Project Summary Commensal microorganisms play critical roles in human physiology and diseases. Despite rapidly expanding knowledge of the composition of the human gut microbiota, our understanding of the ecological principles that govern the assembly and resilience of the highly complex and dynamic ecosystem of the gut microbiota is rudimentary. This knowledge gap becomes more problematic as new approaches to modify the microbiota, such as fecal microbiota transplantation (FMT), are being developed as therapeutic interventions. The overall objective of the proposed studies is to construct an ecological framework to understand the efficacy of FMT in treating recurrent C. difficile infection (rCDI) at the systems level. The central hypothesis is that the functional redundancy of the recipient’s pre-FMT microbiota can be used to predict the extent of donor microbiota engraftment and predict the efficacy of FMT. As a classical concept in ecology, functional redundancy (FR) means that phylogenetically unrelated species perform similar functions in ecosystems so that they can be interchanged with little impact on the overall ecosystem functioning. The rationale for the proposed research is that understanding the efficacy of FMT in treating rCDI has the potential to translate into better understanding of its efficacy in treating a variety of other diseases associated with disrupted microbiomes. Guided by strong preliminary data, the central hypothesis will be tested by pursuing three specific aims: 1) Develop a network-based method to quantify the within-sample FR of human microbiome samples. The applicant’s preliminary results suggest that the FR of a microbiome sample can be calculated from its taxonomic profile and a reference genomic content network. 2) Develop an ecological framework to study the relationship between the FR of a microbial community and its resistance to new species. The working hypothesis is that the higher the within-sample FR of a microbial community, the more resistant it is against species addition, e.g., through FMT. Both ecological modeling/simulations and real data analysis will be performed to verify this hypothesis. 3) Clinical study to test that FMT has a lower efficacy in treating rCDI patients with higher FR in their pre-FMT microbiota. Stool samples from the recipients and their respective donors will be collected for metagenomic whole genome shotgun sequencing. Subsequently, the relationships among the FR of the recipients’ pre-FMT microbiota, the engraftment of donor-specific species in the recipients’ post-FMT microbiota, and the FMT efficacy will be quantitatively analyzed. The approach is innovative because it shifts focus from specific t...