A range of study results indicates that environmental factors may influence the pathogenesis of bipolar disorder (BPD) and other neuropsychiatric disorders.1 Among these, diet has been suggested to contribute to the risk for mania via mechanisms such as manipulation of the gut microbiome,2 neurotoxicity from consumption of foods containing trace metals,3 and several other proposed pathways.1
In a recent study published in Molecular Psychiatry, researchers examined associations between dietary exposure to various meats and fish and mania (n=217), bipolar depression (n=91), major depressive disorder (n=79), schizophrenia (n=371), and nonpsychiatric controls (n=343).1 Adult patients were recruited from a psychiatric setting providing inpatient and day hospital treatment.
The findings show a strong and independent link between current mania and a history of eating nitrated dry cured meat such as beef jerky (adjusted odds ratio, 3.49; 95% CI, 2.24-5.45; P <8.97×10−8). This association was less likely to be present with other psychiatric disorders, and was not observed for other meat or fish products.
The investigators subsequently explored the effects of feeding nitrated meat to rats and found “hyperactivity reminiscent of human mania, alterations in brain pathways that have been implicated in human BPD, and changes in intestinal microbiota,” they reported. “These ﬁndings may lead to new methods for preventing mania and for developing novel therapeutic interventions.”
Psychiatry Advisor interviewed 1 of the study authors, Seva G. Khambadkone, a MD-PhD candidate and researcher in the laboratory of Kellie L. Tamashiro, PhD, at Johns Hopkins School of Medicine, Baltimore, Maryland.
Psychiatry Advisor: What are the potential mechanisms by which nitrated dry cured meat may be connected to mania in BPD, whereas other meats are not?
Dr Khambadkone: Our results suggest that the nitrates in cured meat are driving the association between cured meat consumption and mania. First, after an interim analysis of our human survey indicating an association between cured meat consumption and a diagnosis of mania, a subset of participants was queried on what type of cured meat (beef jerky, turkey jerky, meat sticks, prosciutto, salami, or other) was consumed. Within this subset, consumption of beef jerky, turkey jerky, and meat sticks (cured meat products generally prepared with nitrates/nitrites) were each significantly associated with a diagnosis of mania, whereas consumption of cured meat generally prepared without nitrates (such as prosciutto and salami) did not influence the odds of a mania diagnosis.
Second, when we provided rats with either cured meat prepared with or without nitrates or a purified meat-based diet prepared with or without nitrates in 2 separate experiments, only the rats consuming nitrated meat products displayed mania-like behavioral and brain changes. Rats consuming a meat-based diet prepared without nitrates, whether in the form of cured meat or a purified diet, behaved similarly to controls.
Follow-up studies would be needed to determine specific mechanisms linking nitrated cured meat consumption with mania. However, our rodent studies, as well as several other recent studies in the field suggesting gut microbiota changes in human patients with BPD, suggest that 1 way nitrated cured meat consumption may influence brain and behavior is by manipulating the gut microbiome. How changes to the gut microbiome may act on the brain is still an active area of study, but proposed mechanisms are through activation of the immune system, secretion of neurotransmitter metabolites, and changes to gut permeability, altering bloodstream access to both bacterial and host metabolites.
Interestingly, dietary nitrate content has previously been shown to affect plasma levels of nitric oxide, and nitric oxide in turn has been implicated in BPD, with significantly increased plasma nitric oxide found in patients with BPD compared with healthy control patients. Nitric oxide is also known to interact with several physiological pathways that have previously been implicated in BPD, and are also the same pathways we found to be dysregulated in rats consuming a nitrated meat diet. We are currently planning studies to better elucidate this and other potential mechanisms.
Psychiatry Advisor: What are the current and future treatment implications of these findings for our clinician audience: Should they advise patients to limit their intake of nitrated dry cured meats, for example?
Dr Khambadkone: At this point we are not able to speculate on treatment implications for individuals at risk for mania. As they stand, our findings only tell us that patients hospitalized with mania had an increased history of cured meat consumption compared with healthy control patients, and that in animal studies, the consumption of nitrated cured meat led to mania-like behavior and brain changes in rats. Although this suggests that reducing intake of nitrate-prepared processed meat may have a beneficial effect in individuals at risk for mania, we would need additional studies to determine whether and how a change in diet could reduce incidence or severity of manic symptomatology.
Psychiatry Advisor: What are additional important takeaways you would like to note regarding this topic?
Dr Khambadkone: Although follow-up studies would be required to speculate on specific dietary recommendations, this study adds to the growing body of evidence that environmental risk factors, including dietary components, play a role in mediating the emergence and severity of neuropsychiatric disease. In turn, it suggests that modification of the environment may have preventative or therapeutic consequences. By adding to this field, we hope not only to better understand the etiology of neuropsychiatric illness but also to contribute to the development of environmental interventions that, in combination with existing treatment, could help patients and physicians better manage disease.
Psychiatry Advisor: What are some of the remaining research needs in this area?
Dr Khambadkone: It is critical to evaluate this association in other patient cohorts. Although we attempted to account for potential confounds in our study design and analysis, it would be important to replicate this finding in an independent population. In addition, as the human arm of our study did not evaluate timing or amount of nitrated cured meat exposure, future human studies would aim to better elucidate how the time course and dosage of exposure could relate to symptomatology. We are also planning additional animal studies to investigate putative mechanisms linking dietary exposure to nitrated meat and behavioral and physiological outcomes, building off of our published findings.
- Khambadkone SG, Cordner ZA, Dickerson F, et al. Nitrated meat products are associated with mania in humans and altered behavior and brain gene expression in rats [published online July 18, 2018]. Mol Psychiatry. doi: 10.1038/s41380-018-0105-6
- 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(40):6076-6086.
- Gonzalez-Estecha M, Trasobares EM, Tajima K, et al. Trace elements in bipolar disorder. J Trace Elem Med Biol. 2011;25(Suppl 1):S78-S83.