Associations of the gut microbiome and clinical factors with acute GVHD in allogeneic HSCT recipients

Abstract

Acute graft-versus-host disease (aGVHD) is a leading cause of transplantation-related mortality after allogeneic hematopoietic stem cell transplantation (aHSCT). 16S ribosomal RNA (16S rRNA) gene-based studies have reported that lower gut bacterial diversity and the relative abundance of certain bacteria after aHSCT are associated with aGVHD. Using shotgun metagenomic sequencing and a large cohort, we aimed to confirm and extend these observations. Adult aHSCT recipients with stool samples collected from day −30 to day 100 relative to aHSCT were included. One sample was selected per patient per period (pre-aHSCT (day −30 to day 0), early post-aHSCT (day 1 to day 28), and late post-aHSCT (day 29 to day 100)), resulting in 150 aHSCT recipients and 259 samples. Microbial and clinical factors were tested for differences between time periods and an association with subsequent aGVHD. Patients showed a decline in gut bacterial diversity posttransplant, with several patients developing a dominance of Enterococcus. A total of 36 recipients developed aGVHD at a median of 34 days (interquartile range, 26-50 days) post-aHSCT. Lower microbial gene richness (P = .02), a lower abundance of the genus Blautia (P = .05), and a lower abundance of Akkermansia muciniphila (P = .01) early post-aHSCT was observed in those who developed aGVHD. Myeloablative conditioning was associated with aGVHD along with a reduction in gene richness and abundance of Blautia and A muciniphila. These results confirm low diversity and Blautia being associated with aGVHD. Crucially, we add that pretransplant conditioning is associated with changes in gut microbiota. Investigations are warranted to determine the interplay of gut microbiota and conditioning in the development of aGVHD.

Dental biofilm microbiota dysbiosis is associated with the risk of acute graft-versus-host disease after allogeneic hematopoietic stem cell transplantation

“…In our study, DBM diversity was not associated with the risk of aGVHD in any transplantation phase evaluated, which is in line with a recent IM study that did not find differences in IM diversity between aGVHD groups neither pre-nor post-transplantation 48 . Also, despite the presence (as expected 49 ) of many Clostridia class genera in DBM (such as Oribacterium ), we did not find DBM Clostridia class members significantly associated with the risk of aGVHD.…”

Dental Biofilm Microbiota Dysbiosis Is Associated With the Risk of Acute Graft-Versus-Host Disease After Allogeneic Hematopoietic Stem Cell Transplantation

“…Low levels of these metabolites compromise mucosal integrity (42,43), promoting extravasation of bacterial lipopolysaccharide and activation of donor reactive T cells (40). Additionally, Enterococcus faecalis might contribute to aGVHD development via production of metalloproteases that impair barrier function (44) and by stimulating macrophages to secrete TNF (45). Accordingly, low IM diversity at the time of stem cell engraftment (6, 7), low abundance of commensal bacteria from Clostridia class (7,8), and intestinal enterococci dominance during allo-HSCT (10) have been all associated with worsened aGVHD-related outcomes in studies evaluating stool specimens from allo-HSCT recipients (28,29,40).…”

Gut Microbiota–Host Interactions in Inborn Errors of Immunity

“…Of note, the effect of gut microbiota in HSCT is an active research field, also in diseases other than IEI [ 90 , 91 ]. Compelling evidence shows that the gut microbiota has a role in the development of graft-versus-host disease (GvHD) both in adult and pediatric patients [ 92 , 93 ], but the exact mechanisms of this relationship need to be elucidated [ 94 ]. In this context, the manipulation of the gut microbiota, through pharmacologic modification/decontamination [ 95 , 96 ] or fecal microbiota transplantation (FMT) [ 97 , 98 ], may shape the microbiota composition and modulate immune responses after HSCT to benefit the host.…”