Curr Stem Cell Rep (2015) 1:39–47
DOI 10.1007/s40778-014-0002-0
MICROBIOME AND STEM CELL FUNCTION (KE NELSON AND MB JONES, SECTION EDITORS)
The Microbiome and Graft Versus Host Disease
Nathan Mathewson & Pavan Reddy
Published online: 16 January 2015
# Springer International Publishing AG 2015
Abstract Allogeneic hematopoietic bone marrow transplantation (BMT) is an established and curative treatment for
many aggressive hematological malignancies. However, the
success of allogeneic BMT is limited by graft versus host
disease (GVHD) due to the attack of recipient organs. There
is growing evidence that the commensal microbiota is dysregulated following allogeneic BMT. Recent studies have made
significant strides in examining the role of the host and donor
microbiome on GVHD severity and pathogenesis. In this
review, we summarize the current knowledge of the complex
roles of the microbiome on GVHD, as well as the role of the
metabolome through which it confers its effects.
Keywords Microbiota . GVHD . Metabolome . Pathogen
recognition receptors . Antimicrobial peptides . Short-chain
fatty acids
Introduction: Graft Versus Host Disease
Allogeneic hematopoietic bone marrow transplantation
(BMT) is a curative therapy for many patients who would
This article is part of the Topical Collection on Microbiome and Stem Cell
Function
N. Mathewson : P. Reddy (*)
Department of Internal Medicine, Division of Hematology and
Oncology, Blood and Marrow Transplantation Program, University
of Michigan Comprehensive Cancer Center, 3312 CCC, 1500 E.
Medical Center Drive, Ann Arbor, MI 48105-1942, USA
e-mail: reddypr@med.umich.edu
N. Mathewson
e-mail: nmathew@med.umich.edu
N. Mathewson
Graduate Program in Immunology, University of Michigan Medical
School, Ann Arbor, MI, USA
otherwise succumb to hematological malignant diseases [1•].
Although BMT increases survival of these patients, 40–50 %
of recipients experience complications or secondary disease
associated with BMT known as graft versus host disease
(GVHD) [2]. GVHD is a complex disease that is modified
by the extent of the conditioning regimen, degree of human
leukocyte antigen (HLA) mismatch, activation of donor cells,
and destruction of target tissues [3, 4].
Conditioning of the host with myeloablative therapy results
in damage to host tissues. Damaged tissues respond by producing proinflammatory cytokines (TNFα, IL-1β, IL-6), increased expression of adhesion molecules, and chemokines
[5–8]. This inflammatory milieu activates host antigen presenting cells (APC) and results in the upregulation of major
histocompatibility complex (MHC) antigens and costimulatory molecules [3]. In addition, damage conferred on
the gastrointestinal tract sets up the milieu for future stimulation of the immune cells by pathogen-associated molecular
patterns (PAMPs) and metabolic by-products produced by the
microbiome.
We are beginning to understand the impact of the GI
microbiome on GVHD. In this review, we will therefore
primarily focus on the GI microbiome and its impact on
GVHD and not on the microbiota from other mucosal
surfaces.
The Microbiome of the GI Tract
The body is colonized by commensals including bacteria,
fungi, and viruses. The human GI tract contains trillions of
microorganisms, which is estimated to outnumber human
cells 10 to 1 [9, 10]. The gut of a human adult is largely
dominated by the phyla Bacteroidetes, Firmicutes,
Proteobacteria, and Actinobacteria [11]. While only a small
fraction of these microorganisms may be pathogenic, it is now
40
appreciated that the relationship between the host and the
commensal microbiome as a whole impacts several aspects
of the host biology [12, 13•]. Microbiota-associated molecular
patterns are directly recognized by pathogen recognition receptors (PRRs). In addition, they secrete a multitude of metabolites that also affect host immunity and biology.
Pathogen Recognition Receptors
Innate immune cells of the host express certain PRRs encoded
in the germ-line to detect pathogen-associated molecular patterns (PAMPs) associated with microbes [14]. Recognition of
PAMPs through PRRs results in the activation of innate immune cells, such as neutrophils and APCs. In addition to cells
of hematopoietic origin, such as the innate and adaptive immune system, PRRs are also expressed on epithelial and
endothelial cells.
Several categories of PRRs exist to recognize PAMPs in
various cellular surfaces and compartments. One type of PRR
is known as toll-like receptors (TLRs). Many TLRs have been
described and are known to recognize various PAMPs. These
include TLR4 recognition of lipopolysaccharide (LPS), TLR2
of bacterial lipoproteins, TLR5 of flagellin, TLR3 and 7 of
RNA, and TLR9 of DNA [15]. The engagement of extracellular TLR receptors requires the adaptor protein known as
myeloid differentiation primary response protein 88
(MYD88) for downstream signaling [16]. TLRs have a vast
array of functions; however, for the purpose of this review,
below, we will focus on those known for affecting the pathogenesis of GVHD. For an in-depth description of general
TLRs, we would refer the reader to several comprehensive
reviews focused on PRRs [16, 17].
While TLRs are both extracellular and intracellular, another type of PRR, known as NOD-like receptors (NLR), is found
in the intracellular compartment [18]. Indeed, NLRs function
through the recognition of intracellular PAMPs and dangerassociated molecular patterns (DAMP) [19]. NOD1 and
NOD2 are the most well studied members of the NLR family
and are often viewed as the prototypical NLRs. NOD1 is
ubiquitously expressed, where NOD2 expression is restricted
to innate immune cells and intestinal Paneth cells [18]. Signaling through the NLR has differential functional effects
dependent upon which class of NLR is stimulated. NLR
signaling is critical for the function of the inflammasome, a
multiprotein complex that plays an important role in inflammatory responses. Activation of NOD1 and NOD2 triggers
MAPK and NF-κB pathways, where activated NLRP1,
NLRP3, and NLRC4 act as scaffolding platforms for the
formation of inflammasomes. A commonality of these three
inflammasomes is their association with the protein apoptosisassociated speck-like protein containing a CARD (ASC),
which enables the recruitment of caspase-1. The activation
of caspase-1 by the inflammasome is required for the
Curr Stem Cell Rep (2015) 1:39–47
processing of IL-1β and IL-18. Although NLRs and TLRs
have disparate cellular locations, these PRRs can have both
non-redundant and complimentary functions. For example,
when cells have become refractory to TLR agonists,
NOD1/2 signaling is not mitigated highlighting the nonredundant roles for these PRRs. However, TLR-mediated
NF-κB is required for the production of pro-IL-1β, where
NLR activation of caspase-1 is required for the cleavage of
pro-IL-1β to active IL-1β, leading to its secretion.
Sialic acid-binding Ig-like lectins (Siglecs) are yet another
type of PRR. Siglecs, in contrast to other PRRs, are largely
inhibitory receptors expressed by neutrophils, monocytes, NK
cells, eosinophils, and basophils. Most Siglecs contain
immunoreceptor tyrosine-based inhibitory motifs (ITIMs)
which enable the attenuation of DAMP-mediated inflammation. The ligation of Siglecs by DAMPs reduces NF-κB
activation and prevents uncontrolled inflammation in the context of tissue damage [20].
The Metabolome
The microbiota are known to perform key metabolic functions
[21]. The microbiota of the gut can metabolize not only
material directly ingested by the host but also produce byproducts of its own metabolism. The intestinal metabolome
thus consists of products from discrete host metabolism, microbial metabolism, and mammalian-microbial co-metabolism [22]. The critical impact of microbiota-derived metabolites is being increasingly appreciated. Donohoe et al. demonstrates that the microbiota plays a critical effect on the energy
homeostasis of colonocytes through the generation of shortchain fatty acids (SCFAs). Recent studies show that
colonocytes from germ-free mice are in an energy-deprived
state demonstrating a decreased ratio of NADH/NAD+, oxidative phosphorylation, and levels of ATP which in turn
resulted in autophagy [23].
In addition to the effects of microbial metabolites on nonimmune cells, the impact of the metabolome on immune cells
is now increasingly being understood. Recent studies have
shown that 17 rationally selected strains of Clostridia, known
to produce the SCFA butyrate, directly result in the increased
presence of regulatory T cells (Tregs) in the gut. Tregs play a
critical role in maintaining gastrointestinal homeostasis by
modulating inflammatory responses via the release of the
anti-inflammatory molecule IL-10, which also directly impact
macrophages [24–27]. Similarly, other groups have utilized a
cocktail of altered Schaedler flora which too resulted in the de
novo generation of colonic Tregs [28].
With the emerging importance of the effects of microbial
metabolites on host biology beginning to be appreciated,
recent studies have shown diet to play a role in regulating
rapid changes in the taxonomic composition of the gut
microbiome [29, 30]. These findings suggest that an
Curr Stem Cell Rep (2015) 1:39–47
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It has long been established that colonization of commensal microflora provides protection against invading
pathogenic bacteria, referred to as colonization resistance [33]. Further, intestinal epithelial cells (IECs)
provide a physical barrier against contaminating factors
found in the lumen of the gut (Fig. 1). IECs are known
to produce both antimicrobial peptides (AMPs) which
inhibit the growth of and kill microorganisms, and a
polysaccharide-rich mucus layer which functions in a
manner similar to biofilms [34]. The biofilm-like mucus promotes various functions of the microbiota including metabolism of luminal contents, fortification of
host defenses, and resistance to hydrodynamic forces
due to peristalsis [34].
Defensins and cathelicidins are AMPs that have been identified in many mammals. Defensins interact with, and potentially destroy, both Gram-negative and Gram-positive bacteria
through membrane disruption [35, 36]. Several studies have
also described the ability of defensins to sequester components of the bacterial cell wall, thus inhibiting its synthesis [35,
37]. These findings emphasize the ability of defensins to
mount a multifaceted attack on bacterial targets.
Recent studies have demonstrated the rapid release of
defensins not only neutralizes pathogenic bacteria, but they
are also sufficient to initiate and amplify an adaptive immune
response resulting in both Th1-dependant cellular responses
and Th2-dependent humoral responses by activation of immature dendritic cells (DC) [38].
Cathelicidin (LL-37) is chiefly produced and stored in
granules of neutrophils; however, it is also an inducible product of epithelial cells, T cells, and monocytes [39].
Another type of AMP, RegIIIα (RegIIIγ in mice), is a
C-type lectin, found primarily in the intestine, and is
generated by Paneth cells. RegIII is composed of a combination of α-helical structures and beta sheets [40] and
binds to peptidoglycan carbohydrates of Gram-positive
bacterial cell walls, in a calcium independent process.
Fig. 1 The intestinal barrier and gut homeostasis. The intestinal lumen
contains microbial by-products particularly SCFAs, PAMPs, and other
metabolites such as indoles. Host intestinal epithelial cells (IECs) provide
a physical barrier against contaminating PAMPs and produce cytokines
and DAMPs that are found in the lumen. Specialized IECs, known as
Paneth cells, produce antimicrobial peptides (AMPs) that selectively
inhibit pathogenic bacteria while preserving commensal microbiota and
providing critical trophic factors for intestinal stem cells. Damage to IEC
homeostasis results in loss of barrier function and activation of immune
cells
appropriate diet conducive to homeostatic microbiota may be
an important factor when treating comorbidities as the associated metabolome is correspondingly altered [31, 32].
Together, these data suggest the microbial metabolome
could impact GVHD, although this hypothesis remains to be
formally tested.
Antimicrobial Peptides
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Studies have shown that RegIIIα adopts a hexameric
membrane-permeating pore structure to kill bacteria [41,
42].
In addition to AMPs, IECs also secrete chemotactic cytokines (chemokines) resulting in the recruitment of innate
immune cells (Table 1) and produce proinflammatory enzymes such as inducible nitric oxide synthase (iNOS) and
cyclooxygenase-2 (COX-2) which activate neutrophils
resulting in their degranulation upon pathogenic stimuli [43].
Thus, in coordination with immune cells, IECs can have a
significant influence on both the microbiota and homeostasis
of the host tissue.
The Role of the Microbiome in GVHD
Early Experimental Studies
A role for the microbiome in modulating the severity of
GVHD was first identified in the early 1960s by the seminal
studies of van Bekkum et al. using germ-free recipient mice.
The authors made the observation that the severity of GVHD
was markedly decreased when compared to conventional
BMT controls [44, 45]. Subsequent studies by the same and
other groups confirmed and expanded these findings [46, 47].
Further studies by van Bekkum et al. isolated colonization
resistant microflora which inhibited colonization of
Escherichia coli, K. pneumoniae, and P. aeruginosa by
treating conventionally housed mice with antibiotics (streptomycin, neomycin, and pimaricin) [48]. The colonization resistant microflora were then transferred to germ-free mice
prior to BMT resulting in decreased GVHD severity, thus
indicating that select microorganisms may be beneficial in
the context of BMT. These studies formed the basis for clinical
utilization of antibiotic prophylaxis prior to BMT and the
Table 1
Chemokines secreted by IECs
Chemokine
Cell type
attracted
Human: IL-8; CXCL8 Neutrophils
ENA-78; CXCL5
Gro-α; CXCL1
Gro-β; CXCL2
Murine: KC
Human: MCP-1;
Monocytes
CCL2
MIP1α; CCL3
RANTES; CCL5
Human: IP-10
T cells
Mig
I-TAC
Function
Regulation of chemotaxis.
IL-8 is released faster than
the longer acting ENA-78.
Regulate monocyte
recruitment.
MIP1α plays a major role in
recruiting mucosal DCs.
Constitutively expressed.
Consistent with the fact that
intraepithelial lymphocytes
(IEL) are normally present
in the mucosa.
establishment of standard practice gut decontamination prior
to BMT in the clinic, at many transplants centers.
Clinical Studies
The early experimental studies described above led to initial
clinical trials designed to determine the role of GI bacterial
decontamination in BMT patients. In a study performed nearly
30 years ago, patients were divided into 3 groups: administration of oral nonabsorbable antibiotics with isolation and decontamination in laminar airflow isolation (LAF) rooms, prophylactic granulocyte transfusions from a single family member donor, or conventional treatment in single rooms with
hand-washing and mask precautions [49]. Following engraftment, significantly fewer infections were observed in patients
isolated in LAF rooms and acute GVHD occurred much later
than control groups. More importantly, day 100 overall survival was significantly improved in patients in LAF isolation
(92 %) compared to groups in conventional treatment (64 %)
[49]. Another study in which patients were either treated with
meropenem, a broad-spectrum antibiotic, starting on the first
day of febrile episode, or prophylactically treated beginning
the first day with <500/mm3 granulocytes, demonstrated fewer febrile episodes in patients receiving meropenem prophylaxis. Prophylactic use of meropenem during the period of
neutropenia favorably affected the morbidity of the BMT
procedure suggesting that reduced febrile episodes were due
to decreased bacterial infections [50].
Other studies indicate that increased survival in patients
treated in LAF rooms resulted in less transplant-related mortality (TRM) independent of prophylactic antibiotic use [51],
whereas other studies indicated that there is no benefit to
isolation in LAF room following BMT [52]. Several groups
have performed additional studies utilizing antibiotic prophylaxis prior to BMT or during granulocytopenic period following BMT with conflicting results. One such study housed all
patients in LAF rooms with one group receiving prophylactic
systemic antibiotics (PSA). However, overall survival at day
100 of groups in LAF rooms with PSA was 72.2 % where
groups in LAF rooms only was 70.6 % suggesting no improvement in survival, even though LAF + PSA groups had
significantly lower incidence of infections [53]. However,
many of these studies have sought to answer disparate questions and lacked sufficient power to determine the validity of
prophylactic antibacterial use on GVHD severity in the
patients.
The Impact of the Microbiome of the Host on GVHD: Recent
Observations
Despite early observations as noted above, the role that the
host microbiome plays in the severity of GVHD was largely
unexplored until recent years. Recent studies have made
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significant strides in illuminating alterations in the intestinal
microbiota following allogeneic BMT in mice and humans
[54••, 55]. Jenq et al. described observations utilizing clinical
models of BMT (B10.BR→B6) where recipients were subjected to lethal irradiation and received donor BM with or
without isolated T cells. A loss of overall diversity was seen
consisting of an expansion of Lactobacillales with a simultaneous loss of Clostridiales in allo-recipients of BM with
isolated T cells. Elegant experiments where the predominant
pre-BMT species of Lactobacillus (L. johnsonii) was
reintroduced following gut decontamination and allo-BMT,
resulted in improved overall survival compared to recipients
of allo-BMT receiving only gut decontamination [54••]. Likewise, unpublished observations from our laboratory suggest
that intragastric introduction of a cocktail of 17 rationally
selected strains of predominantly Clostridiales [24] with salutary effects on the GI epithelium, results in decreased GVHD
and improved overall survival [56].
Another recent study illuminated the impact of the loss of
diversity in the gut further, following allo-BMT. The study
observed that Paneth cells are targets of GVHD [55]. Paneth
cells, located next to intestinal stem cells (ISC) within the
crypts of the intestinal lumen (Fig. 1), are essential regulators
of the composition of the intestinal microbiota [57, 58]. Further, Paneth cells are known to secrete antimicrobial peptides
and α-defensins which largely function by forming pores in
bacterial cell walls [59, 60]. Eriguchi et al. revealed that the
loss of Paneth cells from GVHD resulted in decreased expression of α-defensins. The authors further suggest that αdefensins selectively kill non-commensal bacteria while preserving commensal microbiota [55]. The study suggests that
the decrease in the expression of α-defensins resulted in the
loss of microbial diversity (as also observed in Jenq et al.) and
an overwhelming expansion of E. coli, leading to septicemia.
A recent study demonstrated the importance of bacterial
diversity in the intestinal tract on mortality outcomes following BMT. The authors collected fecal specimens from patients
that received allo-BMT, at the time of stem cell engraftment
[61]. Microbial diversity was then determined by performing
bacterial 16S rRNA gene sequencing. Patients with lower
bacterial diversity exhibited significantly worse mortality.
Overall survival at 3 years was 36 % for low, 60 % for
intermediate, and 67 % for high diversity groups [61]. These
results suggest that diversity of the intestinal microbiota at
time of engraftment may be a predictor of mortality in recipients of allo-BMT and thus highlight the consequences of
dysbiosis of the intestinal flora.
The Impact of the Microbiome of the Donor
The microbiome is known to play a key role in the development and maturation of T cells [24, 62, 63]. The influence of
the donor microbiota on the donor allograft and its impact on
43
GVHD was recently examined [64]. Using clinically relevant
murine models of BMT, the authors observed the severity of
GVHD induced by T cells harvested from germ-free (GF)
donors and specific pathogen-free (SPF) donors. Interestingly,
there was no difference in the frequency of Treg cells in the
periphery of the host or levels of lineage-specific cytokines in
the sera such as IFNγ, IL-5, IL-17, or the anti-inflammatory
cytokine IL-10. Further, clinical observation revealed that
GVHD progression and severity was similar between recipients of the GF and SPF donor T cells with no difference in
histopathological scores of the small intestine and liver. In
addition, no survival benefit was observed in the recipients of
donor T cells from GF or SPF donor T cells. Furthermore,
when SPF donor mice were treated with broad-spectrum
antibiotics prior to T cell isolation, no difference in survival
was determined.
These data indicate that absence of the effects of the
microbiome on T cells may be lost once they have been
removed from the germ-free environment.
PAMPs and GVHD
There is mounting evidence that microorganisms and PRRs of
the innate immune system play a critical role in the pathogenesis of acute GVHD [45, 54••, 65]. Products of Gram-negative
bacteria, such as LPS, were suggested to be contributors to the
severity and progression of GVHD in certain experimental
models [66–68]. Cooke et al. utilized a potent antagonist of
LPS and observed significantly reduced production of TNFα
and intestinal damage. While donor T cell responses were
unaltered, overall GVHD severity was reduced [67]. However, a recent study utilized a different model system with
myeloid differentiation primary response gene (88)
(MYD88) and TIR-domain-containing adapter-inducing
interferon-β (TRIF) double knockout cells, thus the donor
allograft was deficient in all TLR signaling [69]. The authors
demonstrated that loss of TLR signaling did not protect from
GVHD nor improve overall survival, suggesting that TLR
signaling is dispensable for GVHD severity.
Human genetic association studies wherein patients
possessing TLR4 polymorphisms, who also received grafts
from HLA-matched donor siblings, demonstrated an increased risk for Gram-negative bacteremia and GVHD
severity [70].
In another study, TLR9 deficient recipients of alloBMT have demonstrated decreased systemic GVHD
[71]. The authors observed that APCs isolated from
TLR9−/− mice had a decreased ability to stimulate allogeneic T cells. Further, utilizing cytosine-phosphorothioateguanine oligodeoxynucleotides (CpG ODNs), which
mimics bacterial and viral DNA and stimulates TLR9,
Blazar et al. found that CpG treatment enhanced allo-T
cell responses leading to increased GVHD severity and
44
mortality [72]. These TLR9 dependent studies emphasize
the importance of TLR signaling for host APC function
during GVHD [73]. The analysis of TLR9 gene associated
polymorphisms on the clinical outcome of 413 donors
showed no association of the TLR9 polymorphisms with
incidence or severity of GVHD [70, 73]. However, patients with the T1486C mutation exhibited significantly
improved survival due to reduced TRM and relapse rate.
The importance of TLRs in neutrophils on the severity of
GVHD has recently been demonstrated. Neutrophils are the
largest human white blood cell population and have important
roles in cleaving chemokines and the production of reactive
oxygen species (ROS). During allogeneic immune responses,
neutrophils amplify tissue damage caused by conditioning
regimens [74]. Schwab et al. utilized clinical models of
BMT where donor neutrophils were TLR2, TLR3, TLR4,
TLR7, and TLR9 deficient. GVHD severity was significantly
reduced suggesting that TLR signaling is important for
neutrophil-mediated inflammation in the context of allo-BMT.
The role of NLRs in GVHD has been examined in several
recent studies. NOD2 deficiency in recipients of experimental
BMT resulted in increased GVHD of both MHC-mismatched
and MHC-matched models [75, 76] corresponding with enhanced activation and proliferation of donor T cells, due to
increased activation status of DCs.
The presence of certain cytokines, such as IL-1β, was
suggested to predict the outcome and severity of GVHD [6].
IL-1β is one such proinflammatory cytokine that is released
following NLR stimulation. A study examining the genotypes
of 133 patients undergoing BMT from (HLA)-matched donor
siblings demonstrated a strong correlation between genetic
variants of NLRP2 and NLRP3 genes and the clinical outcome and severity of GVHD [77].
Immune-mediated tissue destruction, which is often found
in acute GVHD, is a result of cellular damage or response to
DAMPs. Although critical for the function of the cell, extracellular ATP released from a damaged cell is subsequently
internalized and serves as a strong activating signal of NLRP3
[78]. In response to accumulated ATP and NLRP3 stimulation, APCs increased expression of co-stimulatory molecules
which resulted in enhanced proinflammatory signals and expansion of donor T cells with a reduction of Treg cells and
increased GVHD severity [79].
Siglec-G recognition of non-infectious DAMPs regulates
innate immune responses [80]. A recent study examined the
role of Siglec-G expression on host APCs, specifically on
hematopoietic cells, and its ability to negatively regulate
GVHD in multiple clinically relevant murine models [81].
The authors demonstrate that recipients deficient in Siglec-G
exhibit significantly increased GVHD severity and mortality,
in a CD24 dependent manner. Upon administration of CD24
fusion protein to WT recipients of allo-BMT, improved overall survival is observed. However, administration of CD24
Curr Stem Cell Rep (2015) 1:39–47
fusion protein to recipients deficient in Siglec-G did not
improve survival, suggesting that Siglec signaling is required
for the effects of CD24 [81].
These data suggest that the Siglec-G–CD24 axis controls
the severity of GVHD and that enhancing this interaction may
represent a method of mitigating clinical GVHD.
The Metabolome and GVHD
Many recent studies have made strides to identify the taxonomic composition and activity of the host microbiome [24,
32, 54••]. However, few publications examine the role of
microbial metabolites (e.g., SCFAs) in the homeostasis of host
physiology. While it is increasingly evident that alterations in
the microbiome correlate with many disease states [82–84],
the mechanism through which these alterations confer their
effects is poorly understood.
The most studied microbial metabolites are SCFAs, of
which butyrate, acetate, and propionate are the most abundant.
As described earlier in this review, SCFAs are produced by
microbial fermentation of complex polysaccharides in the gut
and are subsequently absorbed by the intestinal epithelium
[21]. Butyrate is utilized as a major energy source for IECs
and is a known histone deacetylase inhibitor (iHDAC) [85].
Thus, microbial metabolites may play an important role in
maintaining the health of the physical barrier of the gut epithelium as well as protecting the host from the influences of
PAMPs and DAMPs.
SCFAs may have a particularly important role in the protection of the host from GVHD. Unpublished observations
from our lab demonstrate that there is a significantly decreased
concentration of butyrate found in the tissue of the GI tract
following allo-BMT. In addition, this coincides with a substantial and significant decrease in the acetylation state of
histones in IECs of allo-BMT recipients. When butyrate was
supplemented via intragastric gavage, it increased histone
acetylation in IECs and significantly improved junction integrity mitigating GVHD severity [56].
AMPs and GVHD
AMPs, produced by Paneth cells, have been shown to be a
critical “first line of defense” of the innate immune system
among epithelial barriers [86, 87]. As discussed above, a
recent study observed a loss of α-defensins in the gut due to
a GVHD-mediated decrease of Paneth cells [55]. Furthermore, non-commensal bacteria were selectively targeted and
killed by α-defensins, while commensal microbiota were
preserved. Equally, several studies have observed that the
composition of the intestinal microbiome is directly influenced by alterations in the expression of AMPs [88, 89].
Another recent study by Ferrara et al. identified the AMP
RegIIIα as a biomarker found in the plasma indicative of acute
Curr Stem Cell Rep (2015) 1:39–47
GVHD in the lower GI tract. The authors found RegIIIα to be
3-fold higher at GI GVHD onset in a large cohort of patients,
compared to control cohorts [90].
Conclusions
45
9.
10.
11.
The effects of the microbiome on GVHD, and that of GVHD
on the microbiome, are now being increasingly appreciated.
The differential role that the microbiota plays in the host [54••,
55] and the donor [64] and the effects of polymorphisms of
PRRs on GVHD severity highlight the complex interactions
between the microbiome and GVHD that remain to be meticulously examined further. Further studies examining the functions and mechanisms are needed to identify new targets for
treating GVHD and other diseases affected by dysbiosis of the
microbiota.
16.
Compliance with Ethics Guidelines
17.
Conflict of Interest Nathan Mathewson and Pavan Reddy declare that
they have no conflict of interest.
18.
Human and Animal Rights and Informed Consent This article does
not contain any studies with human or animal subjects performed by any
of the authors.
19.
12.
13.•
14.
15.
20.
21.
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