The gut microbiome composition associates with bipolar disorder and illness severity
Introduction
Accumulated evidence over the past decade supports a bi-directional relationship between the modifiable gut microbiome, mood and cognitive dysfunction. Schizophrenic and bipolar subjects show increased markers of bacterial translocation from the intestinal lumen (compared to controls), which may underlie increased inflammation (Severance et al., 2013) known to be a component of these disorders. In depressed subjects compared to controls, a survey of the stool microbiota showed increased Bacteroidetes, Proteobacteria and Actinobacteria and reduced Firmicutes Faecalibacterium, the latter of which negatively associated with severity of depression (Naseribafrouei et al., 2014, Jiang et al., 2015). Intervention studies in humans suggest a benefit of microbiome manipulation for clinical psychiatric outcomes. Supplementation of L. helviticus and Bifobacterium longum, which reduce anxiety-like behavior in rats, reduced psychological distress in humans (Messaoudi et al., 2011). Patients with gastrointestinal disorder, which is highly comorbid with psychiatric conditions, who consumed fermented milk that contained B. bifidum, showed improvement in gastrointestinal and psychological symptoms (Urita et al., 2015). In a small, randomized control trial of a multi-species pro-biotic in depressed adults, the pro-biotic treatment significantly reduced cognitive activity toward depressed mood when compared to placebo (Steenbergen et al., 2015). These studies suggest that targeted manipulation of the microbiome can be beneficial for mood state in a psychiatric population.
Animal studies support a neurochemical mechanism for the effect of microbiome manipulation on behavior. Treating mice with pre-biotics (Savignac et al., 2013) or antibiotics (Desbonnet et al., 2015) influenced brain derived neurotrophic factor activity, NMDA glutamate receptors, oxytocin, vasopressin and central tryptophan metabolism. Diet induced disruption of the mouse microbiome is concomitant with changes in anxiety-like behavior (Kang et al., 2014, Pyndt Jorgensen et al., 2014), depressive-like behaviors (Pyndt Jorgensen et al., 2014), and cognitive performance (Kang et al., 2014, Magnusson et al., 2015). Disruption of the mouse enteric microbiota by infection can mediate stress-induced memory dysfunction and this can be normalized by probiotic (Gareau et al., 2011) and prebiotic treatment (Savignac et al., 2016). Taken together, these studies demonstrate that the gut microbiome is responsive to many physiological stimuli associated with the induction of affective disorders and relevant central circuitry, and that targeting the integrity of the microbiome with prebiotic and probiotic therapies may attenuate or prevent dysregulation.
In the current study we surveyed the stool microbiome of bipolar and control subjects from the Prechter Longitudinal Study of Bipolar Disorder, housed at the University of Michigan. This is a deep phenotyping longitudinal study for which we collect bi-monthly self-report measures of physical and mental health, allowing us to compare the taxonomical complement of the stool microbiome with self-reported burden of disease measures.
Section snippets
Methods and materials
Human Subjects: All subjects in the current study were recruited from the Heinz C. Prechter Longitudinal Study of Bipolar Disorder at the University of Michigan Depression Center (Langenecker et al., 2010). All individuals were diagnosed using the Diagnostic Interview for Genetic Studies (DIGS) (Nurnberger et al., 1994) and included in this current study are bipolar individuals adhering to the DSM IV diagnostic criteria (American Psychiatric Association, 2000) and healthy unaffected controls
Results
Of the 825 stool collection kits mailed out to our longitudinal study participants with request to opt-in to the current sub study, 247 were returned and submitted for microbiome analysis. Quality 16S rRNA-encoding gene sequence data was generated from 233 (a 5.7% failure to generate quality sequence data) and 179 were used in the current analysis. The remaining 54 were excluded with their diagnosis yet to be confirmed (n = 38) or a non-bipolar DSM IV diagnosis of Schizo Affective, 295.70 M
Discussion
In the current study we report an analysis of stool microbiome samples collected from bipolar individuals and healthy controls who are participants of the Prechter Longitudinal Study of Bipolar Disorder at the University of Michigan. We found significant differences between the global microbiome communities and specific OTUs in individuals with bipolar disorder, compared to controls. We also found significant relationships between fractional representation of several OTUs and self-reported
Conflict of interest
Dr. McInnis reports having served as a consultant for Janssen Pharmaceuticals. Dr. Young reports having received consulting fees from Merck and Vedanta, and research funding from MedImmune. No other authors have anything to disclose.
Contributors
SJE designed the study, organized the collection of data and wrote the manuscript; CMB performed the microbiome analysis assays, aided in the bioinformatics analysis and edited the manuscript; RH performed the bioinformatics analyses, SA aided in the secondary statistical analyses of processed data and edited the manuscript; SAF performed the analysis of psychiatric medication effects and edited the manuscript; MBK aided in subject recruitment; VBY aided supervised the bioinformatics and
Role of funding sources
This work is supported by the Heinz C. Prechter Bipolar Research Fund and the Richard Tam Foundation at the University of Michigan Depression Center; NIH Grant # 5-K01-MH-093708-04 (Evans); and The University of Michigan Medical School Host Microbiome Initiative.
Acknowledgments
The authors would like the thank the team at the ARC, http://arc.umich.edu/flux-and-other-hpc-resources/flux/citations/, for their technical assistance with the flux computational power used for analysis of microbial genetic data.
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