Gut Microbiota Dysbiosis Enhances Migraine-Like Pain Via TNFα Upregulation

  • Yuanyuan Tang
  • Sufang Liu
  • Hui Shu
  • Lora Yanagisawa
  • Feng TaoEmail author


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.


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


Funding information

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.).

Compliance with Ethical Standards

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.

Conflict of Interest

The authors declare that they have no conflicts of interest.

Supplementary material

12035_2019_1721_Fig5_ESM.png (101 kb)
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)

12035_2019_1721_MOESM1_ESM.tif (34.4 mb)
High resolution image (TIF 35178 kb)


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Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2019

Authors and Affiliations

  1. 1.Department of Biomedical SciencesTexas A&M University College of DentistryDallasUSA
  2. 2.School of Basic Medical SciencesXinxiang Medical UniversityXinxiangChina
  3. 3.Department of Physiology and NeurobiologyZhengzhou University School of MedicineZhengzhouChina
  4. 4.Department of Veterinary Integrative Biosciences, College of Veterinary Medicine & Biomedical SciencesTexas A&M UniversityCollege StationUSA
  5. 5.Center for Craniofacial Research and DiagnosisTexas A&M University College of DentistryDallasUSA

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