Review

Impact of the Microbiota on

Bacterial Infections during
Cancer Treatment
Jessica Galloway-Peña,1 Chelcy Brumlow,1 and
Samuel Shelburne1,2,*
Patients being treated for cancer are at high risk for infectious complications,
Trends
generally due to colonizing organisms that gain access to sterile sites via
Bacterial infections occur frequently in
disrupted epithelial barriers. There is an emerging understanding that the ability the oncologic setting, and antibiotic
of bacterial pathogens, including multidrug-resistant organisms, to colonize treatment is increasingly problematic.
Therefore, alternative prognostic and
and subsequently infect humans is largely dependent on protective bacterial treatment strategies for infection are
species present in the microbiome. Thus, herein we review recent studies necessary.
demonstrating strong correlations between the microbiome of the oncology
Recent characterization of the micro-
patient and infections occurring during chemotherapy. An increased knowl- organisms (bacteria, fungi, and
edge of the interplay between potential pathogens, protective commensals, viruses) inhabiting the human body
has revealed the microbiome as an
and the host immune system may facilitate the development of novel biomark-
important contributor to host physiol-
ers or therapeutics that could help ameliorate the toll that infections take during ogy and pathology.
the treatment of cancer.
The importance of host immune
system–microbiota interface has been
Infections during Cancer Treatment highlighted by studies demonstrating
Infections are among the gravest threat to patients being treated for cancer, with multiple that microbiota dysbiosis is associated
studies finding infection to be one of the leading causes of death in patients with a wide array of with immune dysfunction, mucosal
barrier disruption, and impaired colo-
malignancies [1–6]. Moreover, rising rates of multidrug resistance often render prophylactic and
nization resistance against translocat-
empirical antibiotic therapy ineffective in the oncologic setting [7–10]. Recent studies have ing microbes.
solidified our understanding that commensal microorganisms, or the microbiome, can prevent
colonization and subsequent infection by pathogenic bacteria [11–13]. In addition, there is Novel microbiome-based therapeutic
strategies, using fecal microbiome
growing appreciation that healthy gut microbes serve to induce specific immune components, transplant, probiotics, or prebiotics,
promote intestinal immune tolerance, balance inflammatory processes, and improve epithelial are being studied in order to mitigate
barrier and systemic immune function [14–17]. Thus, in the cancer patient the intestinal mucosa infections as well as improve cancer
and immune system are highly influenced by pathobionts and autobionts (see Glossary) alike outcomes through
immunomodulation.
with regard to risk of infection.

In this review, we first discuss the epidemiology, including the types and etiological agents, of
bacterial infections that affect cancer patients, with special focus on bacteremia among
hematological malignancies. Second, we examine the involvement of the microbiome in
1
the pathogenesis of infection among cancer patients, to include the impact of the gastroin- The Department of Infectious
Diseases, Infection Control, and
testinal microbiota on epithelial integrity and immune responses during cancer treatment, Employee Health, The University of
and how this may play into bacterial translocation, and thus, infection. Third, we assess Texas MD Anderson Cancer Center,
possible solutions for the treatment and minimization of infectious risk during cancer therapy Houston, TX, USA
2
The Department of Genomic
in the context of the microbiome. Finally, we discuss possible future areas of investigation Medicine, The University of Texas MD
within this field. Anderson Cancer Center, Houston,
TX, USA

992 Trends in Microbiology, December 2017, Vol. 25, No. 12 http://dx.doi.org/10.1016/j.tim.2017.06.006

© 2017 Elsevier Ltd. All rights reserved.
 *Correspondence:
Epidemiology of Bacteremia and Clostridium difficile in the Cancer Patient
sshelburne@mdanderson.org (S.
There is a broad array of infections suffered by oncology patients, including those that are Shelburne).
relatively specific to the particular cancer, such as postobstructive pneumonia due to lung
cancer, or those that afflict a broad variety of patients, such as catheter-related bacteremia due
to indwelling vascular access devices [18]. Moreover, cancer patients are infected by a diverse
array of microorganisms ranging from viruses to parasites [19]. Given that the vast majority of
current microbiome data concern bacteria, this review focuses on bacterial infections. Similarly,
the preponderance of microbiome information is derived from studies of the gastrointestinal
tract, which serves as the source for a high percentage of bacteremia, particularly in patients
with hematologic malignancy [20,21]. Thus, in this section, we outline the epidemiology,
etiology, and clinical impact of bacteremia and C. difficile enterocolitis in the cancer patient,
which we use as models for understanding how the microbiome impacts cancer-treatment-
related infections. Potential influences of the microbiome on non-gastrointestinal infections,
however, are discussed in Box 1. We believe that advances in the characterizing of the entire
microbial components of the microbiome will facilitate a better understanding of interkingdom
interactions that influence infection and the full range of pathogens that affect the cancer patient
in the near future (see Outstanding Questions).

Bacterial bloodstream infections (BSIs) are particularly common in the neutropenic patient as
a result of a combination of epithelial damage due to chemotherapy and immunosuppression
[19]. The source of BSIs in cancer patients can be difficult to ascertain, but the majority arise
either from indwelling vascular catheters or as a result of translocation of intestinal microbes
across the gastrointestinal (GI) epithelium [22]. The incidence of BSI ranges widely, depending
on the types of cancer patient studied with hematopoietic stem-cell transplant (HSCT)
recipients having particularly high rates (15% per year) [23]. Similarly, mortality rates from BSI in
the cancer patient vary depending on the group and infection types studied but can reach
>50% for highly resistant organisms in the setting of neutropenia [4,5,10,24].

The major causes of BSI in the cancer patient are shown in Table 1 [25,26]. In general,
staphylococcal infections originate from vascular catheters, whereas the GI tract is the source
of infection for the other organisms shown in Table 1. Around the year 2000, Gram-positive

Box 1. Impact of Microbiota on Cancer-Related Infections Originating from outside the

Gastrointestinal Tract
Although the vast majority of information regarding the interplay between commensal microbiota and infection is derived
from studies of the gastrointestinal (GI) flora, sinopulmonary, skin–soft tissue, and urinary sources account for up to 75%
of infections experienced by the cancer patient [19]. Nevertheless, it is theoretically possible that the GI microbiota may
play a critical role in infections at distal sites, as was recently demonstrated for pulmonary infiltrates in recipients of stem
cell transplants, considering that the GI flora influences the function of the immune system [123].

Similar to the situation with the GI microflora, the commensal microbiota at each epithelial interface is likely to be involved
in epithelial health and resistance to pathogen colonization, thereby providing a direct mechanism by which commensal
microbiota influence site-specific infections in the cancer patient [124]. For example, the presence of Staphylococcus
epidermidis in the nasopharynx was found to inhibit Staphylococcus aureus biofilm formation and nasal colonization, a
key determinant of subsequent S. aureus infection [125]. Cancer patients often have indwelling venous catheters for
prolonged periods of time and thus are at high risk for catheter-related bloodstream infections due to bacteria colonizing
the skin [126]. Analogous to what is observed in the GI microflora, commensal skin bacteria prime the release of
antimicrobial peptides that mitigate dominance by bacterial pathogens [127]. Moreover, low diversity of the urinary
microbiome has been associated with development of symptomatic urinary-tract infection [128]. A common emerging
theme in the range of infections afflicting cancer patients is low microbial diversity, resulting in overgrowth and
subsequent disease due to pathogens. A recent study from the critical care setting observed a concurrent loss of
microbiota diversity at multiple sites during severe illness, but it is not currently known whether this also occurs in cancer
patients [129]. Thus, an interesting future research question is whether site-specific microbiomes contribute to non-GI-
derived infections (see Outstanding Questions).

Trends in Microbiology, December 2017, Vol. 25, No. 12 993

Table 1. Epidemiology of Bloodstream Infections in Hematological Malignancy Patients (2011–2016)a Glossary
Organism Frequencies (%) Resistance Resistance rates (%) a-diversity: the number and
distribution of taxa present in a single
Gram-positive bacteria
population or specimen.
CoNSb 8–50 Methicillin 33–100 b-diversity: the taxonomic diversity
differences between two populations
Staphylococcus aureus 3–25 Methicillin 18–100
or samples.
Enterococcus spp. 3–21 Vancomycin 0–50 Antimicrobial peptides: bactericidal
peptides produced by
VGSc 1–18 b-lactam 10–20
microorganisms or host cells.
Gram-negative bacteria Autobionts: immunomodulatory
members of the microbiota.
Escherichia coli 11–50 Carbapenem 0–15
Bacteriocins: toxins secreted by
d
ESBL -producing 11–69 bacteria to kill other bacteria.
Bacteriotherapy: administration of
Klebsiella spp. 12–23 Carbapenem 0–12
live bacteria, (e.g., the probiotic
ESBL-producing 16–40 which refers to the specific organism
or cocktail of organisms) in order to
Pseudomonas aeruginosa 2–30 Carbapenem 3–66
restore health or cure disease.
ESBL-producing 1–50 Butyrate: a short-chain fatty acid
Acinetobacter spp. 0–16 Carbapenem 0–10 important as an energy source for
colonic epithelium.
ESBL-producing 2–9 Colonization resistance: direct or
Enterobacter spp. 0–8.5 indirect protection against pathogen
or pathobiont colonization exerted by
Stenotrophomonas maltophilia 0–25 commensal bacteria.
a
Dysbiosis: a change from steady-
All information comes from [19,26,130–134].
b state composition within a microbial
Coagulase-negative staphylococci.
c ecosystem.
Viridans group streptococci.
d
ESBL, extended-spectrum b-lactamase. Fecal microbiome transplant
(FMT): restoration of the colonic
microflora by introducing healthy
bacterial flora through infusion of
stool obtained from a healthy donor.
organisms accounted for the majority of BSIs, likely due to widespread fluoroquinolone Hematological malignancies:
cancers that affect the blood and
prophylaxis, which significantly reduces the presence of Proteobacteria, the phylum which lymph system.
includes most of the Gram-negative bacteria causing bacteremia in the GI tract [22,27–29]. Hematopoetic stem-cell
However, more recent surveillance studies report an increase in Gram-negative BSIs, surpass- transplant: the transplantation of
ing Gram-positive infections [8,30,31]. This is clinically relevant as neutropenia-related BSIs multipotent hematopoietic stem cells,
usually derived from bone marrow,
secondary to Gram-negative bacteria are significantly more likely to be lethal compared to peripheral blood, or umbilical cord
those caused by Gram-positive organisms [25]. The relative proportion of Gram-negative blood.
bacteria that accounts for bacteremia in the neutropenic patient varies depending on locations Histone acetylation: the processes
by which the lysine residues within
but, in general, in descending order, consist of Escherichia coli, Pseudomonas aeruginosa,
the N-terminal tail of the histone core
Klebsiella pneumoniae, Enterobacter spp., Acinetobacter spp., and Stenotrophomonas mal- of a nucleosome are acetylated as
tophilia [32]. part of gene regulation.
Intestinal domination: a particular
genus contributing >30% of 16S
Antimicrobial resistance is increasingly common among bacteria causing infection in the cancer
rRNA reads retrieved from a
patient, which threatens a return to the early days of leukemia therapy when Pseudomonas BSI gastrointestinal microbiome sample.
carried up to a 70% mortality rate [33]. Systematic studies have found extended-spectrum Microbiome: the collection of
b-lactamase (ESBL) production in up to 40% of BSIs caused by Enterobacteriaceae, most microorganisms and microbial
genomes that contribute to the
commonly due to E. coli and K. pneumoniae, with mortality rates in such infection approaching
metagenome of a human.
50% [30,34]. Moreover, carbapenem resistance in P. aeruginosa, K. pneumoniae, and Aci- Microbiota: the collection of
netobacter baumannii is being increasingly reported, such as an Italian multicenter survey microorganisms that live on and
which found 29% susceptibility to meropenem among P. aeruginosa causing BSI in hemato- within humans.
Mucin: heavily glycosylated proteins
logic malignancy patients [10]. Antimicrobial resistance among Gram-positive organisms produced by epithelial tissues which
causing BSI originating from the GI tract is also of major concern, with up to 20% of viridans comprise mucus and other
group streptococci being resistant to cephalosporins, and vancomycin-resistant enterococci secretions.
(VRE) causing the vast majority of enterococcal BSIs in some institutions [9,35]. As a result of

994 Trends in Microbiology, December 2017, Vol. 25, No. 12

cancer-treatment-related damage to the GI epithelium and prevalent use of antimicrobials, the Mucositis: damage that occurs to
rates of C. difficile infection (CDI) are some 30% higher among cancer patients compared to the the mucosal lining of the
gastrointestinal tract typically during
general medical population [36]. Moreover, the rates of CDI in cancer patients have nearly chemotherapy or radiation.
doubled over the past decade, and the presence of CDI is associated with a 20% increase in Myeloblation: killing of cells in the
mortality over patients with cancer alone [36,37]. In short, infections among hematological bone marrow, including both normal
malignancy patients are epidemiologically unique from other patient populations and excep- blood-forming cells and cancer cells,
during high-dose chemotherapy.
tionally difficult to treat as a result of high rates of antibiotic resistance. Neutropenic: abnormally low level of
neutrophils in the blood.
The Role of Microbiota in Intestinal Domination and Colonization Resistance Nucleotide-binding
oligomerization domain (NOD)
Microbial diversity is usually defined using ecologic based measurements which may assess
receptors: intracellular sensors,
a-diversity (e.g., Shannon or inverse Simpson indices) or b-diversity (e.g., Bray–Curtis dissimi- found in lymphocytes, macrophages,
larity index, Unifrac distance) [38]. In general, a microbiome with higher diversity is thought to be an dendritic cells, and other cells, that
indicator of overall health [39,40]. However, some patients undergoing cancer therapy experience regulate inflammatory and apoptotic
responses.
expansion of a particular pathobiont or pathogen. This scenario is referred to as ‘intestinal
Pathobiont: any potentially
domination’, which is thought to be associated with eventual infection [41]. Taur et al. went on to pathological organism which, under
describe that Gram-negative bloodstream infections were preceded by intestinal domination by normal circumstances, lives as a
Proteobacteria, while VRE infections were preceded by intestinal domination with Enterococcus in symbiont.
Prebiotics: substances that induce
allogeneic stem cell transplant (SCT) recipients [42]. Pretreatment intestinal a-diversity, as well as the growth or activity of
decreases in intestinal a-diversity over the course of cancer treatment, have been shown to be microorganisms that contribute to
associated with a prediction of infectious risk during and after cancer therapy, respectively, in host health.
leukemia, lymphoma, and HSCT patients [41–44]. In addition, temporal variability of a- and Regulatory T cells (Tregs): CD4+ T
cells which produce IL-10, express
b-diversity has also been associated with recurrent risk of infection in leukemia patients [45]. FoxP3, and are crucial to maintaining
However, further studies are needed to confirm if the majority of infections thought to stem from tolerance to self-antigens.
intestinal bacterial translocation are dependent upon intestinal domination/pathogen density in Segmented filamentous bacteria
(SFB): in mice, nonpathogenic
the immunocompromised host (see Outstanding Questions). Moreover, it is not currently under-
members of the gut microbiota that
stood what are the critical species in a diverse microbiome that prevent pathogen domination and preferentially attach to the intestinal
whether such species are distinct for different pathogens. epithelium and potently induce
immune responses.
Short-chain fatty acids (SCFAs):
In addition to preventing pathogen domination, a healthy microbiota can also protect against
fatty acids, produced by bacteria
pathogens becoming established at any density in the microbiome, a process referred to as through fermentation of fiber/
colonization resistance [46]. Colonization resistance can occur directly (i.e., outcompeting starches, which act as signaling
pathogens for nutrients, or production of inhibitory substances such as bacteriocins) or molecules.
Th17 cells: a subset of
indirectly (i.e., modulating immune function, or production of metabolites) (Figure 1) [13]. For
proinflammatory CD4+ T cells, which
example, enterohemorrhagic E. coli colonization of the mouse intestine is prevented by the produce Il-17 and RORgt,
presence of multiple strains of commensal E. coli via nutritional competition [47]. Bacteroides specializing in maintaining mucosal
thuringiensis secretes a bacteriocin that specifically targets C. difficile and Listeria monocy- barriers and pathogen clearance.
Toll-like receptors (TLRs):
togenes, and it was discovered that Clostridium scindens can convert primary bile salts to receptors that recognize structurally
secondary bile salts which are highly associated with resistance to CDI [48,49]. More recently it conserved structures from microbes
was show that an ampicillin-resistant microbiota consortium of four bacteria, consisting of and activate innate immune
Bacteroides sartorii, Parabacteroides distasonis, Clostridium bolteae, and Blautia producta, responses.
Tolerogenic: producing
prevents and eliminates VRE colonization in mice during antibiotic treatment [50]. immunologic tolerance.

There have been several recent clinical examples in the oncology setting of how the commensal
microbiota protect against pathogens. For example, in allogeneic SCT recipients, colonization
with Barnesiella, a genus within Bacteroidetes, conferred protection against subsequent Entero-
coccus (VRE) intestinal domination [51]. Similarly, fecal samples collected prior to allogenic HSCT
from lymphoma patients who developed subsequent BSI exhibited significantly decreased
abundance of members of Bacteroidetes (e.g., Barnesiellaceae, Butyricimonas) and Rumino-
cocceae compared to patients who did not develop subsequent BSI [44]. Among these lym-
phoma patients, those who developed subsequent BSI were enriched in functional categories
associated with xenobiotic biodegradation/metabolism and reduced in functional categories
associated with transcription, amino acid metabolism, and lipid biosynthesis proteins using

Trends in Microbiology, December 2017, Vol. 25, No. 12 995

Figure 1. Factors Contributing to Gastrointestinal Microbiome-Mediated Infection in Treated Cancer Patients. In the treated cancer patient there is a
balance that exists between a healthy microbiome, with maintained mucosal integrity, and dysbiosis concurrent with mucosal barrier injury, with regard to
gastrointestinal microbiome-mediated infection. In the noninfected host, a diverse microbiota promotes colonization resistance against invading pathogens and a
healthy mucosa. In the treated cancer patient, multiple factors contribute to gastrointestinal microbiome-mediated infection, to include antibiotics and other drugs which
cause microbial dysbiosis and pathogen domination, and host factors such as malignancy and cancer treatment which contribute to immune dysfunction and
mucositis. This scenario allows for the translocation of dominating pathogens across the intestinal epithelium, leading to blood-stream infections. Abbreviation: SCFA,
short-chain fatty acid.

functional metagenomic analyses [44]. Additionally, a recent study showed colonization with
Bacteriodetes, Lachnospiraceae, and Ruminococcaceae at the time of engraftment was associ-
ated with protection against CDI in HSCT patients [52]. Thus, extensive knowledge of the role of the
taxonomic groups in infectious complications and future real-time monitoring of the microbiome
has the potential to enhance patient outcomes, reduce the risk of infection, and improve treatment
strategies in the cancer setting (Table 2).

The Role of the Microbiome in Mucosal Barrier Disruption and Function

It is thought that most infections occur via bacterial translocation across mucosal barriers
during radiation and chemotherapy in cancer patients, particularly in scenarios of impaired
colonization resistance and intestinal domination by pathobionts (Figure 1). The loss of epithelial
integrity during myeloblation markedly increases the risk for bacteremia. During the ulcerative
phase of mucositis, the protective barrier that protects the lamina propria is eliminated. At this
point, resident bacteria can colonize the ulcer and release substances which penetrate the
connective tissue and activate mononuclear cells, causing the release of other proinflammatory
cytokines. Thus, the presence of proinflammatory microbiota may exacerbate the mucosal
damage and tissue injury that occurs as a result of cytotoxic cancer therapy which could
increase the likelihood of portals of entry for bacteria to enter the bloodstream and cause sepsis
[16,53,54].

996 Trends in Microbiology, December 2017, Vol. 25, No. 12

Table 2. Summary of Taxonomic Associations with Infectious Complications in Hematologic Malignancy
Taxanomic change Method Source Clinical outcomes Refs

Enterococcal dominationa 454 Pyrosequencing of the Human allo-HSCTc recipients Increased risk of vancomycin- [42]
V1–V3 region of 16S rRNA resistant Enterococcus bacteremia
genes

Proteobacterial domination 454 Pyrosequencing of the Human allo-HSCT recipients Increased the risk of Gram- [42]
V1-V3 region of 16S rRNA negative rod bacteremia
genes

Increased relative abundance of 454 Pyrosequencing of the V5 Human non-Hodgkin Associated with protection [44]
Barnesiellaceae, Faecalibacterium, and and V6 region of 16S rRNA lymphoma patients from BSIe
Christensenellab genes undergoing allo-SCTd

Presence of Clostridium scindens Illumina MiSeq of V4 and V5 Human allo-HSCT recipients, Resistance to CDIf [49]
regions of 16S rRNA, and and murine models
adoptive transfer

Relative abundance of Bacteroidetes, Illumina MiSeq of V4 and V5 Human allo-HSCT recipients Lower risk of CDI [52]
Lachnospiraceae, and regions of 16S rRNA
Ruminococcaceae

g-Proteobacteria domination 454 Pyrosequencing of the Human allo-HSCT recipients Higher risk of pulmonary [123]
V1–V3 region of 16S rRNA complications
genes

a
Defined as >30% relative abundance by a single predominating bacterial taxon.
b
This reference found a panel of 13 microbes that were differentiated between patients who did and did not develop bacterial bloodstream infection (BSI) which
determined the best BSI risk index. Microbes tested individually to discriminate between patients who did and did not develop subsequent BSI with predictive accuracy
are listed above.
c
HSCT, hematopoietic stem-cell transplant.
d
SCT, stem-cell transplant.
e
BSI, bacterial bloodstream infection.
f
CDI, Clostridium difficile infection.

Conversely, several commensal bacteria have been shown to improve epithelial barrier func-
tion, which could help to explain the association between loss of microbial diversity and
infection during chemotherapy. Bacteroides spp., Bifidobacterium infantis, Faecalibacterium
prausnitzii, and Lactobacillus spp. have all been observed to regulate epithelial barrier function
via enhancing tight junctions, reducing intestinal permeability, augmenting epithelial repair, and
increasing mucus production from goblet cells [14,55–64]. The composition of the intestinal
mucus layer is important for protection against bacterial infections and inflammatory processes
[65]. It has also been shown that reduced mucin production renders mice more susceptible to
infection by intestinal pathogens [66]. The genes encoding mucins are directly regulated by
bacteria and their byproducts. Several members of the genus Lactobacillus increase the
expression of the MUC genes, whereas members of Akkermansia have been shown to degrade
mucin [67–69]. In addition to microbial composition associations with mucin regulation,
butyrate production has also been associated with mucin production as well as the preser-
vation of the epithelial integrity development and decreased severity of chemotherapy-induced
mucositis [16,70–72]. Specifically, butyrate derived from microbes has been shown to stimu-
late epithelial consumption, and thus, depletion of intracellular oxygen, resulting in HIF-1
activation and HIF-1-regulated increased epithelial barrier function (Figure 2) [73,74]. Therefore,
the marked heterogeneity in microbiome composition present in cancer patients at the time of
initiation of treatment may help to explain why some, but not all, patients who become
profoundly neutropenic develop serious infections.

The Role of the Microbiota in Immunity

In addition to effecting epithelial integrity, components of the microbiome may influence
infection via modulating immune function. In the healthy human, autobionts perform

Trends in Microbiology, December 2017, Vol. 25, No. 12 997

Figure 2. The Role of the Microbiome in Epithelial Barrier Function and Immunity. Specific bacteria, as well as butyrate, are associated with increased the
expression of MUC2 and MUC3 genes, increasing mucus production by goblet cells. In addition, butyrate stimulates epithelial consumption, and thus, depletion of
intracellular oxygen, resulting in HIF-1 activation and an HIF-1-regulated increase in tight junction function. Maintenance of the mucosal immune system is dependent on
commensal products, such as flagellin and lipopolysaccharides (LPS), being recognized by Toll-like receptors (TLRs) and nucleotide-binding oligomerization domain
NOD receptors, which activate the basal expression of RegIIIg and other antimicrobial peptides (AMPs). Recognition by TLRs of bacterial antigens, as well as the short-
chain fatty acid (SCFA) butyrate, stimulate CD103+ and MyD88-expressing DCs and macrophages of the lamina propria to induce tolerance by production of IL-10 and
retinoic acid, which stimulates the differentiation of naïve T cells to Tregs. Bacteroides fragilis, and the production of polysaccharide A (PSA), enhances T cell
differentiation and suppression of Th17 responses. Clostridia clusters XIVa and IV have also been correlated with transforming growth factor beta (TGF-b) production
and Treg development. Lastly, segmented filamentous bacteria (SFB) (in mice) induce Th17 cell differentiation and an increase the release of the proinflammatory
cytokine IL-17.

immunomodulatory functions and sustain immune homeostasis [14,15,75]. Immune elements

that have been shown to be influenced by the microbiome include neutrophils, dendritic cells
(DCs), and T cell subsets [14,76–81]. Among cancer patients, these components can be
deficient due to myeloblative chemotherapy and the nature of malignancy. As most studies to
date are in murine models or immune-intact individuals, it is important to study how the
microbiota may serve to improve immune recovery in immunocompromised or hematologic
malignancy patients in order to avoid treatment-related toxicities, like infections, which occur as
a result of dysfunctional immunity. In the future, it will also be imperative to consider how host
factors, such as genetic abnormalities, may drive microbiome alterations and susceptibility to
infection during cancer therapy (see Outstanding Questions) [82,83]. This section reviews the
recent findings on how the microbiome influences immunity (Figure 2).

A tricky balance exists at the host immune system–microbiota interface, where the host must
maintain the beneficial autobionts, without allowing proliferation of pathobionts. Commensal
flora perform tolerogenic activities by providing signals which dampen the activity of mono-
nuclear phagocytes in the intestine, reducing presentation of bacterial antigens to mesenteric
lymph nodes, thus, preventing the triggering of adaptive immune responses against commen-
sal flora. For example, luminal bacteria recruit CD103+ DCs to the intestinal epithelium to
sample bacterial antigens for presentation, whereby CD103+ DCs transport bacteria and
antigens to draining mesenteric lymph nodes and induce tolerance by production of retinoic

998 Trends in Microbiology, December 2017, Vol. 25, No. 12

acid [84,85]. Diehl et al. found that antibiotic treatment (or MyD88 deficiency) increases the
delivery of bacteria to mesenteric lymph nodes and enhances specific T cell and antibody
responses to commensal organisms [86]. Thus, dysbiosis due to cancer therapy or extended
antibiotic use commonly seen in cancer patients not only threatens the priming of innate
immune responses against potential pathogens but also threatens the tolerance of beneficial
microbes important in colonization resistance and mucosal integrity [75,87,88].

Maintenance of the mucosal immune system is partially dependent on commensal microbes in

the intestinal lumen triggering innate immune receptors such as Toll-like receptors (TLRs)
and nucleotide-binding oligomerization domain (NOD) receptors, which activate release
of antimicrobial peptides (AMPs) [14,75,89–91]. Intestinal epithelial cells express basal
levels of antimicrobial molecules, including the bactericidal C-type lectin RegIIIg, in response to
commensal-derived molecules, such as lipopolysaccharide (LPS) or flagellin, which drive
RegIIIg expression via stimulating TLRs [92,93]. Studies have shown that RegIIIg expression
not only creates a tolerance of intestinal commensals via reducing colonization of the dense
mucous layer, and thus, microbial contact with the epithelium, but also provides significant
protection against intestinal colonization by vancomycin-resistant Enterococcus (VRE) and
infection by C. difficile [94–96]. However, it was shown that antibiotic treatment impairs RegIIIg
expression, leaving mice susceptible to infections, suggesting a potential mechanism by which
the high antibiotic administration to cancer patients may result in subsequent infection [94].

Another common theme among recent publications is the microbiota-dependent effect of

modulation of immune responses through microbial metabolites, like short-chain fatty acids
(SCFA). For example, butyrate stimulates DCs and macrophages, through Gp43 and Gpr109a
activation, to produce IL-10 and retinoic acid, which also stimulates the development of IL-10-
producing regulatory T cells (Tregs) in the colon. Butyrate also elicits histone acetylation,
enhancing FoxP3+ expression, which drives naive T cell differentiation into Treg cells, which are
also crucial for the maintenance of immunological tolerance [97–100].

Specific bacteria that have been experimentally implicated in immune cell processes are
Bacteroides fragilis, Cluster IV and XIVa Clostridia, and segmented filamentous bacteria
(SFBs). Specifically, B. fragilis induces the development of IL-10-producing Foxp3+ Tregs and
promotes Th1 cell systemic development. Studies show that colonization of the murine gut with
B. fragilis and production of polysaccharide A (PSA) enhances T cell differentiation [101,102].
Similarly, levels of Clostridia clusters XIVa and IV have also been correlated with increased
colonic Treg numbers [76,77]. Moreover, in murine models, SFBs induce Th17 cell differenti-
ation in the lamina propria [78]. Recent studies have shown that antibiotic-treated mice have a
markedly reduced number of Th17 cells and thus are more susceptible to Clostridium roden-
tium and E. coli infections [79]. Thus, cancer patients who lack microorganisms involved in
immunological processes, or lose them as a result of chemotherapy or antibiotics, may be
particularly susceptible to infectious complications.

Possible Microbiome-Based Solutions to Mitigate Infections in the Cancer

Patient
In addition to providing mechanistic insights into infections, it is hoped that therapeutic
modulation of the microbiome could be used to reduce the risk of infection. Several studies
have demonstrated the clinical efficacy of fecal microbiome transplant (FMT) in the
treatment of recurrent CDI as well as for decolonization of antibiotic-resistant bacteria
[103–105]. However, carefully controlled studies or randomized clinical trials among immu-
nosuppressed patients are lacking, particularly in cancer patients (Table 3) [106,107]. Much of
the caution surrounding FMT in patients with immunodeficiency is due to the theoretical
potential for introducing new infections. This is of particular concern in those receiving

Trends in Microbiology, December 2017, Vol. 25, No. 12 999

Table 3. Case Reports and Clinical Trials of Microbiota-Based Treatment for Infection in Cancer Patients
Method Type and number of patients Results Refs

Enema FMTa One lymphoma patient post-HSCTb CDIc resolved [135]

FMT via endoscopy One ALL patient post-HSCT CDI Resolved [136]

FMT via nasogastric tube One ALLd patient post-HSCT CDI Resolved [137]

FMT via endoscopy One lymphoma patient CDI Resolved [138]

Prebiotic combination of glutamine, fiber, 22 HSCT recipients Reduction in diarrhea and mucositis, but [119]
and a fructo-oligosaccharide no significant differences in infection rates

Lactobacillus rhamnosus GG probiotic 31 HSCT recipients Trial terminated when no difference seen [139]
in microbiome or outcomes

a
Fecal microbiota transplant.
b
HSCT, hematopoietic stem-cell transplant.
c
Clostridium difficile infection.
d
ALL, acute lymphoblastic leukemia.

immunosuppressive reagents (such as high-dose corticosteroids in HSCT patients), or in those

with mucosal barrier damage, as many FMTs are done via colonoscopy or naso-gastro tubes
[108]. However, recently published studies have demonstrated the efficacy of lyophilized
encapsulated microbiota, and thus the fear of introducing or aggravating epithelial injury could
be alleviated [109,110].

Another drawback to FMT is that donor and fecal screening are time-consuming and represent
an obstacle to timely administration of FMT for infections [106]. Thus, bacteriotherapy or
probiotics have been suggested as an alternative approach where a ‘universal' or defined
bacterial mixture can be introduced to minimize the risk of infection. Recent clinical studies have
described the treatment of CDI using different defined mixtures of bacterial strains [111,112].
For example, the RePOOPulate study, utilized a defined mixture of 33 fecal bacterial strains to
treat recurrent CDI [113]. However, clinical studies are still in their infancy as it is still largely
unknown what microbial ecosystems would be safe and effective. Experimental studies in both
humans and animal models have attempted to identify individual commensal microbes asso-
ciated with colonization resistance or susceptibility to CDI. In general, the majority of studies
have identified Bacteroidetes, Ruminococcaceae, Blautia, Clostridia cluster XIVa, and Lach-
nospiraceae to be associated with colonization resistance against CDI. By contrast, Proteo-
bacteria, Escherichia, Enterococcus, Lactobacillus, Streptococcus, and Enterobacteriaceae
are correlated with increased susceptibility to CDI [49,52,114,115]. However, very little has
been done to understand the efficacy of either FMT or bacteriotherapy for infections other than
CDI. Animal studies comparing FMT and defined bacterial consortia found both approaches
quickened the re-establishment of the microbiota after antibiotics and the recovery of intestinal
epithelial MUC2 levels [116]. Thus, continued carefully designed studies defining microbial
composition, metabolites, and immune responses pre- and post-effective FMT and bacter-
iotherapy are critical to understanding the mechanisms underlying colonization resistance and
could lead to the development of more defined therapeutics to ameliorate infectious disease in
cancer patients.

In theory, the provision of particular nutrients to intestinal microbiome could result in outgrowth
or maintenance of beneficial microbes. Prebiotics have been considered as a safer alternative
to FMT or live probiotics for cancer patients, particularly in regard to possible introduction of
infection. Most of the current investigations include supplementation with resistant starches,
oligosaccharides, or SCFA. Randomized clinical trials and pilot studies using oligosaccharides
have shown increased Bifidobacterium growth and SCFA concentration [117,118]. However,

1000 Trends in Microbiology, December 2017, Vol. 25, No. 12

to date, clinical studies have mostly included healthy volunteers or patients with Crohn's Outstanding Questions
disease. One retrospective cohort study looked at the efficacy and safety of a prebiotic where What are the contributions of other
patients undergoing HSCT were given a combination of glutamine, fiber, and a fructo-oligo- kingdoms within the microbiome (i.e.,
fungi, viruses, etc.) to infections in can-
saccharide (FOS) [119]. The use of FOS supplementation correlated with a significant decrease cer patients? What are the consequen-
in diarrhea and mucositis, and increased survival. However, no differences in infection were ces of interkingdom interactions?
noted. Ruminococcus and Roseburia, both tied to butyrate production, have been shown to Cancer patients suffer infections from
an array of microbes, often including
increase with resistant starch supplementation [120,121]. Moreover, Faecalibacterium has
pathogens from more than one king-
been shown to respond to prebiotics using mixed-chain fructan supplementation [122]. These dom (e.g., cytomegalovirus/Aspergil-
data suggest that dietary manipulation of the cancer patient during treatment could help with lus coinfection). It will be critical to
the mitigation of infectious complications by promoting organisms that maintain colonization understand how fungi and viruses
impact nonbacterial infections as well
resistance against invading pathogens and/or improve the health of the GI epithelium.
as how these microbes interact with
bacteria to influence bacterial
Concluding Remarks infections.
It is increasingly understood that the microbiome strongly influences the occurrence of serious
human infections. Given the highly susceptible nature of cancer patients to a range of Is bacterial translocation from the GI
tract of the immunocompromised host
infections, these patients may serve as an excellent model for advancing knowledge of
density-dependent? It was shown that
how commensal microbiota impact the risk of infection. Herein, we have highlighted micro- intestinal domination of the GI micro-
biome associations with infectious outcomes in treated cancer patients, although mechanistic biome was predictive of BSI in HSCT
studies on the basis of these outcomes are still in their infancy. In the future, improved recipients, confirming nonquantitative
reports that VRE colonization was pre-
understanding of human microbial ecosystems could assist with early detection of dysbiosis dictive of future BSI in immunocom-
and serve as biomarkers for the risk of infection. Moreover, preliminary data show that patients promised patients. If confirmed in
can potentially be given individualized microbiota-based treatment for the prevention of larger studies, this raises the possibility
subsequent infection. Precision microbiome-based medicine also holds extraordinary potential that real-time monitoring of intestinal
microflora could be used to pre-emp-
for therapeutic approaches aimed at immunomodulation. Over the coming years, it is likely that tively target high-risk patients.
microbiome-based medicine will become increasingly integrated into mitigating the impact of
infections in the oncology setting. What host factors drive alterations in
microbiome composition during can-
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