 4 | JANUARY 2019 | 35–45 | www.nature.com/naturemicrobiology
NATuRe MicRoBiology
Prebiotics. Prebiotics can result in a decrease in the use of antibiot-
ics required for infectious episodes and a decrease in infection rates
in the paediatric population118,119. There are multiple mechanisms
by which prebiotics may work to inhibit infectious diseases. In vitro
studies show that prebiotics work to promote the growth of some
members of the indigenous microbiota by acting as a substrate for
fermentation120–123, and many indigenous Bifidobacterium species
are able to breakdown galactooligosaccharide and fructooligosac-
chardie linkage bonds124. In the clinical setting, prebiotics may result
in the expansion of targeted species within the community, and work
to inhibit the growth of the pathogen through niche exclusion. The
major fermentation products of prebiotics are SCFAs125. Therefore,
prebiotics may also work by restoring either bacterial metabolism
(for example, butyrate), their secondary by-products (bile acid/
salt metabolism) or immune responses regulated by SCFAs126,127,
or through limiting the growth of pathogens58,62. In vivo, dietary
supplementation in healthy adults with resistant starch shows an
overall increase in butyrate production, but with high inter-indi-
vidual variation128. Prebiotics may also work by reducing adherence
of the pathogen to the host epithelium by mimicking ligands for
host-cell receptor sites129. This has been shown in an in vitro tissue
model in which pretreatment of cells with galactooligosaccharides
before exposure to enteropathogenic E. coli reduced the adherence
of enteropathogenic E. coli by as much as 70%130.
Probiotics. Probiotics are hypothesized to prevent or treat infec-
tions by competing with pathogens for nutritional and functional
resources. Mouse models have shown that non-toxigenic C. difficile
spores can prevent the colonization of toxigenic C. difficile131 and
can greatly reduce recurrent infection132. In addition to occupying a
vacant niche, probiotics may also modulate the microbiota by pre-
venting the growth of pathogens through the production of antimi-
crobial substances such as bacteriocins133,134. In vitro studies have
also suggested that probiotics may block the adhesion of pathogenic
bacteria to epithelial cells through direct interaction via lectin-like
adhesion components135.
Synbiotics—substances containing both prebiotics and probiot-
ics—have shown some recent success. Sepsis is a life-threatening
condition initiated by an infection that causes systemic inflam-
mation, and is a major cause of morbidity and mortality in the
neonatal population in the developing world136. For infants in the
developing world, death by sepsis occurs independent of antibi-
otic treatment, with no prevention method currently available136,137.
A recent randomized, double-blind, placebo-controlled trial tested
the efficacy of an oral synbiotic (containing Lactobacillus plantarum
and a fructooligosaccharide) in the prevention of sepsis and sub-
sequent death in neonates from India138. The results showed a sig-
nificant reduction of sepsis and death in infants that received the
synbiotic. This synbiotic is currently the most cost-effective inter-
vention for neonatal sepsis, costing US$1 for one week of treat-
ment, so there is great potential for this intervention given the
efficacy and the low cost.
FMT. FMT is the delivery of a faecal suspension from a healthy
donor to a recipient, with the intention of modulating the micro-
biota in an attempt to resolve infection or, in some cases, disease
(either through structural or functional changes to the micro-
biota). FMT has gained significant attention over the past decade
as it has proven to be a highly effective treatment for recurrent or
refractory CDI139,140. It has also shown some success in intestinal
decolonization of multidrug-resistant organisms to resolve disease,
including vancomycin-resistant enterococci, multidrug-resistant
Staphylococcus aureus, and extended-spectrum β​-lactamase- and
carbapenemase-producing Enterobacteriaceae141.
The mechanism by which FMT works is currently unknown,
but evidence suggests multiple possible mechanisms. One possible
NATuRe MicRoBiology Review Article
a Prebiotic and probiotics

Prebiotics Probiotics SCFAs Invading non-indigenous microorganism

2

Indigenous 3
microbiota
1

b Faecal microbiota transplantation

FMT 2 Metabolite
production

3 Bacteriophage

1 Engraftment
Indigenous
microbiota

Fig. 3 | Hypothesized mechanisms for therapies preventing the colonization or clearance of pathogens. Prebiotics and probiotics can be used as
separate therapies or as a joint therapy (synbiotic) to prevent the colonization of pathogens, whereas FMT is used to clear the pathogen. a, Prebiotics are
hypothesized to work by facilitating the expansion of indigenous community members that are able to digest non-soluble fibre sources (1)120–123. These
members of the community may also increase SCFA production, which has been shown to regulate virulence expression in some pathogens (2)60,61.
Prebiotics may also inhibit pathogen binding to epithelial receptors via competition (3)130. Probiotics are hypothesized to work by filling a vacant niche
(either nutritional or functional)132. Depending on the strain of probiotics, SCFA production may increase as well (2). Using these therapies together
may give the live bacterial strain a better opportunity to occupy an available niche. b, It is unclear how FMT works, but it may be through restoration of
community structure and function via engraftment (1), or through restoration of the metabolome (2). Bacteriophages may also be transferred through
FMT (3), which may result in treatment success149.

mechanism is transplantation or engraftment of donor species to
the recipient microbiome, resulting in the replacement of missing
function142. Engraftment is possible in the case of C. difficile as anti-
biotic use results in the creation of nutritional niches. Many studies
have shown a shift in the recipient’s microbiota following success-
ful FMT143,144, although an increase in diversity does not necessar-
ily occur145. In a recent study, bacterial engraftment from donor to
host was determined using a machine-learning technique to pre-
dict the presence of operational taxonomic units following FMT
from metagenomics data146. However, actual engraftment of the
entire faecal community may not be necessary for treatment suc-
cess. Staley and colleagues have shown that engraftment does not
determine successful FMT in the treatment of recurrent or refrac-
tory CDI147. Even more compelling evidence is provided from stud-
ies that have used filtrates from donor stools (called faecal filtrate
transfer) to treat patients with chronic-relapsing CDI to resolve dis-
ease148. The success of faecal filtrate transfer suggests that engraft-
ment or competition between bacteria may not have any influence
on success, but rather the transfer of bacterial components, metabo-
lites and/or bacteriophages may mediate the observed beneficial
effects of FMT. In a recent study, the virome of CDI patients was
evaluated before FMT, and disease was associated with high abun-
dance of Caudovirales bacteriophages and low Caudovirales diver-
sity (richness and evenness) compared with healthy controls149.
Positive clinical outcomes following FMT were associated with
alterations to the enteric virome and bacterial microbiota, and those
who received donor faeces had a higher richness of Caudovirales
and greater treatment success.
Summary and conclusions
Advances in surveying the complex, dynamic and diverse com-
munities of microorganisms, both through culture-dependent and
culture-independent techniques, have allowed us to understand
how our microbiota plays an important role in homoeostasis and
infectious disease susceptibility. Altering the structure of a micro-
bial community can affect function, and is associated with infec-
tious disease susceptibility and outcomes. Major strides have been
taken towards understanding the mechanistic relationship between
the microbiota and infectious diseases, but many unanswered ques-
tions remain. For infectious diseases that have been associated
with alterations of the microbiota (for example, bacterial vaginosis
and increased risk of acquiring HIV), are these alterations to the

Nature Microbiology | VOL 4 | JANUARY 2019 | 35–45 | www.nature.com/naturemicrobiology 41

Review Article
microbiota causative? If so, what are the potential mechanisms?
Most of what we know about the microbiota and its relationship to
infectious diseases comes from studies that have focused on cata-
loguing and measuring structure (taxonomy and diversity, respec-
tively). Since structure can dictate function, how do alterations of in
situ function affect disease outcomes? To date, indigenous bacterial
communities have received the most attention. What do viruses and
fungi contribute to infectious disease susceptibility? We now know
that infectious diseases are not a singular microorganism problem,
and as research shifts from a reductionist approach to understand-
ing the complex dynamics between the microbial community and
the host, we will gain a greater understanding of the human micro-
biota, learn how infectious diseases can be prevented, refine treat-
ments and create novel therapeutics.
Received: 14 March 2017; Accepted: 28 September 2018;
Published online: 13 December 2018
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Acknowledgements Reprints and permissions information is available at www.nature.com/reprints.
The authors thank D. R. Hill, K. Rao and C. M. Bassis for helpful feedback on earlier Correspondence should be addressed to V.B.Y.
versions of this manuscript, and D. R. Hill for many helpful conversations regarding
this manuscript. This work was supported by a grant awarded to V.B.Y. from the Publisher’s note: Springer Nature remains neutral with regard to jurisdictional claims in
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