Dr Jonathan Peled speaks to ecancer at ASH 2018 about the relationship between complications from haematopoietic cell transplantation and the composition of microbes residing in the gut.
He explains that low diversity of gut flora prior to bone marrow transplantation was associated with worse outcomes.
Dr Peled suggests that there not only appears to be association but also causality between gut microbiota and transplantation outcomes, that could be taken advantage of using prebiotic, probiotic or postbiotic approaches prior to transplantation.
The gut microbiota, the bacteria that live with us in our intestines, have a profound effect and interaction with host, meaning us, our physiology. That occurs in the realm of immunology and in the realm of metabolism and several other disease and physiologic areas as well. In the setting of bone marrow transplantation we've found that a lot of the clinical outcomes of patients are predictable by the composition of the gut microbiome in patients or in animal models we can actually manipulate and drive the outcome of the mouse who has been transplanted by manipulating the gut flora, suggesting that it's not just an association but there's actually a causality there.
What did you look at?
In this abstract what we're presenting is an analysis of the diversity of the gut microbiome, that is how many different species of bacteria are present and how evenly are they distributed; what's the association of diversity with patient long-term outcomes? In other work that we've presented recently we looked at the post-transplant period, around the time that the donor immune system is recovering, but in this abstract we move the lens to an earlier time point before the transplant and we find that even at that earlier time point there's an opportunity to assess the health of the flora and use that to predict longer term patient outcomes.
Before a bone marrow transplant we assess many aspects of the patient's health – heart function, liver function, lung function, their frailty or their functional status and so on. The gut microbiome is the forgotten organ and we'd like to move to an era where we're actually assessing the health of the gut microbiota before the transplant as well because it might indicate opportunities to intervene.
What did you find and what were the implications?
What we found is that patients who have a low diversity before the transplant go on to have a higher mortality rate and that patients with a healthy microbiome before the transplant do better in the long run. That's largely driven by transplant related mortality as opposed to relapse related mortality, meaning that it's the toxicities of the cancer treatment and not the cancer coming back that seem to be the way through which this is occurring. You asked about the implications, so the implications of our work are that if one had a way to intervene to either prevent or remediate microbiome injury, you could select the pre-transplant time point as a moment to intervene with a clinical trial.
What intervention might there be?
The interventions to either prevent or remediate microbiome damage are myriad and we group them into four broad categories. One is a probiotic approach which could be a faecal microbiota transplantation and our centre has done a study with that. Although you might try to become even more refined and construct a probiotic that's an assembly of just the right strains that we think are the right ones to promote patient benefit, that would be a probiotic approach. Alternatively you could try a prebiotic approach which is to give the patient certain foods that promote the growth of healthy bacteria. A third approach we term a post-biotic approach where if we can identify the metabolites that bacteria are producing that are migrating across the gut barrier and into the bloodstream, if we find the right metabolite perhaps we could just give that metabolite. The prebiotic and post-biotic approaches may be attractive in an immunocompromised patient to whom you might feel hesitant about giving a live bacterium to. A fourth approach is an antibiotic approach which might involve thoughtful strategies about which antibiotics to deploy and when. So, as an example of that we have an ongoing clinical trial at our centre, Memorial Sloan Kettering, that randomises patients to two different antibiotic regimens for treatment of fever and neutropenia.