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

ABSTRACT:

Aflatoxin B1 (AFB1)-induced hepatic inflammation poses severe global health burdens with limited interventions. Here, we demonstrated that ferulic acid (FA), a cereal-derived polyphenol, alleviated AFB1 hepatotoxicity by remodeling gut microbiota and activating microbial tryptophan metabolism. FA enriched Peptostreptococcus anaerobius (P. anaerobius), enhancing its conversion of tryptophan to 3-indoleacrylic acid (IA) via transcriptional upregulation of key enzymes (Aromatic amino acid aminotransferase, Phenylacetate dehydrogenase, Pylacetate dehydratase (fldBC)). The recombinant fldBC enzyme catalyzed the production of IA from indole-3-lactic acid in vitro. P. anaerobius attenuated AFB1-induced hepatic inflammation and ferroptosis in mice was attributable to bacterial production of IA. Mechanistically, IA competitively inhibited AFB1 binding to the aryl hydrocarbon receptor (AhR), thereby suppressing AhR-driven ferroptosis, evidenced by rescued GPX4/xCT expression and reduced iron overload. Crucially, integrated single-cell RNA sequencing and flow cytometry revealed that IA mitigated AFB1-induced hepatitis by polarizing Kupffer cells toward an M2-reparative phenotype. In summary, FA modulates gut microbiota composition and tryptophan metabolism, particularly by increasing the relative abundance of P. anaerobius and enhancing IA production, thereby inhibiting AFB1-induced AhR activation, ferroptosis, and macrophage polarization, ultimately alleviating hepatic inflammation. Our findings establish a gut microbiota-IA-AhR-ferroptosis axis as a therapeutic target for mycotoxin-induced liver inflammation.

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

PROVIDER: MTBLS12942 | MetaboLights | 2026-08-14

REPOSITORIES: MetaboLights