Quercetin-Driven Akkermansia Muciniphila Alleviates Obesity by Modulating Bile Acid Metabolism via an ILA/m6A/CYP8B1 Signaling

Abstract

Global health is increasingly challenged by the growing prevalence of obesity and its associated complications. Quercetin, one of the most important dietary flavonoids, is being explored as an effective therapy for obesity with its mechanism remains understudied. Here in this study, it is demonstrated that quercetin intervention significantly reverses obesity-related phenotypes through reshaping the overall structure of microbiota, especially boosting colonization of the beneficial gut commensal Akkermansia muciniphila (A. muciniphila). Enrichment of A. muciniphila leads to generate more indole-3-lactic acid (ILA) to upregulate the expression of 12α-hydroxylase (CYP8B1) via fat mass and obesity-associated protein (FTO)/ N⁶-methyladenosine (m⁶A)/YTHDF2 manner, thereby facilitating cholesterol converts to cholic acid (CA). CA in turn drastically suppresses lipid accumulation via activating the farnesoid X receptor (FXR) in adipose tissue. This work introduces a novel therapeutic target for addressing obesity and expands upon the current limited understanding of the mediator function of m⁶A modifications in microorganism-influenced bile acid (BA) metabolism.