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I. Henig et al.
obesity, type 2 diabetes, inflammatory bowel disease, rheumatoid arthritis and multiple sclerosis.14-17 This associ- ation is also suggested to be true for cancer18 and response to cancer immunotherapy.19 The gut microbiota has a close and reciprocal relationship with the host immune system. Intestinal epithelial cells, goblet and paneth cells produce the luminal protective mucosal layer and antimicrobial peptides, allowing the transcellular transport of immunoglobulin A (IgA) antibodies. These functions regu- late luminal microbial colonization.20
Homeostasis of the immune response in the gut mucosa is maintained by the balance between pro-inflammatory cells, which include T-helper 1 (Th1) cells producing inter- feron γ (IFNγ), Th17 cells producing IL-17A and IL-22, diverse innate lymphoid cells with cytokine effector fea- tures resembling those of Th2 and Th17 cells, the anti- inflammatory Foxp3+ regulatory T-cells (Tregs) and IgA- secreting B-cells. This homeostasis can be modulated by the gut microbiota.21-23 In pre-clinical studies, intestinal microbiota has been shown to regulate the expression of pro-inflammatory cytokines, human leukocyte antigen (HLA) type I and type II molecules and increase T-cell pro- liferation.18 Effects of the microbiota on cytokine expres- sion and immune cell subsets are not limited to the gut, and are extended to regional mesenteric and systemic lymph nodes.24 Furthermore, while some bacterial strains can induce pro-inflammatory intestinal Th17 cells,25 others induce anti-inflammatory Tregs26,27 and can thus ameliorate inflammatory colitis.28 Moreover, human host gut micro- biota has been shown to correlate with expression pattern of the cytokines secreted from peripheral blood mononu- clear cells isolated from the host.29 Microbial metabolites such as the short chain fatty acid (SCFA) butyrate or indole derivatives produced by tryptophan metabolism act to maintain the intestinal epithelial cell health, mucosal barri- er, and to promote anti-inflammatory responses.30,31
Currently available molecular techniques allowing rapid and wide genomic sequencing enable extensive explo- ration of the microbiome. The most commonly used method is the 16S ribosomal RNA sequencing by PCR. Bioinformatics analysis tools assign the sequences to microbial taxon at different taxonomic levels. Other meth- ods include shotgun next-generation metagenomics sequencing enabling massive and deeper genomic sequenc- ing and allowing better identification of taxonomic species and potential functional pathways of the organisms, meta- transcriptomics using high throughput RNA sequencing to profile gene expression, metaproteomics capable to pro- vide large-scale characterization of the entire proteins in the environmental sample and metabolomics, identifying and quantifying all metabolites in the tested samples.32,33 The two main microbiome features that have been widely characterized in health and disease are its diversity and the abundance of specific bacteria or bacterial subgroups.34
The revelation of significant relationship between the microbiome, the immune system and disease has led to interventional studies aiming to normalize the microbiome composition and diversity thus ameliorating disease condi- tions. One of such interventions is the use of fecal micro- biota transplantation (FMT), the term referring to the trans- fer of the fecal microbial content from a healthy individual into the intestine of a diseased individual. FMT, the stan- dard of care for refractory or recurrent Clostridium difficile infection (CDI), proved to be highly effective in this condi- tion. At the same time, mixed results were demonstrated
in the studies evaluating the use of FMT for the manage- ment of inflammatory bowel disease, irritable bowel syn- drome and hepatic encephalopathy. To date, FMT applica- tion for indications other than CDI has been limited to the experimental setting only.35,36
The setting of allo-HSCT imposes a significant disrup- tion on the gut microbiome homeostasis through a variety of mechanisms (all part of the transplantation procedure), such as the use of broad-spectrum antibiotics, dietary changes (restriction), gut epithelial damage by conditioning regimens and introduction of a donor immune system.
Data from clinical studies support the association of alterations in the gut microbiome profile, mainly loss of diversity and change in composition during allo-HSCT, with patient outcomes such as aGvHD, GvHD-related mortality, non-relapse mortality (NRM) and overall sur- vival (OS).37-40 Moreover, the gut microbial composition is reported to have an impact on infection risk, including CDI and blood stream infections (BSI), in this clinical set- ting.38,41 Findings of these associations have led to a prepon- derance of research in this field,42 and although the cause- and-effect relationship between the microbiome and trans- plant complications has not been unequivocally estab- lished, many ongoing clinical trials are implementing vari- ous interventions aiming to maintain microbiome diversi- ty, thus potentially preventing transplant-related complica- tions and treating aGvHD. These interventions include the use of probiotics,43 prebiotics,44 change in antibiotic pro- phylaxis45 and administration of FMT.46 This review appraises the currently available evidence on the associa- tion of gut microbiota and allo-HSCT and analyzes a potential role of FMT in allo-HSCT, by presenting two illustrative clinical cases, where effects on the gut micro- biota composition could be employed either as a prophy- lactic or therapeutic measure.
Case 1
A 54-year old male, with mutated FLT3-ITD acute myeloid leukemia (AML) in complete remission (CR) after induction and re-induction chemotherapies, during which he acquired gut colonization with carbapenem- resistant Klebsiella pneumoniae. He underwent an allo- HSCT from a mismatched 9/10 unrelated female donor with myeloablative conditioning (busulfan, fludarabine) and received levofloxacin for infection prophylaxis. During the transplantation period, he had a BSI event with extended spectrum β lactamase Escherichia coli (E. coli) treated with meropenem for 10 days, followed by a CDI event treated with oral vancomycin. His neutrophils engrafted on day +15 and on day +33 he developed diar- rhea and was diagnosed with grade 3 acute lower gas- trointestinal (GI) GvHD that was steroid refractory.
This case raises a number of important questions relat- ed to the role of gut flora in allo-HSCT.
Is the microbiome already disrupted prior to allogeneic hematopoietic stem cell transplantation conditioning?
There is ample evidence suggesting that the pre-trans- plant patient microbiome is already disrupted. The insult to the microbiome starts with preceding chemotherapy and
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haematologica | 2021; 106(4)