Targeting Gut Microbiota-derived β-glucuronidase to Reduce Enterotoxicity: Research Progress on Strategies and Prospects for the Application of Food and Medicine Homology

The gut microbiome-encoded β-glucuronidases (GUS) play a significant role in human health by metabolizing both endogenous and exogenous substances in the gastrointestinal (GI) tract. These enzymes catalyze the hydrolysis of β-D-glucuronides, reversing glucuronidation reactions carried out by the liver. While this process is essential for certain metabolic functions, it can also lead to harmful consequences, including drug toxicity and intestinal damage. In recent years, the inhibition of bacterial β-glucuronidases (BGUSs) has emerged as a promising strategy for mitigating drug-induced toxicity and improving therapeutic outcomes. However, the genetic diversity, functional complexity, and variable inhibitor responses of GUS enzymes present significant challenges in developing effective inhibitors tailored to specific pharmacological and pathological contexts. This review provides an in-depth examination of GUS enzyme function, structural characteristics, and sources, followed by a discussion of GUS-mediated intestinal toxicity arising from both endogenous and exogenous compounds. We also highlight recent advances in the development and application of GUS inhibitors, with particular emphasis on natural compounds derived from food and medicinal sources. Finally, we explore the prospects and challenges associated with GUS-targeting strategies, underscoring their potential for therapeutic applications.