Transcriptome analysis in whole blood reveals increased microbial diversity in schizophrenia

The role of the human microbiome in health and disease is increasingly appreciated. We studied the composition of microbial communities present in blood across 192 individuals, including healthy controls and patients with three disorders affecting the brain: schizophrenia, amyotrophic lateral sclerosis, and bipolar disorder. By using high-quality unmapped RNA sequencing reads as candidate microbial reads, we performed profiling of microbial transcripts detected in whole blood. We were able to detect a wide range of bacterial and archaeal phyla in blood. Interestingly, we observed an increased microbial diversity in schizophrenia patients compared to the three other groups. We replicated this finding in an independent schizophrenia case–control cohort. This increased diversity is inversely correlated with estimated cell abundance of a subpopulation of CD8+ memory T cells in healthy controls, supporting a link between microbial products found in blood, immunity and schizophrenia.

[1]  E. H. Simpson Measurement of Diversity , 1949, Nature.

[2]  T. Dinan,et al.  Mind-altering Microorganisms: the Impact of the Gut Microbiota on Brain and Behaviour , 2022 .

[3]  Alexey Fedorov From Correlation to Causation via High-Throughput Experimentation , 2018 .

[4]  B. Tjaden,et al.  Computational analysis of bacterial RNA-Seq data , 2013, Nucleic acids research.

[5]  K. Turner,et al.  Metatranscriptomics of the Human Oral Microbiome during Health and Disease , 2014, mBio.

[6]  T. Dinan,et al.  Genomics of schizophrenia: time to consider the gut microbiome? , 2014, Molecular Psychiatry.

[7]  Alex E. Lash,et al.  Gene Expression Omnibus: NCBI gene expression and hybridization array data repository , 2002, Nucleic Acids Res..

[8]  Zhen Lin,et al.  Microbial Contamination in Next Generation Sequencing: Implications for Sequence-Based Analysis of Clinical Samples , 2014, PLoS pathogens.

[9]  Kevin J. Gaston,et al.  Measuring beta diversity for presence–absence data , 2003 .

[10]  E. Castro-Nallar,et al.  Composition, taxonomy and functional diversity of the oropharynx microbiome in individuals with schizophrenia and controls , 2015, PeerJ.

[11]  Jun Sun,et al.  Leaky intestine and impaired microbiome in an amyotrophic lateral sclerosis mouse model , 2015, Physiological reports.

[12]  Sharon I. Greenblum,et al.  Metagenomic systems biology of the human gut microbiome reveals topological shifts associated with obesity and inflammatory bowel disease , 2011, Proceedings of the National Academy of Sciences.

[13]  Rafael A. Irizarry,et al.  Minfi: a flexible and comprehensive Bioconductor package for the analysis of Infinium DNA methylation microarrays , 2014, Bioinform..

[14]  E. Mardis,et al.  An obesity-associated gut microbiome with increased capacity for energy harvest , 2006, Nature.

[15]  Yuko Sakurai,et al.  Gut Dysbiosis and Detection of “Live Gut Bacteria” in Blood of Japanese Patients With Type 2 Diabetes , 2014, Diabetes Care.

[16]  H. Vali,et al.  Are There Naturally Occurring Pleomorphic Bacteria in the Blood of Healthy Humans? , 2002, Journal of Clinical Microbiology.

[17]  W. D. de Vos,et al.  Genetic Diversity of Viable, Injured, and Dead Fecal Bacteria Assessed by Fluorescence-Activated Cell Sorting and 16S rRNA Gene Analysis , 2005, Applied and Environmental Microbiology.

[18]  J. Petrosino,et al.  Microbiota Modulate Behavioral and Physiological Abnormalities Associated with Neurodevelopmental Disorders , 2013, Cell.

[19]  R. Wank,et al.  Associations between Chlamydophila infections, schizophrenia and risk of HLA-A10 , 2007, Molecular Psychiatry.

[20]  W. D. de Vos,et al.  Role of the intestinal microbiome in health and disease : from correlation to causation , 2012 .

[21]  E. Quigley,et al.  The role of the gut microbiota in nonalcoholic fatty liver disease , 2010, Nature Reviews Gastroenterology &Hepatology.

[22]  Devin C. Koestler,et al.  DNA methylation arrays as surrogate measures of cell mixture distribution , 2012, BMC Bioinformatics.

[23]  I. Amit,et al.  Host microbiota constantly control maturation and function of microglia in the CNS , 2015, Nature Neuroscience.

[24]  J. Doré,et al.  Involvement of tissue bacteria in the onset of diabetes in humans: evidence for a concept , 2011, Diabetologia.

[25]  Y. Belkaid,et al.  Role of the Microbiota in Immunity and Inflammation , 2014, Cell.

[26]  C. Huttenhower,et al.  Metagenomic microbial community profiling using unique clade-specific marker genes , 2012, Nature Methods.

[27]  Paul Turner,et al.  Reagent and laboratory contamination can critically impact sequence-based microbiome analyses , 2014, BMC Biology.

[28]  D. Kell,et al.  The dormant blood microbiome in chronic, inflammatory diseases , 2015, FEMS microbiology reviews.

[29]  D. Relman,et al.  Does Blood of Healthy Subjects Contain Bacterial Ribosomal DNA? , 2001, Journal of Clinical Microbiology.

[30]  L. Jost Partitioning diversity into independent alpha and beta components. , 2007, Ecology.

[31]  Holly M. Bik,et al.  PhyloSift: phylogenetic analysis of genomes and metagenomes , 2014, PeerJ.

[32]  C. Spencer,et al.  Biological Insights From 108 Schizophrenia-Associated Genetic Loci , 2014, Nature.

[33]  Anis Larbi,et al.  Multiparameter flow cytometric analysis of CD4 and CD8 T cell subsets in young and old people , 2008, Immunity & Ageing.

[34]  B. Roe,et al.  A core gut microbiome in obese and lean twins , 2008, Nature.

[35]  E. Severance,et al.  The microbiome, immunity, and schizophrenia and bipolar disorder , 2017, Brain, Behavior, and Immunity.

[36]  F. Servant,et al.  Comprehensive description of blood microbiome from healthy donors assessed by 16S targeted metagenomic sequencing , 2016, Transfusion.

[37]  Simon C. Potter,et al.  Genome-wide Association Analysis Identifies 14 New Risk Loci for Schizophrenia , 2013, Nature Genetics.

[38]  R. Whittaker Evolution and measurement of species diversity , 1972 .

[39]  J Licinio,et al.  Gut microbiome remodeling induces depressive-like behaviors through a pathway mediated by the host’s metabolism , 2016, Molecular Psychiatry.

[40]  E. Dejana,et al.  A gut-vascular barrier controls the systemic dissemination of bacteria , 2015, Science.

[41]  M. Daly,et al.  An Atlas of Genetic Correlations across Human Diseases and Traits , 2015, Nature Genetics.

[42]  W. M. Vos,et al.  Role of the intestinal microbiome in health and disease: from correlation to causation , 2012 .

[43]  Rob Knight,et al.  Human oral, gut, and plaque microbiota in patients with atherosclerosis , 2010, Proceedings of the National Academy of Sciences.

[44]  J Licinio,et al.  From gut dysbiosis to altered brain function and mental illness: mechanisms and pathways , 2016, Molecular Psychiatry.

[45]  M. Blaser,et al.  The human microbiome: at the interface of health and disease , 2012, Nature Reviews Genetics.

[46]  S. Horvath,et al.  HIV-1 Infection Accelerates Age According to the Epigenetic Clock , 2015, The Journal of infectious diseases.

[47]  G. Getz,et al.  PathSeq: software to identify or discover microbes by deep sequencing of human tissue , 2011, Nature Biotechnology.

[48]  P. Scully,et al.  The microbiome-gut-brain axis during early life regulates the hippocampal serotonergic system in a sex-dependent manner , 2013, Molecular Psychiatry.

[49]  N. Thomson,et al.  Studying bacterial transcriptomes using RNA-seq , 2010, Current opinion in microbiology.

[50]  Jack A Gilbert,et al.  Community ecology as a framework for human microbiome research , 2019, Nature Medicine.

[51]  Michael Y. Galperin,et al.  Complete genome sequence of the extremely acidophilic methanotroph isolate V4, Methylacidiphilum infernorum, a representative of the bacterial phylum Verrucomicrobia , 2008, Biology Direct.

[52]  T. Dinan,et al.  Breaking down the barriers: the gut microbiome, intestinal permeability and stress-related psychiatric disorders , 2015, Front. Cell. Neurosci..

[53]  Katherine H. Huang,et al.  Structure, Function and Diversity of the Healthy Human Microbiome , 2012, Nature.

[54]  J. Foster,et al.  Gut–brain axis: how the microbiome influences anxiety and depression , 2013, Trends in Neurosciences.

[55]  Ning Ma,et al.  BLAST+: architecture and applications , 2009, BMC Bioinformatics.