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Gut Microbiota Dysbiosis Enhances Migraine-Like Pain Via TNFα Upregulation

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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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References

  1. Jacobs B, Dussor G (2016) Neurovascular contributions to migraine: moving beyond vasodilation. Neuroscience 338:130–144. https://doi.org/10.1016/j.neuroscience.2016.06.012

    Article  CAS  PubMed  Google Scholar 

  2. Hindiyeh N, Aurora SK (2015) What the gut can teach us about migraine. Curr Pain Headache Rep 19(7):33. https://doi.org/10.1007/s11916-015-0501-4

    Article  PubMed  Google Scholar 

  3. Camara-Lemarroy CR, Rodriguez-Gutierrez R, Monreal-Robles R, Marfil-Rivera A (2016) Gastrointestinal disorders associated with migraine: a comprehensive review. World J Gastroenterol 22(36):8149–8160. https://doi.org/10.3748/wjg.v22.i36.8149

    Article  PubMed  PubMed Central  Google Scholar 

  4. van Hemert S, Breedveld AC, Rovers JM, Vermeiden JP, Witteman BJ, Smits MG, de Roos NM (2014) Migraine associated with gastrointestinal disorders: review of the literature and clinical implications. Front Neurol 5:241. https://doi.org/10.3389/fneur.2014.00241

    Article  PubMed  PubMed Central  Google Scholar 

  5. Fung TC, Olson CA, Hsiao EY (2017) Interactions between the microbiota, immune and nervous systems in health and disease. Nat Neurosci 20(2):145–155. https://doi.org/10.1038/nn.4476

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Ross SM (2017) Microbiota-gut-brain Axis, part 1: an integrated system of immunological, neural, and hormonal signals. Holist Nurs Pract 31(2):133–136. https://doi.org/10.1097/HNP.0000000000000203

    Article  PubMed  Google Scholar 

  7. Schroeder BO, Backhed F (2016) Signals from the gut microbiota to distant organs in physiology and disease. Nat Med 22(10):1079–1089. https://doi.org/10.1038/nm.4185

    Article  CAS  PubMed  Google Scholar 

  8. Li D, Wang P, Wang P, Hu X, Chen F (2016) The gut microbiota: a treasure for human health. Biotechnol Adv 34(7):1210–1224. https://doi.org/10.1016/j.biotechadv.2016.08.003

    Article  PubMed  Google Scholar 

  9. Marchesi J, Shanahan F (2007) The normal intestinal microbiota. Curr Opin Infect Dis 20(5):508–513. https://doi.org/10.1097/QCO.0b013e3282a56a99

    Article  PubMed  Google Scholar 

  10. Carroll IM, Ringel-Kulka T, Siddle JP, Ringel Y (2012) Alterations in composition and diversity of the intestinal microbiota in patients with diarrhea-predominant irritable bowel syndrome. Neurogastroenterol Motil 24(6):521–530, e248. https://doi.org/10.1111/j.1365-2982.2012.01891.x

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Galipeau HJ, Verdu EF (2014) Gut microbes and adverse food reactions: focus on gluten related disorders. Gut Microbes 5(5):594–605. https://doi.org/10.4161/19490976.2014.969635

    Article  PubMed  PubMed Central  Google Scholar 

  12. Jeffery IB, O'Toole PW, Ohman L, Claesson MJ, Deane J, Quigley EM, Simren M (2012) An irritable bowel syndrome subtype defined by species-specific alterations in faecal microbiota. Gut 61(7):997–1006. https://doi.org/10.1136/gutjnl-2011-301501

    Article  PubMed  Google Scholar 

  13. Sheehan D, Moran C, Shanahan F (2015) The microbiota in inflammatory bowel disease. J Gastroenterol 50(5):495–507. https://doi.org/10.1007/s00535-015-1064-1

    Article  CAS  PubMed  Google Scholar 

  14. Borre YE, O'Keeffe GW, Clarke G, Stanton C, Dinan TG, Cryan JF (2014) Microbiota and neurodevelopmental windows: implications for brain disorders. Trends Mol Med 20(9):509–518. https://doi.org/10.1016/j.molmed.2014.05.002

    Article  PubMed  Google Scholar 

  15. Cryan JF, O'Mahony SM (2011) The microbiome-gut-brain axis: from bowel to behavior. Neurogastroenterol Motil 23(3):187–192. https://doi.org/10.1111/j.1365-2982.2010.01664.x

    Article  CAS  PubMed  Google Scholar 

  16. Gulden E, Wong FS, Wen L (2015) The gut microbiota and type 1 diabetes. Clin Immunol 159(2):143–153. https://doi.org/10.1016/j.clim.2015.05.013

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Hartstra AV, Bouter KE, Backhed F, Nieuwdorp M (2015) Insights into the role of the microbiome in obesity and type 2 diabetes. Diabetes Care 38(1):159–165. https://doi.org/10.2337/dc14-0769

    Article  CAS  PubMed  Google Scholar 

  18. Chen X, D'Souza R, Hong ST (2013) The role of gut microbiota in the gut-brain axis: current challenges and perspectives. Protein Cell 4(6):403–414. https://doi.org/10.1007/s13238-013-3017-x

    Article  PubMed  PubMed Central  Google Scholar 

  19. Collins SM, Surette M, Bercik P (2012) The interplay between the intestinal microbiota and the brain. Nat Rev Microbiol 10(11):735–742. https://doi.org/10.1038/nrmicro2876

    Article  CAS  PubMed  Google Scholar 

  20. Cryan JF, Dinan TG (2012) Mind-altering microorganisms: the impact of the gut microbiota on brain and behaviour. Nat Rev Neurosci 13(10):701–712. https://doi.org/10.1038/nrn3346

    Article  CAS  PubMed  Google Scholar 

  21. El Aidy S, Dinan TG, Cryan JF (2015) Gut microbiota: the conductor in the orchestra of immune-neuroendocrine communication. Clin Ther 37(5):954–967. https://doi.org/10.1016/j.clinthera.2015.03.002

    Article  CAS  PubMed  Google Scholar 

  22. Koh A, De Vadder F, Kovatcheva-Datchary P, Backhed F (2016) From dietary fiber to host physiology: short-chain fatty acids as key bacterial metabolites. Cell 165(6):1332–1345. https://doi.org/10.1016/j.cell.2016.05.041

    Article  CAS  PubMed  Google Scholar 

  23. Mayer EA, Knight R, Mazmanian SK, Cryan JF, Tillisch K (2014) Gut microbes and the brain: paradigm shift in neuroscience. J Neurosci 34(46):15490–15496. https://doi.org/10.1523/JNEUROSCI.3299-14.2014

    Article  PubMed  PubMed Central  Google Scholar 

  24. Sommer F, Backhed F (2013) The gut microbiota--masters of host development and physiology. Nat Rev Microbiol 11(4):227–238. https://doi.org/10.1038/nrmicro2974

    Article  CAS  PubMed  Google Scholar 

  25. Bercik P, Collins SM, Verdu EF (2012) Microbes and the gut-brain axis. Neurogastroenterol Motil 24(5):405–413. https://doi.org/10.1111/j.1365-2982.2012.01906.x

    Article  CAS  PubMed  Google Scholar 

  26. De Palma G, Collins SM, Bercik P (2014) The microbiota-gut-brain axis in functional gastrointestinal disorders. Gut Microbes 5(3):419–429. https://doi.org/10.4161/gmic.29417

    Article  PubMed  PubMed Central  Google Scholar 

  27. De Palma G, Collins SM, Bercik P, Verdu EF (2014) The microbiota-gut-brain axis in gastrointestinal disorders: stressed bugs, stressed brain or both? J Physiol 592(14):2989–2997. https://doi.org/10.1113/jphysiol.2014.273995

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Dinan TG, Stilling RM, Stanton C, Cryan JF (2015) Collective unconscious: how gut microbes shape human behavior. J Psychiatr Res 63:1–9. https://doi.org/10.1016/j.jpsychires.2015.02.021

    Article  PubMed  Google Scholar 

  29. Dash S, Clarke G, Berk M, Jacka FN (2015) The gut microbiome and diet in psychiatry: focus on depression. Curr Opin Psychiatry 28(1):1–6. https://doi.org/10.1097/YCO.0000000000000117

    Article  PubMed  Google Scholar 

  30. Davis DJ, Doerr HM, Grzelak AK, Busi SB, Jasarevic E, Ericsson AC, Bryda EC (2016) Lactobacillus plantarum attenuates anxiety-related behavior and protects against stress-induced dysbiosis in adult zebrafish. Sci Rep 6:33726. https://doi.org/10.1038/srep33726

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Dinan TG, Cryan JF (2017) Gut instincts: microbiota as a key regulator of brain development, ageing and neurodegeneration. J Physiol 595(2):489–503. https://doi.org/10.1113/JP273106

    Article  CAS  PubMed  Google Scholar 

  32. Inoue R, Sakaue Y, Sawai C, Sawai T, Ozeki M, Romero-Perez GA, Tsukahara T (2016) A preliminary investigation on the relationship between gut microbiota and gene expressions in peripheral mononuclear cells of infants with autism spectrum disorders. Biosci Biotechnol Biochem 80(12):2450–2458. https://doi.org/10.1080/09168451.2016.1222267

    Article  CAS  PubMed  Google Scholar 

  33. Pistollato F, Sumalla Cano S, Elio I, Masias Vergara M, Giampieri F, Battino M (2016) Role of gut microbiota and nutrients in amyloid formation and pathogenesis of Alzheimer disease. Nutr Rev 74(10):624–634. https://doi.org/10.1093/nutrit/nuw023

    Article  PubMed  Google Scholar 

  34. Scheperjans F (2016) Gut microbiota, 1013 new pieces in the Parkinson’s disease puzzle. Curr Opin Neurol 29(6):773–780. https://doi.org/10.1097/WCO.0000000000000389

    Article  CAS  PubMed  Google Scholar 

  35. Winek K, Dirnagl U, Meisel A (2016) The gut microbiome as therapeutic target in central nervous system diseases: implications for stroke. Neurotherapeutics 13(4):762–774. https://doi.org/10.1007/s13311-016-0475-x

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Aamodt AH, Stovner LJ, Hagen K, Zwart JA (2008) Comorbidity of headache and gastrointestinal complaints. The head-HUNT study. Cephalalgia 28(2):144–151. https://doi.org/10.1111/j.1468-2982.2007.01486.x

    Article  CAS  PubMed  Google Scholar 

  37. Bates EA, Nikai T, Brennan KC, Fu YH, Charles AC, Basbaum AI, Ptacek LJ, Ahn AH (2010) Sumatriptan alleviates nitroglycerin-induced mechanical and thermal allodynia in mice. Cephalalgia 30(2):170–178. https://doi.org/10.1111/j.1468-2982.2009.01864.x

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Markovics A, Kormos V, Gaszner B, Lashgarara A, Szoke E, Sandor K, Szabadfi K, Tuka B et al (2012) Pituitary adenylate cyclase-activating polypeptide plays a key role in nitroglycerol-induced trigeminovascular activation in mice. Neurobiol Dis 45(1):633–644. https://doi.org/10.1016/j.nbd.2011.10.010

    Article  CAS  PubMed  Google Scholar 

  39. Tang Y, Liu S, Shu H, Xing Y, Tao F (2018) AMPA receptor GluA1 Ser831 phosphorylation is critical for nitroglycerin-induced migraine-like pain. Neuropharmacology 133:462–469. https://doi.org/10.1016/j.neuropharm.2018.02.026

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Mahmoudi J, Mohaddes G, Erfani M, Sadigh-Eteghad S, Karimi P, Rajabi M, Reyhani-Rad S, Farajdokht F (2018) Cerebrolysin attenuates hyperalgesia, photophobia, and neuroinflammation in a nitroglycerin-induced migraine model in rats. Brain Res Bull 140:197–204. https://doi.org/10.1016/j.brainresbull.2018.05.008

    Article  CAS  PubMed  Google Scholar 

  41. Perini F, D'Andrea G, Galloni E, Pignatelli F, Billo G, Alba S, Bussone G, Toso V (2005) Plasma cytokine levels in migraineurs and controls. Headache 45(7):926–931. https://doi.org/10.1111/j.1526-4610.2005.05135.x

    Article  PubMed  Google Scholar 

  42. Kang M, Mischel RA, Bhave S, Komla E, Cho A, Huang C, Dewey WL, Akbarali HI (2017) The effect of gut microbiome on tolerance to morphine mediated antinociception in mice. Sci Rep 7:42658. https://doi.org/10.1038/srep42658

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Kigerl KA, Hall JC, Wang L, Mo X, Yu Z, Popovich PG (2016) Gut dysbiosis impairs recovery after spinal cord injury. J Exp Med 213(12):2603–2620. https://doi.org/10.1084/jem.20151345

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. D'Mello C, Ronaghan N, Zaheer R, Dicay M, Le T, MacNaughton WK, Surrette MG, Swain MG (2015) Probiotics improve inflammation-associated sickness behavior by altering communication between the peripheral immune system and the brain. J Neurosci 35(30):10821–10830. https://doi.org/10.1523/JNEUROSCI.0575-15.2015

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Packey CD, Shanahan MT, Manick S, Bower MA, Ellermann M, Tonkonogy SL, Carroll IM, Sartor RB (2013) Molecular detection of bacterial contamination in gnotobiotic rodent units. Gut Microbes 4(5):361–370. https://doi.org/10.4161/gmic.25824

    Article  PubMed  PubMed Central  Google Scholar 

  46. Farkas S, Bolcskei K, Markovics A, Varga A, Kis-Varga A, Kormos V, Gaszner B, Horvath C et al (2016) Utility of different outcome measures for the nitroglycerin model of migraine in mice. J Pharmacol Toxicol Methods 77:33–44. https://doi.org/10.1016/j.vascn.2015.09.006

    Article  CAS  PubMed  Google Scholar 

  47. Afridi SK, Matharu MS, Lee L, Kaube H, Friston KJ, Frackowiak RS, Goadsby PJ (2005) A PET study exploring the laterality of brainstem activation in migraine using glyceryl trinitrate. Brain 128(Pt 4):932–939. https://doi.org/10.1093/brain/awh416

    Article  CAS  PubMed  Google Scholar 

  48. Christiansen I, Thomsen LL, Daugaard D, Ulrich V, Olesen J (1999) Glyceryl trinitrate induces attacks of migraine without aura in sufferers of migraine with aura. Cephalalgia 19(7):660–667; discussion 626. https://doi.org/10.1046/j.1468-2982.1999.019007660.x

    Article  CAS  PubMed  Google Scholar 

  49. Iversen HK, Olesen J, Tfelt-Hansen P (1989) Intravenous nitroglycerin as an experimental model of vascular headache. Basic characteristics. Pain 38(1):17–24

    Article  CAS  PubMed  Google Scholar 

  50. Olesen J (2008) The role of nitric oxide (NO) in migraine, tension-type headache and cluster headache. Pharmacol Ther 120(2):157–171. https://doi.org/10.1016/j.pharmthera.2008.08.003

    Article  CAS  PubMed  Google Scholar 

  51. Pradhan AA, Smith ML, McGuire B, Tarash I, Evans CJ, Charles A (2014) Characterization of a novel model of chronic migraine. Pain 155(2):269–274. https://doi.org/10.1016/j.pain.2013.10.004

    Article  CAS  PubMed  Google Scholar 

  52. Calvo M, Dawes JM, Bennett DL (2012) The role of the immune system in the generation of neuropathic pain. Lancet Neurol 11(7):629–642. https://doi.org/10.1016/S1474-4422(12)70134-5

    Article  CAS  PubMed  Google Scholar 

  53. de Miguel M, Kraychete DC, Meyer Nascimento RJ (2014) Chronic pain: cytokines, lymphocytes and chemokines. Inflamm Allergy Drug Targets 13(5):339–349

    Article  PubMed  Google Scholar 

  54. Ren K, Dubner R (2010) Interactions between the immune and nervous systems in pain. Nat Med 16(11):1267–1276. https://doi.org/10.1038/nm.2234

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Choi JI, Svensson CI, Koehrn FJ, Bhuskute A, Sorkin LS (2010) Peripheral inflammation induces tumor necrosis factor dependent AMPA receptor trafficking and Akt phosphorylation in spinal cord in addition to pain behavior. Pain 149(2):243–253. https://doi.org/10.1016/j.pain.2010.02.008

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Zhang L, Berta T, Xu ZZ, Liu T, Park JY, Ji RR (2011) TNF-alpha contributes to spinal cord synaptic plasticity and inflammatory pain: distinct role of TNF receptor subtypes 1 and 2. Pain 152(2):419–427. https://doi.org/10.1016/j.pain.2010.11.014

    Article  CAS  PubMed  Google Scholar 

  57. Li C, Yang Y, Liu S, Fang H, Zhang Y, Furmanski O, Skinner J, Xing Y et al (2014) Stress induces pain transition by potentiation of AMPA receptor phosphorylation. J Neurosci 34(41):13737–13746. https://doi.org/10.1523/JNEUROSCI.2130-14.2014

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Liu S, Zhao Z, Guo Y, Shu H, Li C, Tang Y, Xing Y, Tao F (2018) Spinal AMPA receptor GluA1 Ser831 phosphorylation controls chronic alcohol consumption-produced prolongation of postsurgical pain. Mol Neurobiol 55(5):4090–4097. https://doi.org/10.1007/s12035-017-0639-7

    Article  CAS  PubMed  Google Scholar 

  59. Hartmann B, Ahmadi S, Heppenstall PA, Lewin GR, Schott C, Borchardt T, Seeburg PH, Zeilhofer HU et al (2004) The AMPA receptor subunits GluR-A and GluR-B reciprocally modulate spinal synaptic plasticity and inflammatory pain. Neuron 44(4):637–650. https://doi.org/10.1016/j.neuron.2004.10.029

    Article  CAS  PubMed  Google Scholar 

  60. Youn DH, Royle G, Kolaj M, Vissel B, Randic M (2008) Enhanced LTP of primary afferent neurotransmission in AMPA receptor GluR2-deficient mice. Pain 136(1–2):158–167. https://doi.org/10.1016/j.pain.2007.07.001

    Article  CAS  PubMed  Google Scholar 

  61. Erny D, Hrabe de Angelis AL, Jaitin D, Wieghofer P, Staszewski O, David E, Keren-Shaul H, Mahlakoiv T et al (2015) Host microbiota constantly control maturation and function of microglia in the CNS. Nat Neurosci 18(7):965–977. https://doi.org/10.1038/nn.4030

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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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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  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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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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