Gut microbiota-derived 3-indoleacrylic acid mediates ferulic acid protection against aflatoxin B1 hepatotoxicity via AhR-ferroptosis inhibition

ABSTRACT:

Given that Aflatoxin B1 exposure drives 5% to 28% of global hepatocellular carcinoma cases, the critical paucity of effective interventions for Aflatoxin B1-induced liver injury represents an urgent need. Here, we discover that a cereal-derived polyphenol, ferulic acid, alleviates Aflatoxin B1-induced hepatotoxicity by remodeling gut microbiota and activating microbial tryptophan metabolism. Specifically, dietary ferulic acid enriches Peptostreptococcus anaerobius , enhancing microbial conversion of tryptophan to 3-indoleacrylic acid both in vivo and in vitro. Mechanistically, by combining single-cell RNA sequencing and surface plasmon resonance, we demonstrate that 3-indoleacrylic acid functionally antagonizes Aflatoxin B1-induced hyperactivation of the AhR pathway, thereby suppressing AhR-driven ferroptosis. This functional mechanism was validated through genetic knockdown and pharmacological interventions. Crucially, we reveal that 3-indoleacrylic acid ameliorates Aflatoxin B1-induced liver inflammation by reprogramming the subset composition and function of macrophages, which was confirmed by macrophage-depletion models. Collectively, our findings unveil a precise molecular mechanism of host-microbe crosstalk, identifying the Peptostreptococcus anaerobius-derived tryptophan metabolite 3-indoleacrylic acid as a critical signaling mediator that inhibits Aflatoxin B1-induced hepatic AhR hyperactivation, ferroptosis, and macrophage reprogramming. This study not only proposes a viable dietary strategy to combat global aflatoxicosis but also provides insights into how specific microbial metabolites can be harnessed to therapeutically modulate hepatic injury and immune homeostasis.

INSTRUMENT(S): Liquid Chromatography MS - alternating - reverse-phase

PROVIDER: MTBLS13667 | MetaboLights | 2026-08-13

REPOSITORIES: MetaboLights