BACKGROUND: Alterations of the gut microbiota after allogeneic hematopoietic cell transplantation (allo-HCT) are a key factor in the development of transplant-related complications such as graft-versus-host disease (GVHD). Interventions that preserve the gut microbiome hold promise to improve HCT-associated morbidity and mortality. Murine models demonstrate that prebiotics such as fructo-oligosaccharides (FOS) may increase gut levels of short-chain fatty acids (SCFAs) such as butyrate, and consequently induce proliferation of immunomodulatory FOXP3+ CD4+ T-regulatory cells (Tregs), that impact GVHD risk.METHODS: We conducted a pilot Phase I trial to assess the investigate the maximum tolerated dose of FOS in patients undergoing reduced-intensity (RIC) allo-HCT (n=15) compared to concurrent controls (n=16). We administered FOS starting at pretransplant conditioning and continuing for a total of 21 days. We characterized the gut microbiome using shotgun metagenomic sequencing, measured stool SCFAs using LC-MS, and determined peripheral T-cell concentrations using CyTOF.RESULTS: We found that FOS was safe and well-tolerated at 10g per day without significant adverse effects in patients undergoing allo-HCT. Community-level gut microbiota composition was significantly different on the day of transplant (day 0) between patients receiving FOS compared to concurrent controls, however FOS-associated alterations of the gut microbiota were not sustained after transplant. Although the impact of FOS was fleeting, transplantation itself impacted a substantial number of taxa over time. In our small pilot trial, no significant differences were observed in gut microbial metabolic pathways, stool SCFAs, or in peripheral Tregs although Tregs trended higher in those patients who received FOS. A marker of CD4+ T-cell activation, namely CTLA4+, was significantly higher in patients receiving FOS, whereas a non-significant trend existed for FOP3+CD4+ T-regulatory cells that were higher in those receiving FOS compared to controls.CONCLUSIONS: FOS is well-tolerated at 10g per day in patients undergoing RIC allo-HCT. While alterations in the gut microbiota and peripheral immune cell composition in those receiving FOS are intriguing, additional studies are required to investigate the use of prebiotics in HCT recipients.
View details for DOI 10.1016/j.jtct.2021.07.009
View details for PubMedID 34274493