The microbiome has emerged as a functional microbial organ system that plays a key role in human health and disease including obesity, cancer, and inflammation. Dietary and host factors broadly regulate the composition and function of the microbiome and are associated with health outcome, but the tools available to profile this organ system in humans are limited. Despite advances in sequencing technologies that infer microbial metabolic function, there remains a significant unmet need for the direct characterization of functional metabolic pathways within the microbiome that play a pivotal role in human health and disease. This proposal application aims to use activity-based probes in the study of the microbiome. This novel approach allows for direct measurement of protein function, bypassing the reliance on downstream metabolites as indirect indicators of microbial activity. By focusing on functionally active enzymes and linking them to specific taxa, the study will achieve a level of molecular resolution and specificity not previously attainable, thus revolutionizing our understanding of the microbiome's functional role. We will further leverage this technology to enrich for microbial consortia or isolate specific taxa with functional capabilities that will be translated to pre-clinical and clinical studies to complete the pipeline of precision microbial therapeutics. Successful execution of this research will have a profound impact on scientific understanding of the microbiome's contribution to human health and disease, specifically highlighting the impact of diet and intestinal inflammation. By uncovering the specific microbial metabolic pathways associated with clinical response and treatment efficacy, the study opens up new avenues to develop targeted therapies to modulate the microbiome, enhancing treatment outcomes for patients. This technology has the potential to revolutionize how we investigate microbial function, emphasizing the microbiome's function and resultant activities due to disease, thus paving the way for personalized therapies and interventions targeting specific microbial metabolic pathways.