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Y.F. van Lier et al.
after HCT (<day 100) than patients who were not on pre- biotic treatment, but this advantage had disappeared 1 year after allogeneic HCT.87
A number of small studies have evaluated the safety and feasibility of probiotic use prior to allogeneic HCT but studies evaluating their potency with respect to min- imization of transplantation-related complications have not been performed.88,89 Oral administration of Lactobacillus rhamnosus GG in mice, starting from day 7 prior to transplantation and continuing throughout the transplantation period, limited bacterial translocation, mitigated acute GvHD and improved survival.90 Microbiome analysis was not included in this study, thus further studies are needed to understand the precise mechanism of the observed effects.
Donor FMT effectively reversed antibiotic- and chemotherapy-induced dysbiosis in a murine model, returning the composition of the microbiome to the naïve, pre-treatment configuration within 16 days after FMT.91 In five allogeneic HCT recipients, donor FMT was successfully used for decolonization of antibiotic-resis- tant bacteria prior to HCT but the enteric microbiome of these patients was not analyzed.92,93
Apart from these studies, data on the impact of micro- biota-targeting therapies on the pre-transplant microbio- me are scarce. Large, prospective trials are needed to assess to what extent these pre-emptive treatments can overcome treatment-induced microbiota injury and pro- tect against post-transplant complications.
Diet
It is well-established that dietary changes influence the enteric microbiome and thus it is likely that specific alter- ations in nutritional support could provide an extra stim- ulus for the growth and activity of anaerobic bacteria in the peri-transplant setting.94 A recent study in mice showed that administration of a tyrosine-enriched diet prior to HCT positively modulated the gut microbiome and metabolome, which was accompanied by reduced acute GvHD pathology and improved survival.95 Whether a specific diet could help to preserve a healthy microbio- me in allogeneic HCT recipients or improve intestinal health prior to allogeneic HCT remains to be elucidated. A study in pediatric patients (n=20) found that patients receiving enteral nutrition after allogeneic HCT had increased fecal diversity, higher concentrations of fecal SCFA and a higher relative abundance of certain butyrate- producing populations than patients receiving parenteral nutrition.96 In adult patients (n=23), fecal microbial diver- sity was similar in groups receiving either enteral or par- enteral nutrition. However, minimal oral intake for a pro- longed period was associated with less diversity, as well as less abundance of intestinal Blautia.97 Earlier studies had reported the superiority of enteral over parenteral nutri- tion in terms of transplant-related complications and sur- vival.98,99
There remains a gap in our knowledge regarding the impact of diet on the microbiome of allogeneic HCT recipients. It has been described that there is a high inter- personal variability in microbiome response to types of nutrition and it might prove difficult to formulate univer- sal dietary recommendations.94,100,101 To what extent a spe- cific diet, e.g., devoid of lactose-containing products, could benefit the health of transplant patients needs to be investigated in randomized trials.
Post-transplant recovery of the microbiome
It is likely that even with the best preventive strategies, some abnormalities in the microbiome will remain after the acute post-transplant period. For those patients with extensive microbial damage, probiotics or (donor) FMT might offer a way to directly repair the microbial commu- nity itself. Commercially available probiotic formulations contain bacterial strains predominantly belonging to the Lactobacillus and Bifidobacterium genera. The efficacy of probiotics as a preventive or therapeutic measure has been studied in the context of various disease entities with mixed results.102 In fact, the use of probiotics after antibiotic therapy delayed recovery of the indigenous microbiota in healthy individuals.103 As for allogeneic HCT recipients, a number of case reports raised safety concerns after systemic infections developed in immuno- compromised patients upon probiotic use, even though the bacterial strains that are commonly incorporated in commercially available probiotics are infrequently the cause of bloodstream infections.104-109 Probiotic therapy, comprising Lactobacillus rhamnosus GG capsules adminis- tered from the time of neutrophil engraftment, did not appreciably alter the microbiome or reduce acute GvHD incidence in a randomized trial (n=31) and was therefore prematurely terminated.110
A second option for the re-introduction of a whole community of microorganisms is via transfer of a healthy “previous self” or a donor-derived fecal suspension. In a randomized, controlled trial by Taur et al., allogeneic HCT recipients received either an autologous FMT (n=14), using the patient’s banked stool sample that was collected prior to transplant conditioning and carried a high microbial diversity but no intestinal pathogens, or no intervention (n=11).29 Autologous FMT improved microbial diversity and reinstated commensal members of the patient’s gut microbiome which had disappeared after allogeneic HCT. While effective, autologous FMT can be logistically challenging, as it requires upfront col- lection of a patient’s healthy stool; for this reason, most current studies have used related or unrelated healthy donors as the source for FMT.
High success rates have been reported for single or repeated donor FMT in patients to restore symbiosis, eradicate antibiotic-resistant bacteria or treat recurrent Clostridioides difficile infections, which coincidently also relieved GvHD symptoms in one patient.92,93,111-118 Resolution of steroid-refractory acute GvHD using donor FMT has been described in a number of case reports.119-122 Additionally, a pilot study from our group showed that donor FMT alleviated steroid-refractory or steroid-depen- dent acute GvHD in ten of 15 participants, which was accompanied by an increase of fecal microbial diversity, expansion of butyrate-producing bacteria, and enhanced donor species engraftment.123 The intrinsic and extrinsic factors that facilitate donor species engraftment remain to be elucidated and blinded, randomized clinical trials are needed to determine the additive value of donor FMT in GvHD treatment.
Safety has been one of the major concerns regarding the use of donor FMT in immunocompromised patients. For this reason, FMT trials have, thus far, largely post- poned administration until allogeneic HCT recipients have achieved neutrophil engraftment. The number of reported infection-related adverse events associated with donor FMT administration is low but transmission of
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haematologica | 2021; 106(8)