The aryl hydrocarbon receptor: A promising target for intestinal fibrosis therapy

Intestinal fibrosis, a severe complication of inflammatory bowel disease, leads to intestinal stenosis. Effective therapies for this condition are lacking. The aryl hydrocarbon receptor (AhR), a highly conserved nuclear transcription factor activated by diverse ligands, plays dual roles in fibrogenesis, but its relationship to intestinal fibrosis has not been comprehensively reviewed. This review explores the pathogenesis of intestinal fibrosis, and places particular focus on the mechanistic role of AhR signaling pathways, which may be mediated by dietary, microbial, and environmental ligands. We propose a new strategy for the targeting of AhR-related dietary ligands to prevent intestinal fibrosis. Dietary AhR ligands, such as glucobrassicin, flavonoids, and curcumin, exert anti-fibrotic effects by modulating the gut microbiota, suppressing collagen deposition, and inhibiting transforming growth factor-β pathways. Conversely, environmental pollutants (e.g., polycyclic aromatic hydrocarbons, microplastics, and propiconazole) exacerbate fibrosis via AhR activation. In multiple disease models, 16S rRNA sequencing has revealed positive and negative linear relationships between the gut microbiota and fibrosis. Intestinal microbiota-derived metabolites also affect fibrosis, including via immune cell regulation to indirectly reduce collagen deposition and direct action on extracellular matrix-related proteins to relieve intestinal fibrosis. The interaction among the AhR, microbiota, and diet suggests new therapeutic strategies, such as dietary interventions and fecal microbiota transplantation, to restore the microbial balance and inhibit fibrosis. The promotion of intestinal fibrosis by AhR agonists in environmental pollutants further emphasizes the need to reduce exposure to environmental toxins while following a plant-based diet rich in AhR agonists.