Advertisement

Inflammation

pp 1–10 | Cite as

The Presence of High Levels of Circulating Trimethylamine N-Oxide Exacerbates Central and Peripheral Inflammation and Inflammatory Hyperalgesia in Rats Following Carrageenan Injection

  • Yanan Zhang
  • Chunlian Zhang
  • Haiou Li
  • Jingdong HouEmail author
Original Article

Abstract

Gut microbiota-derived metabolite trimethylamine N-oxide (TMAO) has recently been shown to promote inflammation in peripheral tissues and the central nervous system (CNS), contributing to the pathogenesis of various human diseases. Here, we examined whether the presence of high levels of circulating TMAO would influence central and peripheral inflammation and inflammatory hyperalgesia in a carrageenan (CG)-induced rat model of inflammation. Rats were treated with vehicle or TMAO in drinking water. After 2 weeks of treatment, rats received intraplantar injection of saline or CG into the hind paw. Acute nociception was unaltered in TMAO-treated rats that had elevated plasma TMAO. Following CG injection, TMAO-treated rats were significantly more sensitive to thermal and mechanical stimulation of the inflamed paw and displayed greater paw edema. Molecular studies revealed that CG injection induced increases in recruitment of neutrophils/macrophages in the paw and activation of microglia in the spinal cord, along with increased activation of nuclear factor (NF)-kB and production of proinflammatory mediators in both vehicle-treated rats and TMAO-treated rats. However, the increases in the above parameters were more pronounced in TMAO-treated rats. Moreover, TMAO treatment decreased protein levels of anti-inflammatory mediator regulator of G protein signaling (RGS)-10 in both saline-injected rats and CG-injected rats. These findings suggest that the presence of high levels of circulating TMAO downregulates anti-inflammatory mediator RGS10 in both peripheral tissues and the CNS, which may increase the susceptibility to inflammatory challenge-induced NF-kB activity, leading to greater increase in production of inflammatory mediators and consequent exacerbation of peripheral inflammation and inflammatory hyperalgesia.

KEY WORDS

inflammatory hyperalgesia trimethylamine N-oxide NF-kB activity inflammation regulator of G protein signaling-10 

Notes

Acknowledgments

The present study was supported by Jining No. 1 People’s Hospital.

References

  1. 1.
    Kidd, B.L., and L.A. Urban. 2001. Mechanisms of inflammatory pain. British Journal of Anaesthesia 87 (1): 3–11.  https://doi.org/10.1093/bja/87.1.3.CrossRefGoogle Scholar
  2. 2.
    Matsuda, M., Y. Huh, and R.R. Ji. 2019. Roles of inflammation, neurogenic inflammation, and neuroinflammation in pain. Journal of Anesthesia 33 (1): 131–139.  https://doi.org/10.1007/s00540-018-2579-4.CrossRefGoogle Scholar
  3. 3.
    Park, T.J., Y. Lu, R. Juttner, E.S. Smith, J. Hu, A. Brand, C. Wetzel, et al. 2008. Selective inflammatory pain insensitivity in the African naked mole-rat (Heterocephalus glaber). PLoS Biology 6 (1): e13.  https://doi.org/10.1371/journal.pbio.0060013.CrossRefGoogle Scholar
  4. 4.
    Iannitti, T., A. Graham, and S. Dolan. 2012. Increased central and peripheral inflammation and inflammatory hyperalgesia in Zucker rat model of leptin receptor deficiency and genetic obesity. Experimental Physiology 97 (11): 1236–1245.  https://doi.org/10.1113/expphysiol.2011.064220.CrossRefGoogle Scholar
  5. 5.
    Wang, J., Q. Zhang, L. Zhao, D. Li, Z. Fu, and L. Liang. 2014. Down-regulation of PPARalpha in the spinal cord contributes to augmented peripheral inflammation and inflammatory hyperalgesia in diet-induced obese rats. Neuroscience 278: 165–178.  https://doi.org/10.1016/j.neuroscience.2014.07.071.CrossRefGoogle Scholar
  6. 6.
    Guida, F., S. Boccella, C. Belardo, M. Iannotta, F. Piscitelli, F. De Filippis, S. Paino, et al. 2019. Altered gut microbiota and endocannabinoid system tone in vitamin D deficiency-mediated chronic pain. Brain, Behavior, and Immunity.  https://doi.org/10.1016/j.bbi.2019.04.006.
  7. 7.
    Shen, S., G. Lim, Z. You, W. Ding, P. Huang, C. Ran, J. Doheny, P. Caravan, S. Tate, K. Hu, H. Kim, M. McCabe, B. Huang, Z. Xie, D. Kwon, L. Chen, and J. Mao. 2017. Gut microbiota is critical for the induction of chemotherapy-induced pain. Nature Neuroscience 20 (9): 1213–1216.  https://doi.org/10.1038/nn.4606.CrossRefGoogle Scholar
  8. 8.
    Janeiro, M.H., M.J. Ramirez, F.I. Milagro, J.A. Martinez, and M. Solas. 2018. Implication of Trimethylamine N-Oxide (TMAO) in Disease: Potential Biomarker or New Therapeutic Target. Nutrients 10 (10).  https://doi.org/10.3390/nu10101398.
  9. 9.
    Subramaniam, S., and C. Fletcher. 2018. Trimethylamine N-oxide: breathe new life. British Journal of Pharmacology 175 (8): 1344–1353.  https://doi.org/10.1111/bph.13959.CrossRefGoogle Scholar
  10. 10.
    Zeisel, S.H., and M. Warrier. 2017. Trimethylamine N-Oxide, the Microbiome, and Heart and Kidney Disease. Annual Review of Nutrition 37: 157–181.  https://doi.org/10.1146/annurev-nutr-071816-064732.CrossRefGoogle Scholar
  11. 11.
    Chen, K., X. Zheng, M. Feng, D. Li, and H. Zhang. 2017. Gut Microbiota-Dependent Metabolite Trimethylamine N-Oxide Contributes to Cardiac Dysfunction in Western Diet-Induced Obese Mice. Frontiers in Physiology 8: 139.  https://doi.org/10.3389/fphys.2017.00139.Google Scholar
  12. 12.
    Li, T., Y. Chen, C. Gua, and X. Li. 2017. Elevated Circulating Trimethylamine N-Oxide Levels Contribute to Endothelial Dysfunction in Aged Rats through Vascular Inflammation and Oxidative Stress. Frontiers in Physiology 8: 350.  https://doi.org/10.3389/fphys.2017.00350.CrossRefGoogle Scholar
  13. 13.
    Seldin, M.M., Y. Meng, H. Qi, W. Zhu, Z. Wang, S.L. Hazen, A.J. Lusis, and D.M. Shih. 2016. Trimethylamine N-Oxide Promotes Vascular Inflammation Through Signaling of Mitogen-Activated Protein Kinase and Nuclear Factor-kappaB. Journal of the American Heart Association 5 (2).  https://doi.org/10.1161/JAHA.115.002767.
  14. 14.
    Sun, G., Z. Yin, N. Liu, X. Bian, R. Yu, X. Su, B. Zhang, and Y. Wang. 2017. Gut microbial metabolite TMAO contributes to renal dysfunction in a mouse model of diet-induced obesity. Biochemical and Biophysical Research Communications 493 (2): 964–970.  https://doi.org/10.1016/j.bbrc.2017.09.108.CrossRefGoogle Scholar
  15. 15.
    Shan, Z., T. Sun, H. Huang, S. Chen, L. Chen, C. Luo, W. Yang, X. Yang, P. Yao, J. Cheng, F.B. Hu, and L. Liu. 2017. Association between microbiota-dependent metabolite trimethylamine-N-oxide and type 2 diabetes. The American Journal of Clinical Nutrition 106 (3): 888–894.  https://doi.org/10.3945/ajcn.117.157107.Google Scholar
  16. 16.
    Del Rio, D., F. Zimetti, P. Caffarra, M. Tassotti, F. Bernini, F. Brighenti, A. Zini, and I. Zanotti. 2017. The Gut Microbial Metabolite Trimethylamine-N-Oxide Is Present in Human Cerebrospinal Fluid. Nutrients 9 (10).  https://doi.org/10.3390/nu9101053.
  17. 17.
    Meng, F., N. Li, D. Li, B. Song, and L. Li. 2019. The presence of elevated circulating trimethylamine N-oxide exaggerates postoperative cognitive dysfunction in aged rats. Behavioural Brain Research 368: 111902.  https://doi.org/10.1016/j.bbr.2019.111902.CrossRefGoogle Scholar
  18. 18.
    Mert, T., M. Sahin, E. Sahin, and S. Yaman. 2019. Anti-inflammatory properties of Liposome-encapsulated clodronate or Anti-Ly6G can be modulated by peripheral or central inflammatory markers in carrageenan-induced inflammation model. Inflammopharmacology. 27: 603–612.  https://doi.org/10.1007/s10787-019-00563-y.CrossRefGoogle Scholar
  19. 19.
    Zhang, H., J. Meng, and H. Yu. 2017. Trimethylamine N-oxide Supplementation Abolishes the Cardioprotective Effects of Voluntary Exercise in Mice Fed a Western Diet. Frontiers in Physiology 8: 944.  https://doi.org/10.3389/fphys.2017.00944.CrossRefGoogle Scholar
  20. 20.
    Zhang, Y., C. Song, H. Li, J. Hou, and D. Li. 2016. Ursolic acid prevents augmented peripheral inflammation and inflammatory hyperalgesia in high-fat diet-induced obese rats by restoring downregulated spinal PPARalpha. Molecular Medicine Reports 13 (6): 5309–5316.  https://doi.org/10.3892/mmr.2016.5172.CrossRefGoogle Scholar
  21. 21.
    Paterniti, I., D. Impellizzeri, M. Cordaro, R. Siracusa, C. Bisignano, E. Gugliandolo, A. Carughi, E. Esposito, G. Mandalari, and S. Cuzzocrea. 2017. The Anti-Inflammatory and Antioxidant Potential of Pistachios (Pistacia vera L.) In Vitro and In Vivo. Nutrients 9 (8).  https://doi.org/10.3390/nu9080915.
  22. 22.
    Ufnal, M., R. Jazwiec, M. Dadlez, A. Drapala, M. Sikora, and J. Skrzypecki. 2014. Trimethylamine-N-oxide: a carnitine-derived metabolite that prolongs the hypertensive effect of angiotensin II in rats. The Canadian Journal of Cardiology 30 (12): 1700–1705.  https://doi.org/10.1016/j.cjca.2014.09.010.CrossRefGoogle Scholar
  23. 23.
    Pan, G.J., B.S. Rayner, Y. Zhang, D.M. van Reyk, and C.L. Hawkins. 2018. A pivotal role for NF-kappaB in the macrophage inflammatory response to the myeloperoxidase oxidant hypothiocyanous acid. Archives of Biochemistry and Biophysics 642: 23–30.  https://doi.org/10.1016/j.abb.2018.01.016.CrossRefGoogle Scholar
  24. 24.
    Zhu, M.D., L.X. Zhao, X.T. Wang, Y.J. Gao, and Z.J. Zhang. 2014. Ligustilide inhibits microglia-mediated proinflammatory cytokines production and inflammatory pain. Brain Research Bulletin 109: 54–60.  https://doi.org/10.1016/j.brainresbull.2014.10.002.CrossRefGoogle Scholar
  25. 25.
    Zucoloto, A.Z., M.F. Manchope, S.M. Borghi, T.S. Dos Santos, V. Fattori, S. Badaro-Garcia, D. Camilios-Neto, R. Casagrande, and W.A. Verri Jr. 2019. Probucol Ameliorates Complete Freund's Adjuvant-Induced Hyperalgesia by Targeting Peripheral and Spinal Cord Inflammation. Inflammation. 42: 1474–1490.  https://doi.org/10.1007/s10753-019-01011-3.CrossRefGoogle Scholar
  26. 26.
    Lee, J.K., J. Chung, G.T. Kannarkat, and M.G. Tansey. 2013. Critical role of regulator G-protein signaling 10 (RGS10) in modulating macrophage M1/M2 activation. PLoS One 8 (11): e81785.  https://doi.org/10.1371/journal.pone.0081785.CrossRefGoogle Scholar
  27. 27.
    Lee, J.K., and M.G. Tansey. 2015. Physiology of RGS10 in Neurons and Immune Cells. Progress in Molecular Biology and Translational Science 133: 153–167.  https://doi.org/10.1016/bs.pmbts.2015.01.005.CrossRefGoogle Scholar
  28. 28.
    Wang, Z., E. Klipfell, B.J. Bennett, R. Koeth, B.S. Levison, B. Dugar, A.E. Feldstein, et al. 2011. Gut flora metabolism of phosphatidylcholine promotes cardiovascular disease. Nature 472 (7341): 57–63.  https://doi.org/10.1038/nature09922.CrossRefGoogle Scholar
  29. 29.
    Velasquez, M.T., A. Ramezani, A. Manal, and D.S. Raj. 2016. Trimethylamine N-Oxide: The Good, the Bad and the Unknown. Toxins (Basel) 8 (11).  https://doi.org/10.3390/toxins8110326.
  30. 30.
    Canyelles, M., M. Tondo, L. Cedo, M. Farras, J.C. Escola-Gil, and F. Blanco-Vaca. 2018. Trimethylamine N-Oxide: A Link among Diet, Gut Microbiota, Gene Regulation of Liver and Intestine Cholesterol Homeostasis and HDL Function. International Journal of Molecular Sciences 19 (10).  https://doi.org/10.3390/ijms19103228.
  31. 31.
    Missailidis, C., J. Hallqvist, A.R. Qureshi, P. Barany, O. Heimburger, B. Lindholm, P. Stenvinkel, and P. Bergman. 2016. Serum Trimethylamine-N-Oxide Is Strongly Related to Renal Function and Predicts Outcome in Chronic Kidney Disease. PLoS One 11 (1): e0141738.  https://doi.org/10.1371/journal.pone.0141738.CrossRefGoogle Scholar
  32. 32.
    Lever, M., P.M. George, S. Slow, D. Bellamy, J.M. Young, M. Ho, C.J. McEntyre, J.L. Elmslie, W. Atkinson, S.L. Molyneux, R.W. Troughton, C.M. Frampton, A.M. Richards, and S.T. Chambers. 2014. Betaine and Trimethylamine-N-Oxide as Predictors of Cardiovascular Outcomes Show Different Patterns in Diabetes Mellitus: An Observational Study. PLoS One 9 (12): e114969.  https://doi.org/10.1371/journal.pone.0114969.CrossRefGoogle Scholar
  33. 33.
    Hayashi, T., T. Yamashita, H. Watanabe, K. Kami, N. Yoshida, T. Tabata, T. Emoto, N. Sasaki, T. Mizoguchi, Y. Irino, R. Toh, M. Shinohara, Y. Okada, W. Ogawa, T. Yamada, and K.I. Hirata. 2018. Gut Microbiome and Plasma Microbiome-Related Metabolites in Patients With Decompensated and Compensated Heart Failure. Circulation Journal 83 (1): 182–192.  https://doi.org/10.1253/circj.CJ-18-0468.CrossRefGoogle Scholar
  34. 34.
    Coras, R., A. Kavanaugh, T. Boyd, D. Huynh, K.A. Lagerborg, Y.J. Xu, S.B. Rosenthal, M. Jain, and M. Guma. 2019. Choline metabolite, trimethylamine N-oxide (TMAO), is associated with inflammation in psoriatic arthritis. Clinical and Experimental Rheumatology 37 (3): 481–484.Google Scholar
  35. 35.
    Vogt, N.M., K.A. Romano, B.F. Darst, C.D. Engelman, S.C. Johnson, C.M. Carlsson, S. Asthana, K. Blennow, H. Zetterberg, B.B. Bendlin, and F.E. Rey. 2018. The gut microbiota-derived metabolite trimethylamine N-oxide is elevated in Alzheimer’s disease. Alzheimer's Research & Therapy 10 (1): 124.  https://doi.org/10.1186/s13195-018-0451-2.CrossRefGoogle Scholar
  36. 36.
    Mert, T., E. Sahin, S. Yaman, and M. Sahin. 2018. Pain-Relieving Effectiveness of Co-Treatment with Local Tramadol and Systemic Minocycline in Carrageenan-Induced Inflammatory Pain Model. Inflammation 41 (4): 1238–1249.  https://doi.org/10.1007/s10753-018-0771-1.CrossRefGoogle Scholar
  37. 37.
    Ruiz-Miyazawa, K.W., A.C. Zarpelon, F.A. Pinho-Ribeiro, G.F. Pavao-de-Souza, R. Casagrande, and W.A. Verri Jr. 2015. Vinpocetine reduces carrageenan-induced inflammatory hyperalgesia in mice by inhibiting oxidative stress, cytokine production and NF-kappaB activation in the paw and spinal cord. PLoS One 10 (3): e0118942.  https://doi.org/10.1371/journal.pone.0118942.CrossRefGoogle Scholar
  38. 38.
    Calixto-Campos, C., T.T. Carvalho, M.S. Hohmann, F.A. Pinho-Ribeiro, V. Fattori, M.F. Manchope, A.C. Zarpelon, et al. 2015. Vanillic Acid Inhibits Inflammatory Pain by Inhibiting Neutrophil Recruitment, Oxidative Stress, Cytokine Production, and NFkappaB Activation in Mice. Journal of Natural Products 78 (8): 1799–1808.  https://doi.org/10.1021/acs.jnatprod.5b00246.CrossRefGoogle Scholar
  39. 39.
    D'Agostino, G., G. La Rana, R. Russo, O. Sasso, A. Iacono, E. Esposito, G.M. Raso, et al. 2007. Acute intracerebroventricular administration of palmitoylethanolamide, an endogenous peroxisome proliferator-activated receptor-alpha agonist, modulates carrageenan-induced paw edema in mice. The Journal of Pharmacology and Experimental Therapeutics 322 (3): 1137–1143.  https://doi.org/10.1124/jpet.107.123265.CrossRefGoogle Scholar
  40. 40.
    Alqinyah, M., F. Almutairi, M.Y. Wendimu, and S.B. Hooks. 2018. RGS10 Regulates the Expression of Cyclooxygenase-2 and Tumor Necrosis Factor Alpha through a G Protein-Independent Mechanism. Molecular Pharmacology 94 (4): 1103–1113.  https://doi.org/10.1124/mol.118.111674.CrossRefGoogle Scholar
  41. 41.
    Lee, J.K., J. Chung, F.E. McAlpine, and M.G. Tansey. 2011. Regulator of G-protein signaling-10 negatively regulates NF-kappaB in microglia and neuroprotects dopaminergic neurons in hemiparkinsonian rats. The Journal of Neuroscience 31 (33): 11879–11888.  https://doi.org/10.1523/JNEUROSCI.1002-11.2011.CrossRefGoogle Scholar
  42. 42.
    Lee, J.K., M.K. McCoy, A.S. Harms, K.A. Ruhn, S.J. Gold, and M.G. Tansey. 2008. Regulator of G-protein signaling 10 promotes dopaminergic neuron survival via regulation of the microglial inflammatory response. The Journal of Neuroscience 28 (34): 8517–8528.  https://doi.org/10.1523/JNEUROSCI.1806-08.2008.CrossRefGoogle Scholar

Copyright information

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

Authors and Affiliations

  • Yanan Zhang
    • 1
  • Chunlian Zhang
    • 1
  • Haiou Li
    • 1
  • Jingdong Hou
    • 1
    Email author
  1. 1.Department of Anesthesiology and SurgeryJining No. 1 People’s HospitalJiningChina

Personalised recommendations