Dietary α‐Mangostin Alleviates Steatotic Liver Phenotypes by Remodeling Gut Microbial Tryptophan Metabolism

Abstract

α‐Mangostin (α‐MA), the major xanthone in mangosteen pericarp, is a food‐derived bioactive compound with potential metabolic benefits. However, whether its beneficial effects are linked to gut microbial metabolism remains unclear. In this study, α‐MA was first chemically characterized and subsequently evaluated in an aged laying hen model exhibiting steatotic liver phenotypes induced by a high‐fat, low‐protein diet. Dietary α‐MA markedly alleviated hepatic steatosis, liver injury, and dyslipidemia, while suppressing hepatic lipogenic gene expression and promoting genes involved in fatty acid oxidation and transport. Integrated 16S rRNA gene sequencing and metabolomic analyses showed that α‐MA reduced microbial dysbiosis, partially restored bacterial diversity, increased the abundances of Lactobacillus , Olsenella , Subdoligranulum , and Peptococcus , and decreased Alistipes . These microbial changes were accompanied by enhanced tryptophan metabolism and a marked increase in indole‐3‐acetic acid (IAA). Fecal microbiota transplantation from α‐MA‐treated donors successfully reproduced the improvements in hepatic steatosis and inflammatory cytokine profiles in recipient hens, supporting a transferable microbiota‐dependent effect. Targeted metabolite analysis further showed increased circulating IAA, together with enhanced hepatic aryl hydrocarbon receptor (AhR) signaling. Consistently, dietary IAA supplementation in vivo ameliorated steatotic liver phenotypes. In OA/PA‐induced hepatocyte steatosis, IAA reduced lipid accumulation and inflammatory activation, and these effects were partly abrogated by AhR antagonism. Overall, these findings identify the microbiota‐derived tryptophan metabolite IAA as an important functional mediator of the beneficial effects of dietary α‐MA and support a microbiota‐derived indole metabolite–AhR axis that contributes to improved hepatic metabolic and inflammatory status.