The gut microbiome possesses numerous biochemical enzymes that biosynthesize metabolites that impact human health. Bile acids comprise a diverse collection of metabolites that have important roles in metabolism and immunity. The gut microbiota-associated enzyme that is responsible for the gateway reaction in bile acid metabolism is bile salt hydrolase (BSH), which controls the host’s overall bile acid pool. Despite the critical role of these enzymes, the ability to profile their activities and substrate preferences remains challenging due to the complexity of the gut microbiota, whose metaproteome includes an immense diversity of protein classes. Using a systems biochemistry approach employing activity-based probes, we have identified gut microbiota-associated BSHs that exhibit distinct substrate preferences, revealing that different microbes contribute to the diversity of the host bile acid pool. We envision that this chemoproteomic approach will reveal how secondary bile acid metabolism controlled by BSHs contributes to the etiology of various inflammatory diseases.

肠道微生物组拥有大量生化酶，可以生物合成影响人类健康的代谢物。胆汁酸包含多种代谢物，在代谢和免疫中具有重要作用。负责胆汁酸代谢中网关反应的肠道微生物相关酶是胆汁盐水解酶 (BSH)，它控制着宿主的整体胆汁酸库。尽管这些酶发挥着关键作用，但由于肠道微生物群的复杂性，分析其活性和底物偏好的能力仍然具有挑战性，其宏蛋白质组包括巨大多样性的蛋白质类别。通过使用基于活性的探针的系统生物化学方法，我们已经确定了与肠道微生物群相关的 BSH，它们表现出不同的底物偏好，揭示了不同的微生物有助于宿主胆汁酸库的多样性。我们设想这种化学蛋白质组学方法将揭示 BSH 控制的次级胆汁酸代谢如何影响各种炎症性疾病的病因。