Integrative Computational and Experimental Approaches to Assess Metabolic Complementarity for Precision Microbiota Transplantation Therapies

About This Grant

ABSTRACT The gut microbiome is a cornerstone of host health, shaping immune responses, metabolism, and resilience to disease. However, attempts to treat dysbiosis via fecal microbiota transplantation (FMT) are frequently limited by colonization resistance, where resident microbes inhibit new strains from being introduced. Current reliance on broad-spectrum antibiotics to mitigate this competition typically results in only transient engraftment and limited therapeutic efficacy. Furthermore, despite refinements in donor selection and administration, no models or pipelines exist to allow clinicians to accurately predict FMT outcomes or systematically introduce microbiota into the highly variable patient microbiomes. There is a critical gap in understanding how to identify which microbial communities and donor microbiomes can integrate robustly into individual recipients. This proposal addresses this gap by leveraging computational and experimental approaches to identify “orthogonal” donor communities that bypass metabolic niche competition. We hypothesize that donor consortia whose metabolic requirements differ when compared to the FMT recipient microbiota are more likely to stably engraft. In Aim 1, we will use metabolic models (MICOM) to extract metabolic features from microbial communities and train statistical classifiers that predict FMT engraftment outcomes between microbiomes in both murine and human cohorts. In Aim 2, we will develop a culturomics-based strategy to experimentally profile unused niches within recipient microbiomes and introduce donor-derived communities specific to those niches. We anticipate that these aims will yield a novel computational framework for donor-recipient matching as well as an experimental pipeline to identify niche-associated microbial communities that are capable of engrafting in target recipients. These precise and predictable microbial engraftment strategies will allow for personalized microbiome therapies and more durable non-pharmacological treatments for conditions linked to dysbiosis.