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Y.F. van Lier et al.
infections (e.g., cytomegalovirus) or because of the indi- rect influence of diminished nutritional intake. Dietary carbohydrates normally serve as the main source of nutri- tion for the gut microbiota, but in their absence the mucus layer can become an alternative source of energy. As an example, Akkermansia muciniphila is thought to have mucolytic capacities and its relative abundance increases in mice with acute GvHD after imipinem/cilastatin treat- ment.32,63 Another study showed that a diet lacking fiber resulted in thinning of the mucus layer, which increased proximity of microbes to the epithelium.64 Enteral feeding (diet or prebiotics) could thus enhance intestinal homeo- stasis by directly stimulating preservation of commensal populations as well as indirectly by preventing damage to the mucus layer. An alternative way to promote the integrity of the mucus layer is by activating goblet cells which are responsible for the formation of the intestinal mucus layer but are often lost upon development of acute GvHD. It was recently described that stimulation of gob- let cells via IL-25 could prevent bacterial translocation and dampened inflammation in an experimental acute GvHD model.65 Exogenous supplementation of butyrate or indoles was also able to enhance epithelial integrity and mitigate acute GvHD in experimental mouse models whereas deletion of the SCFA receptor GPR43 increased acute GvHD.66-68 However, butyrate can have opposite effects and may delay mucosal wound repair by inhibit- ing proliferation of intestinal epithelial stem/progenitor cells in a dose-dependent manner.69 Whether butyrate has a net-protective or net-pathogenic effect may depend on the time after transplantation, the state of underlying tis- sue damage, or the activation status of effector T cells and further work is needed to assess the translatability of these preclinical findings to clinical practice and whether they may be targeted for therapeutic benefit.
Another candidate for promoting mucosal repair is IL- 22. IL-22, secreted by recipient innate lymphoid cells type 3, protected intestinal stem cells from immune-mediated damage during murine acute GvHD.70 Similarly, recombi- nant IL-22 enhanced intestinal stem cell recovery, stimu- lated epithelial regeneration and reduced intestinal acute GvHD pathology. However, pro-inflammatory and destructive effects of donor-derived Il-22 have also been described, suggesting a dual, context-dependent role for this cytokine, which needs further investigation.71
Immune modulation
The cycle of dysbiosis, tissue damage and lymphocyte activation that characterizes the early post-transplant environment and is even more exaggerated when acute GvHD has developed, contains many potential pathways for intervention (Figure 2). Therapies that alter the micro- biome and thereby break these feed-forward loops may offer an attractive target in GvHD prevention or treat- ment.
A number of preclinical studies have determined the immunomodulatory properties of microbiome-targeting or microbiome-adjunct therapies. A prebiotic mixture of glutamine, fiber and oligosaccharides (GFO) as well as FMT lowered colonic expression of IL-1b in dextran sodi- um sulfate-induced colitis in mice.72,73 In addition, FMT reduced the MHCII-dependent antigen-presenting capac- ities of colonic dendritic cells, monocytes and macrophages while simultaneously enhancing IL-10 pro- duction by these antigen-presenting cells, as well as in
CD4+ T cells and invariant natural killer T cells.73 FMT also appeared to limit CD4+ T-cell proliferation while increasing the frequency of FoxP3+ regulatory T cells. Induction of regulatory T cells was also accomplished by oral administration of a rationally selected mixture of bacterial strains which mitigated experimental colitis and allergic diarrhea and mainly comprised clusters IV, XIVa and XVIII Clostridia.74
While it remains to be clarified whether these mecha- nisms are also involved in FMT-mediated resolution of steroid-refractory acute GvHD, microbial metabolites might be involved in this process. In addition to SCFA, secondary bile acids, such as lithocholic acid and 3b- hydroxydeoxycholic acid, are other products of microbio- ta-mediated biotransformation that are thought to have immunomodulatory properties. For example, lithocholic acid, 3b-hydroxydeoxycholic acid and other bile acid metabolites have been implicated in the induction of reg- ulatory T-cell populations.75,76 A number of studies have shown that bile acid metabolism is altered in patients with acute or chronic GvHD, which might impact disease severity.77-79 A randomized controlled trial examining the use of the secondary bile acid ursodeoxycholic acid (also known as ursodiol) for prevention of hepatic complica- tions (e.g., veno-occlusive disease) found a lower inci- dence of severe acute GvHD and intestinal GvHD in the treatment group that used ursodiol from the start of con- ditioning through 90 days post-transplantation compared with control-treated patients.80 Furthermore, a study of patients with recurrent Clostridioides difficile infections (n=16), which included seven allogeneic HCT recipients, successfully used ursodiol to prevent recurrence of dis- ease.81 While the effects of ursodiol on the microbiome of allogeneic HCT recipients requires further investigation, these data suggest that therapeutic interventions targeting microbial bile acid metabolism might be worth exploring.
Opportunities for intervention
Therapies aimed at modulating intestinal microbiota function can target bacterial energy sources (prebiotics, diet), the bacterial community itself (antibiotic choice, probiotics, FMT) or its metabolites (postbiotics). Their protective or therapeutic potential has been studied in a number of interventional, predominantly single-arm studies.
Prevention of damage by antimicrobials: making the best antimicrobial choices
Antibiotic stewardship is most commonly considered in terms of its benefits in preventing the emergence of pathogens, but broadly speaking it involves the critical evaluation of antibiotic prescribing and use, to protect patients from all harms (including microbiome disrup- tion) caused by the use of antibiotics, while at the same time effectively treating infections. For example, in a ret- rospective study, Weber and colleagues observed that rifaximin, a broad-spectrum antibiotic with minimal sys- temic absorption, was equally effective at preventing infectious complications in allogeneic HCT recipients as ciprofloxacin/metronidazole, while sparing bacterial gut communities.82 Another retrospective analysis found that treatment of neutropenic fever with broad-spectrum antibiotics, specifically imipenem/cilastatin and
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