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The post-HCT microbiome: effects and targeted therapy
pathogenic microorganisms has been described and can be fatal.124,125 While there is no debate that potential donors of fecal material should undergo stringent screen- ing, the donor screening protocols have been and, for the foreseeable future, will be subject to change as our expe- rience with FMT therapy increases. International guide- lines for donor screening protocols, for example as pub- lished by the European FMT working group, may help to reduce the variability of screening protocols used in FMT trials.126 In addition to donor screening and selection, other steps in the FMT procedure could be reviewed for optimization. For example, potentially beneficial obligate anaerobic organisms may be lost in the process of FMT preparation unless care is taken to process potential donor material in an anaerobic fashion. Additionally, the best route of administration of the FMT product is unknown, with options including capsules, nasoduodenal infusion and enema.
Microbial metabolites
Finally, one could bypass the bacterial community and directly supply microbial metabolites, such as the SCFA, acetate, butyrate or propionate. Fecal SCFA concentra- tions decrease in patients with acute GvHD in proportion to the severity of their disease.46 Similarly, the plasma concentrations of butyrate and propionate were reduced in patients who developed chronic GvHD.54 Exogenous butyrate supplementation as well as administration of a consortium of 17 known butyrate-producing bacterial strains mitigated murine GvHD in a study by Mathewson and colleagues.66 In contrast, a high relative abundance of butyrogenic bacteria in allogeneic HCT with acute GvHD has been associated with steroid-resistance, although luminal butyrate concentrations were not measured.127 These contrasting results highlight that we still have more work to do to understand the biology of butyrate signaling in the post-transplant setting, particularly with respect to GvHD.
Outstanding questions and future perspective
Considering that the field of microbiome research in hematologic patients is relatively young, significant advances have been made in recent years. Large cohort studies have robustly shown that microbiota injury dur- ing allogeneic HCT is common and associated with adverse outcomes. This has already led to some changes in practice – e.g., the favoring of anaerobe-sparing empiric antibiotics in many centers. Results from the first, predominantly single-arm trials have demonstrated potential for microbiota-modulating therapies to improve transplant outcomes (e.g., our recent study of FMT for steroid-refractory acute GvHD), paving the way for eagerly awaited randomized controlled trials that will confirm the clinical efficacy of these therapies in preventing or treating transplantation-related complica- tions. The accessibility of these biological, often already commercially available treatments has facilitated rapid translation from bench to bedside, with a large number of clinical trials currently being undertaken to target dys- biosis in allogeneic HCT recipients. In order to move the field forward in the coming years, several fundamental questions will need to be addressed (summarized inTable 2).
Several microbiome-targeting approaches have shown promising results in preclinical and clinical studies but the key players that underlie this beneficial effect are yet to be defined. Thus far, Blautia as well as butyrate-producing Clostridia appear to be prominent candidates based on fecal microbiome analysis. Still, it is important to keep in mind that there is only partial overlap between the fecal microbiome and the intestinal microbial composition and that the taxa that we have associated with positive trans- plant outcomes might only be a reflection of a balanced microbiota community.128 More invasive sampling (e.g., consecutive colon biopsies) will be needed to confirm the taxa present at the most immunologically active sites within the gastrointestinal tract, and access to these sam- ples will also further enhance our understanding of the working mechanisms of these therapies. Apart from the bacterial constituents of the microbiome, it is going to be important to examine other microbial kingdoms present in the enteric flora such as viruses, including bacterio- phages, fungi and archaea. A small study demonstrated that a sterile fecal transplant, filtered from bacterial microbiota, was sufficient to cure Clostridioides difficile infection, implying that non-bacterial microorganisms and/or microbial metabolites are also capable of disease resolution.129
In addition to identifying protective bacterial taxa and their related metabolites, the long-term effects of treat- ment response warrant further investigation. It is not known whether the different therapies discussed here only induce a local and temporary reset of the microbio- me or whether they elicit a systemic and durable response to dampen ongoing inflammatory processes. Yoshifuji and colleagues observed that after termination of prebiotics (at day 28 post-HCT), the incidence of late- onset acute GvHD (>day 100) was higher in the prebiotic group than in historical controls, suggesting that more work is needed to understand the potential mechanisms of prebiotic activity after HCT.86 The same holds true for FMT in which donor bacterial strains are eventually undermined by environmental and/or host factors in modeling the bacterial composition.118 This is supported by the finding in our FMT trial that early use of antibi- otics after donor FMT appeared to abrogate treatment response. Antibiotic treatment might thus be taken into account in clinical trial design for microbiome-targeting therapies, for example by including an additional/escape intervention in the case of antibiotic treatment. Once intestinal homeostasis is restored, disappearance of donor strains might be less problematic; while taxonomic simi- larity to the donor’s microbiome declined in the study by Moss et al., the functional similarity persisted at a high level. Future studies including long-term follow-up and longitudinal sampling will help to determine the optimal interval for intervention or whether, for example, lifelong dietary restrictions or prebiotic or postbiotic supplemen- tation should be encouraged.
Ideally, in the near future, microbiome analysis should be included in the routine work-up/follow-up for HCT, just as other organ function is measured, since the micro- biome can function as a biomarker for transplant-related complications, as well as being potentially modifiable in the pre-transplant period.130,131 The microbiome is a signif- icant focus of many research groups internationally, and it is likely that the coming years will continue to yield important results in both the pre-clinical and clinical set-
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