Rotavirus infects human biliary epithelial cells and stimulates secretion of cytokines IL-6 and IL-8 via MAPK pathway

Biliary atresia (BA) is an infantile inflammatory cholangiopathy of unknown etiology although epidemiologic studies and animal models utilizing rotavirus (RV) have suggested a role for viral infection. Proinflammatory and profibrotic cytokines have been detected in infants with BA.The purpose of our study was to investigate the susceptibility of human cholangiocytes (H69 cells) to infection with RRV and to determine if this infection resulted in cytokine secretion. Infection ofH69 cells by RRV was noncytolytic and resulted in a time-dependent increase in the release of both infectious virions and cytokines IL-6 and IL-8 into the supernate. The greatest difference in cytokine supernatant levels between infected and mock-infected cells was noted at 24 hours postinfection (h p.i.) for IL-8, 556 ± 111 versus 77 ± 68 pg/mL ( < 0.0001), and at 48 h p.i. for IL-6, 459 ± 64 versus 67 ± 2 pg/mL ( < 0.0001). Production of both cytokines following RRV infection was significantly reduced by pretreating the H69 cells with inhibitors of mitogen-activated protein kinase (MAPK). Conclusion. RRV can infect human cholangiocytes resulting in the production of proinflammatory and profibrotic cytokines via the MAPK pathway. RRV-infected H69 cells could be a useful model system for investigating the viral hypothesis of BA

Toxoplasma gondii infection and common mental disorders in the Finnish general population

Objective: We investigated whether T. gondii seropositivity is associated with 12-month depressive, anxiety and alcohol use disorders and current depressive symptoms and whether inflammation, measured by C-reactive protein (CRP) level, explains these associations. Method: Health 2000 study (BRIF8901), conducted in years 2000-2001, is based on a nationally representative sample of Finns aged 30 and above, with 7112 participants and 88.6% response rate. DSM-IV depressive, anxiety and alcohol use disorders were assessed with the Composite International Diagnostic Interview and depressive symptoms with the Beck Depressive Inventory (BDI-21). We used logistic regression to investigate the association of T. gondii seropositivity with mental disorders and linear regression with BDI-21 scores. Results: T. gondii seroprevalence was significantly associated with 12-month generalized anxiety disorder but not with other anxiety, depressive or alcohol use disorders. T. gondii seropositivity was associated with higher BDI-21 scores (beta 0.56, 95% CI 0.12-1.00, P = 0.013) and with having a comorbid depressive and anxiety disorder (OR 1.86, 95% CI 1.16-2.97, P = 0.010). Higher CRP levels were associated with these outcomes and with T. gondii seropositivity, but adjusting for CRP did not change the effect of T. gondii seropositivity. Limitations: Cross-sectional study design with no information on the timing of T. gondii infection. Conclusion: T. gondii seropositivity is associated with generalized anxiety disorder, depressive symptoms and comorbid depressive and anxiety disorders, which is not mediated by inflammation.Peer reviewe

The association between toxoplasma and the psychosis continuum in a general population setting

Toxoplasma gondii infection is associated with increased risk for psychosis. However, the possible association between T. gondii and psychotic-like symptoms in the general adult population is unknown. We investigated whether T. gondii is associated with psychotic-like symptoms and psychosis diagnoses using data from Health 2000, a large cross-sectional health survey of the Finnish general population aged 30 and above. Seropositivity to toxoplasma was defined as a cutoff of 50 IU/ml of IgG antibodies. Lifetime psychotic-like symptoms were identified with section G of the Composite International Diagnostic Interview, Munich version (M-CIDI). Symptoms were considered clinically relevant if they caused distress or help-seeking or there were at least three of them. Lifetime psychotic disorders were screened from the sample and were diagnosed with DSM-IV using SCID-I interview and information from medical records. All data were available for 5906 participants. We adjusted for variables related to T. gondii seropositivity (age, gender, education, region of residence, cat ownership, and C-reactive protein measuring inflammation) in regression models. We found that T. gondii seropositivity was significantly associated with clinically relevant psychotic-like symptoms (OR 1.77, p = 0.001) and with the number of psychotic-like symptoms (IRR = 1.55, p = 0.001). The association between toxoplasma and diagnosed psychotic disorders did not reach statistical significance (OR 1.45 for schizophrenia). In a large sample representing the whole Finnish adult population, we found that serological evidence of toxoplasma infection predicted psychotic-like symptoms, independent of demographic factors and levels of C-reactive protein. Toxoplasma infection may be a risk factor for manifestation of psychotic-like symptoms. (c) 2017 Elsevier B.V. All rights reserved.Peer reviewe

Association of cytomegalovirus and Epstein-Barr virus with cognitive functioning and risk of dementia in the general population : 11-year follow-up study

Background: Earlier studies have documented an association between cytomegalovirus and cognitive impairment, but results have been inconsistent. Few studies have investigated the association of cytomegalovirus and Epstein-Barr virus with cognitive decline longitudinally. Our aim was to examine whether cytomegalovirus and Epstein-Barr virus are associated with cognitive decline, in adults. Method: The study sample is from the Finnish Health 2000 Survey (BRIF8901, n = 7112), which is representative of the Finnish adult population. The sample was followed up after 11 years in the Health 2011 Survey. In addition, persons with dementia were identified from healthcare registers. Results: In the Finnish population aged 30 and over, the seroprevalence of cytomegalovirus was estimated to be 84% and the seroprevalence of Epstein-Barr virus 98%. Seropositivity of the viruses and antibody levels were mostly not associated with cognitive performance. In the middle-aged adult group, cytomegalovirus serointensity was associated with impaired performance in verbal learning. However, the association disappeared when corrected for multiple testing. No interactions between infection and time or between the two infections were significant when corrected for multiple testing. Seropositivity did not predict dementia diagnosis. Conclusions: The results suggest that adult levels of antibodies to cytomegalovirus and Epstein-Barr virus may not be associated with a significant decline in cognitive function or with dementia at population level. (C) 2018 Published by Elsevier Inc.Peer reviewe

Exposure to common infections and risk of suicide and self-harm : a longitudinal general population study

Common infectious agents, such as Toxoplasma gondii (T. gondii) and several human herpes viruses, have been linked to increased risk of self-harm. The aim of this study was to investigate the associations between self-harm and seropositivity to T. gondii, Epstein-Barr virus (EBV), Herpes Simplex virus Type 1 (HSV-1), and Cytomegalovirus (CMV). IgM and IgG antibodies to these infections were measured in the Health 2000 project nationally representative of the whole Finnish adult population, and 6250 participants, age 30 and over, were followed for 15 years via registers. In addition, lifetime suicidal ideation and suicide attempts based on medical records and interview were assessed within a subsample of 694 participants screened to a substudy for possible psychotic symptoms or as controls. Among the 6250 participants, 14 individuals died of suicide and an additional 4 individuals had a diagnosis of intentional self-harm during follow-up. Serological evidence of lifetime or acute infections was not found to be associated with these suicidal outcomes. However, in the subsample, those seropositive for CMV had fewer suicide attempts compared to those seronegative, adjusting for gender, age, educational level, childhood family size, regional residence, CRP, and screen status (OR for multiple attempts = 0.40, 95% confidence interval 0.20-0.83, p = 0.014). To conclude, common infections were not associated with risk of death by suicide or with self-harm diagnoses at a 15-year follow-up in the general population sample. Our finding of an increased number of suicide attempts among persons seronegative for CMV calls for further research.Peer reviewe

Studying the virome in psychiatric disease

An overlooked aspect of current microbiome studies is the role of viruses in human health. Compared to bacterial studies, laboratory and analytical methods to study the entirety of viral communities in clinical samples are rudimentary and need further refinement. In order to address this need, we developed Virobiome-Seq, a sequence capture method and an accompanying bioinformatics analysis pipeline, that identifies viral reads in human samples. Virobiome-Seq is able to enrich for and detect multiple types of viruses in human samples, including novel subtypes that diverge at the sequence level. In addition, Virobiome-Seq is able to detect RNA transcripts from DNA viruses and may provide a sensitive method for detecting viral activity in vivo. Since Virobiome-Seq also yields the viral sequence, it makes it possible to investigate associations between viral genotype and psychiatric illness. In this proof of concept study, we detected HIV1, Torque Teno, Pegi, Herpes and Papilloma virus sequences in Peripheral Blood Mononuclear Cells, plasma and stool samples collected from individuals with psychiatric disorders. We also detected the presence of numerous novel circular RNA viruses but were unable to determine whether these viruses originate from the sample or represent contaminants. Despite this challenge, we demonstrate that our knowledge of viral diversity is incomplete and opportunities for novel virus discovery exist. Virobiome-Seq will enable a more sophisticated analysis of the virome and has the potential of uncovering complex interactions between viral activity and psychiatric disease. (c) 2021 Elsevier B.V. All rights reserved.Peer reviewe

Immunomodulatory effects of probiotic supplementation in schizophrenia patients: A randomized, placebo-controlled trial

Although peripheral immune system abnormalities have been linked to schizophrenia pathophysiology, standard antipsychotic drugs show limited immunological effects. Thus, more effective treatment approaches are required. Probiotics are microorganisms that modulate the immune response of the host and, therefore, may be beneficial to schizophrenia patients. The aim of this study was to examine the possible immunomodulatory effects of probiotic supplementation in chronic schizophrenia patients. The concentrations of 47 immune-related serum proteins were measured using multiplexed immunoassays in samples collected from patients before and after 14 weeks of adjuvant treatment with probiotics (Lactobacillus rhamnosus strain GG and Bifidobacterium animalis subsp. lactis strain Bb12; n = 31) or placebo (n = 27). Probiotic add-on treatment significantly reduced levels of von Willebrand factor (vWF) and increased levels of monocyte chemotactic protein-1 (MCP-1), brain-derived neurotrophic factor (BDNF), RANTES, and macrophage inflammatory protein-1 beta (MIP-1) beta with borderline significance (P ≤ 0.08). In silico pathway analysis revealed that probiotic-induced alterations are related to regulation of immune and intestinal epithelial cells through the IL-17 family of cytokines. We hypothesize that supplementation of probiotics to schizophrenia patients may improve control of gastrointestinal leakage

Composition, taxonomy and functional diversity of the oropharynx microbiome in individuals with schizophrenia and controls.

The role of the human microbiome in schizophrenia remains largely unexplored. The microbiome has been shown to alter brain development and modulate behavior and cognition in animals through gut-brain connections, and research in humans suggests that it may be a modulating factor in many disorders. This study reports findings from a shotgun metagenomic analysis of the oropharyngeal microbiome in 16 individuals with schizophrenia and 16 controls. High-level differences were evident at both the phylum and genus levels, with Proteobacteria, Firmicutes, Bacteroidetes, and Actinobacteria dominating both schizophrenia patients and controls, and Ascomycota being more abundant in schizophrenia patients than controls. Controls were richer in species but less even in their distributions, i.e., dominated by fewer species, as opposed to schizophrenia patients. Lactic acid bacteria were relatively more abundant in schizophrenia, including species of Lactobacilli and Bifidobacterium, which have been shown to modulate chronic inflammation. We also found Eubacterium halii, a lactate-utilizing species. Functionally, the microbiome of schizophrenia patients was characterized by an increased number of metabolic pathways related to metabolite transport systems including siderophores, glutamate, and vitamin B12. In contrast, carbohydrate and lipid pathways and energy metabolism were abundant in controls. These findings suggest that the oropharyngeal microbiome in individuals with schizophrenia is significantly different compared to controls, and that particular microbial species and metabolic pathways differentiate both groups. Confirmation of these findings in larger and more diverse samples, e.g., gut microbiome, will contribute to elucidating potential links between schizophrenia and the human microbiota

DNA Methylation Signatures within the Human Brain

DNA methylation is a heritable modification of genomic DNA central to development, imprinting, transcriptional regulation, chromatin structure, and overall genomic stability. Aberrant DNA methylation of individual genes is a hallmark of cancer and has been shown to play an important role in neurological disorders such as Rett syndrome. Here, we asked whether normal DNA methylation might distinguish individual brain regions. We determined the quantitative DNA methylation levels of 1,505 CpG sites representing 807 genes with diverse functions, including proliferation and differentiation, previously shown to be implicated in human cancer. We initially analyzed 76 brain samples representing cerebral cortex (n=35), cerebellum (n=34), and pons (n=7), along with liver samples (n=3) from 43 individuals. Unsupervised hierarchical analysis showed clustering of 33 of 35 cerebra distinct from the clustering of 33 of 34 cerebella, 7 of 7 pons, and all 3 livers. By use of comparative marker selection and permutation testing, 156 loci representing 118 genes showed statistically significant differences—a ⩾17% absolute change in DNA methylation (P<.004)—among brain regions. These results were validated for all six genes tested in a replicate set of 57 samples. Our data suggest that DNA methylation signatures distinguish brain regions and may help account for region-specific functional specialization