Intensified Conditioning Is Associated with Loss of Stool Bacterial Diversity and Pronounced Gastrointestinal Graft-Versus-Host Disease in Allogeneic Hematopoitic Stem Cell Transplantation

Abstract

In allogeneic hematopoitic stem cell transplantation (allo-HSCT), intestinal microbiota and acute graft-versus-host disease (aGVHD) were impacted by broad-spectrum antibiotics. Whereas besides the influence of antibiotics, other factors may influence intestinal microbiota and aGVHD but were undetermined, and the correlations between microbiota and immune homeostasis were still poorly understood. We performed a prospective study group (n =57) whose antibiotics was balanced, including III-IV intestinal acute GVHD (n = 12), Ӏ-II intestinal aGVHD (n = 14) and non-aGVHD (n = 31) groups, retrospective analysis of the intestinal microbiota among the groups by 16S rRNA gene sequencing at engraftment time post-transplantation. Meanwhile, we detected T cell related cytokines. And then T lymphocyte subsets were detected at day 28 following allo-HSCT. Samples of intestinal biopsies from the above III-IV aGVHD patients were stained by immunofluorescence histology. Our results demonstrated that intensive conditioning was likely to be associated with lower microbiota diversity compared with standard conditioning (61.1% vs. 25.6%, P = 0.017). Abundance of Lachnospiraceae, Ruminococcaceae and Clostridiaceae was lower in III-IV aGVHD than in non-aGVHD (P = 0.001, 0.016 and 0.028, respectively). Then, loss of microbiota diversity was associated with the subsequent aGVHD after engraftment. Whereas the III-IV aGVHD patients with low diversity accompanied by depletion of RORγt Tregs. Furthermore, our findings suggested that microbiota diversity correlated with the levels of IL-17A (r = -0.341, P = 0.010) and the amounts of Th1, Th17 cells negatively (r = -0.329 and -0.265; P= 0.012 and 0.046, respectively). In conclusion, loss of microbial diversity and development of aGVHD may begin with the intensive conditioning besides the administration of antibiotics during allo-HSCT, and microbiota diversity might correlate with immune homeostasis at early stage.

Keywords: conditioning, intestinal microbiota, immune homeostasis, acute graft-versus-host disease, allogeneic hematopoietic stem cell transplantation