The potential role of the lung–brain axis in the pathophysiology of epilepsy: A hypothesis-driven perspective

The pathophysiology of epilepsy remains poorly understood. One of the less explored areas is the role of the lung‒brain axis, a sophisticated and intricate bidirectional connection between these two vital organs. Inhaled air pollutants can disrupt lung microbiome homeostasis. This disruption, analogous to gut dysbiosis implicated in neurological conditions, may contribute to epilepsy pathogenesis. Here, we review the existing evidence and theoretical foundations supporting the hypothesis that dysbiosis within the lung microbiota may play a role in the pathophysiology of epilepsy. This includes the links between environmental factors (particularly air pollution) and epilepsy susceptibility; the associations between lung-intrinsic microbiota dysregulation and neurological dysfunction; and the underlying molecular, immunological, and neural mechanisms that enable the lung–brain axis to modulate epileptogenesis. Furthermore, we outline the possible potential pathogenic mechanisms of epilepsy from the perspective of the microbiota–lung–brain axis, offer fresh perspectives on the pathophysiology of epilepsy, and explore potential new research directions related to the lung–brain axis and epilepsy. We propose that a deeper understanding of the function of the lung–brain axis will provide new insights into the etiology, diagnosis, prognosis, and treatment of epilepsy.