Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Article
  • Published:

Nitrated meat products are associated with mania in humans and altered behavior and brain gene expression in rats

Molecular Psychiatry volume 25, pages 560–571 (2020)Cite this article

Subjects

Abstract

Mania is a serious neuropsychiatric condition associated with significant morbidity and mortality. Previous studies have suggested that environmental exposures can contribute to mania pathogenesis. We measured dietary exposures in a cohort of individuals with mania and other psychiatric disorders as well as in control individuals without a psychiatric disorder. We found that a history of eating nitrated dry cured meat but not other meat or fish products was strongly and independently associated with current mania (adjusted odds ratio 3.49, 95% confidence interval (CI) 2.24–5.45, p < 8.97 × 10−8). Lower odds of association were found between eating nitrated dry cured meat and other psychiatric disorders. We further found that the feeding of meat preparations with added nitrate to rats resulted in hyperactivity reminiscent of human mania, alterations in brain pathways that have been implicated in human bipolar disorder, and changes in intestinal microbiota. These findings may lead to new methods for preventing mania and for developing novel therapeutic interventions.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Fig. 1
Fig. 2
Fig. 3
Fig. 4

Similar content being viewed by others

References

  1. Uher R. Gene-environment interactions in severe mental illness. Front Psychiatry. 2014;5:48.

    PubMed  PubMed Central  Google Scholar 

  2. Reyes TM. Diet, inflammation and the brain: commentary on the 2014 named series. Brain Behav Immun. 2014;42:6–9.

    PubMed  Google Scholar 

  3. Jacka FN, Pasco JA, Mykletun A, Williams LJ, Nicholson GC, Kotowicz MA, et al. Diet quality in bipolar disorder in a population-based sample of women. J Affect Disord. 2011;129:332–7.

    PubMed  Google Scholar 

  4. Rios AC, Maurya PK, Pedrini M, Zeni-Graiff M, Asevedo E, Mansur RB, et al. Microbiota abnormalities and the therapeutic potential of probiotics in the treatment of mood disorders. Rev Neurosci. 2017;28:739–49.

    PubMed  Google Scholar 

  5. Dickerson F, Stallings C, Origoni A, Vaughan C, Khushalani S, Yolken R. Markers of gluten sensitivity in acute mania: a longitudinal study. Psychiatry Res. 2012;196:68–71.

    CAS  PubMed  Google Scholar 

  6. Saunders EF, Ramsden CE, Sherazy MS, Gelenberg AJ, Davis JM, Rapoport SI. Reconsidering dietary polyunsaturated fatty acids in bipolar disorder: a translational picture. J Clin Psychiatry. 2016;77:e1342–7.

    PubMed  PubMed Central  Google Scholar 

  7. Gonzalez-Estecha M, Trasobares EM, Tajima K, Cano S, Fernandez C, Lopez JL, et al. Trace elements in bipolar disorder. J Trace Elem Med Biol. 2011;25(Suppl 1):S78–83.

    CAS  PubMed  Google Scholar 

  8. Anderson G, Maes M. Bipolar disorder: role of immune-inflammatory cytokines, oxidative and nitrosative stress and tryptophan catabolites. Curr Psychiatry Rep. 2015;17:8.

    PubMed  Google Scholar 

  9. Severance EG, Tveiten D, Lindstrom LH, Yolken RH, Reichelt KL. The gut microbiota and the emergence of autoimmunity: relevance to major psychiatric disorders. Curr Pharm Des. 2016;22:6076–86.

    CAS  PubMed  PubMed Central  Google Scholar 

  10. Brown NC, Andreazza AC, Young LT. An updated meta-analysis of oxidative stress markers in bipolar disorder. Psychiatry Res. 2014;218:61–8.

    CAS  PubMed  Google Scholar 

  11. Severance EG, Lin J, Sampson HA, Gimenez G, Dickerson FB, Halling M, et al. Dietary antigens, epitope recognition, and immune complex formation in recent onset psychosis and long-term schizophrenia. Schizophr Res. 2011;126:43–50.

    PubMed  Google Scholar 

  12. Johnson IT. The cancer risk related to meat and meat products. Br Med Bull. 2017;121:73–81.

    PubMed  Google Scholar 

  13. Li Z, Rava M, Bedard A, Dumas O, Garcia-Aymerich J, Leynaert B, et al. Cured meat intake is associated with worsening asthma symptoms. Thorax. 2017;72:206–12.

    PubMed  Google Scholar 

  14. Dickerson F, Stallings C, Origoni A, Vaughan C, Katsafanas E, Khushalani S, et al. A combined marker of inflammation in individuals with mania. PLoS ONE. 2013;8:e73520.

    CAS  PubMed  PubMed Central  Google Scholar 

  15. Dickerson F, Katsafanas E, Schweinfurth LA, Savage CL, Stallings C, Origoni A, et al. Immune alterations in acute bipolar depression. Acta Psychiatr Scand. 2015;132:204–10.

    CAS  PubMed  Google Scholar 

  16. Dickerson FB, Boronow JJ, Stallings C, Origoni AE, Ruslanova I, Yolken RH. Association of serum antibodies to herpes simplex virus 1 with cognitive deficits in individuals with schizophrenia. Arch Gen Psychiatry. 2003;60:466–72.

    PubMed  Google Scholar 

  17. Spitzer RL, Williams JB, Gibbon M, First MB. The Structured Clinical Interview for DSM-III-R (SCID). I: history, rationale, and description. Arch Gen Psychiatry. 1992;49:624–9.

    CAS  PubMed  Google Scholar 

  18. Mesuere B, Debyser G, Aerts M, Devreese B, Vandamme P, Dawyndt P. The Unipept metaproteomics analysis pipeline. Proteomics. 2015;15:1437–42.

    CAS  PubMed  Google Scholar 

  19. Dickerson F, Stallings C, Sullens A, Origoni A, Leister F, Krivogorsky B, et al. Association between cognitive functioning, exposure to Herpes Simplex Virus type 1, and the COMT Val158Met genetic polymorphism in adults without a psychiatric disorder. Brain Behav Immun. 2008;22:1103–7.

    CAS  PubMed  Google Scholar 

  20. Randolph C, Tierney MC, Mohr E, Chase TN. The Repeatable Battery for the Assessment of Neuropsychological Status (RBANS): preliminary clinical validity. J Clin Exp Neuropsychol. 1998;20:310–9.

    CAS  PubMed  Google Scholar 

  21. Dickerson FB, Boronow JJ, Stallings CR, Origoni AE, Cole S, Yolken RH. Association between cognitive functioning and employment status of persons with bipolar disorder. Psychiatr Serv. 2004;55:54–8.

    PubMed  Google Scholar 

  22. Tsikas D, Fuchs I, Gutzki FM, Frolich JC. Measurement of nitrite and nitrate in plasma, serum and urine of humans by high-performance liquid chromatography, the Griess assay, chemiluminescence and gas chromatography-mass spectrometry: interferences by biogenic amines and N(G)-nitro-L-arginine analogs. J Chromatogr B Biomed Sci Appl. 1998;715:441–4. discussion 445-8.

    CAS  PubMed  Google Scholar 

  23. Dailey MJ, Stingl KC, Moran TH. Disassociation between preprandial gut peptide release and food-anticipatory activity. Endocrinology. 2012;153:132–42.

    CAS  PubMed  Google Scholar 

  24. Malkoff-Schwartz S, Frank E, Anderson BP, Hlastala SA, Luther JF, Sherrill JT, et al. Social rhythm disruption and stressful life events in the onset of bipolar and unipolar episodes. Psychol Med. 2000;30:1005–16.

    CAS  PubMed  Google Scholar 

  25. Sylvia LG, Alloy LB, Hafner JA, Gauger MC, Verdon K, Abramson LY. Life events and social rhythms in bipolar spectrum disorders: a prospective study. Behav Ther. 2009;40:131–41.

    PubMed  Google Scholar 

  26. Curing and smoking meats for home food preservation literature review and critical preservation points. http://nchfp.uga.edu/publications/nchfp/lit_rev/cure_smoke_rev.html 2002.

  27. Ellenbroek B, Youn J. Rodent models in neuroscience research: is it a rat race? Dis Model Mech. 2016;9:1079–87.

    CAS  PubMed  PubMed Central  Google Scholar 

  28. Meijer MK, Sommer R, Spruijt BM, van Zutphen LF, Baumans V. Influence of environmental enrichment and handling on the acute stress response in individually housed mice. Lab Anim. 2007;41:161–73.

    CAS  PubMed  Google Scholar 

  29. Kant AK, Graubard BI. 40-year trends in meal and snack eating behaviors of American adults. J Acad Nutr Diet. 2015;115:50–63.

    PubMed  Google Scholar 

  30. Walker R. Nitrates, nitrites and N-nitrosocompounds: a review of the occurrence in food and diet and the toxicological implications. Food Addit Contam. 1990;7:717–68.

    CAS  PubMed  Google Scholar 

  31. Zhu S, Cordner ZA, Xiong J, Chiu CT, Artola A, Zuo Y, et al. Genetic disruption of ankyrin-G in adult mouse forebrain causes cortical synapse alteration and behavior reminiscent of bipolar disorder. Proc Natl Acad Sci USA. 2017;114:10479–84.

    CAS  PubMed  Google Scholar 

  32. Young JW, Henry BL, Geyer MA. Predictive animal models of mania: hits, misses and future directions. Br J Pharmacol. 2011;164:1263–84.

    CAS  PubMed  PubMed Central  Google Scholar 

  33. Scott J, Murray G, Henry C, Morken G, Scott E, Angst J, et al. Activation in bipolar disorders: a systematic review. JAMA Psychiatry. 2017;74:189–96.

    PubMed  Google Scholar 

  34. Cheniaux E, Filgueiras A, Silva Rde A, Silveira LA, Nunes AL, Landeira-Fernandez J. Increased energy/activity, not mood changes, is the core feature of mania. J Affect Disord. 2014;152-4:256–61.

    Google Scholar 

  35. Kirshenbaum GS, Clapcote SJ, Duffy S, Burgess CR, Petersen J, Jarowek KJ, et al. Mania-like behavior induced by genetic dysfunction of the neuron-specific Na+,K+-ATPase alpha3 sodium pump. Proc Natl Acad Sci USA. 2011;108:18144–9.

    CAS  PubMed  Google Scholar 

  36. Abulseoud OA, Camsari UM, Ruby CL, Mohamed K, Abdel Gawad NM, Kasasbeh A, et al. Lateral hypothalamic kindling induces manic-like behavior in rats: a novel animal model. Int J Bipolar Disord. 2014;2:7.

    PubMed  PubMed Central  Google Scholar 

  37. Nowland MH, Hugunin KM, Rogers KL. Effects of short-term fasting in male Sprague-Dawley rats. Comp Med. 2011;61:138–44.

    CAS  PubMed  PubMed Central  Google Scholar 

  38. Henry BL, Minassian A, Young JW, Paulus MP, Geyer MA, Perry W. Cross-species assessments of motor and exploratory behavior related to bipolar disorder. Neurosci Biobehav Rev. 2010;34:1296–306.

    PubMed  PubMed Central  Google Scholar 

  39. Perry W, Minassian A, Henry B, Kincaid M, Young JW, Geyer MA. Quantifying over-activity in bipolar and schizophrenia patients in a human open field paradigm. Psychiatry Res. 2010;178:84–91.

    PubMed  PubMed Central  Google Scholar 

  40. Logan RW, McClung CA. Animal models of bipolar mania: the past, present and future. Neuroscience. 2016;321:163–88.

    CAS  PubMed  Google Scholar 

  41. Oliveira J, Busson M, Etain B, Jamain S, Hamdani N, Boukouaci W, et al. Polymorphism of Toll-like receptor 4 gene in bipolar disorder. J Affect Disord. 2014;152:395–402.

    PubMed  Google Scholar 

  42. Bueno BG, Caso JR, Madrigal JLM, Leza JC. Innate immune receptor Toll-like receptor 4 signalling in neuropsychiatric diseases. Neurosci Biobehav Rev. 2016;64:134–47.

    Google Scholar 

  43. Elhaik E, Zandi P. Dysregulation of the NF-kappa B pathway as a potential inducer of bipolar disorder. J Psychiatr Res. 2015;70:18–27.

    PubMed  Google Scholar 

  44. Frye MA, McElroy SL, Prieto ML, Harper KL, Walker DL, Kung S, et al. Clinical risk factors and serotonin transporter gene variants associated with antidepressant-induced mania. J Clin Psychiatry. 2015;76:174–80.

    PubMed  Google Scholar 

  45. Xu W, Cohen-Woods S, Chen Q, Noor A, Knight J, Hosang G, et al. Genome-wide association study of bipolar disorder in Canadian and UK populations corroborates disease loci including SYNE1 and CSMD1. BMC Med Genet. 2014;15:2.

    PubMed  PubMed Central  Google Scholar 

  46. Bondonno CP, Croft KD, Ward N, Considine MJ, Hodgson JM. Dietary flavonoids and nitrate: effects on nitric oxide and vascular function. Nutr Rev. 2015;73:216–35.

    PubMed  Google Scholar 

  47. Andreazza AC, Kauer-Sant’anna M, Frey BN, Bond DJ, Kapczinski F, Young LT, et al. Oxidative stress markers in bipolar disorder: a meta-analysis. J Affect Disord. 2008;111:135–44.

    CAS  PubMed  Google Scholar 

  48. Moreira FA, Guimaraes FS. Role of serotonin receptors in panic-like behavior induced by nitric oxide in the rat dorsolateral periaqueductal gray: effects of chronic clomipramine treatment. Life Sci. 2005;77:1972–82.

    CAS  PubMed  Google Scholar 

  49. Ukil A, Biswas A, Das T, Das PK. 18 Beta-glycyrrhetinic acid triggers curative Th1 response and nitric oxide up-regulation in experimental visceral leishmaniasis associated with the activation of NF-kappa B. J Immunol. 2005;175:1161–9.

    CAS  PubMed  Google Scholar 

  50. Abdul-Cader MS, Amarasinghe A, Abdul-Careem MF. Activation of toll-like receptor signaling pathways leading to nitric oxide-mediated antiviral responses. Arch Virol. 2016;161:2075–86.

    CAS  PubMed  Google Scholar 

  51. Schmitz EI, Potteck H, Schuppel M, Manggau M, Wahydin E, Kleuser B. Sphingosine 1-phosphate protects primary human keratinocytes from apoptosis via nitric oxide formation through the receptor subtype S1P(3). Mol Cell Biochem. 2012;371:165–76.

    CAS  PubMed  Google Scholar 

  52. Evans SJ, Bassis CM, Hein R, Assari S, Flowers SA, Kelly MB, et al. The gut microbiome composition associates with bipolar disorder and illness severity. J Psychiatr Res. 2017;87:23–9.

    PubMed  Google Scholar 

  53. Schwarz E, Maukonen J, Hyytiainen T, Kieseppa T, Oresic M, Sabunciyan S, et al. Analysis of microbiota in first episode psychosis identifies preliminary associations with symptom severity and treatment response. Schizophr Res. 2017;92:398–403.

    Google Scholar 

  54. Dickerson F, Severance E, Yolken R. The microbiome, immunity, and schizophrenia and bipolar disorder. Brain Behav Immun. 2017;62:46–52.

    CAS  PubMed  Google Scholar 

  55. Guida F, Turco F, Iannotta M, De Gregorio D, Palumbo I, Sarnelli G, et al. Antibiotic-induced microbiota perturbation causes gut endocannabinoidome changes, hippocampal neuroglial reorganization and depression in mice. Brain Behav Immun. 2017;67:230–45.

    PubMed  Google Scholar 

  56. Gacias M, Gaspari S, Santos PM, Tamburini S, Andrade M, Zhang F, et al. Microbiota-driven transcriptional changes in prefrontal cortex override genetic differences in social behavior. eLife. 2016;5:e13442.

    PubMed  PubMed Central  Google Scholar 

  57. Magnusson KR, Hauck L, Jeffrey BM, Elias V, Humphrey A, Nath R, et al. Relationships between diet-related changes in the gut microbiome and cognitive flexibility. Neuroscience. 2015;300:128–40.

    CAS  PubMed  Google Scholar 

  58. Gomez-Arango LF, Barrett HL, McIntyre HD, Callaway LK, Morrison M, Dekker Nitert M, et al. Connections between the gut microbiome and metabolic hormones in early pregnancy in overweight and obese women. Diabetes. 2016;65:2214–23.

    CAS  PubMed  Google Scholar 

  59. Cooper DN, Kable ME, Marco ML, De Leon A, Rust B, Baker JE, et al. The effects of moderate whole grain consumption on fasting glucose and lipids, gastrointestinal symptoms, and microbiota. Nutrients. 2017;9:E173.

    PubMed  Google Scholar 

  60. Pereira C, Ferreira NR, Rocha BS, Barbosa RM, Laranjinha J. The redox interplay between nitrite and nitric oxide: from the gut to the brain. Redox Biol. 2013;1:276–84.

    CAS  PubMed  PubMed Central  Google Scholar 

  61. Rohrmann S, Linseisen J. Processed meat: the real villain? Proc Nutr Soc. 2016;75:233–41.

    CAS  PubMed  Google Scholar 

Download references

Acknowledgements

This work was supported by a NIMH P50 Silvio O. Conte Center at Johns Hopkins (grant# MH-94268), the American Academy of Neurology Medical Student Research Award, the William C. Walker fund of the Johns Hopkins Department of Psychiatry and Behavioral Science, and by the Stanley Medical Research Institute.

Author information

Author notes

  1. Gretha J. Boersma

    Present address: GGZ Drenthe Mental Health Institute, Department of Forensic Psychiatry, Assen, The Netherlands

Authors and Affiliations

  1. Department of Psychiatry and Behavioral Sciences, Johns Hopkins School of Medicine, Baltimore, MD, USA

    Seva G. Khambadkone, Zachary A. Cordner, Mikhail Pletnikov, Gretha J. Boersma, Timothy H. Moran & Kellie L. Tamashiro

  2. Cellular and Molecular Medicine Graduate Program, Johns Hopkins University School of Medicine, Baltimore, MD, USA

    Seva G. Khambadkone, Timothy H. Moran & Kellie L. Tamashiro

  3. Sheppard Pratt Health System, Baltimore, MD, USA

    Faith Dickerson

  4. Department of Pediatrics, Johns Hopkins University School of Medicine, Baltimore, MD, USA

    Emily G. Severance, Emese Prandovszky, Jianchun Xiao, Ye Li & Robert H. Yolken

  5. Institute for Basic Biomedical Sciences, Johns Hopkins University School of Medicine, Baltimore, MD, USA

    C. Conover Talbot Jr.

  6. Department of Nutrition Science, Purdue University, West Lafayette, IN, USA

    Wayne W. Campbell & Christian S. Wright

  7. Mobtown Meatsnacks, Baltimore, MD, USA

    C. Evan Siple

Authors
  1. Seva G. Khambadkone
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Zachary A. Cordner
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Faith Dickerson
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Emily G. Severance
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Emese Prandovszky
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Mikhail Pletnikov
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Jianchun Xiao
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Ye Li
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Gretha J. Boersma
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. C. Conover Talbot Jr.
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Wayne W. Campbell
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Christian S. Wright
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. C. Evan Siple
    View author publications

    You can also search for this author in PubMed Google Scholar

  14. Timothy H. Moran
    View author publications

    You can also search for this author in PubMed Google Scholar

  15. Kellie L. Tamashiro
    View author publications

    You can also search for this author in PubMed Google Scholar

  16. Robert H. Yolken
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Robert H. Yolken.

Ethics declarations

Conflict of interest

The authors declare that they have no conflict of interest.

Electronic supplementary material

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Khambadkone, S.G., Cordner, Z.A., Dickerson, F. et al. Nitrated meat products are associated with mania in humans and altered behavior and brain gene expression in rats. Mol Psychiatry 25, 560–571 (2020). https://doi.org/10.1038/s41380-018-0105-6

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41380-018-0105-6

This article is cited by

Search

Advanced search

Quick links