Many current methods to study the microbiome do not directly report on protein expression or metabolic activities of the gut microbiota because they rely on metagenomic sequencing, which only informs on microbial taxonomy. We develop chemoproteomic approaches to probe the metabolism of the gut microbiome by targeting critical enzymes that biosynthesize important classes of metabolites that regulate myriad functions within the host. Our approach enables us to identify the activities of key enzymes during different diseases. These studies have the potential to uncover new and interesting biology, as little is known regarding the metabolic activity of the intestinal bacteria.