(P26-013-25) Critical Role of Gut Microbiota in the In Vivo Biotransformation of Nobiletin: Insights Into Metabolic Pathways and Bioactive Metabolite Formation
Professor University of Massachusetts Amherst Amherst, Massachusetts, United States
Disclosure(s):
Yilu Chen, PhD Candidate: No relevant financial relationship(s) with ineligible companies to disclose.
Objectives: Nobiletin, a major citrus polymethoxyflavone, offers significant health benefits, which are closely related to its metabolism in vivo. However, the metabolic pathways and the role of gut microbiota in the biotransformation of nobiletin are poorly understood. Herein, our objectives are to (i) elucidate in vivo metabolic pathways of nobiletin and (ii) establish the functions of gut microbiota in the biotransformation of nobiletin.
Methods: In this study, conventional mice and antibiotic-treated mice were employed to elucidate in vivo metabolic pathways of nobiletin. We first utilized UPLC-Q-TOF mass spectrometry to comprehensively identify nobiletin metabolites in the feces and urine of nobiletin-fed mice. Subsequently, UPLC-Q-Trap mass spectrometry was used to quantify the distribution of metabolites in both feces and urine of nobiletin-fed mice with or without antibiotic treatment. By comparing the metabolic profile of nobiletin metabolites between control and antibiotic-treated mice, we determined the role of gut microbiota on the in vivo biotransformation of nobiletin.
Results: Q-TOF mass spectroscopic analysis of fecal and urine samples of nobiletin-fed mice identified nineteen demethylated metabolites of nobiletin, including six mono-demethylated, eight di-demethylated, and five tri-demethylated nobiletin. It is noteworthy that eight of these metabolites were newly discovered. After depletion of gut microbiota, antibiotic-treated mice showed distinct metabolite profiles of nobiletin compared to that of conventional mice. It was found that gut microbiota is critical in producing demethylated metabolites. In particular, several di- and all tri-demethylated nobiletin were exclusively generated by gut microbiota. Additionally, gut microbiota facilitated the deconjugation of glucuronide and sulfate conjugates of demethylated nobiletin, converting them to bioactive free forms.
Conclusions: Overall, our findings reveal the essential role of gut microbiota in the in vivo biotransformation of nobiletin, which is pivotal for the biological functions of nobiletin and other related citrus polymethoxyflavones.
