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Abstract Background Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is one of the most efficient therapeutic options available to cure many hematological malignancies. However, severe complications derived from this procedure, including graft-versus-host disease (GVHD) and infections, can limit its success and negatively impact survival. Previous studies have shown that alterations in the microbiome are associated with the development of allo-HSCT-derived complications. However, most studies relied on single techniques that can only analyze a unique aspect of the microbiome, which hinders our ability to understand how microbiome alterations drive allo-HSCT-associated diseases. Results Here, we have applied multiple “omic” techniques (16S rRNA and shotgun sequencing, targeted and un-targeted metabolomics) in combination with machine learning approaches to define the most significant microbiome changes following allo-HSCT at multiple modalities (bacterial taxa, encoded functions, and derived metabolites). In addition, multivariate approaches were applied to study interactions among the various microbiome modalities (the interactome). Our results show that the microbiome of transplanted patients exhibits substantial changes in all studied modalities. These include depletion of beneficial microbes, mainly from the Clostridiales order, loss of their bacterial encoded functions required for the synthesis of key metabolites, and a reduction in metabolic end products such as short chain fatty acids (SCFAs). These changes were followed by an expansion of bacteria that frequently cause infections after allo-HSCT, including several Staphylococcus species, which benefit from the reduction of bacteriostatic SCFAs. Additionally, we found specific alterations in all microbiome modalities that distinguished those patients who subsequently developed GVHD, including depletion of anti-inflammatory commensals, protective reactive oxygen detoxifying enzymes, and immunoregulatory metabolites such as acetate or malonate. Moreover, extensive shifts in the homeostatic relationship between bacteria and their metabolic products (e.g., Faecalibacterium and butyrate) were detected mainly in patients who later developed GVHD. Conclusions We have identified specific microbiome changes at different modalities (microbial taxa, their encoded genes, and synthetized metabolites) and at the interface between them (the interactome) that precede the development of complications associated with allo-HSCT. These identified microbial features provide novel targets for the design of microbiome-based strategies to prevent diseases associated with stem cell transplantation. Video Abstract