Autor:innen:
E. Thiele Orberg (München, DE)
E. Meedt (Regensburg, DE)
A. Hiergeist (Regensburg, DE)
J. Xue (München, DE)
P. Herhaus (München, DE)
M. Verbeek (München, DE)
F. Bassermann (München, DE)
T. Eismann (München, DE)
A. Pianka (München, DE)
S. Göldel (München, DE)
S. Ghimire (Regensburg, DE)
W. Herr (Regensburg, DE)
D. Weber (Regensburg, DE)
M. Edinger (Regensburg, DE)
D. Wolff (Regensburg, DE)
L. Deng (München, DE)
A. Gessner (Regensburg, DE)
E. Holler (Regensburg, DE)
H. Poeck (Regensburg, DE)
Background: The intestinal microbiome directly effects outcomes in patients undergoing allogeneic stem cell transplantation (ASCT). Loss of bacterial diversity and domination of single taxa was linked to increased incidence of graft-versus-host-disease (GvHD) and mortality. New developments in microbiome research allow us to look beyond bacteria at the composition of the intestinal fungal and viral communities. We present the first study to integrate these three communities in the ASCT setting together with functional profiling by metabolomics.
Methods: We designed a multiomics approach to identify signatures in bacteriome, mycobiome, virome and metabolome in relation to timing and outcomes in ASCT. 353 longitudinal stool samples from 80 ASCT patients were obtained at two centers (Munich and Regensburg). Changes in metabolite composition were evaluated via mass spectrometry, accompanied by bacterial, fungal and viral sequencing. Results were linked among each other and with clinical outcomes. All samples were annotated with treatment data, including antibiotic history.
Results: Longitudinal profiling of ASCT patients revealed a significant loss of bacterial and viral diversity following ASCT. Lower diversity was associated with reduced survival and increased incidence of GvHD. Metabolite analysis provided functional correlates of shifting microbial communities: At baseline, patients had rich metabolite expression profiles, including protective short-chain fatty acids and indoles. Post-transplantation, metabolite levels became progressively more depleted, especially in GvHD patients. We performed network analysis to identify clinical factors that had the highest impact on microbial communities. We discovered that administration of antibiotics had a profound impact of bacteria, fungi and viruses; but most of all had a significant negative effect on metabolites levels. Lastly, we report on a case of successful treatment of severe, steroid refractory GI-GvHD with fecal microbiota transplantation. Response to treatment was characterised by the recipient adopting the FMT donor’s rich metabolite expression profile.
Conclusions: To our knowledge, this is the first multicenter study that combines bacteriome, mycobiome, virome and metabolome in a longitudinal fashion in matched patient cohorts. Our results are consistent with previous findings that there are major alterations in gut microbiome and metabolite composition after ASCT. We expand upon those findings by characterizing the time course of phylogenetic alterations and their functional consequences, and linking these changes with clinical outcomes. Patients that retain high-level metabolite expression are protected, and metabolites might serve as biomarkers for lethal GvHD. Our results highlight two strategies for microbiome-based interventions: (1) preventing loss of protective communities and their function by restrictive use of antibiotics and (2) prophylactic administration of metabolites.