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Gut Microbiota Dysbiosis Enhances Migraine-Like Pain Via TNFα Upregulation

Molecular Neurobiology volume 57, pages 461–468 (2020)Cite this article

Abstract

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.

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Funding

This work was supported by National Institutes of Health Grants R01 DE022880 (F.T.) and K02 DE023551 (F.T.) as well as Texas A&M University Interdisciplinary Faculty T3 Award (F.T.).

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Author notes

  1. Yuanyuan Tang and Sufang Liu contributed equally to this work.

Authors and Affiliations

  1. Department of Biomedical Sciences, Texas A&M University College of Dentistry, 3302 Gaston Ave, Dallas, TX, 75246, USA

    Yuanyuan Tang, Sufang Liu, Hui Shu & Feng Tao

  2. School of Basic Medical Sciences, Xinxiang Medical University, Xinxiang, Henan, China

    Yuanyuan Tang

  3. Department of Physiology and Neurobiology, Zhengzhou University School of Medicine, Zhengzhou, Henan, China

    Sufang Liu

  4. Department of Veterinary Integrative Biosciences, College of Veterinary Medicine & Biomedical Sciences, Texas A&M University, College Station, TX, USA

    Lora Yanagisawa

  5. Center for Craniofacial Research and Diagnosis, Texas A&M University College of Dentistry, 3302 Gaston Ave, Dallas, TX, 75246, USA

    Feng Tao

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  1. Yuanyuan Tang
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Correspondence to Feng Tao.

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All animal procedures were carried out in accordance with the National Institutes of Health guide for the care and use of laboratory animals and were approved by the Texas A&M University College of Dentistry Institutional Animal Care and Use Committee.

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Supplemental Figure 1

Antagonism of TNFα receptors in the Sp5C after NTG significantly inhibits ABX treatment-prolonged migraine-like pain. Orofacial pain tests for baseline-1 and baseline-2 measurements were carried out before and after 10-day oral gavage of ABX, respectively. NTG was injected (10 mg/kg, i.p.) into WT mice after baseline-2 measurement (n = 6 per group). Bilateral intra-Sp5C injection of R-7050 (0.5 μl, 0.1 mM in 0.9% saline) was carried out on day 1 after NTG. We observed that R-7050 significantly inhibited ABX treatment-produced prolongation of NTG-induced migraine-like pain (*P < 0.05 vs. the “ABX + Vehicle” group by two-way ANOVA with the post-hoc Student-Newman-Keuls test). Data are shown as mean ± SEM. (PNG 100 kb)

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Tang, Y., Liu, S., Shu, H. et al. Gut Microbiota Dysbiosis Enhances Migraine-Like Pain Via TNFα Upregulation. Mol Neurobiol 57, 461–468 (2020). https://doi.org/10.1007/s12035-019-01721-7

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Keywords

  • Gut microbiota
  • Migraine headache
  • Tumor necrosis factor-alpha
  • Spinal trigeminal nucleus caudalis