β-Glucuronidase at the Microbiota-Host Interface: Dual Regulatory Roles and Precision Modulation by Natural Products.

Gut microbial β-glucuronidase (GUS) plays a pivotal role at the microbiota-host interface by hydrolyzing glucuronide conjugates, thereby influencing xenobiotic metabolism, enterohepatic circulation, and systemic homeostasis. Dysregulated GUS activity has been increasingly linked to adverse health outcomes, including drug-induced toxicity, inflammation, and cancer. However, current literature often overlooks the enzyme's dual role in maintaining physiological balance and promoting disease progression, as well as the multidimensional ways in which natural products interact with GUS. This work reviews recent advances in GUS research, emphasizing its structural diversity, functional complexity, and regulatory impact on host health. It also highlights the potential of natural products as precision modulators of GUS activity, capable of direct enzyme inhibition or indirect modulation through reshaping the gut microbiota. These mechanisms collectively influence drug efficacy, toxicity, and the systemic availability of endogenous metabolites. By integrating structural, pharmacological, and microbiological perspectives, this work provides a theoretical foundation for the development of microbiota-targeted therapies centered on GUS. Such approaches may support the rational design of natural product-derived inhibitors and promote their application in disease models, ultimately advancing personalized therapeutic strategies.