Gut microbiota recovery via butyrate supplementation prevents acute graft-versus-host disease after allogeneic hematopoietic stem cell transplantation Free

Background Acute graft-versus-host disease (aGVHD) is a significant cause of morbidity and mortality in patients undergoing allogeneic hematopoietic stem cell transplantation (allo-HSCT). During allo-HSCT, the diversity of the gut microbiota markedly decreases, primarily due to conditioning chemotherapy, prophylactic or therapeutic antibiotics, and dietary alterations. Numerous studies have demonstrated that a further decline in microbiota diversity during the engraftment period is associated with an increased risk of aGVHD and higher transplant-related mortality. Emerging evidence suggests that interventions aimed at restoring gut microbiota diversity may significantly mitigate the risk of aGVHD. Postbiotics—bioactive metabolites produced by probiotic bacteria—have garnered considerable interest as potential therapeutic agents. Among these, butyrate, a short-chain fatty acid, exhibits potent immunomodulatory effects and plays a critical role in maintaining intestinal epithelial integrity and regulating systemic immune responses. This study aims to assess the clinical efficacy of butyrate supplementation in allo-HSCT recipients, with a focus on its ability to preserve gut microbiota diversity and reduce the incidence of aGVHD.

Methods A prospective study was conducted to evaluate the clinical effects and microbial changes associated with postbiotic intake in allo-HSCT recipients. Thirty-nine patients who underwent allo-HSCT at Soonchunhyang University Seoul Hospital between September 2022 and December 2024 were enrolled in the intervention group. The patients received oral sodium butyrate (600 mg, two capsules daily) starting from the engraftment period (day +14 to +21) and continued until day +100 post-transplant. A historical control group of eighteen patients, who underwent allo-HSCT between March 2021 and June 2022, was also included for comparison. Stool samples were collected at three time points: pre-transplant (baseline), during engraftment, and at day +100 post-transplant. Clinical data from the control group were obtained retrospectively from medical records. Metagenomic analysis was performed on all collected stool samples to assess microbial composition and diversity.

Results A total of 57 patients were included in the analysis: 18 in the historical control group and 39 in the butyrate group. Sex distribution was comparable between groups (male: 61.5% vs. 61.1%). Underlying diagnoses in the control group included AML (n=7), ALL (n=3), MDS (n=3), and other hematologic malignancies (n=5); in the butyrate group, AML (n=16), ALL (n=11), MDS (n=8), and others (n=4) were represented. Donor types included matched sibling donors (MSD: 6 vs. 11), matched unrelated donors (MUD: 3 vs. 9), mismatched unrelated donors (MMUD: 1 vs. 3), and haploidentical donors (8 vs. 16) in the control and butyrate groups, respectively. Myeloablative conditioning (MAC) was more common in the butyrate group than in the control group (64.1% vs. 50.0%). GVHD prophylaxis strategies for haploidentical and MMUD transplants evolved over time. Prior to 2022, patients received anti-thymocyte globulin (ATG 3 mg/kg for 3 days) alone. From 2022 onward, a combined regimen of post-transplant cyclophosphamide (40 mg/kg for 2 days) and reduced-dose ATG (1.25 mg/kg for 2 days) was implemented.

By day +100, the cumulative incidence of acute GVHD (grade 2–4 and grade 3–4) was significantly lower in the butyrate group compared to the control group. While the incidence of skin GVHD was comparable between groups, the cumulative incidence of lower gastrointestinal aGVHD was markedly reduced in the butyrate group (5.13%) compared to the control group (40.42%) (P < 0.001). Although gut microbiota diversity decreased in both groups during transplantation, patients in the butyrate group exhibited more rapid recovery of microbial diversity following engraftment. In addition, stool butyrate concentrations were found to be increased at three months post-transplant in the butyrate group, supporting sustained delivery and potential metabolic activity of the supplemented compound.

Conclusions In conclusion, oral butyrate supplementation may contribute to the prevention of acute GVHD in allo-HSCT recipients by supporting gut microbial recovery and reducing the incidence of lower gastrointestinal GVHD. However, to confirm these findings and establish causality, randomized phase 3 trials comparing butyrate to placebo are warranted.