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

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.

Fig. 1

Adjusted odds ratios associated with a food exposure and having the indicated psychiatric diagnosis as compared to controls. Adjusted odds ratios are calculated by multiple logistic regression and adjusted for age, sex, race, socioeconomic status, body mass index, current cigarette smoking, and multiple comparisons. *p < 9 × 10⁻⁸

Fig. 2. a–g

Rats consuming nitrated cured meat or a purified beef-based diet dosed with sodium nitrate exhibit mania-like hyperactivity. a–c Longitudinal activity monitoring. Rats consuming nitrated cured meat exhibit locomotor hyperactivity in comparison to rats consuming standard chow only or cured meat prepared with no preservatives. Rats consuming a purified beef-based diet with added sodium nitrate display locomotor hyperactivity within the first 2 h of a 22-h longitudinal activity monitoring test in comparison to rats consuming an identical purified beef-based diet without added sodium nitrate. d–g Activity in a novel environment. Rats consuming nitrated cured meat or a purified beef-based diet dosed with sodium nitrate exhibit novelty-induced hyperactivity over a 10-min period compared to rats consuming either a purified standard chow diet or an identical purified beef-based diet without added sodium nitrate. *p < 0.05 compared to the indicated groups

Fig. 3. a–d

Rats consuming a purified beef-based diet dosed with sodium nitrate exhibit alterations in gene expression in the hippocampus. Ingenuity pathways depicted with member genes are color-coded to show expression fold change within the hippocampus of rats fed ChowAIN+Beef+Nitrate (33.9 mg/kg nitrate) as compared to rats fed ChowAIN+Beef (0 mg/kg nitrate). Genes demonstrating >2 SD fold changes are highlighted. The numbers shown represent the log ratio of expression change between the two groups. Additional explanation of the color coding can be seen in supplemental figure S2. Individual genes that comprise the pathways are depicted in supplemental Table S7. The pathways depicted represent a serotonin receptor signaling (p < 0.0009), b role of pattern recognition receptors in recognition of bacteria and viruses (p < 0.001), c NF-κB signaling (p < 0.009), and d sphingosine-1-phosphate signaling (p < 0.009)

Fig. 4

Comparison of the microbiota of rats fed control and nitrate-added diets. Arrows and coloring indicate the microbial taxa that differ significantly between the groups: Lachnospiraceae (pink, p < 0.002) and Erysipelotrichales (orange, p < 0.009). Phyla shown are Firmicutes (brown), Actinobacteria (blue), Fusobacteria (green), and Proteobacteria (purple)