Allogeneic bone marrow transplantation (BMT) is the most potent form of immune therapy against a number of malignant diseases, with its graft-versus-leukemia/tumor effect. In recent years, knowledge about gut microbiota interactions with host immunity has been studied in many disease states. The effects of alterations in gut microbiota on allogeneic haematopoietic stem cell transplantation (allo-HSCT) and on graft-versus-host disease (GVHD)-a major life-threating complication of allo-HSCT- are poorly understood. Thus, altering the gut microbiota to manage the critical clinical outcomes after allo-HSCT is a recent area of research.
A recent comment published in Nature points out that taking into account microbiota-host interactions in clinical protocols for patients undergoing allo-HSCT may constitute a new approach for clinical intervention. Allo-HSCT is accompanied by dramatic immunological, gastrointestinal and microbiota perturbations, which in part originate from the treatment with broad-spectrum antibiotics and the compromised oral intake secondary to chemotherapy and radiation after the transplant.
The closely monitored sequence of an allo-HSCT allows the in-depth study of changes in the gut microbiota and their relationship with patient clinical outcomes. Jonathan Peled and colleagues reviewed several types of interventions on the gut microbiota in this field: faecal transplant, commensal-sparing antibiotic regimens, prebiotics and administration of gut microbiota-derived metabolites.
When it comes to introducing beneficial bacteria into the host, the researchers mentioned that there is a process of autologous faecal microbiota transplantation (auto-FMT) for prophylaxis of Clostridium difficile infection in recipients of allo-HSCT. It is also reported that the administration of some strains of Lactobacillus spp. in mice may protect them from experimental GVHD. These approaches are relevant as most patients have decreased commensal gut microbiota diversity in the weeks following allo-HSCT.
Antibiotic strategies can also be used to minimize microbiota injury while still treating infections. The basis of this approach is that commensal-sparing regimens can target anaerobes that are responsible for causing GVHD, although complete gut decontamination may also help confer significant protection from GVHD. In mice, the broad-spectrum antibiotic rifaximin can reduce intestinal inflammation while preserving Lactobacillus spp.
Administration of prebiotics for benefiting specific commensal bacteria is a less studied area. Inulin-type fructans and arabinoxylans have been suggested as prebiotics to evaluate in further studies.
Postbiotics, defined as metabolic products of commensal bacteria, have been proposed as supplements for a better intestinal homeostasis in GVHD. A new study, led by Dr. Pavan Reddy from the Division of Hematology/Oncology, Department of Internal Medicine at the University of Michigan Comprehensive Cancer Centre in Michigan (USA), found that gut microbiota-derived metabolites may mitigate graft-versus-host disease (GVHD) severity through improving intestinal epithelial cell damage in mice. Up to half of patients who receive a BMT from a donor are at risk of developing severe gastrointestinal damage from GVHD, which worsens clinical outcomes of transplants. The researchers found that gut microbiota-derived butyrate was significantly reduced in the intestinal tract of experimental mice that received BMT. Local administration of exogenous butyrate led to improved intestinal epithelial cell junctional integrity and decreased apoptosis, mitigating GVHD. In addition, alteration of the indigenous gut microbiota with 17 rationally selected strains of high butyrate-producing Clostridia also decreased GVHD. “Our findings suggest we can prevent GVHD by bolstering the amount of the microbiome-derived metabolite butyrate”, says study lead author Pavan Reddy. On the other hand, certain subsets of the gut microbiota may be involved in synthesizing metabolites that can be monitorized in organic fluids and may offer diagnostic or prognostic opportunities in the future.
In conclusion, clinical interventions on the gut microbiota constitute a new approach for preventing side effects of bone marrow transplant. However, the majority of scientific evidence comes from experimental studies in mice and, thus, it is too early to make any clear recommendations based on clinical interventions on the gut microbiota for improving side effects or overall survival in patients undergoing allo-HSCT.
Mathewson ND, Jenq R, Mathew AV, et al. Gut microbiome-derived metabolites modulate intestinal epithelial cell damage and mitigate graft-versus-host disease. Nat Immunol. 2016; 17(5):505-13.
Peled JU, Jenq R, Holler E, van den Brink M. Role of gut flora after bone marrow transplantation. Nat Microbiol. 2016; 1(16036):1-2.