Department of Biomedical Sciences, Texas A&M University College of Dentistry, 3302 Gaston Ave, Dallas, TX, 75246, USA.
School of Basic Medical Sciences, Xinxiang Medical University, Xinxiang, Henan, China.
Mol Neurobiol. 2020 Jan;57(1):461-468. doi: 10.1007/s12035-019-01721-7. Epub 2019 Aug 4.
Migraine is one of the most disabling neurological diseases worldwide; however, the mechanisms underlying migraine headache are still not fully understood and current therapies for such pain are inadequate. It has been suggested that inflammation and neuroimmune modulation in the gastrointestinal tract could play an important role in the pathogenesis of migraine headache, but how gut microbiomes contribute to migraine headache is unclear. In the present study, we investigated the effect of gut microbiota dysbiosis on migraine-like pain using broad-spectrum antibiotics and germ-free (GF) mice. We observed that antibiotics treatment-prolonged nitroglycerin (NTG)-induced acute migraine-like pain in wild-type (WT) mice and the pain prolongation was completely blocked by genetic deletion of tumor necrosis factor-alpha (TNFα) or intra-spinal trigeminal nucleus caudalis (Sp5C) injection of TNFα receptor antagonist. The antibiotics treatment extended NTG-induced TNFα upregulation in the Sp5C. Probiotics administration significantly inhibited the antibiotics-produced migraine-like pain prolongation. Furthermore, NTG-induced migraine-like pain in GF mice was markedly enhanced compared to that in WT mice and gut colonization with fecal microbiota from WT mice robustly reversed microbiota deprivation-caused pain enhancement. Together, our results suggest that gut microbiota dysbiosis contributes to chronicity of migraine-like pain by upregulating TNFα level in the trigeminal nociceptive system.
偏头痛是全球最致残的神经疾病之一；然而，偏头痛头痛的发病机制仍不完全清楚，目前针对这种疼痛的治疗方法也不充分。有人提出，胃肠道的炎症和神经免疫调节可能在偏头痛头痛的发病机制中发挥重要作用，但肠道微生物组如何导致偏头痛还不清楚。在本研究中，我们使用广谱抗生素和无菌（GF）小鼠研究了肠道微生物失调对偏头痛样疼痛的影响。我们观察到，抗生素治疗延长了野生型（WT）小鼠硝化甘油（NTG）诱导的急性偏头痛样疼痛，而肿瘤坏死因子-α（TNFα）基因缺失或 Sp5C 中 TNFα 受体拮抗剂的注射完全阻断了疼痛延长。抗生素治疗延长了 Sp5C 中 NTG 诱导的 TNFα 上调。益生菌给药显著抑制了抗生素引起的偏头痛样疼痛延长。此外，与 WT 小鼠相比，GF 小鼠的 NTG 诱导的偏头痛样疼痛明显增强，而来自 WT 小鼠的粪便微生物群定植则强烈逆转了微生物群剥夺引起的疼痛增强。总之，我们的结果表明，肠道微生物失调通过上调三叉神经痛觉系统中的 TNFα 水平导致偏头痛样疼痛的慢性化。
