Transplant Outcomes and Toxicities Are Associated with Changes in Relative Abundance, Diversity and Richness of the Oral and Gastrointestinal Microbiome during Autologous Transplantation for Multiple Myeloma: Results of a Prospective Pilot Study

Abstract

We conducted a prospective study to determine the longitudinal microbial profile in patients undergoing HCT for multiple myeloma (MM), and whether changes in microbial composition correlate with HCT outcomes and/or toxicities. Samples were collected from 15 patients at baseline (T-2), during marrow aplasia (T+7) and after engraftment (T+30). Ion-Torrent PGM workflow was used. Amplicons generated from 16s rRNA and the ITS genes were sequenced for bacterial and fungal identification, respectively. Relative abundance, diversity and richness were determined at the phylum and genus levels at each time point, in oral and fecal microbiome. Diversity and richness of the oral mycobiome decreased at T+7 from baseline with further decrease noted at T+30. Fecal mycobiome diversity (T-2 vs T+7, p=0.05) and richness decreased from baseline to T+7, and richness trended towards significance (p=0.06) with further decrease at T+30. In fecal samples, lower bacterial diversity at T+7 associated with more severe diarrhea (p= 0.03). Anaerobic targeting antibiotic exposure on or before T+7 affected the bacterial genus diversity (p=0.015) and richness at T+7 (p=0.014). The bacterial genus richness at baseline (p=0.03) and the diversity/richness at T+7 (p=0.01) were associated with fever development on or after T+7. Exposure to anaerobic depleting antibiotics correlated with oral mycobiome genus richness at T+30 (p=0.04). At the bacterial phylum level, the oral community composition changed at T+30 compared to baseline (Bray-curtis p=0.046) and T+7 (Bray-curtis p=0.025). When examining the changes in the mycobiome composition, test for dissimilarity showed a significant difference in the fecal fungal genus between baseline and T+30 (BrayPA p=0.025). In fecal samples, a higher abundance of Bacteriodetes present at T+7 was associated with the severity of diarrhea experienced (p=0.03). Blautia and Ruminococcus, both belonging to the Firmicutes phylum and Clostridium Class, when detected at T+7 were associated with a higher severity of vomiting (p=0.05). In oral samples, the presence of the genus Glomerella at T+7 was negatively associated with rates of neutrophil engraftment (p=0.03). Our results show that oral and fecal microbiota undergo dynamic changes in diversity, composition and relative abundance during the course of transplantation. Bacterial and fungal microbiota present specifically at count nadir could be important players. The relative abundance of particularly the anaerobic bacterial phyla, Bacteroidetes and Firciumtes during marrow aplasia, correlated with post transplant toxicities. We identified a correlation between exposure to anaerobic organism depleting antimicrobials and changes in genus diversity and richness. Baseline microbial diversity/richness and changes coinciding with marrow aplasia correlate with the incidence and severity of post transplant toxicities.