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Fecal microbial transplant in HSCT
Can prophylactic fecal microbiota transplantation reduce the risk of acute graft-versus-host disease or transplant-related mortality?
The incidence of clinically significant aGvHD ranges between 22% in allo-HSCT from a matched related donor to 29% in case of a mismatched unrelated donor, with grade 3-4 disease incidence being 8.6% and 12%, respectively.24 Whether any intervention that restores the microbiome composition could also decrease aGvHD rates is yet to be revealed. Hitherto, only two small stud- ies have reported results of using prophylactic FMT in the post-engraftment period. In the study by Defillip et al.,25 aiming to evaluate safety and feasibility of early restora- tion of the gut microbiome, frozen capsules of FMT derived from unrelated donors were administered to 13 allo-HSCT recipients 4 weeks after neutrophil engraft- ment. No FMT-related bacteremia events occurred and two cases of acute GI GvHD were registered. Analysis of stool composition indicated improvement in intestinal microbiome diversity after FMT that was mainly attrib- uted to operational taxonomic units (OTU) originating from the FMT donor.25 In the study by Taur et al.,53 within 3-28 days of engraftment, patients not receiving broad- spectrum antibiotics, not critically ill and with low abun- dance of Bacteroides (<0.1% of the total 16S sequencing) at that time period, were randomized to either receive autologous FMT (n=14) or to a control group (n=11).
Solely the FMT group was found to reconstitute their microbiome diversity and composition to the pre-trans- plant state. Of note, the use of autologous FMT raises concern for disrupted microbiota due to prior antibiotic exposure.53
These data suggest feasibility and safety of prophylac- tic FMT; however, its clinical benefit has not been demonstrated yet.
Should additional interventions along with fecal microbiota transplantation aiming to attenuate mircobiome disruption be considered?
Given that a variety of factors could affect the micro- biome diversity and composition during the transplanta- tion course, their adequate control might potentially pre- clude such microbiome changes. The question remains whether FMT alone is sufficient enough or it should be combined with other interventions to provide the required control.
Transplant conditioning
Conditioning chemotherapy itself has a disruptive effect on the microbiome, as found by Montassier et al.26 who evaluated eight lymphoma patients undergoing autologous HSCT with the BEAM (carmustine, etopo- side, cytarabine arabine, melphalan) protocol. Since none of the patients received nasogastric tube nutrition, total parenteral nutrition, ciprofloxacin prophylaxis or sys- temic antibiotic treatment, only the chemotherapy effect on the microbiome was measured. Compared to pre- transplant samples, those drawn at 1 week post-condi- tioning demonstrated significantly reduced diversity, decreased abundance of Firmicutes and Actinobacteria and increased presence in bacteroides and proteobacteria,
indicating chemotherapy-induced disruption of the intes- tinal microbiota.26 Of note, this disruptive effect might be related to etoposide, which has bacterial inhibitory activ- ity.27,28 Remarkably, the post-transplant decrease in micro- biome diversity appeared to be more profound when more intensive conditioning was applied.74 However, reducing the conditioning intensity was not shown to consistently decrease the rate of aGvHD.75 Moreover, it might increase the relapse rate and decrease long-term OS.76,77 Therefore, changing the conditioning regimen in an attempt to attenuate the insult on the microbiome is not currently recommended.
Diet
Dietary interventions such as TPN, prebiotics and pro- biotics could potentially influence the microbiome com- position before or during the transplantation course. TPN administration was reported to be associated with decreased recovery of post-transplant (up to day +120) diversity compared to enteral nutrition. In addition, SCFA levels in the gut content were found to be lower in the TPN group.78 Iyama et al. retrospectively compared a group of patients whose diet was supplemented with pre- biotics, i.e., glutamine, fiber and oligosaccharides (GFO) with a group that did not receive such supplementation. GFO was started 7 days before conditioning and contin- ued up to day +28. In the GFO group, duration of diar- rhea, mucositis and TPN requirement was shorter and the weight loss was also less prominent.44 An ongoing prospective trial (clinicaltrials gov. Identifier: 02763033) is evaluating the efficacy of resistant potato starch supple- mentation between day -7 and day +100 in HSCT recipi- ents. This starch is a non-absorbable carbohydrate that is metabolized by the anaerobic commensal bacteria to pro- duce the SCFA butyrate,79 shown to reduce the severity of acute GI GvHD in an experimental model.31 Preliminary results demonstrate the feasibility of this approach in terms of patient compliance, increase in intestinal butyrate levels and abundance of butyrate producing bac- teria.80 As for probiotic supplementation, the available data do not suggest its influence on the microbiome com- position or clinical outcomes. It is worth mentioning that the products used in the studies contained only one bac- terial strain and not a diversity of bacteria,43,81 and safety of probiotic administration is of concern in immunocom- promised patients.82
The loss of diversity during the transplantation course is accompanied with microbiome domination by single taxonomic units such as Enterococcus.37 This enterococcal expansion has been found to be most prominent in patients developing acute GI GvHD.52 Stein-Thoeringer et al. have shown in a gnotobiotic mouse model of allo- HSCT that enterococcal expansion in the gut depends on lactose and its depletion decreases the enterococcal abun- dance and thus attenuates GvHD severity. Furthermore, in patients with a lactose malabsorption genotype, Enterococcus abundance appears to be higher than in patients without this genotype.83 This finding may give rise to a new approach to dietary intervention during HSCT. Interestingly, in the study by Khandelwal et al., where pediatric allo-HSCT patients under the age of 5 were treated with ready to eat human milk and breast feeding (n=24) or formula (n=14), plasma levels of IL6, IL10, and Reg3α were significantly lower in the group receiving human milk. The microbiome composition also
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