Microbiota Manipulation With Prebiotics and Probiotics in Patients Undergoing Stem Cell Transplantation

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, fungi, and microeukaryotes) that make up the gut microbiota, there is increasing evidence of the microbiota’s contribution to the development of post-transplant complications. Antibiotics 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 decrease rates of graft-versus-host disease (GVHD) and post-transplant infection.

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 experiencing clinically significant diarrhea. While many clinical factors related to host factors and cancer-targeted pharmacological interventions are implicated in the pathogenesis of gastrointestinal toxicity, an increasing awareness of the contribution of the environment 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 microbiota is comprised of a diverse ecosystem of microbial organisms, 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 between 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 majority 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].

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 complication 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 increasing, likely in part due to the increasing at-risk population living longer, as overall transplant outcomes improve [19]. Conventional approaches to the prevention and treatment of chronic GVHD have been disappointing and ineffective: despite decades of pre-clinical and clinical investigation, the standard first-line treatment for chronic GVHD remains glucocorticoids, 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, prophylaxis 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 mortality rates, indicating a potentially deleterious effect of antibiosis 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 organisms 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 bacteria 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 particularly heightened level of scrutiny. These studies call into question our routine use of broad-spectrum antibiotics in prophylaxis and gut decontamination and argue for other strategies 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 organisms and rising rates of antibiotic resistance. In normal subjects and patients with other GI-related diseases, alternative approaches to “precision microbiota manipulation” have been found to impact the microbiota positively and dramatically at much less cost to individual and public health. These alternative 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.

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

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 suggests a link between the diet, the microbiota, and clinical outcomes [32]. Specific elements of our diet called prebiotics are particularly influential in the structure and function of the microbiota [33]. The term “prebiotic” has traditionally been applied 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 oligoand 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 [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 prebiotics. Xylo-oligosaccharides and galacto-oligosaccharides also 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 understanding potential diet-microbiota effects applicable to future research in transplant patients. Experimental evidence in the pathogenesis of IBD demonstrates support for both an abnormal immune response to normal microbiota and a normal immune response to an abnormal microbiota. Studies of patients with IBD have demonstrated decreased diversity, reduced proportions of Firmicutes, and increased proportions of Proteobacteria and Actinobacteria [42]. Dietary supplements 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 patients 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 patients to oligofructose-enriched inulin or a control and found a similar increase in fecal bifidobacteria and decrease in disease 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 patients 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 microbiota in patients with GVHD. To date, only one study has looked at the efficacy and safety of a prebiotic in patients 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 supplementation 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 patients included in this trial received a preparation of the probiotic Lactobacillus throughout their transplant without any resulting documented infections. While this trial is small and retrospective, it does suggest that a prebiotic in HSCT patients is likely safe and may improve clinical outcomes 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, nutritional support by the enteral route is preferred in order to maintain digestive function and the mucosal barrier, preventing bacterial 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 addition of fiber, vegetables, and fruits in order to prevent GVHD and to assist in gut healing after GI GVHD. Immunomodulatory 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 receptors, 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 supplements that may positively influence our microbiota. The timing of these dietary interventions may also be important. 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 prebiotics and early enteral nutrition will be vital in furthering our knowledge of host-microbiota dynamics important in the prevention of GVHD.

Probiotics

Probiotics, defined as the administration of live microorganisms to improve health, have been used for centuries and likely for millennia. The most commonly used probiotic organisms—Lactobacillus spp. and Bifidobacterium spp.—are consumed in large quantities as part of traditional foods across the globe. Examples include natto and miso (from soybean), sauerkraut (from cabbage), and kombucha (fermented tea), among others. Alterations in the human microbiota are associated with disease and therapeutic manipulation of the microbiota with probiotics has the potential to improve health and well-being. IBD and GVHD are both associated with decreased 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 diarrhea 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 microbial 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 combination of bacteria and to employ a more diverse group of bacteria. In a systematic review of probiotics in patients with IBD, three RCTs found improved outcomes in patients with ulcerative colitis using the probiotic VSL#3, a highly concentrated mixture of multiple species from the genera Bifidobacterium 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 microbiota transplantation (FMT) as the ultimate probiotic has garnered 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. However, 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 before 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 minimal adverse effects [84–86] (See Table 1). In these cases, FMT may be the only non-surgical option for patients failing antibiotic therapy for CDAD, and the safety of this approach should improve with the implementation of broader and more comprehensive screening of donor stool. Currently, there are no formal guidelines for stool donor screening, although the literature to date universally favors blood and stool screening for HIV, hepatitis 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 recommended in Table 2. Improving our understanding of the microorganisms comprising the fecal transplant will undoubtedly make this a safer procedure, although the possibility of endogenous 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 autologous 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 immunocompromised patients (https://clinicaltrials.gov/ct2/show/study/ NCT02269150).

Table 1.

Case reports of patients post-HSCT who have undergone fecal microbiota transplant

Patient	Donor	Method of delivery	Follow-up	CDAD status at last follow-up	Authors
64-year-old male 11 months  post autologous HSCT for  diffuse large B cell lymphoma	Unknown donors given  at 2 time points 6  months apart	Enema	7 months	Resolved	Mittal et al. 2015 [84]
60 year-old female 13 months  post allogeneic HSCT for acute  lymphoblastic leukemia	Two unidentified donors	Push enteroscopy	10 months	Resolved	De Castro et al. 2015 [85]
21 year-old female 1 year post  allogeneic HSCT for acute  lymphoblastic leukemia	Husband	Nasogastric tube	2 months	Resolved	Neemann et al. 2012 [86]

Table 2.

Stool donor screening of blood and stool in FMT studies for CDAD with at least one immunocompromised patient

	Aas et al 2003[94]	Hamilton et al. 2012[95]	Zainah et al. 2012[96]	Duplessis et al. 2012[97]	Pathak et al. 2013[98]	Friedman- Moraco et al. 2014[99]	Trubiano et al. 2014[100]	Potential comprehensive 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

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 notion 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 infection [88]. The resolution of symptoms was robust in these individuals; even after receiving antibiotics for other infections, these patients did not experience recurrent CDAD. The use of multiple non-pathogenic organisms as a synthetic “designer microbiota” may be safer than FMT. To this end, recent metagenomic studies of the gut microbiome have resulted in the identification of novel organisms—most of which are likely obligate anaerobes—that may be used specifically 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 commensal [89]. In patients with Crohn’s disease, it was discovered that F. prausnitzii levels were lower in patients who developed endoscopic recurrence of the disease compared to those who remained in remission. In a mouse model of inflammatory colitis, oral administration of F. prausnitzii or its supernatant reduced the severity of colitis and contributed to the normalization of the microbiota through mechanisms involving 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 “designer microbiota,” researchers in Japan used a mixture of rationally selected strains of Clostridia to induce the expansion 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 immunocompromised 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 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 pharmacologic 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 infections 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 evidence 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 interactions. 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 “precision” prebiotics that are even more powerful in expanding commensal flora or that influence organisms towards a particular shift of the gastrointestinal metabolome. Probiotics could potentially be engineered to support the gut microbiota while also having a biological “off-switch” that could be triggered at the first suspicion 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 enhance 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 prevention and treatment of GVHD and infections in HSCT patients. Significant opportunity exists for further research into the development of targeted and individualized dysbiosis prevention and treatment regimens applicable to HSCT patients, and we anticipate great potential for the microbiota as a potentially modifiable biomarker of disease in this vulnerable patient population.