Ligand-specific duality of aryl hydrocarbon receptor signaling in cognitive health: from environmental neurotoxicity to microbiome-mediated neuroprotection

The aromatic hydrocarbon receptor (AhR) is a key molecular interface integrating environmental chemical signals with host-microbiome metabolism, with profound effects on brain function. This review systematically addresses the ligand-specific duality of AhR signaling in cognitive health, comparing the predominantly neurotoxic signaling driven by environmental polycyclic aromatic hydrocarbons (PAHs) with the predominantly neuroprotective signaling mediated by gut microbiota-derived tryptophan metabolites. However, this dichotomy is context-dependent rather than absolute. PAHs activate AhR in a sustained, high-affinity manner, engaging downstream NF-κB neuroinflammation, NLRP3 inflammasome activation, oxidative stress, synaptic dysfunction, and transgenerational epigenetic alterations. In contrast, microbiota-derived metabolites such as indole-3-propionic acid (IPA) and kynurenic acid (KYNA) elicit transient, low-affinity AhR activation that engages cell-type-specific programs promoting anti-inflammatory responses, neurogenesis, blood, brain barrier integrity, and neuronal homeostasis. Critically, the outcome of AhR activation is modulated by ligand pharmacokinetics, cell-type identity, temporal dynamics of receptor engagement, and tissue-specific co-factor availability. These contextual variables determine whether AhR functions as a driver of neurodegeneration or a guardian of cognitive resilience. We further examine the divergent roles of AhR in Alzheimer’s and Parkinson’s diseases, where the balance between detrimental and protective ligands determines disease progression. Finally, we discuss therapeutic strategies targeting the AhR, gut, brain axis, including dietary modulation, probiotic interventions, and selective AhR modulators. Understanding the context-dependent outcomes of AhR activation provides a framework for developing precision approaches to preserve cognitive function and prevent neurodegeneration.