Review
Fecal Microbiota Transplantation for Acute Graft-versus-Host Disease after Allogeneic Hematopoietic Cell Transplantation: Expanding the Horizon into Pediatrics

https://doi.org/10.1016/j.jtct.2023.05.007Get rights and content

Highlights

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    Pediatric-specific variables may influence the application of fecal microbiota transplantation (FMT) in this population.

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    Future trials of FMT and other microbiome-targeted therapeutics for graft-versus-host disease should include children.

ABSTRACT

The microbiome plays a vital role in maintaining homeostasis of the intestinal microenvironment and the immune response in allogeneic hematopoietic cell transplantation (HCT) recipients. Disruption of the intestinal microbiome has been associated with the development of acute graft-versus-host disease (GVHD) of the lower gastrointestinal tract and worse survival. Fecal microbiota transplantation (FMT) can achieve clinical responses in refractory GVHD, establishing the promise of microbiome-directed interventions in this population. Although most data on microbial changes in HCT recipients have been generated from the adult population, children with refractory GVHD represent an important group that may benefit from FMT. In this review, we first highlight characteristics that distinguish the pediatric intestinal microbiome from the adult intestinal microbiome. We then explore multiple clinical factors that warrant careful consideration to optimize the application of FMT and other microbiome-directed therapeutics to children.

Section snippets

INTRODUCTION

Disruption of the intestinal microbiota is implicated in the pathophysiology of numerous health conditions, including Clostridioides difficile infection [1], metabolic syndrome [2], and inflammatory bowel disease (IBD) [3]. These studies have prompted investigation into microbiome-directed therapeutics as a class of interventions to treat clinical disease. The most well-established approach is fecal microbiota transplantation (FMT), a procedure in which stool from a healthy donor is transferred

ACUTE LOWER GI GVHD AND FMT

Studies in the 1970 and 1980s demonstrated that selective decontamination of gut bacteria decreased the risk of GI GVHD, but in recent years, a more nuanced and sophisticated understanding of microbial communities and GI GVHD has emerged 25, 26, 27. An association between gut dysbiosis and increased morbidity and mortality in adult and pediatric HCT recipients has been reported [12,28]. In a seminal study, Taur et al. [21] showed that adult patients with lower bacterial diversity profiles in

AGE-RELATED MICROBIOTA CONSIDERATIONS

Establishment of a child's gut microbiota is greatly influenced by their primary source of nutrients within the first year of life and by their mode of delivery. In the United States, a longitudinal study of 107 healthy mother-infant pairs showed that breastfeeding infants received microbes such as Bifidobacterium and Enterobacteriaceae from the breastmilk and areola skin in a dose-dependent manner, which contributed to their bacterial composition even after the introduction of solid food,

SAFETY OF FMT ADMINISTRATION FOR ACUTE LOWER GI GVHD

Over the last 2 decades, FMT has been associated with a 19% rate of adverse events (AEs), with mostly mild AEs, including diarrhea and abdominal pain, reported. Severe AEs have been reported in just 1.4% of FMT recipients (4241 patients who received a total of 5688 FMT doses), although some events have been fatal [63]. With these safety considerations in mind, FMT remains a promising therapeutic intervention for patients with GI GVHD.

A major concern in the early experience of FMT for GVHD has

FMT DONOR SOURCE

Fecal source of FMT can be separated into 2 major categories: autologous FMT and traditional allogeneic donor FMT, which can be obtained from family members or unrelated donors. The rationale for using autologous FMT is that this approach can reestablish the patient's previous intestinal microbiota while obviating the risk of transmitting foreign pathogenic organisms. As described above, autologous FMT has proven able to restore the microbiome following allogeneic HCT [64]; however, several

MODE OF DELIVERY

Mode of delivery represents one of the greatest barriers to FMT access in children with GVHD. FMT products can be administered as oral capsules, endoscopically (gastric, duodenal, or colonic), and by nasointestinal tube or enema. FMT traditionally has been administered in liquid form directly into the GI tract, although this approach has limitations. Patients with GI GVHD, especially those with stage 3-4 or steroid-refractory disease, represent a high-risk population for complications, such as

DOSING REGIMENS

There is no established FMT dosing regimen for patients with GVHD (Tables 1 and 2), and the number of reported doses ranges from 1 to 5. Dosing regimens appear to vary widely owing in part to an individual patient's response following an FMT dose. Many investigators provided additional FMT when a patient experienced a partial response or for a relapse of symptoms after initial response. In the current GI GVHD population, regardless of age, 20% of patients (48 out of 237; Tables 1 and 2)

FUTURE DIRECTIONS

The availability of targeted intestinal microbiota therapies has expanded greatly in the last decade. Aside from traditional FMT, several novel microbial restorative therapeutics have shown promising Phase III data for the treatment of C. difficile infection [77,78]. As promising data continue to be shared about these products, companies and investigators should pursue clinical trials that include children, possibly within a separate cohort, to examine safety and efficacy. Collaboration between

CONCLUSION

Multiple national [79] and international [63] studies have shown FMT to be both safe and effective in C. difficile infections and more recently in the GI GVHD population. Although the published pediatric cases represent a small cohort, it appears that FMT in the GI GVHD population has a safety profile that is at least similar to, and potentially better than, their adult counterparts. The current review provides investigators with up-to-date clinical data while highlighting pediatric-specific

Declaration of Competing Interest

There are no conflicts of interest to report.

ACKNOWLEDGMENTS

Financial disclosure: Gray and Defillipp have no financial disclosures.

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    • Financial disclosure: See Acknowledgments on page 484.

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