To (the) brain or not to (the) brain? Distal signaling and non-neural players in brain hyperexcitability.

The brain is a highly dynamic organ whose functions depend on the intricate interplay among neurons, glial cells, endothelial cells, and immune components. Traditionally viewed as the domain of neuronal signaling, emerging evidence underscores the crucial role of the neurovascular unit, where neuronal, glial, vascular, and immune interactions collectively sustain brain health and adaptability. In this study, we explored the modulation of neuronal excitability, a fundamental property underlying cognition, sensory processing, and movement, by focusing on the interplay between immune signaling and the microbiota-gut-brain axis. Neuronal excitability is finely regulated by the balance of excitatory and inhibitory signals, and disruptions in this equilibrium are often implicated in pathological conditions such as epilepsy and neurodegenerative diseases. A central focus of our investigation was CXCL17, a chemokine widely expressed in mucosal tissues. Our findings revealed its expression not only in intestinal mucosal tissues but also in key brain regions such as the hippocampus and cerebellum. Through its receptor, GPR25, CXCL17 may influence not only immune cell recruitment, but also neuronal function and plasticity. This suggests a potential role in memory and learning, as well as involvement in pathological mechanisms, including epilepsy and multiple sclerosis. Experimental evidence supports the hypothesis that CXCL17 and its receptor GPR25 modulate inflammation, immune cell recruitment, and may influence neuronal excitability, offering new insights into disease mechanisms and potential therapeutic avenues. We also investigated the role of gut microbiota in brain excitability via the microbiota-gut-brain axis. Our findings provide evidence that mice receiving microbiota from epileptic animals exhibit greater susceptibility to status epilepticus compared to those receiving “healthy” microbiota, following a subclinical dose of pilocarpine. The lower seizure thresholds observed in these animals support the hypothesis that the microbiota influences neuronal excitability in the brain. Moreover, using a mouse model of temporal lobe epilepsy, we characterized dynamic shifts in microbiota composition during acute and chronic disease phases. Notably, we identified an abundance increase of Desulfovibrio, a bacterium that produces hydrogen sulfide, an agent with dual roles in neuroprotection and neurotoxicity. Conversely, Akkermansia Muciniphila, which emerged in the chronic phase, may exert neuroprotective effects by maintaining gut barrier integrity and modulating immune responses. These findings highlight the complexity of microbial interactions, where certain bacteria exacerbate neuroinflammation and lower seizure thresholds, whereas others contribute to neuroprotection and seizure resistance. By integrating the study of chemokine signaling, neuroinflammatory pathways, and microbiota dynamics, our work underscores the intricate connections between the immune system, gut, and brain. This research opens new perspectives on targeting these interactions to develop innovative therapeutic strategies for neurological disorders such as epilepsy. Future studies should further investigate the complex relationship between immune signaling, microbiota, and neuronal excitability to uncover novel approaches for disease prevention and treatment.