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                         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, gastrointestinal 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. 

Following 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 multiple factors, and influences human health throughout the life of the
host5
. The microbial communities that inhabit the human body provide essential functions for the host, including immunomodulation,
breakdown of complex carbohydrates required for complete nutrition, 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 function 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, persistence and subsequent infection by non-native microorganisms9
.
Classically, the study of infectious diseases has focused primarily on
non-indigenous microorganisms, commonly referred to as ‘pathogens’, 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–pathogen interaction and discuss how the indigenous microbiota is an
additional element that plays a critical role in determining susceptibility 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 balance is maintained through mechanisms of colonization resistance,
which can be both directly and indirectly mediated by the microbiota13. The microbiota can indirectly mediate colonization resistance
by stimulating host mucosal immune defences to prevent invasion 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 colonization. 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 microorganisms provides an opportunity for them to come into close contact with the host through direct contact with the epithelium or via
secreted products.
Community ecology principles can be applied to the microbiota 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 invading 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 probiotic 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 utilization, resulting in higher resource availability, or a niche opportunity 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 gut microbiota, rendering the community susceptible to the vegetative growth of C. difficile spores19. Murine models and human
studies show that antibiotic administration can alter the composition 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 administered 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 bacterial 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 indigenous 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 primary bile acid taurocholate. This disruption is important because
deoxycholate can inhibit the growth of C. difficile, whereas taurocholate promotes the germination of spores. Therefore, antibiotics 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 peptides (AMPs) and dynamic and adaptive production of targeted
immunoglobulins, forms a robust system for regulating the composition 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
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 surfaces. The major components of the mucus layer are glycoproteins
called mucins, which are differentially expressed within the gastrointestinal 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 mucosal defence is clear in mice deficient in the major intestinal mucin,
muc2. These muc2−/− animals have a diminished mucus layer, allowing 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 composition of the indigenous microbiota, as germ-free mice show a reduction in MUC2 production and the mucous layer is protected by
species belonging to the genera Bifidobacterium in SPF (specificpathogen-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 intestinal epithelial mucins. In addition to indigenous microbiota influencing 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 rodentium 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 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 complexes 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 common 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 example, 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 disruption 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 epithelial barrier permeability in the presence of invading microorganisms is essential for the maintenance of homoeostasis and inhibition
of infection.
Alterations to the microbiota resulting from dietary composition (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 barrier function46. More recent studies have demonstrated that mice
fed a high-fat diet exhibit remodelling and claudin switching
affecting paracellular permeability47. Given the established relationship between microbiota composition and diet, and new evidence that points to barrier function abnormalities resulting from
dietary composition, this may be an under-appreciated mechanism 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 membrane integrity48–50. AMPs are secreted at all mucosal surfaces
and their expression can be enhanced by the presence of specific 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 fermentation from non-digestible carbohydrates that act as an energy
source for colonocytes, and have been shown to alter the production 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 concentrations, 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 homoeostasis58. 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 levels 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 (essential 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. difficilemediated inflammation in murine models62.
Another host factor influenced by the composition of the microbiota, immunoglobulin A (IgA), is constitutively secreted at mucosal 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 filamentous 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 mucosal 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 clinical 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 susceptibility 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 inflammation. The synthesis of this molecule is regulated by the proinflammatory 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 Gramnegative 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 microbial 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 diversity, consisting of mostly Lactobacillus species, or high diversity (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, including 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 vaginosis, 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 identification 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, including Lactobacillus iners and Lactobacillus crispatus, and this is consistent 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 inflammatory 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 understanding 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 considered to be sterile in healthy individuals100. Culture protocols
within the clinical microbiology laboratory were developed to identify 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 conditions102. The invasive nature of sampling the LRT via bronchoalveolar 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 oropharyngeal community105–109. In 2015, Bassis and colleagues characterized 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 postulated that the oral community seeds the LRT. Other studies have
supported this hypothesis and identified the mechanism as subclinical microaspiration in healthy individuals110. Dickson and colleagues 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 microbiome 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 metabolic 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 chemoattractant cytokines (for example, IL-1α and IL-1β)114. This elevated
inflammatory state may allow for increased infection susceptibility 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 associated with impaired pathogen clearance. Aspergillus fumigatus is a
fungal pathogen that can result in pneumonia in immunocompromised 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 inflammatory 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 colonization 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 prevent colonization by pathogens or promote the clearance of pathogens. 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 mechanisms underlying these therapies (outlined in Fig. 3).
Prebiotics. Prebiotics can result in a decrease in the use of antibiotics 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 fructooligosacchardie 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-individual 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 infections 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 preventing the growth of pathogens through the production of antimicrobial 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 probiotics—have shown some recent success. Sepsis is a life-threatening
condition initiated by an infection that causes systemic inflammation, 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 antibiotic 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 subsequent death in neonates from India138. The results showed a significant reduction of sepsis and death in infants that received the
synbiotic. This synbiotic is currently the most cost-effective intervention for neonatal sepsis, costing US$1 for one week of treatment, 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 microbiota in an attempt to resolve infection or, in some cases, disease
(either through structural or functional changes to the microbiota). 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 

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 antibiotic use results in the creation of nutritional niches. Many studies
have shown a shift in the recipient’s microbiota following successful FMT143,144, although an increase in diversity does not necessarily occur145. In a recent study, bacterial engraftment from donor to
host was determined using a machine-learning technique to predict 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 success. Staley and colleagues have shown that engraftment does not
determine successful FMT in the treatment of recurrent or refractory CDI147. Even more compelling evidence is provided from studies that have used filtrates from donor stools (called faecal filtrate
transfer) to treat patients with chronic-relapsing CDI to resolve disease148. The success of faecal filtrate transfer suggests that engraftment or competition between bacteria may not have any influence
on success, but rather the transfer of bacterial components, metabolites 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 abundance of Caudovirales bacteriophages and low Caudovirales diversity (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 communities 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 microbial community can affect function, and is associated with infectious disease susceptibility and outcomes. Major strides have been
taken towards understanding the mechanistic relationship between
the microbiota and infectious diseases, but many unanswered questions 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 

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 cataloguing and measuring structure (taxonomy and diversity, respectively). 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 understanding the complex dynamics between the microbial community and
the host, we will gain a greater understanding of the human microbiota, learn how infectious diseases can be prevented, refine treatments and create novel therapeutics
                      
                                       
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