Psychiatry - Journal Articles
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Item More than just a number: the gut microbiota and brain function across the extremes of life(Taylor & Francis, 2024) Nuzum, Nathan D.; Deady, Clara; Kittel-Schneider, Sarah; Cryan, John F.; O'Mahony, Siobhain M.; Clarke, Gerard; Science Foundation IrelandUnderstanding the interrelationship between the gut microbiota and host physiology, although still in its relative infancy, has taken important steps forward over the past decade. In the context of brain disorders including those characterized by neurodevelopmental and neurodegenerative changes there have been important advances. However, initially research involved correlational analyses, had limited translational scope, and lacked functional assessments. Thus, largescale longitudinal clinical investigations that assess causation and underlying mechanisms via in depth analysis methods are needed. In neurodegeneration research, strong causal evidence now links the gut microbiome to Alzheimer's (AD), and Parkinson's Disease (PD), as supported by human-to-animal transplantation studies. Longitudinal interventions are being conducted in AD, PD, amyotrophic lateral sclerosis, Huntington's disease, and multiple sclerosis. Neurodevelopmental research has also seen a boon in microbiome-related clinical research including in autism, Attention-deficit/hyperactivity disorder, and schizophrenia, which is confirming prior animal model work regarding the key time-windows in the gut microbiome important for infant cognition. While recent research advances represent important progress, fundamental knowledge gaps and obstacles remain. Knowing how and why the gut microbiome changes at the extremes of life will develop our mechanistic understanding and help build the evidence base as we strive toward counteracting microbial missteps with precision therapeutic interventions.Item Differential cortical aspartate uptake across the oestrous cycle is associated with changes in gut microbiota in Wistar-Kyoto rats(Elsevier B.V., 2024-12-26) Sajjad, Jahangir; Morael, Jennifer; Melo, Thieza G.; Foley, Tara; Murphy, Amy; Keane, James; Popov, Jelena; Stanton, Catherine; Dinan, Timothy G.; Clarke, Gerard; Cryan, John F.; Collins, James M.; O’Mahony, Siobhain M.; Science Foundation IrelandPain and psychological stress are intricately linked, with sex differences evident in disorders associated with both systems. Glutamatergic signalling in the central nervous system is influenced by gonadal hormones via the hypothalamic–pituitary–adrenal axis and is central in pain research. Emerging evidence supports an important role for the gut microbiota in influencing pain signalling. Here, the functional activity of excitatory amino acid transporters (EAATs) in the anterior cingulate cortex (ACC) and lumbosacral spinal cord of male and female Wistar-Kyoto rats, an animal model of comorbid visceral hypersensitivity and enhanced stress responsivity, was investigated across the oestrous cycle. Correlations between the gut microbiota and changes in the functional activity of the central glutamatergic system were also investigated. EAAT function in the lumbosacral spinal cord was similar between males and females across the oestrous cycle. EAAT function was higher in the ACC of dioestrus females compared to proestrus and oestrus females. In males, aspartate uptake in the ACC positively correlated with Bacteroides, while aspartate uptake in the spinal cord positively correlated with the relative abundance of Lachnospiraceae NK4A136. Positive associations with aspartate uptake in the spinal cord were also observed for Alistipes and Bifidobacterium during oestrus, and Eubacterium coprostanoligenes during proestrus. Clostridium sensu stricto1 was negatively associated with aspartate uptake in the ACC in males and dioestrus females. These data indicate that glutamate metabolism in the ACC is oestrous stage-dependent and that short-chain fatty acid-producing bacteria are positively correlated with aspartate uptake in males and during specific oestrous stages in females.Item Occurrence and co-occurrence of hallucinations by modality in schizophrenia-spectrum disorders(Elsevier B.V., 2017-03-06) McCarthy-Jones, Simon; Smailes, David; Corvin, Aiden; Gill, Michael; Morris, Derek W.; Dinan, Timothy G.; Murphy, Kieran C.; O′Neill, F. Anthony; Waddington, John L.; Donohoe, Gary; Dudley, RobertIt is not only unclear why hallucinations in schizophrenia occur with different prevalence by modality, but also to what extent they do. Reliable prevalence estimates of hallucinations by modality in schizophrenia are currently lacking, particularly for non-auditory hallucinations. Studies have also tended to report lifetime, not point prevalence by modality. This study assessed the prevalence and co-occurrence of hallucinations, for both lifetime and point prevalence, across the auditory, visual, olfactory, and tactile modalities, in people diagnosed with chronic schizophrenia-spectrum disorders in Ireland (N=693) and Australia (N=218). Lifetime prevalence was 64–80% auditory, 23–31% visual, 9–19% tactile, and 6–10% olfactory. Past month prevalence was 23–27% auditory, 5–8% visual, 4–7% tactile, and 2% olfactory. The majority of participants had only hallucinated in one modality, with this nearly always being the auditory. Approximately one-third had hallucinated in two modalities, most commonly the auditory and visual. Most currently hallucinating patients also hallucinated in a single modality, again, nearly always the auditory. Whereas 30–37% of patients with lifetime auditory hallucinations had experienced visual hallucinations, 83–97% of patients with experience of visual hallucinations had experienced auditory hallucinations. These findings help delineate the modality distribution of hallucinations in schizophrenia, and provide an explanatory target for theoretical models.Item Gene expression imputation across multiple brain regions provides insights into schizophrenia risk(Springer Nature Ltd., 2019-03-25) Huckins, Laura M.; Dobbyn, Amanda; Ruderfer, Douglas M.; Hoffman, Gabriel; Wang, Weiqing; Pardiñas, Antonio F.; Rajagopal, Veera M.; Als, Thomas D.; Nguyen, Hoang T.; Girdhar, Kiran; Boocock, James; Roussos, Panos; Fromer, Menachem; Kramer, Robin; Domenici, Enrico; Gamazon, Eric R.; Purcell, Shaun; Demontis, Ditte; Børglum, Anders D.; Walters, James T. R.; O’Donovan, Michael C.; Sullivan, Patrick; Owen, Michael J.; Devlin, Bernie; Sieberts, Solveig K.; Cox, Nancy J.; Kyung Im, Hae; Sklar, Pamela; Stahl, Eli A.; Dinan, Timothy; Takeda Pharmaceuticals U.S.A.; F. Hoffmann-La Roche; National Institutes of Health; National Institute on Aging; Illinois Department of Public Health; Translational Genomics Research Institute; Lundbeck Foundation; Stanley Medical Research Institute; European Research Council; Strategiske Forskningsråd; Novo Nordisk Fonden; Aarhus Universitet; Københavns UniversitetTranscriptomic imputation approaches combine eQTL reference panels with large-scale genotype data in order to test associations between disease and gene expression. These genic associations could elucidate signals in complex genome-wide association study (GWAS) loci and may disentangle the role of different tissues in disease development. We used the largest eQTL reference panel for the dorso-lateral prefrontal cortex (DLPFC) to create a set of gene expression predictors and demonstrate their utility. We applied DLPFC and 12 GTEx-brain predictors to 40,299 schizophrenia cases and 65,264 matched controls for a large transcriptomic imputation study of schizophrenia. We identified 413 genic associations across 13 brain regions. Stepwise conditioning identified 67 non-MHC genes, of which 14 did not fall within previous GWAS loci. We identified 36 significantly enriched pathways, including hexosaminidase-A deficiency, and multiple porphyric disorder pathways. We investigated developmental expression patterns among the 67 non-MHC genes and identified specific groups of pre- and postnatal expression.Item Prebiotic administration modulates gut microbiota and faecal short-chain fatty acid concentrations but does not prevent chronic intermittent hypoxia-induced apnoea and hypertension in adult rats(Elsevier, 2020) O'Connor, Karen M.; Lucking, Eric F.; Bastiaanssen, Thomaz F. S.; Peterson, Veronica L.; Crispie, Fiona; Cotter, Paul D.; Clarke, Gerard; Cryan, John F.; O'Halloran, Ken D.; Science Foundation IrelandBackground: Evidence is accruing to suggest that microbiota-gut-brain signalling plays a regulatory role in cardiorespiratory physiology. Chronic intermittent hypoxia (CIH), modelling human sleep apnoea, affects gut microbiota composition and elicits cardiorespiratory morbidity. We investigated if treatment with prebiotics ameliorates cardiorespiratory dysfunction in CIH-exposed rats. Methods: Adult male rats were exposed to CIH (96 cycles/day, 6.0% O2 at nadir) for 14 consecutive days with and without prebiotic supplementation (fructo- and galacto-oligosaccharides) beginning two weeks prior to gas exposures. Findings: CIH increased apnoea index and caused hypertension. CIH exposure had modest effects on the gut microbiota, decreasing the relative abundance of Lactobacilli species, but had no effect on microbial functional characteristics. Faecal short-chain fatty acid (SCFA) concentrations, plasma and brainstem pro-inflammatory cytokine concentrations and brainstem neurochemistry were unaffected by exposure to CIH. Prebiotic administration modulated gut microbiota composition and diversity, altering gut-metabolic (GMMs) and gut-brain (GBMs) modules and increased faecal acetic and propionic acid concentrations, but did not prevent adverse CIH-induced cardiorespiratory phenotypes. Interpretation: CIH-induced cardiorespiratory dysfunction is not dependant upon changes in microbial functional characteristics and decreased faecal SCFA concentrations. Prebiotic-related modulation of microbial function and resultant increases in faecal SCFAs were not sufficient to prevent CIH-induced apnoea and hypertension in our model. Our results do not exclude the potential for microbiota-gut-brain axis involvement in OSA-related cardiorespiratory morbidity, but they demonstrate that in a relatively mild model of CIH, sufficient to evoke classic cardiorespiratory dysfunction, such changes are not obligatory for the development of morbidity, but may become relevant in the elaboration and maintenance of cardiorespiratory morbidity with progressive disease. Funding: Department of Physiology and APC Microbiome Ireland, University College Cork, Ireland. APC Microbiome Ireland is funded byScience Foundation Ireland, through the Government’s National Development Plan.