Characterizing the Microbiome-Immune Axis in Hematopoietic Stem Cell Recipients

Hematologic diseases such as malignant lymphomas and multiple myelomas are potentially life-threatening diseases, that can be treated with high-dose chemotherapy (HDCT) and subsequent autologous stem cell transplantation (HSCT). However, these therapies lead to severe immunosuppression and an increased risk of infection. Recent studies have demonstrated the importance of gut microbiome diversity for treatment efficacy and preclinical data suggests a direct crosstalk between the microbiome and the immune system of the host. Although it is known that the gut microbiome can impact immune cell subsets, the impact of the microbiome on the immune cell reconstitution in transplant recipients is largely unknown. Therefore, we investigated the effect of the gut microbiome on immune cell reconstitution and outcomes in patients receiving HDCT and autologous HSCT.

We collected paired fecal and blood specimens from patients at five defined time points before and up to 100 days after autologous HSCT. The microbiome diversity and composition were assessed using 16S amplicon sequencing and in a subset metagenomics sequencing. To characterize the immune cell changes, we set up a large flow cytometry panel defining NK, B and T cells including a variety of their subsets e.g. regulatory T cells.

Overall, we analyzed 815 stool samples from 222 patients and 151 matched blood samples from 90 patients. Our data show that microbiome diversity decreases rapidly after autologous stem cell transplantation, hitting a nadir around 14 days post-HSCT, and recovers thereafter up to day 100, similarly in lymphoma and multiple myeloma patients.

To model the microbiome data over time, we utilized multi-omics factor analysis accounting for temporal relationships (MEFISTO) among the samples. Here, the bacterial family of Prevotellaceae was frequently represented among the top variance-explaining latent factors. Immune cell profiling revealed that patients with a high abundance of Prevotellaceae had significantly higher CD4+ lymphocyte counts (p = 0.04) and higher activated CD4+ counts after autologous HSCT. Furthermore, high Prevotellaceae abundance was associated with a significantly increased overall survival (p = 0.02) after autologous HSCT. Notably, the main cause of death in these patients were infections (47 %).

Our findings indicate an association between specific bacterial families and certain immune cell subsets in patients receiving autologous HSCT, that translates into clinical outcome differences. This data opens the rationale for microbiome reshaping studies in stem cell recipients to prevent infectious related deaths.