Curr Hematol Malig Rep (2016) 11:19–28
DOI 10.1007/s11899-016-0302-9
STEM CELL TRANSPLANTATION (R MAZIARZ, SECTION EDITOR)
Microbiota Manipulation With Prebiotics and Probiotics
in Patients Undergoing Stem Cell Transplantation
Tessa M. Andermann 1 & Andrew Rezvani 2 & Ami S. Bhatt 2,3,4
Published online: 16 January 2016
# Springer Science+Business Media New York 2016
Abstract Hematopoietic stem cell transplantation (HSCT) is
a potentially life-saving therapy that often comes at the cost of
complications such as graft-versus-host disease and post-
transplant infections. With improved technology to under-
stand the ecosystem of microorganisms (viruses, bacteria, fun-
gi, and microeukaryotes) that make up the gut microbiota,
there is increasing evidence of the microbiota’s contribution
to the development of post-transplant complications. Antibi-
otics have traditionally been the mainstay of microbiota-
altering therapies available to physicians. Recently, interest
is increasing in the use of prebiotics and probiotics to support
the development and sustainability of a healthier microbiota.
In this review, we will describe the evidence for the use of
prebiotics and probiotics in combating microbiota dysbiosis
and explore the ways in which they may be used in future
research to potentially improve clinical outcomes and de-
crease rates of graft-versus-host disease (GVHD) and
post-transplant infection.
Keywords Hematopoietic stem cell transplantation .
Graft-versus-host disease . Post-transplant infection
This article is part of the Topical Collection on Stem Cell Transplantation
* Ami S. Bhatt
asbhatt@stanford.edu
1
Department of Medicine, Division of Infectious Diseases, Stanford
University, Stanford, CA, USA
2
Department of Medicine, Division of Blood and Marrow
Transplantation, Stanford University, Stanford, CA, USA
3
Department of Medicine, Division of Hematology, Stanford
University, 269 Campus Drive, Stanford, CA 94305, USA
4
Department of Genetics, Stanford University, Stanford, CA, USA
Introduction
Hematopoietic stem cell transplantation (HSCT) is a potentially
life-saving therapy for patients with both malignant and non-
malignant hematologic disorders. Transplantation, however,
comes at the cost of potential complications from chemotherapy
and radiation, graft-versus-host disease (GVHD), and post-
transplant infections. Gastrointestinal (GI) toxicity is common
after HSCT, with up to 50 % of transplant recipients experienc-
ing clinically significant diarrhea. While many clinical factors
related to host factors and cancer-targeted pharmacological in-
terventions are implicated in the pathogenesis of gastrointestinal
toxicity, an increasing awareness of the contribution of the envi-
ronment to these disease phenotypes is being explored. One such
potentially modifiable component of the environment is the gut
microbiota, and this is increasingly being explored. The micro-
biota is comprised of a diverse ecosystem of microbial organ-
isms, including bacteria, viruses, and fungi, existing in symbiosis
with the human host [1–3]. New laboratory techniques have
enabled the enumeration of the number, types, and gene content
of microorganisms within these communities [4, 5•], and have
led to a greatly improved understanding of the relationship be-
tween the microbiota and the host. Several microbial niches exist
throughout the human body, including the skin, lungs, nares,
vagina, and gastrointestinal tract, with the majority of organisms
residing in the colon. Four main phyla found in the GI tract are
known to contribute to human health and disease: Firmicutes,
Bacteroidetes, Actinobacteria, and Proteobacteria, with the ma-
jority of species being non-pathogenic [2]. These commensal
microbes play an important role in immune regulation, nutrition,
and maintenance of host barriers against pathogens [6, 7]. The
importance of commensal organisms in pathogen defense is well
illustrated in germ-free mice, which lack the microbial stimulus
necessary for the development of a mature immune system and
are subsequently more susceptible to infection [8, 9].
20
Dysbiosis, or the imbalance of the microbial ecosystem,
has been associated with many diseases including irritable
bowel syndrome, inflammatory bowel disease (IBD), obesity,
and mental health [10–13]. In HSCT recipients, dysbiosis has
been associated with complications including diarrhea,
GVHD, and bacterial infections, often with high morbidity
and mortality [14, 15••, 16••, 17••]. GVHD is a major com-
plication of allogeneic HSCT and a significant barrier to wider
and more successful use of allotransplantation. While overall
outcomes in allogeneic HSCT have continuously improved
and the incidence of most complications has decreased over
time [18], the incidence of chronic GVHD is actually increas-
ing, likely in part due to the increasing at-risk population liv-
ing longer, as overall transplant outcomes improve [19]. Con-
ventional approaches to the prevention and treatment of
chronic GVHD have been disappointing and ineffective: de-
spite decades of pre-clinical and clinical investigation, the
standard first-line treatment for chronic GVHD remains glu-
cocorticoids, and there is no standard or consistently effective
second-line therapy [20]. Thus, novel approaches to GVHD
prevention and treatment are urgently needed.
The microbial milieu of the gastrointestinal tract has long
been linked to the development of GVHD following stem cell
transplant. For example, in the 1970s, germ-free mice were
shown to be less likely to develop GVHD [21, 22]. In the
1980s, human gut decontamination in concert with protective
laminar airflow rooms were found to be potentially helpful in
decreasing GVHD [23]. In more recent publications, prophy-
laxis with broad-spectrum antibiotics in both children and
adults was shown to reduce the development of GVHD [24,
25]. Broad antibiosis has the benefit of reducing not only
GVHD but also the risk for infections associated with HSCT
[24]. However, other experiments attempting to replicate these
findings did not find a similar effect and the use of total gut
decontamination especially in concert with laminar airflow
isolation to prevent GVHD has fallen out of popular use
[26]. Indeed, more recent research has indicated that a loss
of microbial diversity following HSCT results in higher mor-
tality rates, indicating a potentially deleterious effect of anti-
biosis on the microbiome [16••]. Loss of microbial diversity
and commensal flora can result in overgrowth of pathogenic
organisms, thereby increasing the risk for sepsis by antibiotic-
resistant organisms. In addition, the loss of commensal organ-
isms has been associated with higher levels of gastrointestinal
inflammation, which was found to be especially pronounced
in patients with GVHD [17••]. A decrease in anaerobic bacte-
ria and, in particular, the genus Blautia through antibiosis was
associated with an increased incidence of GVHD in those
undergoing allogeneic HSCT [27••]. Unnecessary use of an-
aerobically active antibiotics may therefore require a particu-
larly heightened level of scrutiny. These studies call into ques-
tion our routine use of broad-spectrum antibiotics in prophy-
laxis and gut decontamination and argue for other strategies
Curr Hematol Malig Rep (2016) 11:19–28
that maintain a more diverse microbiome. Still, our ability to
manipulate the microbiota to improve GVHD and infectious
outcomes has significant implications for clinical outcomes in
HSCT patients and further study to clarify the role of various
microbiota manipulating interventions is indicated.
Host-microbiota interactions in stem cell transplant patients
have been reviewed in detail previously [28–31]; this review
aims instead to focus on the ways in which we might use
microbiota-based preventative and therapeutic strategies to
improve clinical outcomes in HSCT patients. While
microbiota-based strategies have traditionally involved the
use of antibiotics, the regular use of antibiotics comes at the
cost of eradication of potentially salutary commensal organ-
isms and rising rates of antibiotic resistance. In normal sub-
jects and patients with other GI-related diseases, alternative
approaches to Bprecision microbiota manipulation^ have been
found to impact the microbiota positively and dramatically at
much less cost to individual and public health. These alterna-
tive strategies primarily include the use of prebiotics—non-
digestible carbohydrate supplements that promote the growth
of commensal organisms in the gut—and the ingestion of live
organisms as probiotics (Fig. 1). These two microbiota-
manipulating strategies, prebiotics and probiotics, will be
reviewed here as potential strategies to improve outcomes in
HSCT patients.
Diet and Prebiotics
While direct effects of dietary metabolites on the human gut
epithelium and secondary target tissues are known, the diet is
also a major modulator of the structure and function of the
human microbiota. The role of diet and nutrition in HSCT
patients is often underappreciated, but growing evidence sug-
gests a link between the diet, the microbiota, and clinical out-
comes [32]. Specific elements of our diet called prebiotics are
particularly influential in the structure and function of the mi-
crobiota [33]. The term Bprebiotic^ has traditionally been ap-
plied to indigestible carbohydrates metabolized by gut bacteria
to produce nutrients utilized by intestinal epithelial cells (IECs)
in such a way as to improve overall health [33]. A commonly
cited benefit of a prebiotic is that of fiber in altering intestinal
immunity. Indigestible plant oligo- and polysaccharides made
up of chains of sugars of varying lengths are fermented in the
colon by commensal bacteria, resulting in the production of
short-chain fatty acids (SCFAs) that serve as a source of energy
for colonocytes [34]. SCFAs—namely butyrate, acetate, and
propionate—have been implicated in promoting anti-
inflammatory cytokine production of helper T cells, intestinal
barrier integrity, and overall regulation of intestinal immune
function [34, 35]. SCFAs also promote resolution of intestinal
inflammation by increasing development of T regulatory cells
(T-regs) through interactions with G-protein-coupled receptors
Curr Hematol Malig Rep (2016) 11:19–28
Fig. 1 Effects of prebiotics,
probiotics, and antibiotics on the
microbiota in stem cell transplant
patients. Diet and antibiotics
interact with host factors
including the patient’s underlying
malignancy, prior chemotherapy,
and conditioning regimens to
affect the composition of the
microbiota. Antibiotics in this
model can lead to a decrease in
microbiota diversity and result in
the development of dysbiosis,
diarrhea, GVHD, and infection.
The microbiota can be returned to
a more symbiotic state
representative of a prior healthier
state of homeostasis with the use
of prebiotics and probiotics that
improve microbiota diversity
[36, 37]. Originally, the term prebiotic was restricted to the
polysaccharide inulin (obtained from vegetables such as the
Jerusalem artichoke) and its derivative fructo-oligosaccharide
(FOS), termed inulin-type fructans (ITF). More recently, other
oligosaccharides have been found to function as beneficial pre-
biotics. Xylo-oligosaccharides and galacto-oligosaccharides al-
so increase bifidobacterium growth and SCFA concentration in
randomized clinical trials; although to date, clinical studies
have only included healthy volunteers [38–41].
Dietary effects on the microbiota have been relatively well
researched in healthy volunteers and are increasingly being
studied in mouse models of colitis and in patients with IBD,
where diet has long been suspected as a contributing factor to
illness. Very little is known about dietary changes in patients
undergoing HSCT, but IBD provides a context for understand-
ing potential diet-microbiota effects applicable to future re-
search in transplant patients. Experimental evidence in the
pathogenesis of IBD demonstrates support for both an abnor-
mal immune response to normal microbiota and a normal
immune response to an abnormal microbiota. Studies of pa-
tients with IBD have demonstrated decreased diversity, re-
duced proportions of Firmicutes, and increased proportions
of Proteobacteria and Actinobacteria [42]. Dietary supple-
ments like prebiotics—in particular inulin and fructo-
oligosaccharides (ITFs)—have been studied in patients with
IBD in a small number of RCTs. The results from these RCTs
vary in their support for clinical improvement [43–45]. In one
pilot trial of patients with ulcerative colitis, the use of ITF was
associated with a significant decrease in calprotectin, a marker
of active disease [46]. A single-arm pilot trial of FOS in pa-
tients with Crohn’s disease found an increase in fecal
bifidobacterial content and a decrease in subjective disease
activity [47]. Another trial randomized Crohn’s disease
21
patients to oligofructose-enriched inulin or a control and found
a similar increase in fecal bifidobacteria and decrease in dis-
ease activity [44], although an earlier randomized double-blind
controlled trial did not find any clinical benefit [45].
The role of dietary changes in improving outcomes pa-
tients undergoing HSCT is even less well understood than
in IBD. Dysbiosis has been implicated in the pathogenesis
of IBD as well as GVHD [48]. Studies of the microbiome
in HSCT patients with GVHD show similarities with IBD;
for example, HSCT patients with GVHD demonstrate a
decrease in microbial diversity with an associated effect
on mortality [16••]. In comparison to patients with IBD,
even less is known about how diet might impact the mi-
crobiota in patients with GVHD. To date, only one study
has looked at the efficacy and safety of a prebiotic in pa-
tients undergoing HSCT. In 2014, Iyama et al. reported a
retrospective cohort study in which 22 patients were given
a combination of glutamine, fiber, and a fructo-
oligosaccharide (GFO) and compared to matched controls
[49]. Researchers found that the use of GFO supplementa-
tion correlated with a significant decrease in the days of
moderate diarrhea (grade 2, p = 0.0001), severe diarrhea
(grade 3–4, p = 0.001), and severe mucositis (grade 3–4,
p = 0.033). There was a significant difference in survival
between those receiving the supplement and those who
did not (100 vs. 77 %, respectively, p = 0.0091), although
this finding must be interpreted cautiously considering the
retrospective nature of the trial. No differences in rates of
infections were observed and the prebiotic supplement was
well tolerated and without adverse effects. Notably, all pa-
tients included in this trial received a preparation of the
probiotic Lactobacillus throughout their transplant without
any resulting documented infections. While this trial is
22
small and retrospective, it does suggest that a prebiotic in
HSCT patients is likely safe and may improve clinical out-
comes related to post-transplant diarrhea and mucositis.
Little is known about the role of prebiotics or probiotics in
HSCT patients, with much of the limited research available
being focused on patients’ overall diet. After HSCT, nutrition-
al support by the enteral route is preferred in order to maintain
digestive function and the mucosal barrier, preventing bacte-
rial translocation [50]. Debate exists, however, about the role
of total parenteral nutrition (TPN) vs. enteral nutrition (EN),
and the effects on the microbiota of long-term TPN are not
well understood. General guidelines in HSCT patients suggest
the use of a graded GVHD diet, which transitions patients
gradually from a liquid diet to an increasingly expansive menu
of solid foods once the volume of diarrhea has decreased
below 500 mL/day [51]. The proposed diet for HSCT patients
with GVHD is recommended to have limited amounts of fats,
fiber, lactose, acidic items, and GI irritants, although little
research has been done to support these recommendations
[51]. In fact, given our understanding of microbiota-based
therapeutics in healthy patients and in those with IBD, patients
undergoing HSCT may benefit from the earlier dietary addi-
tion of fiber, vegetables, and fruits in order to prevent GVHD
and to assist in gut healing after GI GVHD. Immunomodula-
tory diets have been shown to improve immune system cell
function and to reduce inflammation through regulation of T
cell responses [52]. The definition of prebiotics may need to
be expanded to include other nutrients and small molecules,
which could then serve as dietary supplements with the goal of
positively impacting microbiota. Possible therapeutic targets
for intervention include not only fiber and SCFAs but also
small molecules that interact with G-protein-coupled recep-
tors, or fermentative enzymes in the production of SCFAs
[53]. It is therefore reasonable to consider these or similar
interventions in patients undergoing HSCT with the hope of
reducing the incidence of GVHD and/or infection.
In the process of undergoing HSCT, diet and nutrition are
often viewed as a less important form of support compared to
immunosuppressive medication and prophylactic antibiotics.
Given our growing understanding of the importance of the
microbiota in the development of diarrhea, infections, and
GVHD, the role of the diet and nutrition may soon rise to
the level of prevention and treatment in patients undergoing
HSCT. We may want to consider earlier enteral feeding of
HSCT patients and limited use of TPN. As seen in IBD,
TPN in HSCT patients may decrease diarrhea but likely does
not impact clinical outcomes and can negatively impact the
microbiota [27••]. Just as in IBD patients, those with GVHD
may benefit from an early enteral diet even if they are unable
to tolerate solid foods, even in the setting of mucositis. This
elemental diet may also include prebiotics and other supple-
ments that may positively influence our microbiota. The
timing of these dietary interventions may also be important.
Curr Hematol Malig Rep (2016) 11:19–28
By the time patients develop severe steroid-refractory acute
GVHD, it is often too late for effective treatment and recovery
of gastrointestinal mucosal integrity and function. Given the
dismal clinical outcomes associated with steroid-refractory
GVHD, preventive approaches are essential. Perhaps a
thoughtful modulation of the gut microbiota through alteration
in nutrition before and after transplant may decrease the risk of
the development and/or severity of GVHD, with little risk to
the patient. To this end, prospective randomized trials of pre-
biotics and early enteral nutrition will be vital in furthering our
knowledge of host-microbiota dynamics important in the pre-
vention of GVHD.
Probiotics
Probiotics, defined as the administration of live microorgan-
isms to improve health, have been used for centuries and like-
ly for millennia. The most commonly used probiotic organ-
isms—Lactobacillus spp. and Bifidobacterium spp.—are con-
sumed in large quantities as part of traditional foods across the
globe. Examples include natto and miso (from soybean), sau-
erkraut (from cabbage), and kombucha (fermented tea),
among others. Alterations in the human microbiota are asso-
ciated with disease and therapeutic manipulation of the micro-
biota with probiotics has the potential to improve health and
well-being. IBD and GVHD are both associated with de-
creased microbiota diversity. For example, there is moderately
strong evidence supporting the use of probiotics to prevent
Clostridium difficile infection [54]. Probiotics have proven
efficacious in treating a wide variety of diarrheal illnesses,
including antibiotic-associated diarrhea [55–57], infectious di-
arrhea or gastroenteritis [58, 59], irritable bowel syndrome
[60–64], ulcerative colitis [65, 66], necrotizing enterocolitis
[67–69], constipation [70], and pouchitis [71–73], although
they have not yet shown significant efficacy in the treatment
of Crohn’s disease [74]. Proposed mechanisms for probiotic
efficacy include the microorganism-based remodeling of mi-
crobial communities and suppression of pathogens through
direct antimicrobial effects, stimulation of immune responses
that lead to upregulation of anti-inflammatory cytokines and
IgA, and promotion of intestinal barrier function [75, 76].
Interventional studies of probiotics have primarily focused
on the use of organisms that fall within the genera of
Bifidobacterium and Lactobacillus, most likely because of
their predominance in fermentable foods, their overall safety,
and their ease of culture and production. More recent studies
have gone beyond these organisms to encompass a combina-
tion of bacteria and to employ a more diverse group of bacte-
ria. In a systematic review of probiotics in patients with IBD,
three RCTs found improved outcomes in patients with ulcer-
ative colitis using the probiotic VSL#3, a highly concentrated
mixture of multiple species from the genera Bifidobacterium
Curr Hematol Malig Rep (2016) 11:19–28
and Lactobacillus plus Streptococcus thermophiles [77]. In
mouse and human studies, VSL#3 has been demonstrated to
increase anti-inflammatory IL-10 production and decrease
proinflammatory IL-12 production by dendritic cells [78].
Going beyond the use of a few select organisms, fecal mi-
crobiota transplantation (FMT) as the ultimate probiotic has gar-
nered increasing attention for its successful use in refractory
C.difficile-associated disease (CDAD). CDAD is one of the
most frequently studied examples of dysbiosis, and one that is
increasingly more common and refractory as a result of our
overuse of broad-spectrum antibiotics. FMT has been shown
to be safe and effective for CDAD, including in highly refractory
disease [79]. As a result, interest has grown in FMT as a possible
treatment for IBD and for CDAD in patients with IBD. Howev-
er, the enthusiasm for fecal transplant is somewhat attenuated in
this population; in a recent systematic review of case studies and
case series of FMT in patients with IBD with or without CDAD,
several patients in these reports were noted to have developed
adverse effects including bacteremia, worsening of their IBD,
and fevers [80]. No deaths were reported after FMT, even in
patients who were immunosuppressed. Despite these concerns,
71 % of patients were noted to have had resolution or reduction
of IBD or IBD/CDAD symptoms, generally with single fecal
infusions. These results are encouraging, although notably
poorer than those reported for FMT in patients with CDAD
alone (success rate ∼90 %) [79].
Given these findings, it is not surprising that both probiotics
and FMT are used with great hesitation in patients who have
undergone HSCT. There is understandable concern for sepsis as
a result of bacterial translocation, or viral infection, and indeed
case reports have described this phenomenon [81, 82]. However,
mouse models have shown that Lactobacillus administered be-
fore and after HSCT reduced GVHD and improved survival
[83]. In three case reports to date, patients with refractory CDAD
after HSCT have undergone FMT with success and with mini-
mal adverse effects [84–86] (See Table 1). In these cases, FMT
may be the only non-surgical option for patients failing antibi-
otic therapy for CDAD, and the safety of this approach should
improve with the implementation of broader and more compre-
hensive screening of donor stool. Currently, there are no formal
Table 1 Case reports of patients post-HSCT who have undergone fecal microbiota transplant
Patient Donor Method of
delivery
64-year-old male 11 months Unknown donors given Enema
post autologous HSCT for at 2 time points 6
diffuse large B cell lymphoma months apart
60 year-old female 13 months Two unidentified donors Push enteroscopy
post allogeneic HSCT for acute
lymphoblastic leukemia
21 year-old female 1 year post Husband Nasogastric tube
allogeneic HSCT for acute
lymphoblastic leukemia
23
guidelines for stool donor screening, although the literature to
date universally favors blood and stool screening for HIV, hep-
atitis A, hepatitis B, hepatitis C, stool C.difficile, parasitic stool
analysis, and bacterial culture, at a very minimum, prior to FMT
in non-immunocompromised patients. Guidelines for donor
screening prior to FMT in immunocompromised patients will
need to be established and should consider the use of a more
comprehensive screening protocol including the organisms rec-
ommended in Table 2. Improving our understanding of the mi-
croorganisms comprising the fecal transplant will undoubtedly
make this a safer procedure, although the possibility of endog-
enous potentially pathogenic organisms like Eschericia coli or
Enterococcus spp. leading to bacterial translocation, sepsis, and
bacteremia will persist regardless of screening. One option to
consider in HSCT patients is banking of patient stool prior to
HSCT or even prior to chemotherapy, to be used in an autolo-
gous fashion to treat CDAD, antibiotic-associated diarrhea, or
even GVHD. Autologous FMT in HSCT patients is currently
undergoing investigation and represents an exciting prospect in
the future of microbiota-based therapeutics in immunocompro-
mised patients (https://clinicaltrials.gov/ct2/show/study/
NCT02269150).
Apart from single-organism probiotic supplements or
transplant of an entire microbiota via FMT, we may be able
to synthesize an idealized defined microbial ecosystem using
organisms that are less likely to become pathogenic. This no-
tion of microbial ecosystem therapeutics (MET) is not new,
but has yet to enter widespread use. A study in 1989 by Tvede
and Rask-Madsen used a mixture of ten strains of bacteria,
including three strains of Clostridium spp., three of
Bacteroides spp., two strains of E.coli, Peptostreptococcus
spp., and Enterococcus faecalis [87]. In the five patients
who received this enteral mixture for CDAD, all became
asymptomatic and tested negative for C.difficile toxin within
24 h. In 2013, an ecosystem of 33 strains of non-pathogenic
bacteria was isolated from a stool donor and used to treat two
patients who were subsequently cured of their C.difficile in-
fection [88]. The resolution of symptoms was robust in these
individuals; even after receiving antibiotics for other infec-
tions, these patients did not experience recurrent CDAD.
Follow-up CDAD status at Authors
last follow-up
7 months Resolved Mittal et al. 2015 [84]
10 months Resolved De Castro et al. 2015 [85]
2 months Resolved Neemann et al. 2012 [86]
24 Curr Hematol Malig Rep (2016) 11:19–28

Table 2 Stool donor screening of blood and stool in FMT studies for CDAD with at least one immunocompromised patient
Friedman- Potential
Aas et al Hamilton et Zainah et Duplessis et Pathak et Trubiano et
Moraco et al. comprehensive
2003[94] al. 2012[95] al. 2012[96] al. 2012[97] al. 2013[98] al. 2014[100]
2014[99] screening*
Blood
Hepatitis A
Hepatitis B
Hepatitis C
Hepatitis E
HIV 1/2
HTLV-I/II
Syphilis
CMV
EBV
Stool
Clostridium
difficile
Bacterial culture**
Helicobacter
pylori
Ova and parasites
Giardia
Cryptosporidium
Microsporidia
Stronglyoides
stercoralis
Entamoeba
histolytica
Cyclospora
Isospora
Dientamoeba
fragilis
Blastocystis
hominis
Schistosoma
Norovirus
Rotavirus
Adenovirus
JC Virus
*Donor screening prior to FMT in HSCT patients should include consideration for this more comprehensive screening. In the case of Strongyloides
stercoralis and Schistosoma, testing would be recommended only after assessment of donor exposure risk
**Bacterial culture includes the evaluation of standard pathogenic organisms (e.g. Salmonella spp., Shigella spp., Campylobacter spp., Vibrio spp., and
Aeromonas spp., and Escherichia coli 0157:H7). Several studies also screened for drug resistant organisms (specifically VRE and multi-drug resistant
Gram-negative bacteria) which would be recommended in this vulnerable population
EBV Epstein-Barr virus; CMV cytomegalovirus; HIV human immunodeficiency virus, HTLV human T-cell lymphotropic virus

The use of multiple non-pathogenic organisms as a synthetic
Bdesigner microbiota^ may be safer than FMT. To this end,
recent metagenomic studies of the gut microbiome have re-
sulted in the identification of novel organisms—most of
which are likely obligate anaerobes—that may be used specif-
ically to repopulate the human gut microbiota and improve
gastrointestinal health. For example, Faecalibacterium
prausnitzii, a member of the Firmicutes phylum, was first
identified in 2008 as an important anti-inflammatory com-
mensal [89]. In patients with Crohn’s disease, it was discov-
ered that F. prausnitzii levels were lower in patients who de-
veloped endoscopic recurrence of the disease compared to
those who remained in remission. In a mouse model of inflam-
matory colitis, oral administration of F. prausnitzii or its su-
pernatant reduced the severity of colitis and contributed to the
normalization of the microbiota through mechanisms involv-
ing high levels of butyrate production and increased secretion
of IL-10 [90]. While the administration of F. prauznitzii is
complicated by its extreme sensitivity to oxygen, researchers
have recently found a way to stabilize the organism in an
aerobic environment through the use of an inulin and
antioxidant-based matrix [91]. Exemplifying the use of a
Bdesigner microbiota,^ researchers in Japan used a mixture
of rationally selected strains of Clostridia to induce the expan-
sion and differentiation of T-regs in a mouse model of colitis
[92]. Very recently, Clostridium scindens has been found to
provide resistance to CDAD through bile acid production
[93••]. The use of F. prausnitzii in probiotic form along with
other strains such as Clostridium butyrate (another butyrate-
producing organism) and the bile acid-producing C. scindens
may positively influence the microbiota in immunocompro-
mised patients with the possibility of decreased risk for sepsis
or bacteremia in comparison to currently available probiotics.
The discovery of these important organisms as major players
in resistance against disease highlights the increasing focus on
precision microbiota manipulation applicable to
Curr Hematol Malig Rep (2016) 11:19–28
immunocompromised patients. Further research is required to
determine disease-specific or even individually based
probiotics targeted against a variety of dysbiotic states.
Conclusion
A better understanding of our microbiota and its symbiotic
relationship with the human host holds significant promise
for improving health in HSCT recipients. Broad pharmacolog-
ic approaches aimed at immunomodulation for treatment of
GVHD and antimicrobials strategies for treatment of infection
in BMT patients have predominated for decades, with limited
success (particularly in chronic GVHD) and with negative
consequences for increasing susceptibility to opportunistic in-
fections and the promotion of drug-resistant organisms. Anti-
biotics manipulate the microbiota in such a way that dysbiosis
often results, leading to subsequent inflammation, increased
risk for infection, and possibly an increased risk of GVHD. A
completely new approach is offered by the burgeoning evi-
dence in mice and human studies that a more precise alteration
of the microbiota may be an even more effective tool in
preventing and treating disease, particularly in the setting of
HSCT. This approach represents a major shift in our current
understanding of infectious diseases and host-microbe inter-
actions. Microbiota-based therapeutics will include the use of
narrower, more precise antibiotics as well as dietary changes,
nutritional prebiotic supplements that support the growth of
commensal organisms, probiotics, and FMT.
In the future, we may be able to use increasing knowledge
of the microbiota to develop Bprecision^ prebiotics that are
even more powerful in expanding commensal flora or that
influence organisms towards a particular shift of the gastroin-
testinal metabolome. Probiotics could potentially be
engineered to support the gut microbiota while also having a
biological Boff-switch^ that could be triggered at the first sus-
picion of bacteremia. The development of designer microbiota
with non-pathogenic organisms may be of use even in highly
immunocompromised patients undergoing HSCT. An early
detection of dysbiosis could be treated with an individualized
microbiota transfer of commensal organisms necessary to en-
hance diversity for the prevention of subsequent bacteremia
and sepsis. In addition, an improved understanding of the
human ecosystem may allow us to use patients’ microbiota
composition as a biomarker of disease. For example, we can
foresee a future in which a patient’s microbiotic signature
serves as a predictor of risk for steroid-refractory GVHD,
allowing the earlier addition of secondary treatments. Overall,
microbiota-based therapeutics hold great promise for the pre-
vention and treatment of GVHD and infections in HSCT pa-
tients. Significant opportunity exists for further research into
the development of targeted and individualized dysbiosis pre-
vention and treatment regimens applicable to HSCT patients,
25
and we anticipate great potential for the microbiota as a po-
tentially modifiable biomarker of disease in this vulnerable
patient population.
Acknowledgments This work was made possible by the following
awards: American Society of Hematology Scholar Award (A.S.B.),
Amy Strelzer Manasevit award (National Marrow Donor Program and
Be The Match foundation) (A.S.B.), NCI K08 CA184420 (A.S.B), the
American Cancer Society Mentored Research Scholar Grant 122663-
MRSG-12-162-01-LIB (A. R.), and NIH T32 AI007502 (T.M.A.). The
authors would also like to thank Dr. Lucy Tompkins from the Division of
Infectious Diseases at Stanford University for her review of the
manuscript and figures.
Compliance with Ethical Standards
Conflict of Interest The authors declare that they have no competing
interests.
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.
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