Tryptophan Metabolism and White Matter Integrity in Schizophrenia

Chiappelli, Joshua; Postolache, Teodor T.; Kochunov, Peter; Rowland, Laura M.; Wijtenburg, S. Andrea; Shukla, D. K.; Tagamets, Malle A.; Du, Xiaoming; Savransky, Anya; Lowry, Christopher A.; Can, Adem; Fuchs, Dietmar; Hong, L. Elliot

doi:10.1038/npp.2016.66

Cited by 67 publications

(51 citation statements)

References 63 publications

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“…Astrocytes are known to be involved in synaptic metabolism and regulation of neurotransmitter release and reuptake (e.g., GABA and glutamate) and thereby critical for psychosis development[54]. Our pathway analysis found significant enrichment of the module genes in some SCZ-related KEGG metabolic pathways involving the metabolism on fatty acid [55], glycine [56], glutamate [57] and tryptophan [58], as shown in Fig.S9(A) (Supplementary file 1). Compared to the yellow module, the magenta module expression was also up-regulated in SCZ, but more specific to endothelial cells and microglia with genes mainly related with immune response.…”

Section: Discussionmentioning

confidence: 99%

Network modules linking expression and methylation in prefrontal cortex of schizophrenia

Lin

Chen

Perrone‐Bizzozero

et al. 2018

Preprint

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Tremendous work has demonstrated the critical roles of genetics, epigenetics as well as their interplay in brain transcriptional regulations in the pathology of schizophrenia (SCZ). There is great success currently in the dissection of the genetic components underlying risk-conferring transcriptomic networks. However, the study of regulating effect of epigenetics, as a modulator of environmental factors, in the etiopathogenesis of SCZ still faces many challenges. In this work we investigated DNA methylation and gene expression from the dorsolateral prefrontal cortex (DLPFC) region of schizophrenia patients and healthy controls using weighted correlation network approaches. We identified and replicated two expression and two methylation modules significantly associated with SCZ. Among them, one pair of expression and methylation modules were significantly overlapped in the module genes which were enriched in astrocyte-associated functional pathways, and specifically expressed in astrocytes. Another two linked expressionmethylation module pairs were involved aging process with module genes mostly related to oligodendrocyte development and myelination, and specially expressed in oligodendrocytes.Further examination of underlying quantitative trait loci (QTLs) showed significant enrichment in genetic risk of most psychiatric disorders for expression QTLs but not for methylation QTLs.These results support the coherence between methylation and gene expression in a network level, and suggest a combinatorial effect of genetics and epigenetics in regulating gene expression networks specific to glia cells in relation with SCZ and aging process.reported 20~50% of SCZ risk loci [13] showing strong cis-effect to their nearby genes' expression, further elaborating the liability of these risk variants in etiology of SCZ [14, 15]. Coexpression network analyses of brain expression data have identified some modules highly associated with SCZ harboring the SCZ risk loci with strong cis-acting effects [15, 16].However, some co-expression modules show discrepancy in relation with SCZ and the polygenic risk score for SCZ. Several SCZ-related modules fail to be significantly enriched in SCZ genetic susceptibility [14]. In addition, differentially expressed genes could have diverse patterns among brain regions [17], neural cells [18, 19] and neural developmental stages [20]. Collectively, these findings suggest the influence of complex interplay of genetics and environmental factors in determining the process of gene expression.Epigenetics can mediate gene by environment effects in modifying how genes are structured and expressed. DNA methylation is an epigenetic modification widely studied in psychiatric disorders such as SCZ [21, 22]. It changes the genome's response to transcriptional factors by attaching a methyl group in DNA sequence (mostly on cytosine site as CpG). The influence of DNA methylation in gene transcription can be stable and heritable across cell generations, and also reversible according to external condition chang...

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Section: Discussionmentioning

confidence: 99%

Network modules linking expression and methylation in prefrontal cortex of schizophrenia

Lin

Chen

Perrone‐Bizzozero

et al. 2018

Preprint

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“…Increased TDO expression [5,6] and elevated concentrations of kynurenine and KYNA [6][7][8] have been repeatedly found in postmortem brain tissue and in cerebrospinal fluid (CSF; [9][10][11]) of individuals with SZ. In contrast, although increased kynurenine: tryptophan ratios have been reported in the plasma of SZ patients [12][13][14], findings for peripheral KYNA levels in the disease have so far been inconsistent [15,16].…”

Section: Introductionmentioning

confidence: 99%

Influence of plasma cytokines on kynurenine and kynurenic acid in schizophrenia

Chiappelli

Notarangelo

Pocivavsek

et al. 2018

Neuropsychopharmacol

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Abnormalities in the kynurenine pathway (KP) of tryptophan degradation, leading to the dysfunction of neuroactive KP metabolites in the brain, have been implicated in the pathophysiology of schizophrenia (SZ). One plausible mechanism involves dysregulation of various pro-inflammatory cytokines associated with the disease, which affect indoleamine-2,3-dioxygenase (IDO), a key enzyme for tryptophan to kynurenine conversion. In order to test this hypothesis directly, we measured plasma levels of the major KP metabolites kynurenine and kynurenic acid (KYNA), as well as four major cytokines, in a sample of 106 SZ patients and 104 control participants. In contrast to the replicable findings of elevation of KYNA in the central nervous system in SZ, plasma levels of KYNA were significantly lower in SZ compared to controls (p = .004). Kynurenine levels were significantly correlated with levels of interferon-γ (p < .001), which is involved in the regulation of IDO, in both patients and controls. However, although patients had higher levels of interleukin-6 (IL-6) compared to controls (p = .012), IL-6 levels were not correlated with kynurenine or KYNA, and did not explain group differences in KYNA. Based on the lack of evidence that pro-inflammatory cytokines were significantly related to the KP abnormality in SZ despite an adequate sample size, further studies must consider alternative hypotheses to identify the origins of the KP abnormalities in SZ.

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“…Using this database, we identified 27 schizophrenia-associated GBMs, which give clues about how the gut microbiota might modulate the pathophysiology of schizophrenia. Among these GBMs, a few well-known molecular entities associated with schizophrenia were covered, such as several kinds of neurotransmitters 2–4 and tryptophan metabolites 65,66 . Furthermore, some microbes presenting these GBMs were significantly associated with the serum levels of several neurotransmitters and tryptophan metabolites.…”

Section: Discussionmentioning

confidence: 99%

Identification of gut microbiome markers for schizophrenia delineates a potential role of Streptococcus

Zhu

Wang

et al. 2019

Preprint

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46Emerging evidence has linked the gut microbiota to schizophrenia. However, the 47 functional changes in the gut microbiota and the biological role of individual bacterial 48 species in schizophrenia have not been explored systematically. Here, we 49 characterized the gut microbiota in schizophrenia using shotgun metagenomic 50 sequencing of feces from a discovery cohort of 90 drug-free patients and 81 controls, 51 as well as a validation cohort of 45 patients taking antipsychotics and 45 controls. We 52 screened 83 schizophrenia-associated bacterial species and constructed a classifier 53 comprising 26 microbial biomarkers that distinguished patients from controls with a 54 0.896 area under the receiver operating characteristics curve (AUC) in the discovery 55 cohort and 0.765 AUC in the validation cohort. Our analysis of fecal metagenomes 56 revealed that schizophrenia-associated gut-brain modules included short-chain fatty 57 acids synthesis, tryptophan metabolism, and synthesis/degradation of 58 neurotransmitters including glutamate, γ-aminobutyric acid, and nitric oxide. The 59 schizophrenia-enriched gut bacterial species include several oral cavity-resident 60 microbes, such as Streptococcus vestibularis. We transplanted Streptococcus 61 vestibularis into the gut of the mice with antibiotic-induced microbiota depletion to 62 explore its functional role. We observed that this microbe transiently inhabited the 63 mouse gut and this was followed by hyperactivity and deficit in social behaviors, 64 accompanied with altered neurotransmitter levels in peripheral tissues. In conclusion, 65 our study identified 26 schizophrenia-associated bacterial species representing 66 potential microbial targets for future treatment, as well as gut-brain modules, some of 67 which may give rise to new microbial metabolites involved in the development of 68 schizophrenia. 69 70 Schizophrenia is a severe psychiatric disorder associated with hallucinations, 71 delusions, and thought disorders perturbing perception and social interaction 1 . The 72 etiology of schizophrenia is not elucidated, but assumed to be multifactorial involving 73 genetic and environmental factors. Abnormalities of neurotransmitter systems have 74 been extensively studied especially focusing on aberration of signaling involving 75 dopamine, glutamate, and γ-aminobutyric acid (GABA) 2-4 . Increasing evidence 76 indicates that schizophrenia may be a systemic disorder with neuropsychiatric 77 conditions in addition to psychosis 5 . Furthermore, the importance of inflammation 6 78 and the involvement of the gastrointestinal system 7 in schizophrenia have received 79 attention. 80 The gut microbiota is reported to play an important role in neurogenerative 81 processes, and perturbation of the microbiota and microbial products have been 82 demonstrated to affect behavior 8-10 . Changes in the gut microbiota have been 83 associated with neurological 11 and neurodevelopmental disorders 12,13 , including 84 schizophrenia 14 . It was recently reported that fecal tr...

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Tryptophan Metabolism and White Matter Integrity in Schizophrenia

Cited by 67 publications

References 63 publications

Network modules linking expression and methylation in prefrontal cortex of schizophrenia

Network modules linking expression and methylation in prefrontal cortex of schizophrenia

Influence of plasma cytokines on kynurenine and kynurenic acid in schizophrenia

Identification of gut microbiome markers for schizophrenia delineates a potential role of Streptococcus

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