Exploration of the relationship between intestinal flora changes and gut acute graft-versus-host disease after hematopoietic stem cell transplantation

Abstract

Background: Acute graft-versus-host disease (aGVHD) is a life-threatening factor for post-hematopoietic stem cell transplantation (HSCT) patients. To investigate the relationship between intestinal flora changes and gut aGVHD after HSCT, we performed this cross-sectional study.Methods: We selected children from our medical center from July 2016 to January 2017. Fifty-six samples from 42 patients and 6 samples from normal children met the study criteria and were analyzed. Fecal 16S RNA sequencing was completed before transplantation or on days 7, 28 or 100 post-transplantation. The intestinal infection and GVHD clinical data were retrospectively analyzed, and the survival risk factors were analyzed. Correlation analysis was performed with the feces bioinformatic data. Results:The GVHD group alpha diversity was the lowest, which was significantly different than that of the non-diarrhea group (P value=0.032). A richer posttransplantation relative abundance of Moraxellaceae was conducive to survival, while that of Enterococcaceae and Alphaproteobacteria was not. Similarly, a rich relative abundance of Proteobacteria, Gammaproteobacteria and Odoribacteraceae in the intestinal flora before HSCT contributed to patient death thereafter. Regarding diarrhea, the GVHD group exhibited a richer Pasteurellales and Pasteurellaceae relative abundances, which showed strong correlations with diarrhea severity.Peptostreptococcaceae, Bifidobacteriales and Bifidobacteriaceae were richer in relative abundance in the intestinal infection group and correlated with pretransplant characteristics. Conclusions:The gut microbiota diversity was lowest when gut aGVHD occurred, which was consistent with the clinically higher mortality rate and greater treatment difficulty. Pasteurellaceae played an important role in gut aGVHD and diarrhea severity. Bifidobacteriaceae led to infectious diarrhea after HSCT. Specific bacteria were biomarkers for survival: Moraxellaceae, Enterococcaceae and Alphaproteobacteria from the intestinal flora after HSCT and Proteobacteria, Gammaproteobacteria and Odoribacteraceae before HSCT.

Roles of the intestinal microbiota and microbial metabolites in acute GVHD

“…Recipients with lower diversity had a higher mortality; higher bacterial donor diversity was associated with lower risk of the acute GI GvHD 16S rRNA sequencing [24] Human 96 adult patients Low bacterial α-diversity at 10 days after transplantation was significantly correlated with an increased risk of aGvHD 16S rRNA sequencing [27] Human 66 adult patients Lower α-diversity of the stool microbiota was associated with aGVHD 16S rRNA sequencing [28] Human 81 adult patients aGVHD patients had lower microbial diversity than non-aGVHD patients 16S rRNA sequencing [29] Human 141 adult patients Microbial diversity was lower in aGVHD group than non-aGVHD group 16S rRNA sequencing [21] Human 10 pediatric patients Gut microbial diversity showed a downward trend in children with GVHD 16S rRNA sequencing [30] Human 44 adult patients Microbial diversity was associated with increased incidence of acute GI GVHD. Fecal butyrate and indole levels were correlated with microbial diversity 16S rRNA sequencing [31] Human 1362 adult patients Lower diversity was associated with higher GVHD-related mortality 16S rRNA sequencing [20] Human 70 adult patients Bacterial biomass and α-diversity were lower in severe aGVHD 16S rRNA sequencing [32] Human 150 adult patients Low diversity was associated with high risk of aGVHD shotgun metagenomic sequencing [33] Human 100 adult patients Low α-diversity was significantly associated to increased risk of grade II-IV and III-IV acute GvHD 16S rRNA sequencing [19] Human 56 pediatric patients Gut microbial diversity was lowest in GI aGVHD patients, which was consistent with higher mortality 16S rRNA sequencing [34] abundance of Lactobacillaceae developed severe aGVHD and had increased mortality rates [35]. The expansion of Enterococcus, also belonging to the order Lactobacillales, was reported to be associated with aGVHD and to increase the severity and mortality of aGVHD in humans and mice [33,[35][36][37][38][39][40].…”

“…Oral administration of polymyxin B can inhibit the expansion of Escherichia coli and improve GVHD in mice [22]. Pasteurellales is substantially abundant in pediatric patients with GI aGVHD and correlated with diarrhea severity [34].…”