Postbiotic from <i>Lactobacillus acidophilus</i> Inhibits Ferroptosis in Intestinal Stem Cells via Microbiota–AhR Axis to Mitigate Colitis

ABSTRACT Inflammatory bowel disease (IBD) is a chronic, progressive intestinal disorder. Dysbiosis of the gut microbiota is strongly implicated in the onset and progression of IBD. Microbiome‐based interventions offer promising therapeutic potential. Lacidophilin tablets (LP), a postbiotic formulation derived from the fermentation of Lactobacillus acidophilus in milk, effectively modulate the gut microbiota. However, the specific anti‐colitis effects of LP and the mechanisms through which the gut microbiota mediates these beneficial effects remain unclear. In this study, we employed a DSS‐induced colitis mouse model and utilized 16S rRNA microbiome analysis, metabolomics, and colon organoid functional assays to assess the therapeutic potential of LP. Our findings indicate that LP significantly ameliorates colitis symptoms by enhancing gut microbiota diversity and promoting the colonization of Ruminococcus . Notably, LP enhances the production of the microbial metabolite 5‐hydroxyindoleacetic acid (5‐HIAA), which activates the aryl hydrocarbon receptor (Ahr) in Lgr5+ intestinal stem cells, inhibiting ferroptosis and promoting epithelial regeneration. This study underscores the therapeutic potential of LP in IBD by modulating the gut microbiota and identifying 5‐HIAA as a pivotal mediator in maintaining epithelial integrity. These findings provide foundational insights for the future development of microbiome‐inspired treatments for IBD.