Discussion
RS, biopsy-proven, stage 1 acute GI GVHD, decreased disease, inflammatory bowel disease (IBD)Allogeneic HCT, human disease
ACUTE GVHD
In this prospective interventional study, we determined that administration of commonly available RPS as a dietary prebiotic in recipients of allogeneic HCT is clinically feasible, tolerated by patients and may mitigate microbiome and metabolite disruption after allogeneic HCT. We measured the feasibility of administering RPS to human recipients of allogeneic HCT by presetting a goal of 70% or greater adherence to scheduled dosages in 60% or more patients; this was met as eight out of ten patients (80%) received 70% or more of the scheduled doses. We measured the microbial SCFA butyrate, which has been shown to promote salutary effects after allogeneic HCT in mice, and found that it was significantly increased in the stool of recipients of RPS at multiple time points after allogeneic HCT when patients were on RPS.We examined the changes in microbiome structure, specifically the RS degraders and butyrate producers given the significant increase observed in stool butyrate when patients were on RPS. We focused on the specific RPS diet–stool butyrate axis microbes based on previous reports from healthy cohortsIn exploratory analyses, we measured plasma metabolites at baseline and multiple time points after allogeneic HCT in historical controls and recipients of RPS and found that the composition of plasma metabolites changed after allogeneic HCT compared to the individual patient’s baseline. These changes were most pronounced at nadir after allogeneic HCT and normalized by 3 months after allogeneic HCT. We used a new approach of clustering and ordination-based analysis for human plasma metabolomics data to compare plasma metabolites after allogeneic HCT in the RPS and historical control cohorts. Our rationale for using this approach was based on the observation that plasma metabolites were not independent from one another, but rather they were highly correlated. Thus, we hypothesized that plasma metabolite levels may fall into identifiable discrete clusters as shown in Fig. Several studies showed that the prebiotics inulin and fructo-oligosaccharides (FOS) increased intestinal microbiota diversity and decreased disease activity in patients with inflammatory bowel disease (IBD)Allogeneic HCT and therapies after it are complex, widely variable processes, including but not limited to conditioning regimen, antibiotic administration, donor source and immunosuppressive prophylaxis, which can all have effects on the microbiomeMost studies that examined the microbiome and its metabolites in recipients of allogeneic HCT focused on a single time point after allogeneic HCT, particularly at engraftment. In our study, we performed longitudinal, correlative analyses that allowed us to use each patient’s baseline as a reference. Only one of ten patients developed biopsy-proven, stage 1 acute GI GVHD with overall grade II acute GVHD demonstrating very low incidence, although the sample size was small.Our study has limitations. A major limitation is the small number of participants, particularly to determine the impact of an intervention on a clinical end point, such as acute GVHD. A larger cohort of patients is currently being enrolled to determine the clinical impact on acute GVHD. Another limitation is that the RPS diet–stool butyrate axis microbes examined in our study are based on previous reports from healthy cohortsOur study provides preliminary data suggesting that a dietary intervention using RPS altered the intestinal microbial metabolite SCFA, butyrate, and was feasible and safe in recipients of allogeneic HCT. These data demonstrate proof of principle for RPS as a feasible prebiotic intervention in recipients of allogeneic HCT that may moderate disruption of microbiome-derived metabolites, and sets the stage for further exploration of RPS and its effects on the microbiome in human disease.