There has been considerable recent research into the association between acute graft-versus-host disease (aGvHD) and imbalance of the gut microbiome (dysbiosis), although this is still not well understood. Below, two presentations from the 62nd American Society of Hematology (ASH) Annual Meeting and Exposition are summarized, covering new thoughts on the link between dysbiosis and aGvHD.
Parth Gandhi described differences in plasma short chain fatty acids (SCFA) in patients with life-threatening aGvHD and how these may be related to response to treatment.1 In a live Q&A session, Mette Hazenberg discussed the evidence surrounding fecal microbiota transplantation (FMT) in the repair of the damaged microbiome in GvHD and whether reconstitution of a healthy microbiome containing SCFA-producing bacteria by FMT could prevent aGvHD development following hematopoietic stem cell transplant (HSCT), including results from a pilot study.2
Bacteria in the lower gastrointestinal tract produce SCFA that act as modulators of mucosal immunity and fuel for gastrointestinal epithelial cells. Antibiotic treatment and aGvHD can alter the production of SCFA, which is thought to then worsen GvHD risk.
Injection of human chorionic gonadotropin (uhCG) and epidermal growth factor (EGF) has shown to act synergistically to support epithelial cell repair, and was granted orphan drug designation by the U.S. Food and Drug Administration (FDA) for the treatment of aGvHD. Gandhi and colleagues collected plasma samples from 49 patients undergoing treatment with uhCG/EGF alongside standard immunosuppression for Minnesota High Risk or steroid-dependent/refractory aGvHD, as part of the study NCT02525029, and measured plasma levels of common SCFA (acetate, propionate, butyrate, isovalerate, and valerate).
Patients who responded to uhCG/EGF and standard immunosuppression therapy were classified as either complete responders (CR) or partial responders (PR) at Day 28 post-treatment (n = 35), and had increased levels of propionate (p = 0.02) and butyrate (p = 0.008) compared with non-responders or those who died (NR; n = 14). There was a trend towards higher butyrate concentrations in CR/PR than NR over time, although this was only significant on Day 7 (p = 0.018). Levels of propionate and valerate also appeared higher in CR/PR than NR over time. Furthermore, butyrate levels were correlated with propionate and valerate. The overall SCFA profile was more stable for CR/PR in comparison to NR.
Additionally, lower plasma interleukin-6 levels were correlated with higher propionate (Spearman’s rho, −0.33; p = 0.008) and valerate (rho, −0.36; p = 0.002) concentrations, suggesting systemic inflammation could impact negatively on treatment response.
FMT in aGvHD2
Several studies have demonstrated that FMT is able to recover a microbiome that has been damaged by HSCT and improve microbiome diversity.3,4 Hazenberg and colleagues conducted a prospective pilot trial (ISRCTN14530574) to investigate whether FMT might be effective as a treatment for aGvHD and looked at specific components of the transplant product that affect the clinical response.5
A total of 15 patients with steroid-refractory or steroid-dependent aGvHD received a donor FMT via duodenal tube. Ten of these patients initially achieved a complete remission from GvHD symptoms, six of whom maintained this response following tapering of immunosuppressants. Furthermore, response to FMT was significantly associated with better survival. Microbial diversity was low in all patients at baseline but improved in responders, with a higher abundance of SCFA-producing bacteria than in non-responders.
Many factors influence the response to FMT. It is thought that not only bacterial diversity but also other components of the transplant product, such as viruses and bacteriophages, can contribute to outcome, as has been shown by the successful treatment of Clostridium difficile infection by transfer of bacteria-free fecal filtrates. Fungi may also contribute to microbiome integrity, as colonization of the gut by Candida spp. predicted higher incidence of severe aGvHD. Furthermore, compatibility between donor and recipient microbiome increases the success of FMT, and diet and antibiotics intake also have an influence.
Hazenberg concluded that there is a need for larger and randomized trials in order to confirm efficacy of FMT, in addition to investigation of the key factors contributing to FMT response and optimization of safety aspects. The importance of complying with FMT donor screening guidelines6 was highlighted due to the potential transfer of drug resistant bacteria, adenovirus, and cytomegalovirus from donor to patient.
Different therapeutic approaches to repairing dysbiosis induced by HSCT, such as application of FMT or uhCG/EGF, are now being investigated and show promise in treating aGvHD, as presented by Gandhi and Hazenberg. In addition, both presentations highlight the important role of SCFA-producing commensal bacteria for inducing meaningful responses with these treatments. However, further studies into restoration of microbiome integrity are warranted.