Prolonged gut microbial alterations in post‐transplant survivors of allogeneic haematopoietic stem cell transplantation

Abstract

Summary Dysbiosis of the gut microbiota has been reported to increase early complications after allogeneic haematopoietic stem cell transplantation (allo‐HSCT). However, it remains unclear whether gut microbial alterations persist during late complications, such as chronic graft‐versus‐host disease (cGVHD) or secondary cancers. Here, we analysed the gut microbiota of 59 patients who survived for 1–21.7 years (median, 6.4 years) after allo‐HSCT. Long‐term survivors showed lower gut microbial diversity than the age‐ and sex‐matched healthy controls. This decreased diversity was reflected in the reduced abundance of the butyrate‐producing bacteria. Patients with a history of grade 3 acute graft‐versus‐host disease (aGVHD) exhibited higher Veillonella abundance than patients with a history of grade 1–2 or non‐aGVHD cases. The abundance of Faecalibacterium showed no decrease only in limited cGVHD cases. Additionally, the microbial structure in the secondary cancer group was significantly different (p < 0.05) from that in the non‐secondary cancer group. This study is the first to show that microbial dysbiosis is present over a 10‐year lifetime after discharge following allo‐HSCT. Our results suggest that these prolonged gut microbial alterations may be associated with the development and exacerbation of late complications in post‐transplant survivors.

Allogeneic hematopoietic cell transplantation, the microbiome, and graft-versus-host disease

“…Recent reports suggest that microbiome damage incurred upon transplantation is not reversible and persists over time. 27 , 48 This is in contrast to observations in otherwise healthy individuals, in whom a single insult to the microbiome (e.g. course of antibiotics) induces microbiome damage that is reversible, and warrants further investigation into the causes of the irreversible nature of transplantation-related microbiome damage.…”

“… 26 In a cross-sectional study, it was demonstrated that the microbiome of allogeneic HCT survivors who developed secondary malignancies was more perturbed than long-term survivors without secondary malignancies. 27 It is safe to assume that long-term complications in allogeneic HCT survivors are related to microbiome damage encountered early after transplantation, but evidence is lacking thus far.…”

Clostridium butyricum MIYAIRI 588 contributes to the maintenance of intestinal microbiota diversity early after haematopoietic cell transplantation

“…Cluster analysis on days 7, 14, and 21 shortly after transplantation also revealed a noticeably lower proportion of Bacteroides and Enterococcus in the CBM588-treated group. The gut microbiota of patients with haematological cancers is considerably different from that of healthy individuals [ 11 , 12 ]. From these findings, by stabilising the microbiota, CBM588 could prevent the predominance of bacteria potentially associated with post-transplant prognosis.…”

“…Innovations in amplicon sequencing technology, conditioning chemotherapy, HSCT, and subsequent antimicrobial treatment have been shown to significantly influence intestinal microbiota [ 7 – 10 ]. Time-dependent analyses of the intestinal microbiota before and after transplantation have shown that the stability of the intestinal microbiota positively influences prognosis not only during the peri-transplant period but also over the long term [ 11 – 13 ].…”

Gut microbiome in allogeneic HCT survivors: The insults are gone but the damage lingers

“…Short‐term assaults to the microbiome such as a single course of antibiotics in otherwise healthy individuals cause only temporary damage. The data from Hino et al 1 suggest that the lasting and continuous attack on the microbiome that allogeneic HCT recipients experience before and after transplantation disrupts the microbial community to a point where too much damage is done to be healed by the system itself. This may be related to the loss of certain functionalities at population levels, or by the loss of certain ‘keystone species’ (that are not necessarily bacteria but could very well be specific archaea), as postulated by Ley et al in 2006 14 .…”