Microbiome-Derived Tryptophan Metabolites Regulate AhR Signaling to Restore Epithelial Barrier Integrity in...

Inflammatory bowel disease (IBD) is characterized by chronic intestinal inflammation and compromised epithelial barrier integrity. Emerging evidence demonstrates that gut microbiota-derived tryptophan metabolites serve as endogenous ligands for the aryl hydrocarbon receptor (AhR), initiating protective signaling cascades that restore mucosal homeostasis. This review synthesizes current mechanistic insights into how microbial tryptophan catabolites including indole-3-aldehyde, indole-3-propionic acid, indole-3-lactic acid, and indole-3-acetic acid activate AhR to enhance epithelial barrier function. However, this protective capacity is specific to activation by physiological, low-affinity microbial ligands and should not be generalized to AhR signaling irrespective of ligand identity, dose, or duration of exposure. Key bacterial producers include Lactobacillus species (L. reuteri and L. plantarum), Clostridium sporogenes, and Allobaculum species. AhR activation by these metabolites triggers multiple downstream pathways, including AMP-activated protein kinase (AMPK) activation, which promotes autophagy and mitochondrial homeostasis; nuclear factor erythroid 2-related factor 2 (Nrf2)-mediated antioxidant responses; nuclear factor-κB (NF-κB) inhibition, which reduces pro-inflammatory cytokine production; and interleukin-22 (IL-22) induction, which supports epithelial regeneration. These signaling events converge to upregulate tight junction proteins, preserve mucus layer integrity, and reduce actomyosin-mediated permeability through decreased myosin light chain phosphorylation. Preclinical studies demonstrate AhR-dependent barrier restoration, with protective effects abolished by AhR antagonists. Despite these preclinical findings, their therapeutic utility in IBD remains to be established in human interventional studies. Importantly, the protective effects of AhR are highly context-dependent, as kynurenine pathway ligands and sustained receptor activation may exert immunosuppressive or pro-tumorigenic effects, highlighting the importance of ligand selectivity in therapeutic development.