Summaries of plenary, symposia, and oral sessions at the XXII World Congress of Psychiatric Genetics, Copenhagen, Denmark, 12-16 October 2014

The XXII World Congress of Psychiatric Genetics, sponsored by the International Society of Psychiatric Genetics, took place in Copenhagen, Denmark, on 12-16 October 2014. A total of 883 participants gathered to discuss the latest findings in the field. The following report was written by student and postdoctoral attendees. Each was assigned one or more sessions as a rapporteur. This manuscript represents topics covered in most, but not all of the oral presentations during the conference, and contains some of the major notable new findings reported

Beyond the looking glass: recent advances in understanding the impact of environmental exposures on neuropsychiatric disease

The etiologic pathways leading to neuropsychiatric diseases remain poorly defined. As genomic technologies have advanced over the past several decades, considerable progress has been made linking neuropsychiatric disorders to genetic underpinnings. Interest and consideration of nongenetic risk factors (e.g., lead exposure and schizophrenia) have, in contrast, lagged behind heritable frameworks of explanation. Thus, the association of neuropsychiatric illness to environmental chemical exposure, and their potential interactions with genetic susceptibility, are largely unexplored. In this review, we describe emerging approaches for considering the impact of chemical risk factors acting alone and in concert with genetic risk, and point to the potential role of epigenetics in mediating exposure effects on transcription of genes implicated in mental disorders. We highlight recent examples of research in nongenetic risk factors in psychiatric disorders that point to potential shared biological mechanisms—synaptic dysfunction, immune alterations, and gut–brain interactions. We outline new tools and resources that can be harnessed for the study of environmental factors in psychiatric disorders. These tools, combined with emerging experimental evidence, suggest that there is a need to broadly incorporate environmental exposures in psychiatric research, with the ultimate goal of identifying modifiable risk factors and informing new treatment strategies for neuropsychiatric disease

An updated overview on the relationship between human gut microbiome dysbiosis and psychiatric and psychological disorders

Existe mucha evidencia que establece que el desarrollo del sistema nervioso está relacionado con la composición y funciones del microbioma intestinal. Además, el sistema nervioso central (SNC) controla el desequilibrio de la microbiota intestinal, constituyendo un sistema de comunicación bidireccional. En la actualidad, se han descrito varias rutas de comunicación entre el intestino y el cerebro, incluidos circuitos inmunológicos, endocrinos y neuronales a través de la vía vagal. Varios datos empíricos han asociado alteraciones de la microbiota intestinal (disbiosis) con enfermedades neuropsiquiátricas, como Enfermedad de Alzheimer, autismo y enfermedad de Parkinson, y con otros trastornos psicológicos, como ansiedad y depresión. La terapia de trasplante de microbiota fecal (FMT) ha demostrado que la microbiota intestinal puede transferir características de comportamiento a los animales receptores, lo que proporciona pruebas sólidas para establecer una relación causal-efecto. Las intervenciones, basadas en prebióticos, probióticos o simbióticos, han demostrado una importante influencia de la microbiota en los trastornos neurológicos mediante la síntesis de compuestos neuroactivos que interactúan con el sistema nervioso y por la regulación de procesos inflamatorios y endocrinos. Se necesitan más investigaciones para demostrar la influencia de la disbiosis de la microbiota intestinal en los trastornos psiquiátricos y psicológicos, y cómo las intervenciones basadas en la microbiota pueden usarse como posibles herramientas terapéuticas.Funding for open access charge: Universidad de Málaga / CBU

Exploring the role of gut microbiota in major depressive disorder and in treatment resistance to antidepressants

Major depressive disorder (MDD) is a common severe psychiatric illness, exhibiting suboptimal response to existing pharmacological treatments. Although its etiopathogenesis is still not completely understood, recent findings suggest that an altered composition of the gut microbiota might play a role. Here we aimed to explore potential differences in the composition of the gut microbiota between patients with MDD and healthy controls (HC) and to identify possible signatures of treatment response by analyzing two groups of MDD patients characterized as treatment-resistant (TR) or responders (R) to antidepressants. Stool samples were collected from 34 MDD patients (8 TR, 19 R and 7 untreated) and 20 HC. Microbiota was characterized using the 16S metagenomic approach. A penalized logistic regression analysis algorithm was applied to identify bacterial populations that best discriminate the diagnostic groups. Statistically significant differences were identified for the families of Paenibacillaceae and Flavobacteriaceaea, for the genus Fenollaria, and the species Flintibacter butyricus, Christensenella timonensis, and Eisenbergiella massiliensis among others. The phyla Proteobacteria, Tenericutes and the family Peptostreptococcaceae were more abundant in TR, whereas the phylum Actinobacteria was enriched in R patients. Moreover, a number of bacteria only characterized the microbiota of TR patients, and many others were only detected in R. Our results confirm that dysbiosis is a hallmark of MDD and suggest that microbiota of TR patients significantly differs from responders to antidepressants. This finding further supports the relevance of an altered composition of the gut microbiota in the etiopathogenesis of MDD, suggesting a role in response to antidepressants

Consumption of dietary emulsifiers increases sensitivity to social stress in mice: a potential role for the COX molecular pathway

Chronic low-grade inflammation and exposure to stress are key contributing factors in the etiology and progression of many neuropsychiatric disorders. Dietary emulsifiers are commonly added to processed foods and are classified by the Food and Drug Administration (FDA) as generally recognized as safe (GRAS). Recently, however, it has been revealed that these additives at translationally relevant doses can cause low-grade inflammation, gut dysbiosis, and may even increase baseline anxiety-like behavior. The latter finding suggests that dietary emulsifiers impact brain areas that modulate stress responses. We used RNA-Seq to examine whether chronic consumption of either polysorbate 80 (P80) or carboxymethylcellulose (CMC) is associated with changes in gene expression in the amygdala and PVN and used Ingenuity Pathway Analysis to identify enriched molecular pathways that may underlie an anxiety-like phenotype. Emulsifier consumption resulted in alterations in gene expression of various immediate early, stress-related, and immune-related genes in brain regions that are known to be important in the generation of behavioral and neuroendocrine responses to stress-provoking stimuli. We also hypothesized that emulsifier-treated mice exhibit sensitized behavioral, hormonal, and neuronal activity responses to stress. To test this hypothesis, C57Bl6/J mice were subjected to acute defeat conditions after 12 weeks of emulsifier or water consumption. When subjected to social defeat, emulsifier-treated mice showed increases in social avoidance and circulating corticosterone as well as alterations in neuronal activity as measured by c-Fos immunofluorescence. Subsequently, given the observed increased expression of PTGS2 (COX-2) in the amygdala, we tested the hypothesis that increased inflammation through the COX pathway is a mechanism driving emulsifier-induced increases is stress sensitivity. Groups were as described above, but mice were also divided into aspirin (25mg/kg/day) and placebo intervention groups. We found that aspirin, a COX pathway inhibitor, appears to block the increase in social avoidance observed in emulsifier-treated mice. These data demonstrate that ingestion of dietary emulsifiers at concentrations analogous to those ingested by humans increases sensitivity to social stress in mice. Further, it appears that the COX pathway may be a prime mechanistic candidate by which emulsifier-induced increases in sensitivity to social stress occurs

A systematic review of gut microbiota composition in observational studies of major depressive disorder, bipolar disorder and schizophrenia

The emerging understanding of gut microbiota as ‘metabolic machinery’ influencing many aspects of physiology has gained substantial attention in the field of psychiatry. This is largely due to the many overlapping pathophysiological mechanisms associated with both the potential functionality of the gut microbiota and the biological mechanisms thought to be underpinning mental disorders. In this systematic review, we synthesised the current literature investigating differences in gut microbiota composition in people with the major psychiatric disorders, major depressive disorder (MDD), bipolar disorder (BD) and schizophrenia (SZ), compared to ‘healthy’ controls. We also explored gut microbiota composition across disorders in an attempt to elucidate potential commonalities in the microbial signatures associated with these mental disorders. Following the PRISMA guidelines, databases were searched from inception through to December 2021. We identified 44 studies (including a total of 2510 psychiatric cases and 2407 controls) that met inclusion criteria, of which 24 investigated gut microbiota composition in MDD, seven investigated gut microbiota composition in BD, and 15 investigated gut microbiota composition in SZ. Our syntheses provide no strong evidence for a difference in the number or distribution (α-diversity) of bacteria in those with a mental disorder compared to controls. However, studies were relatively consistent in reporting differences in overall community composition (β-diversity) in people with and without mental disorders. Our syntheses also identified specific bacterial taxa commonly associated with mental disorders, including lower levels of bacterial genera that produce short-chain fatty acids (e.g. butyrate), higher levels of lactic acid-producing bacteria, and higher levels of bacteria associated with glutamate and GABA metabolism. We also observed substantial heterogeneity across studies with regards to methodologies and reporting. Further prospective and experimental research using new tools and robust guidelines hold promise for improving our understanding of the role of the gut microbiota in mental and brain health and the development of interventions based on modification of gut microbiota

Current Evidence on the Role of the Gut Microbiome in ADHD Pathophysiology and Therapeutic Implications

Studies suggest that the bidirectional relationship existent between the gut microbiome (GM) and the central nervous system (CNS), or so-called the microbiome–gut–brain axis (MGBA), is involved in diverse neuropsychiatric diseases in children and adults. In pediatric age, most studies have focused on patients with autism. However, evidence of the role played by the MGBA in attention deficit/hyperactivity disorder (ADHD), the most common neurodevelopmental disorder in childhood, is still scanty and heterogeneous. This review aims to provide the current evidence on the functioning of the MGBA in pediatric patients with ADHD and the specific role of omega-3 polyunsaturated fatty acids (!-3 PUFAs) in this interaction, as well as the potential of the GM as a therapeutic target for ADHD. We will explore: (1) the diverse communication pathways between the GM and the CNS; (2) changes in the GM composition in children and adolescents with ADHD and association with ADHD pathophysiology; (3) influence of the GM on the !-3 PUFA imbalance characteristically found in ADHD; (4) interaction between the GM and circadian rhythm regulation, as sleep disorders are frequently comorbid with ADHD; (5) finally, we will evaluate the most recent studies on the use of probiotics in pediatric patients with ADHD

Gastrointestinal Alterations in Two Mouse Models Associated with Social Behavior Deficits

The gastrointestinal (GI) tract is a diverse habitat for multiple microorganisms. Disturbances in the microbiome of the GI tract have been associated with psychiatric disorders including autism spectrum disorder (ASD). Individuals with ASD, when compared to neurotypical individuals, have demonstrated differing gut species. Also, it has been shown that microbial transplant therapies impact ASD symptoms in patients. Animal models of behaviors associated with ASD might offer insight for the actual role these microbial differences may occupy regarding symptoms. Unfortunately, ASD does not have an accepted animal model where the GI alterations have been thoroughly explored. In this study, we sought to determine if the microbiome and other GI alterations were observed in two potential mouse models of social behavior deficits, the genetic BTBR T+Itpr3tf/J (BTBR) mouse strain and an environmental mouse strain consisting of offspring of valproic acid (VA) treated pregnant controls. Both mouse models have been shown to exhibit social and repetitive behaviors that are found in human ASD. Using the Illumina MiSeq, we were able to identify taxonomy associated with 16S ribosomal DNA sequences extracted from fecal matter. We were able to compare the sequencing results from the two affected strains and a control C5BL/6J mouse strain for both female and male animals using the Qiagen CLC Genomics Workbench software. Overall, microbiome composition was found to be significantly different between the male control animals (N=6) when compared to the VA (N=5; p-value=.00216; F-score 11.20904) or the BTBR (N=7; p-value=.00216; F-score 18.47839) males using a PERMANOVA analysis. This was replicated in female groups where composition significantly differed between the control (N=14) and VA (N=14; p-value=.00001; F-score 3.53307) or BTBR (N=14; p-value=.00001; F-score 11.23443) females. Additionally, short-chain fatty acid analysis using gas capillary-based chromatography was used to examine acetate, butyrate, propionate, and valerate levels in feces. Only valerate levels were significantly lower (

Genome-wide multi-trait analysis of irritable bowel syndrome and related mental conditions identifies 38 new independent variants

Irritable bowel syndrome (IBS) is a chronic disorder of gut-brain interaction frequently accompanied by mental conditions, including depression and anxiety. Despite showing substantial heritability and being partly determined by a genetic component, the genetic underpinnings explaining the high rates of comorbidity remain largely unclear and there are no conclusive data on the temporal relationship between them. Exploring the overlapping genetic architecture between IBS and mental conditions may help to identify novel genetic loci and biological mechanisms underlying IBS and causal relationships between them. We quantified the genetic overlap between IBS, neuroticism, depression and anxiety, conducted a multi-trait genome-wide association study (GWAS) considering these traits and investigated causal relationships between them by using the largest GWAS to date. IBS showed to be a highly polygenic disorder with extensive genetic sharing with mental conditions. Multi-trait analysis of IBS and neuroticism, depression and anxiety identified 42 genome-wide significant variants for IBS, of which 38 are novel. Fine-mapping risk loci highlighted 289 genes enriched in genes upregulated during early embryonic brain development and gene-sets related with psychiatric, digestive and autoimmune disorders. IBS-associated genes were enriched for target genes of anti-inflammatory and antirheumatic drugs, anesthetics and opioid dependence pharmacological treatment. Mendelian-randomization analysis accounting for correlated pleiotropy identified bidirectional causal effects between IBS and neuroticism and depression and causal effects of the genetic liability of IBS on anxiety. These findings provide evidence of the polygenic architecture of IBS, identify novel genome-wide significant variants for IBS and extend previous knowledge on the genetic overlap and relationship between gastrointestinal and mental disorders. The online version contains supplementary material available at 10.1186/s12967-023-04107-5

Resilience priming: translational models for understanding resiliency and adaptation to early life adversity

Despite the increasing attention to early life adversity and its long-term consequences on health, behavior, and the etiology of neurodevelopmental disorders, our understanding of the adaptations and interventions that promote resiliency and rescue against such insults are underexplored. Specifically, investigations of the perinatal period often focus on negative events/outcomes. In contrast, positive experiences (i.e. enrichment/parental care//healthy nutrition) favorably influence development of the nervous and endocrine systems. Moreover, some stressors result in adaptations and demonstrations of later-life resiliency. This review explores the underlying mechanisms of neuroplasticity that follow some of these early life experiences and translates them into ideas for interventions in pediatric settings. The emerging role of the gut microbiome in mediating stress susceptibility is also discussed. Since many negative outcomes of early experiences are known, it is time to identify mechanisms and mediators that promote resiliency against them. These range from enrichment, quality parental care, dietary interventions and those that target the gut microbiota