Targeted inhibition of gut bacterial β-glucuronidases by octyl gallate alleviates mycophenolate mofetil-induced gastrointestinal toxicity

• Published in: International journal of biological macromolecules Vol. 264; p. 130145
• Main Authors: Xia, Li-juan, Wan, Lei, Gao, Ang, Yu, Yong-Xin, Zhou, Shi-Ying, He, Qian, Li, Gong, Ren, Hao, Lian, Xin-Lei, Zhao, Dong-Hao, Liao, Xiao-Ping, Liu, Ya-Hong, Qiu, Wei, Sun, Jian
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier B.V 01.04.2024
• Subjects: Gastrointestinal toxicity; Mycophenolate mofetil; Octyl gallate; β-Glucuronidase; Gastrointestinal toxicity; Octyl gallate; β-Glucuronidase; Mycophenolate mofetil
• ISSN: 0141-8130; 1879-0003
• DOI: 10.1016/j.ijbiomac.2024.130145

Mycophenolate mofetil (MMF) is a viable therapeutic option against various immune disorders as a chemotherapeutic agent. Nevertheless, its application has been undermined by the gastrotoxic metabolites (mycophenolic acid glucuronide, MPAG) produced by microbiome-associated β-glucuronidase (βGUS). Therefore, controlling microbiota-produced βGUS underlines the potential strategy to improve MMF efficacy by overcoming the dosage limitation. In this study, the octyl gallate (OG) was identified with promising inhibitory activity on hydrolysis of PNPG in our high throughput screening based on a chemical collection of approximately 2000 natural products. Furthermore, OG was also found to inhibit a broad spectrum of BGUSs, including mini-Loop1, Loop 2, mini-Loop 2, and mini-Loop1,2. The further in vivo experiments demonstrated that administration of 20 mg/kg OG resulted in predominant reduction in the activity of BGUSs while displayed no impact on the overall fecal microbiome in mice. Furthermore, in the MMF-induced colitis model, the administration of OG at a dosage of 20 mg/kg effectively mitigated the gastrointestinal toxicity, and systematically reverted the colitis phenotypes. These findings indicate that the OG holds promising clinical potential for the prevention of MMF-induced gastrointestinal toxicity by inhibition of BGUSs and could be developed as a combinatorial therapy with MFF for better clinical outcomes. [Display omitted]