Gut microbiota injury in allogeneic haematopoietic stem cell transplantation

Abstract

Allogeneic haematopoietic stem cell transplantation (allo-HSCT) is considered to be the strongest curative immunotherapy for various malignancies (primarily, but not limited to, haematologic malignancies). However, application of allo-HSCT is limited owing to its life-threatening major complications, such as graft-versus-host disease (GVHD), relapse and infections. Recent advances in large-scale DNA sequencing technology have facilitated rapid identification of the microorganisms that make up the microbiota and evaluation of their interactions with host immunity in various diseases, including cancer. This has resulted in renewed interest regarding the role of the intestinal flora in patients with haematopoietic malignancies who have received an allo-HSCT and in whether the microbiota affects clinical outcomes, including GVHD, relapse, infections and transplant-related mortality. In this Review, we discuss the potential role of intestinal microbiota in these major complications after allo-HSCT, summarize clinical trials evaluating the microbiota in patients who have received allo-HSCT and discuss how further studies of the microbiota could inform the development of strategies that improve outcomes of allo-HSCT.

Figures

Figure 1 ∣. Allo-HSCT and GVHD.

Patients undergoing allogeneic haematopoietic stem cell transplantation (allo-HSCT) receive a pretransplant regimen including chemotherapeutic agents with or without total body irradiation and/or antibodies. Patients receive donor haematopoietic stem cells after this pretransplant regimen. Graft-versus-host disease (GVHD) occurs when alloreactive donor T cells attack host tissues, including the skin, liver, gastrointestinal tract, central nervous system, thymus, ovary or testis as well as the haematopoietic system.

Figure 2 ∣. Intestinal microbiota injury after allo-HSCT.

Major factors altering microbiota homeostasis after allogeneic haematopoietic stem cell transplantation (allo-HSCT) include conditional chemotherapy and/or irradiation, antibiotic therapy, graft-versus-host disease (GVHD), mucositis and infection (for example, with Clostridium difficile). Patients experience neutropenia after a conditioning regimen, and this often requires treatment with antibiotics. These factors contribute to microbiota dysbiosis, which is represented by decreased bacterial diversity, lower numbers of anaerobic commensal bacteria and expansions of pathobionts.

Figure 3 ∣. Studies on microbiota injuries in allo-HSCT recipients.

A phylogenetic tree of typical gut bacterial species is shown. Shaded bacterial clades represent various levels of taxonomic classification. The blue shading denotes beneficial associations, whereas the red shading denotes association with negative effects. Allo-HSCT, allogeneic haematopoietic stem cell transplantation; GVHD, graft-versus-host disease; OS, overall survival; VRE, vancomycin-resistant Enterococcus. Figure adapted with permission from REF , Taylor & Francis Ltd (www.tandfonline.com), and updated by A. L. Gomes and Y.S.

Figure 4 ∣. The interplay between gut microbiota and host physiology and immunity.

The host immune system maintains gut microbiota diversity and prevents outgrowth of pathobionts. Under steady-state conditions, the gut epithelial surface maintains an intact barrier that prevents bacterial invasion into the host tissue; this is accomplished by antimicrobial peptides (AMPs) produced by Paneth cells that create a sterility gradient, mucus produced by goblet cells that separates the microbiota from host epithelial tissue and secretory immunoglobulin A (SIgA) that neutralizes biologically active microbial antigens. Short-chain fatty acids (SCFAs) are bacterial fermentation products. They can be used as an energy source and also regulate the differentiation, recruitment and activation of immune cells. In the setting of allogeneic haematopoietic stem cell transplantation (allo-HSCT), total body irradiation and chemotherapy reduce the integrity of the intestinal surface. Intestinal bacteria and their components (pathogen-associated molecular patterns (PAMPs)) translocate into the lamina propria and are recognized by antigen-presenting cells such as dendritic cells (DCs), leading to activation of effector cells and aggravation of graft-versus-host disease (GVHD). B cells, Paneth cells and the mucous layer are known to be targets of GVHD, and damage to these creates a vicious circle exacerbating gut inflammation and bacterial translocation and resulting in worse survival after allo-HSCT. IEC, intestinal epithelial cell; NKT, natural killer T; TH17, T helper 17; Treg, regulatory T.

Figure 5 ∣. Microbiota injury and complications after allo-HSCT.

The top panels summarize the profiles of healthy microbiota before and after allogeneic haematopoietic stem cell transplantation (allo-HSCT) compared with those of injured microbiota after allo-HSCT. Microbiota injury results in infections, malignant relapse, graft-versus-host disease (GVHD) and possibly delayed immune reconstitution that contributes to additional infections (cytomegalovirus (CMV) infection and/or certain types of pneumonia that require adaptive immunity to eradicate). All of these can then contribute to reduced overall survival of patients after allo-HSCT.