Microbiome and Infection Prevention in Pediatric Stem Cell Transplants

Abstract

Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is a potentially curative option for children with high-risk hematologic malignancies. Although therapeutically promising, allo-HSCT is fraught with severe infectious complications that are still the primary cause of morbidity and mortality among pediatric recipients. New evidence reflects the central role of the intestinal microbiota in maintaining immune homeostasis, integrity of the mucosal barrier, and infection susceptibility after transplantation. Dysbiosis — defined by decreased diversity and overgrowth of pathogenic organisms — is closely associated with bacterial translocation, bloodstream infection, and graft-versus-host disease (GVHD). This review discusses the developing concept of microbiota modulation as a new method for minimizing infectious complications in pediatric allo-HSCT recipients. It emphasizes techniques like microbiota-sparing antibiotic therapy, prebiotic and probiotic supplementation, fecal microbiota transplantation (FMT), and dietary modulation to achieve microbial balance. Elucidation of the interaction between microbiota, immune engraftment, and risk of infection may transform infection prevention in pediatric transplantation, enhancing outcomes and quality of life. This article integrates existing evidence, addresses clinical implications, and imagines future research directions to maximize pediatric allo-HSCT care.

Introduction

Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is a cornerstone of therapy for children with hematologic malignancies, especially acute leukemia, aplastic anemia, and some hereditary diseases. Through the substitution of the diseased marrow with healthy donor-derived hematopoietic stem cells, allo-HSCT has the potential to be curative. Nevertheless, the procedure is attended by considerable danger, such as graft-versus-host disease (GVHD), immune reconstitution delay, and infectious complications.

Infections represent a very serious risk to pediatric transplant recipients. Immune suppression, mucosal damage in the gut by conditioning regimens, and antibiotic-induced microbial changes all play a role in the increased risk of infection. Recent studies have revealed an interaction between post-transplant infectious outcomes and the intestinal microbiome. This review discusses the promise of microbiota modulation in the prevention of infectious complications following pediatric allo-HSCT, with a focus on the need for individualized, age-appropriate strategies.

The Pediatric Microbiome in the Context of Allo-HSCT

The gut microbiota — a diverse ecosystem of bacteria, viruses, fungi, and archaea — plays essential roles in nutrient metabolism, immune regulation, and intestinal barrier function. In healthy children, the microbiome undergoes dynamic development influenced by diet, antibiotics, infections, and environmental exposures. By the time children undergo allo-HSCT, many have already experienced microbiota-altering interventions, including broad-spectrum antibiotics and chemotherapy.

Microbiome Disruption in Allo-HSCT

Conditioning regimens, which typically include chemotherapy and sometimes radiation, cause significant intestinal mucosal injury. This not only disrupts barrier function but also drives dysbiosis, characterized by:

• Loss of microbial diversity

• Overgrowth of antibiotic-resistant pathogens (e.g., Enterococcus, Escherichia coli)

• Depletion of beneficial taxa (e.g., Faecalibacterium, Bifidobacterium)

These changes are associated with systemic inflammation, mucosal barrier breakdown, and increased translocation of gut-derived pathogens into the bloodstream.

Microbiome and Immune Reconstitution

Following transplant, successful immune reconstitution is essential for infection control. However, microbiota disruption impairs immune homeostasis, skewing immune responses toward pro-inflammatory states that predispose to GVHD and infection. In children, whose immune systems are still maturing, microbiota-immune crosstalk may be even more critical than in adults, underscoring the need for pediatric-specific research.

Infectious Complications Post-Transplant and Microbiota Links

Bacterial Infections

Bloodstream infections (BSIs) are a leading cause of morbidity and mortality post-allo-HSCT. The gut microbiome serves as a primary reservoir for these pathogens. Studies have shown that the loss of commensal diversity and dominance by enterococci or other antibiotic-resistant species correlates with an increased risk of bloodstream infections.

Fungal Infections

Mucosal disruption and broad-spectrum antibiotic use also increase susceptibility to invasive fungal infections. While most microbiome research focuses on bacterial communities, alterations in the fungal microbiome — the "mycobiome" — also contribute to post-transplant infectious risks.

Viral Reactivation

Viral reactivation, particularly cytomegalovirus (CMV) and Epstein-Barr virus (EBV), is another major concern. Though less directly linked to gut dysbiosis, microbial-driven immune dysregulation may impair antiviral immunity, enhancing the risk of viral complications.

Microbiota-Based Interventions for Infection Prevention

Antibiotic Stewardship

Given the critical role of antibiotics in disrupting microbial communities, antimicrobial stewardship is a cornerstone of microbiota protection in pediatric allo-HSCT. Strategies include:

• Narrow-spectrum antibiotic use whenever possible

• Minimizing the duration of prophylactic antibiotics

• Avoiding unnecessary gut-sterilizing agents (e.g., gut decontamination)

Probiotics and Prebiotics

Supplementation with beneficial bacteria (probiotics) or fermentable fibers (prebiotics) has shown promise in restoring microbiota diversity and promoting epithelial integrity. However, pediatric data remain limited, and concerns about probiotic-related sepsis in immunocompromised children warrant caution.

Fecal Microbiota Transplantation (FMT)

FMT, the transfer of stool from a healthy donor to a recipient, is a rapidly emerging tool for microbiota restoration. Small studies in adult allo-HSCT recipients demonstrate its potential to:

• Restore microbial diversity

• Reduce antibiotic-resistant pathogen colonization

• Potentially lower risk of bloodstream infections and GVHD

In pediatrics, early pilot studies are exploring FMT safety and feasibility, with promising preliminary results. However, factors such as donor screening, administration methods, and long-term effects require further research.

Dietary Modification

Diet profoundly shapes the gut microbiome, and tailored nutritional interventions hold promise for microbiome preservation. Strategies include:

• High-fiber diets to promote beneficial short-chain fatty acid-producing bacteria

• Avoidance of ultra-processed foods, which may favor pro-inflammatory species

• Consideration of microbiota-targeted medical foods

Pediatric transplant nutrition guidelines increasingly emphasize microbiome-conscious dietary strategies.

Integrating Microbiota Modulation into Clinical Care

Microbiome Monitoring

Routine microbiome profiling — using next-generation sequencing to assess diversity and composition — may help identify children at the highest risk for infectious complications. Real-time microbiome data could guide individualized interventions, such as early FMT or prebiotic supplementation.

Personalized Microbiome Medicine

Ultimately, the goal is precision microbiome medicine, where interventions are tailored to each child’s microbiota profile, immune status, and infection risk. This requires:

• Large-scale pediatric microbiome databases

• Better understanding of pediatric-specific microbial signatures

• Integration of microbiome data with clinical risk scores

Challenges and Future Directions

Despite its promise, microbiota modulation faces several hurdles:

• Limited Pediatric Data: Most evidence comes from adult studies.

• Regulatory and Ethical Concerns: Especially surrounding FMT in immunocompromised children.

• Inter-individual Variation: Each child’s microbiome is unique, complicating universal approaches.

Future research priorities include:

• Pediatric-specific randomized trials of microbiota interventions

• Longitudinal studies linking microbiome changes to infection outcomes

• Development of pediatric FMT protocols and biobanks

Conclusion

Infectious complications are still a substantial risk for pediatric recipients of allo-HSCT, leading both to early mortality and late morbidity. Gut microbiota contributes importantly to control of infection susceptibility, and early data support modulation of the microbiota as an effective approach to augmenting control of infection. By incorporating antibiotic stewardship, probiotics, dietary intervention, and possibly FMT into the post-transplant regimen, healthcare providers can limit infectious complications and optimize survival. However, to get there, the pediatric research agenda must be guided by considering the children's distinctive development, immunology, and microbiology. With ongoing innovation and cooperation, microbiota-directed interventions could revolutionize infection prevention and improve outcomes for pediatric hematopoietic stem cell transplantation.

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