Previous single-center studies have linked the gut microbiota (via stool sample analysis) to outcomes after hematopoietic cell transplantation (HCT), such as overall mortality, transplant-related mortality, graft-vs-host disease, and graft-vs-host–related mortality.^1-4 Although intriguing, these studies have raised questions about the generalizability and reproducibility of their findings.

David N. Fredricks, MD

Among different transplant centers, patient populations and standard clinical practices differ, including the prevalence of underlying disease, typical conditioning regimens, pre- and posttransplant antibiotic use patterns, graft-vs-host prophylaxis, graft manipulation (eg, T-cell depletion), diet, and approaches for assessing clinical outcomes. This heterogeneity could mean that associations between the gut microbiota and HCT outcomes are local, not general, phenomena. Furthermore, methods for molecular characterization of the gut microbiota have differed among centers, yielding varying levels of taxonomic identification and precluding optimal comparison of results across centers.

The work of Peled et al—recently published in The New England Journal of Medicine⁵ and reviewed in this issue of The ASCO Post—validates the key findings of these single-center studies; associations between high gut bacterial diversity and improved HCT outcomes were similarly observed in this multicenter, international study. Stool samples were collected from 1,362 patients undergoing allogeneic HCT at four different centers around the world and were processed and analyzed in a single lab. This study should build confidence that the gut microbiota is a reproducible marker of HCT outcomes. Although effect size varied among centers, this difference may reflect patient heterogeneity, as noted previously. The magnitude of this effect is striking: Mortality was reduced by half in patients with high gut bacterial diversity.

Gut Bacterial Diversity: A Marker or Driver of HCT Outcomes?

In turn, this study evokes a new question: Is gut bacterial diversity a marker of HCT outcomes (passive) or a driver of these outcomes (active)? In the former instance, the gut microbiota as a predictor of HCT outcomes may be useful in counseling patients about the risk of transplantation, particularly since pretransplant gut bacterial diversity was linked to overall mortality in the first cohort analyzed in this study (though not significantly associated in the second cohort outside New York). In this scenario, low gut bacterial diversity may reflect damage to the gut mucosa accumulated during cancer therapy, previous courses of antibiotics, and poor nutrition and diet, thus serving as an overall marker of gut pathophysiology and host health.

In contrast, if high gut bacterial diversity is a driver of reduced mortality after HCT, then it is appropriate to explore interventions that maintain or restore gut bacterial diversity during transplantation to determine whether this improves survival. These interventions could aim to preserve the diverse anaerobic bacterial communities in the gastrointestinal tract through strategies, including the use of narrower-spectrum antibiotics, both for prophylaxis during neutropenia and for empiric therapy during fever with neutropenia. Complementary efforts could attempt to restore gut bacterial diversity after disruption from transplantation and pretransplantation chemotherapy; these interventions might include fecal microbiota transplantation, dietary interventions to preserve indigenous microbiota (prebiotics), or oral administration of engineered microbial communities (probiotics) to replenish lost community members that play key functional roles.

Microbial Ecology and More

To conceptualize potential mechanisms by which microbial diversity could drive improved outcomes after HCT, an understanding of the metrics of microbial ecology is helpful. Alpha diversity of bacterial communities, as assessed in the Peled study (inverse Simpson index), measures the number of species present and their relative abundances. A high-diversity community may have a large number of different species with an even distribution of abundance, compared with a low-diversity community with fewer species and an uneven distribution of abundance. For example, a gut microbiota dominated by one bacterium, such as Enterococcus faecalis, would be a low-diversity community, whereas a gut microbiota with 100 species and no dominant species would be a high-diversity community.

In gut microbial communities, high diversity is typical with abundant representation of anaerobic bacteria in the Firmicutes phylum and Bacteroidales order of the Bacteroidetes phylum. A high-diversity community brings with it all the genes from the represented bacteria (the microbiome), imparting functional attributes to that community. These functions may include digesting foods, such as plant polysaccharides; generating short-chain fatty acids (butyrate) that serve as an energy source for intestinal epithelial cells; producing metabolites or bacterial cell products that influence human immune cell activity; metabolizing bile acids that then recirculate in the human body; and myriad other processes.⁶

Accordingly, a high-diversity gut bacterial community could be a driver of improved outcomes after HCT by providing key functional attributes that maintain healthy physiology in the host. The challenge before us now is to determine, in a scientifically rigorous way, whether enhancing gut bacterial diversity leads to improved outcomes after HCT and other cancer therapies. Interventional studies are needed to answer this question. 

Dr. Fredricks is Professor, Department of Medicine, Division of Allergy & Infectious Diseases, and Adjunct Professor, Department of Microbiology, University of Washington, and Member, Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Research Center, Seattle.

DISCLOSURE: Dr. Fredricks reported no conflicts of interest.

REFERENCES

1. Jenq RR, Ubeda C, Taur Y, et al: Regulation of intestinal inflammation by microbiota following allogeneic bone marrow transplantation. J Exp Med 209:903-911, 2012.

2. Taur Y, Jenq RR, Perales MA, et al: The effects of intestinal tract bacterial diversity on mortality following allogeneic hematopoietic stem cell transplantation. Blood 124:1174-1182, 2014.

3. Golob JL, Pergam SA, Srinivasan S, et al: Stool microbiota at neutrophil recovery is predictive for severe acute graft vs host disease after hematopoietic cell transplantation. Clin Infect Dis 65:1984-1991, 2017.

4. Holler E, Butzhammer P, Schmid K, et al: Metagenomic analysis of the stool microbiome in patients receiving allogeneic stem cell transplantation: Loss of diversity is associated with use of systemic antibiotics and more pronounced in gastrointestinal graft-vs-host disease. Biol Blood Marrow Transplant 20:640-645, 2014.

5. Peled JU, Gomes ALC, Devlin SM, et al: Microbiota as predictor of mortality in allogeneic hematopoietic-cell transplantation. N Engl J Med 382:822-834, 2020.

6. Fredricks DN: The gut microbiota and graft-vs-host disease. J Clin Invest 129:1808-1817, 2019.