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Microorganisms living in community are critical to life on Earth, playing numerous and profound roles in the environment and human and animal health. Though their essentiality to life is clear, the mechanistic underpinnings of community structure, interactions, and functions are largely unexplored and in need of function-dependent technologies to unravel the mysteries. Activity-based protein profiling offers unprecedented molecular-level characterization of functions within microbial communities and provides an avenue to determine how external exposures result in functional alterations to microbiomes. Herein, we illuminate the current state and prospective contributions of ABPP as it relates to microbial communities. We provide details on the design, development, and validation of probes, challenges associated with probing in complex microbial communities, provide some specific examples of the biological applications of ABPP in microbes and microbial communities, and highlight potential areas for development. The future of ABPP holds real promise for understanding and considerable impact in microbiome studies associated with personalized medicine, precision agriculture, veterinary health, environmental studies, and beyond.

Activity-Based Protein Profiling—Enabling Multimodal Functional Studies of Microbial Communities