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Fecal microbial transplant in HSCT
antibiotic exposure. Galloway-Pena et al.47 analyzed 487 stool samples from 30 AML patients and found that their pre-induction microbiome diversity was not significantly different from that of healthy volunteers participating in the Human Microbiome Project (HMP). However, follow- ing neutrophil recovery, patient microbiome composition changed, with a significant decrease in diversity. Importantly, this reduction in diversity was associated with an increased risk of infections. The use of carbapenem antibiotics for more than 3 days during induction elevated the risk for a subsequent loss of diversity.47 Moreover, expo- sure to anti-anaerobic antibiotics, like piperacillin-tazobac- tam, ticarcillin, meropenem, clindamycin and metronida- zole, within the 3 months preceding allo-HSCT was asso- ciated with a significant decrease in pre-transplant micro- biome diversity.38 With more courses of intensive chemotherapy, such as re-induction or salvage, the micro- biome disruption was shown to enhance, leading to ecosystem instability and outgrowth of pathogenic bacteria like Enterococcus.48 This disruption in patient microbiome continued up to the time of allo-HSCT, as shown in the largest to date inter-center effort, where 8,767 sequential stool samples were collected from 1,362 patients prior to and throughout the transplantation period and analyzed using 16S ribosomal RNA sequencing. The pre-transplant microbiome of patients obtained on days -30 to -6 (n=606), was compared to that of healthy volunteers (n=246), demonstrating a significant reduction in diversity in patient microbiome.37 Additionally, evidence from another recently published study showed that the pre-transplant microbio- me and the one derived from healthy controls differed in composition, displaying decreased abundance of beneficial bacteria of genera Bifidobacterium and butyrate producing genera such as Faecalibacterium and Lachnospiraceae in the former case.49 To conclude, pre-transplant microbiome dis- ruption is clearly evident.
What is the microbiome status during the transplantation period and at time
of recovery?
Data from several studies demonstrate that during the transplantation course, the microbiome diversity signifi- cantly decreases and its composition changes.37,50 The lower-diversity microbiome is reported to be character- ized by abundance of pathogenic bacteria such as Enterococcus, Klebsiella, Escherichia, Staphylococcus and Streptococcus. The single taxonomic unit domination (abundance ≥30%) peaks at 1 week post-transplant, which is followed by a subsequent moderate decrease. The most common dominating taxonomic groups belong to the genera Enterococcus and Streptococcus.37 Along the same lines, other studies have found the Enterococcus genus to be more prolific during the first month post- transplant, with significantly higher abundance in patients with active or subsequent aGvHD.51,52 Following allo-HSCT, the microbiome recovery appears to be pro- longed and incomplete. In a large cohort of patients (n=753), the post-transplant recovery of the gut microbio- ta has been reported to start around day +50, but even by day +100 the composition and bacterial abundance observed pre-transplant have not been fully achieved.53 Moreover, in some patients, microbiota has remained dis- rupted even 1 year after HSCT, this being particularly the
case with butyrate-producing bacteria and Bifidobacterium.54 Eventually, the effect of environmental insult on the intestinal microbiota during allo-HSCT can be so severe that its recovery may require a long time.
Is the disrupted microbiome in allogeneic hematopoietic stem cell transplantation recipients clinically significant?
In the above-mentioned study by Peled et al., reduced microbiome diversity both pre-transplant (days -30 to -6) and peri-engraftment (days +7 to 21), was shown to be significantly associated with lower 2-year OS, while a persistent decrease of this parameter in the latter period was also associated with higher 2-year treatment-related mortality (TRM). Moreover, lower peri-engraftment microbiome diversity in T-cell replete allo-HSCT corre- sponded to increased GvHD-related mortality, which was not observed in T-cell depleted transplantations. This dif- ference suggests a connection between the microbiota and T-cell alloreactivity.37 Liu et al. revealed a similar asso- ciation of pre-transplant diversity with mortality as well as a correlation between post-transplant microbiome dis- ruption and acute GI GvHD risk.55 Furthermore, in a study of 66 patients whose stool specimens were ana- lyzed weekly during the transplantation period up to day +100, Golob et al. found a trend of association between near-engraftment low microbiome diversity and the risk for grade 3-4 aGvHD.56 Likewise, Mancini et al. evaluating a cohort of 100 patients, observed a significant connec- tion between low microbiome diversity by day +10 and an increased risk for early (within 30 days) aGvHD.38
A number of studies also reported an impact of pre- or post-transplant bacterial abundance on patient outcomes (Table 1). Results of a two-cohort study (a total of 115 adult patients) conducted at the Memorial Sloan Kettering Cancer Center (MSKCC) demonstrated that increased abundance of the genus Blautia, including anaerobic com- mensal bacteria, observed 12 days post-transplant, was associated with reduced GvHD-related mortality and improved OS. At the same time, the use of antibiotics with anti-anaerobic activity and total parenteral nutrition (TPN) correlated with loss of Blautia.57 In the pediatric set- ting, Biagi et al. reported an association of pre-transplant high abundance of Blautia and low abundance of Fusobacterium with diminished risk for grade 2-4 acute GI GvHD.58 Additionally, pre-transplant Enterobacteriaceae abundance of >5% was associated with an increased risk of BSI and Lachnospiraceae abundance of ≤10% appeared to correspond to increased mortality.38 In a large study from the MSKCC, very high abundance of a bacterial group, mainly composed of Eubacterium limosum, in pre- transplant samples or the presence of this group in peri- engraftment samples was found to correspond to a decreased relapse risk,59 once again emphasizing the asso- ciation of the microbiome and T-cell immunity. Furthermore, in the study from the Osaka University,54 Enterococcus relative abundance of ≥1% at 1 month post- transplant appeared to be indicative of poor OS, with a 2- year survival of 83.9% for patients with relative abun- dance of Enterococcus <1% versus 47.6% for those in whom this parameter was ≥1%. It is noteworthy that none of the surviving patients at 1 year post-transplant displayed Enterococcus abundance higher than 1%, sug-
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