Multi-omics chemical and biochemical profiling reveals ellagic acid enhances insulin sensitivity via gut microbiota–tryptophan–indole signaling mechanism

Ellagic acid (EA) is a dietary polyphenol with limited systemic bioavailability, resulting in substantial intestinal exposure. However, the biochemical mechanisms by which EA modulates gut microbiota and metabolism remain unclear. Here, EA improved glucose tolerance and enhanced insulin sensitivity, with histology confirming reduced lipid accumulation and restored tissue architecture in liver, skeletal muscle, brown adipose tissue, and mesenteric fat. Consistently, metagenomic analysis showed that EA enriched Akkermansia muciniphila , Muribaculum intestinale , and Duncaniella dubosii , while reducing Lachnoclostridium phocaeense . These microbial shifts were accompanied by elevated levels of tryptophan-derived metabolites—indole-3-propionic acid, indole, and indole-3-acrylic acid—known to enhance insulin sensitivity. Lipidomic revealed EA decreased triacylglycerols and ceramides, along with restored phosphatidylcholine, phosphatidylethanolamine and phosphatidylserine levels. Transcriptomic revealed EA suppressed hepatic lipogenesis, inhibited MAPK signaling in skeletal muscle, activated thermogenic and oxidative phosphorylation in adipose tissues. Our findings highlight EA as a food-derived polyphenol that alleviates insulin resistance through a gut microbiota–indole metabolite–multi-tissue axis.