Probiotic modulation of central and peripheral sensitization in a migraine model via the gut–brain–trigeminal axis

The gut-brain axis has emerged as a pivotal modulator of migraine pathophysiology. This study examined the neurophysiological effects of targeted probiotic supplementation-Lactobacillus plantarum, Bifidobacterium longum, their combination, and a multi-strain formulation (Pro-14)-in a rat model of cortical spreading depression (CSD), a hallmark trigger of migraine. B.longum significantly reduced CSD frequency (p = 0.0045), while L.plantarum and its combination with B.longum markedly attenuated CSD amplitude (p = 0.0003, p = 0.01, respectively), reflecting suppression of cortical hyperexcitability. In small-to-medium-sized trigeminal ganglion (TG) neurons, probiotics significantly lowered total spike counts (p < 0.0001), and induced hyperpolarization of resting membrane potential (p < 0.0001), consistent with peripheral desensitization. Additionally, the threshold-Resting Membrane Potential (RMP) gap increased significantly across all treated groups (p < 0.0001), indicating reduced neuronal excitability. Only B.longum prolonged action potential duration and depolarization time (p = 0.0454 and p = 0.034, respectively), suggesting enhanced modulation of nociceptive signaling. In large-sized TG neurons, similar hyperpolarizing trends in RMP (p < 0.0001) and increased excitability thresholds (p < 0.0001) were observed without changes in spike frequency. These findings reveal strain-specific modulation of central and peripheral sensitization via the gut-brain-trigeminal axis and support the development of precision-targeted, microbiota-based therapies as non-pharmacologic strategies for migraine prophylaxis.