Publications by authors named "Gerard Clarke"

139 Publications

The gut microbiome influences the bioavailability of olanzapine in rats.

EBioMedicine 2021 Apr 1;66:103307. Epub 2021 Apr 1.

APC Microbiome Ireland, University College Cork, Cork, Ireland; School of Pharmacy, University College Cork, Cavanagh Pharmacy Building, Cork, Ireland. Electronic address:

Background: The role of the gut microbiome in the biotransformation of drugs has recently come under scrutiny. It remains unclear whether the gut microbiome directly influences the extent of drug absorbed after oral administration and thus potentially alters clinical pharmacokinetics.

Methods: In this study, we evaluated whether changes in the gut microbiota of male Sprague Dawley rats, as a result of either antibiotic or probiotic administration, influenced the oral bioavailability of two commonly prescribed antipsychotics, olanzapine and risperidone.

Findings: The bioavailability of olanzapine, was significantly increased (1.8-fold) in rats that had undergone antibiotic-induced depletion of gut microbiota, whereas the bioavailability of risperidone was unchanged. There was no direct effect of microbiota depletion on the expression of major CYP450 enzymes involved in the metabolism of either drug. However, the expression of UGT1A3 in the duodenum was significantly downregulated. The reduction in faecal enzymatic activity, observed during and after antibiotic administration, did not alter the ex vivo metabolism of olanzapine or risperidone. The relative abundance of Alistipes significantly correlated with the AUC of olanzapine but not risperidone.

Interpretation: Alistipes may play a role in the observed alterations in olanzapine pharmacokinetics. The gut microbiome might be an important variable determining the systemic bioavailability of orally administered olanzapine. Additional research exploring the potential implication of the gut microbiota on the clinical pharmacokinetics of olanzapine in humans is warranted.

Funding: This research is supported by APC Microbiome Ireland, a research centre funded by Science Foundation Ireland (SFI), through the Irish Government's National Development Plan (grant no. 12/RC/2273 P2) and by Nature Research-Yakult (The Global Grants for Gut Health; Ref No. 626891).
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http://dx.doi.org/10.1016/j.ebiom.2021.103307DOI Listing
April 2021

Activin A and Acvr2b mRNA from Umbilical Cord Blood Are Not Reliable Markers of Mild or Moderate Neonatal Hypoxic-Ischemic Encephalopathy.

Neuropediatrics 2021 Mar 11. Epub 2021 Mar 11.

INFANT Research Centre, Ireland.

Background:  Activin A protein and its receptor ACVR2B have been considered viable biomarkers for the diagnosis of hypoxic-ischemic encephalopathy (HIE). This study aimed to assess umbilical cord blood (UCB) levels of Activin A and messenger RNA (mRNA) as early biomarkers of mild and moderate HIE and long-term neurodevelopmental outcome.

Methods:  One-hundred and twenty-six infants were included in the analyses from the BiHiVE2 cohort, a multi-center study, recruited in Ireland and Sweden (2013 to 2015). UCB serum Activin A and whole blood mRNA were measured using enzyme-linked immunosorbent assay and quantitative polymerase chain reaction, respectively.

Results:  Activin A analysis included 101 infants (controls,  = 50, perinatal asphyxia,  = 28, HIE,  = 23). No differences were detected across groups ( = 0.69). No differences were detected across HIE grades ( = 0.12). mRNA analysis included 67 infants (controls,  = 22, perinatal asphyxia,  = 23, and HIE,  = 22), and no differences were observed across groups ( = 0.75). No differences were detected across HIE grades ( = 0.58). No differences were detected in neurodevelopmental outcome in infants followed up to 18 to 36 months in serum Activin A or in whole blood mRNA ( = 0.55 and  = 0.90, respectively).

Conclusion:  UCB Activin A and mRNA are not valid biomarkers of infants with mild or moderate HIE; they are unable to distinguish infants with HIE or infants with poor neurodevelopmental outcomes.
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http://dx.doi.org/10.1055/s-0041-1725012DOI Listing
March 2021

Diet and the Microbiota-Gut-Brain Axis: Sowing the Seeds of Good Mental Health.

Adv Nutr 2021 Mar 9. Epub 2021 Mar 9.

APC Microbiome Ireland, Cork, Ireland.

Over the past decade, the gut microbiota has emerged as a key component in regulating brain processes and behavior. Diet is one of the major factors involved in shaping the gut microbiota composition across the lifespan. However, whether and how diet can affect the brain via its effects on the microbiota is only now beginning to receive attention. Several mechanisms for gut-to-brain communication have been identified, including microbial metabolites, immune, neuronal, and metabolic pathways, some of which could be prone to dietary modulation. Animal studies investigating the potential of nutritional interventions on the microbiota-gut-brain axis have led to advancements in our understanding of the role of diet in this bidirectional communication. In this review, we summarize the current state of the literature triangulating diet, microbiota, and host behavior/brain processes and discuss potential underlying mechanisms. Additionally, determinants of the responsiveness to a dietary intervention and evidence for the microbiota as an underlying modulator of the effect of diet on brain health are outlined. In particular, we emphasize the understudied use of whole-dietary approaches in this endeavor and the need for greater evidence from clinical populations. While promising results are reported, additional data, specifically from clinical cohorts, are required to provide evidence-based recommendations for the development of microbiota-targeted, whole-dietary strategies to improve brain and mental health.
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http://dx.doi.org/10.1093/advances/nmaa181DOI Listing
March 2021

Personalized Nutrition for Depression: Impact on the Unholy Trinity.

Neuroimmunomodulation 2021 Mar 5:1-5. Epub 2021 Mar 5.

Laboratory of Ultrastructure, Aggeu Magalhães Institute (IAM), Oswaldo Cruz Foundation (FIOCRUZ-PE), Recife, Brazil,

Major depressive disorder (MDD) is a chronic affective disorder that has a strong neuroinflammatory component underpinning its etiology. Recent studies indicate that MDD is also associated with changes in the gut microbiota and that the latter is mainly modulated by diet. Microbiota-based personalized nutrition aims to provide an individual-specific diet that will yield the maximum benefit from a given diet since the gut microbiota is accounted for the variations that individuals present in response to a given food. In this review, we present and discuss 5 possible outcomes of using microbiota-based personalized nutrition. Harnessing this approach is essential to design more accurate therapies to prevent and treat MDD or to even help in drug metabolism, especially in the case of antidepressants.
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http://dx.doi.org/10.1159/000514094DOI Listing
March 2021

Mining microbes for mental health: Determining the role of microbial metabolic pathways in human brain health and disease.

Neurosci Biobehav Rev 2021 Mar 3;125:698-761. Epub 2021 Mar 3.

Department of Anatomy and Neuroscience, University College Cork, Cork, Ireland; APC Microbiome Institute, University College Cork, Cork, Ireland. Electronic address:

There is increasing knowledge regarding the role of the microbiome in modulating the brain and behaviour. Indeed, the actions of microbial metabolites are key for appropriate gut-brain communication in humans. Among these metabolites, short-chain fatty acids, tryptophan, and bile acid metabolites/pathways show strong preclinical evidence for involvement in various aspects of brain function and behaviour. With the identification of neuroactive gut-brain modules, new predictive tools can be applied to existing datasets. We identified 278 studies relating to the human microbiota-gut-brain axis which included sequencing data. This spanned across psychiatric and neurological disorders with a small number also focused on normal behavioural development. With a consistent bioinformatics pipeline, thirty-five of these datasets were reanalysed from publicly available raw sequencing files and the remainder summarised and collated. Among the reanalysed studies, we uncovered evidence of disease-related alterations in microbial metabolic pathways in Alzheimer's Disease, schizophrenia, anxiety and depression. Amongst studies that could not be reanalysed, many sequencing and technical limitations hindered the discovery of specific biomarkers of microbes or metabolites conserved across studies. Future studies are warranted to confirm our findings. We also propose guidelines for future human microbiome analysis to increase reproducibility and consistency within the field.
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http://dx.doi.org/10.1016/j.neubiorev.2021.02.044DOI Listing
March 2021

Of bowels, brain and behavior: A role for the gut microbiota in psychiatric comorbidities in irritable bowel syndrome.

Neurogastroenterol Motil 2021 03 13;33(3):e14095. Epub 2021 Feb 13.

APC Microbiome Ireland, University College Cork, Cork, Ireland.

Background: The gastrointestinal microbiota has emerged as a key regulator of gut-brain axis signalling with important implications for neurogastroenterology. There is continuous bidirectional communication between the gut and the brain facilitated by neuronal, endocrine, metabolic, and immune pathways. The microbiota influences these signalling pathways via several mechanisms. Studies have shown compositional and functional alterations in the gut microbiota in stress-related psychiatric disorders. Gut microbiota reconfigurations are also a feature of irritable bowel syndrome (IBS), a gut-brain axis disorder sharing high levels of psychiatric comorbidity including both anxiety and depression. It remains unclear how the gut microbiota alterations in IBS align with both core symptoms and these psychiatric comorbidities.

Methods: In this review, we highlight common and disparate features of these microbial signatures as well as the associated gut-brain axis signalling pathways. Studies suggest that patients with either IBS, depression or anxiety, alone or comorbid, present with alterations in gut microbiota composition and harbor immune, endocrine, and serotonergic system alterations relevant to the common pathophysiology of these comorbid conditions.

Key Results: Research has illustrated the utility of fecal microbiota transplantation in animal models, expanding the evidence base for a potential causal role of disorder-specific gut microbiota compositions in symptom set expression. Moreover, an exciting study by Constante and colleagues in this issue highlights the possibility of counteracting this microbiota-associated aberrant behavioral phenotype with a probiotic yeast, Saccharomyces boulardii CNCM I-745.

Conclusions And Inferences: Such data highlights the potential for therapeutic targeting of the gut microbiota as a valuable strategy for the management of comorbid psychiatric symptoms in IBS.
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http://dx.doi.org/10.1111/nmo.14095DOI Listing
March 2021

Prebiotic and probiotic supplementation and the tryptophan-kynurenine pathway: A systematic review and meta analysis.

Neurosci Biobehav Rev 2021 Apr 19;123:1-13. Epub 2021 Jan 19.

Deakin University, IMPACT - the Institute for Mental and Physical Health and Clinical Translation, School of Medicine, Barwon Health, Geelong, Australia.

This systematic review aimed to synthesise the results from studies investigating the effects of prebiotics and probiotics on kynurenine pathway metabolism. Thirteen studies were identified for inclusion, comprising 12 probiotic and two prebiotic arms. Participants included healthy individuals and individuals with various clinical conditions. Twelve metabolites were examined across the studies, using a range of biological samples. Across all interventions, 11 reported an effect on ≤ metabolite. Although limited by clinical and methodological heterogeneity, pooled analysis (n = 253) found probiotics to significantly affect serum kynurenine (g = 0.315, CI = 0.070 to 0.560, p = 0.012, 4 studies, I = 0%) and the kynurenine:tryptophan ratio (g = 0.442, CI = 0.074 to 0.810, p = 0.018, 4 studies, I = 42 %). Risk of bias across the studies was generally low. The results provide preliminary evidence that probiotics can modulate kynurenine pathway metabolism, with less evidence available regarding prebiotics. Future studies which further consider methodological confounds and sample characteristics are required, to establish intervention efficacy. PROSPERO registration #CRD42019154677.
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http://dx.doi.org/10.1016/j.neubiorev.2020.12.026DOI Listing
April 2021

Long-term dietary intake from infancy to late adolescence is associated with gut microbiota composition in young adulthood.

Am J Clin Nutr 2021 03;113(3):647-656

Unit of Nutritional Epidemiology, Department of Nutrition and Food Sciences, University of Bonn, Bonn, Germany.

Background: Gut microbiota composition as influenced by long-term diet may be associated with the risk of adult chronic diseases. Thus, establishing the relation of long-term diet, particularly starting from early life, with adult microbiota composition would be an important research advance.

Objective: We aimed to investigate the association of long-term intake of energy, carbohydrate, fiber, protein, and fat from infancy to late adolescence with microbiota composition in adulthood.

Methods: Within the prospective DOrtmund Nutritional and Anthropometric Longitudinally Designed (DONALD) Study, we sampled stool 1 or 2 times within 1 y from 128 adults (median age: 29 y). Microbiota composition was profiled by 16S ribosomal RNA sequencing. Annual dietary records from age 1 to 18 y were retrieved. We estimated trajectories of energy, energy-adjusted carbohydrate, fiber, protein, and fat intake with multilevel models, producing predicted intake at age 1 y and rates of change in intake. A multivariate, zero-inflated, logistic-normal model was used to model the association between intake trajectories and the composition of 158 genera in single-sampled individuals. Associations found in this model were confirmed in double-sampled individuals using a zero-inflated Beta regression model.

Results: Adjusting for covariates and temporal differences in microbiota composition, long-term carbohydrate intake was associated with 3 genera. Specifically, carbohydrate intake at age 1 y was negatively associated with Phascolarctobacterium [coefficient = -4.31; false discovery rate (FDR)-adjusted P = 0.006] and positively associated with Dialister (coefficient = 3.06; FDR-adjusted P = 0.003), and the rate of change in carbohydrate intake was positively associated with Desulfovibrio (coefficient = 13.16; FDR-adjusted P = 0.00039). Energy and other macronutrients were not associated with any genus.

Conclusions: This work links long-term carbohydrate intake to microbiota composition. Considering the associations of high carbohydrate intake and microbiota composition with some diseases, these findings could inform the development of gut microbiota-targeted dietary recommendations for disease prevention.
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http://dx.doi.org/10.1093/ajcn/nqaa340DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7948843PMC
March 2021

Targeting the Gut Microbiota in Chagas Disease: What Do We Know so Far?

Front Microbiol 2020 10;11:585857. Epub 2020 Dec 10.

Laboratory of Ultrastructure, Aggeu Magalhães Institute (IAM), Oswaldo Cruz Foundation (FIOCRUZ-PE), Recife, Brazil.

Chagas disease (CD) is a tropical and still neglected disease caused by that affects >8 million of people worldwide. Although limited, emerging data suggest that gut microbiota dysfunction may be a new mechanism underlying CD pathogenesis. infection leads to changes in the gut microbiota composition of vector insects, mice, and humans. Alterations in insect and mice microbiota due to have been associated with a decreased immune response against the parasite, influencing the establishment and progression of infection. Further, changes in the gut microbiota are linked with inflammatory and neuropsychiatric disorders, comorbid conditions in CD. Therefore, this review article critically analyses the current data on CD and the gut microbiota of insects, mice, and humans and discusses its importance for CD pathogenesis. An enhanced understanding of host microbiota will be critical for the development of alternative therapeutic approaches to target CD, such as gut microbiota-directed interventions.
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http://dx.doi.org/10.3389/fmicb.2020.585857DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7758234PMC
December 2020

Identifying a biological signature of prenatal maternal stress.

JCI Insight 2021 Jan 25;6(2). Epub 2021 Jan 25.

APC Microbiome Ireland and.

Psychological stress affects maternal gastrointestinal (GI) permeability, leading to low-grade inflammation, which can negatively affect fetal development. We investigated a panel of circulating markers as a biological signature of this stress exposure in pregnant women with and without the stress-related GI disorder irritable bowel syndrome (IBS). Markers of GI permeability and inflammation were measured in plasma from healthy and IBS cohorts of women at 15 and 20 weeks' gestation. Biomarkers were evaluated with respect to their degree of association to levels of stress, anxiety, and depression as indicated by responses from the Perceived Stress Scale, State-Trait Anxiety Inventory, and Edinburgh Postnatal Depression Scale. High levels of stress were associated with elevations of soluble CD14, lipopolysaccharide binding protein (LBP), and tumor necrosis factor-α, while anxiety was associated with elevated concentrations of C-reactive protein (CRP) in otherwise healthy pregnancies. Prenatal depression was associated with higher levels of soluble CD14, LBP, and CRP in the healthy cohort. High levels of prenatal anxiety and depression were also associated with lower concentrations of tryptophan and kynurenine, respectively, in the IBS cohort. These markers may represent a core maternal biological signature of active prenatal stress, which can be used to inform intervention strategies via stress reduction techniques or other lifestyle approaches. Such interventions may need to be tailored to reflect underlying GI conditions, such as IBS.
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http://dx.doi.org/10.1172/jci.insight.143007DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7934857PMC
January 2021

The kynurenine pathway in major depressive disorder, bipolar disorder, and schizophrenia: a meta-analysis of 101 studies.

Mol Psychiatry 2020 Nov 23. Epub 2020 Nov 23.

Center of Excellence on Mood Disorders, Faillace Department of Psychiatry and Behavioral Sciences, McGovern Medical School, The University of Texas Health Science Center at Houston (UTHealth), Houston, TX, USA.

The importance of tryptophan as a precursor for neuroactive compounds has long been acknowledged. The metabolism of tryptophan along the kynurenine pathway and its involvement in mental disorders is an emerging area in psychiatry. We performed a meta-analysis to examine the differences in kynurenine metabolites in major depressive disorder (MDD), bipolar disorder (BD), and schizophrenia (SZ). Electronic databases were searched for studies that assessed metabolites involved in the kynurenine pathway (tryptophan, kynurenine, kynurenic acid, quinolinic acid, 3-hydroxykynurenine, and their associate ratios) in people with MDD, SZ, or BD, compared to controls. We computed the difference in metabolite concentrations between people with MDD, BD, or SZ, and controls, presented as Hedges' g with 95% confidence intervals. A total of 101 studies with 10,912 participants were included. Tryptophan and kynurenine are decreased across MDD, BD, and SZ; kynurenic acid and the kynurenic acid to quinolinic acid ratio are decreased in mood disorders (i.e., MDD and BD), whereas kynurenic acid is not altered in SZ; kynurenic acid to 3-hydroxykynurenine ratio is decreased in MDD but not SZ. Kynurenic acid to kynurenine ratio is decreased in MDD and SZ, and the kynurenine to tryptophan ratio is increased in MDD and SZ. Our results suggest that there is a shift in the tryptophan metabolism from serotonin to the kynurenine pathway, across these psychiatric disorders. In addition, a differential pattern exists between mood disorders and SZ, with a preferential metabolism of kynurenine to the potentially neurotoxic quinolinic acid instead of the neuroprotective kynurenic acid in mood disorders but not in SZ.
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http://dx.doi.org/10.1038/s41380-020-00951-9DOI Listing
November 2020

Diet and depression: exploring the biological mechanisms of action.

Mol Psychiatry 2021 01 3;26(1):134-150. Epub 2020 Nov 3.

Deakin University, IMPACT (the Institute for Mental and Physical Health and Clinical Translation), Food & Mood Centre, Geelong, VIC, Australia.

The field of nutritional psychiatry has generated observational and efficacy data supporting a role for healthy dietary patterns in depression onset and symptom management. To guide future clinical trials and targeted dietary therapies, this review provides an overview of what is currently known regarding underlying mechanisms of action by which diet may influence mental and brain health. The mechanisms of action associating diet with health outcomes are complex, multifaceted, interacting, and not restricted to any one biological pathway. Numerous pathways were identified through which diet could plausibly affect mental health. These include modulation of pathways involved in inflammation, oxidative stress, epigenetics, mitochondrial dysfunction, the gut microbiota, tryptophan-kynurenine metabolism, the HPA axis, neurogenesis and BDNF, epigenetics, and obesity. However, the nascent nature of the nutritional psychiatry field to date means that the existing literature identified in this review is largely comprised of preclinical animal studies. To fully identify and elucidate complex mechanisms of action, intervention studies that assess markers related to these pathways within clinically diagnosed human populations are needed.
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http://dx.doi.org/10.1038/s41380-020-00925-xDOI Listing
January 2021

Targeting the perinatal diet to modulate the gut microbiota increases dietary variety and prebiotic and probiotic food intakes: results from a randomised controlled trial.

Public Health Nutr 2021 Apr 12;24(5):1129-1141. Epub 2020 Oct 12.

iMPACT (the Institute for Mental and Physical Health and Clinical Translation), Food & Mood Centre, Deakin University, Health Education and Research Building (HERB), Level 3, PO Box 281, Geelong, VIC3220, Australia.

Objective: To evaluate the hypothesis that a perinatal educational dietary intervention focused on 'eating for the gut microbiota' improves diet quality of pregnant women pre- and postnatally.

Design: The Healthy Parents, Healthy Kids study is a prospectively registered randomised controlled trial designed to evaluate the efficacy of a dietary intervention in altering the maternal and infant gut microbiota and improving perinatal diet quality. Eligible pregnant women were randomised to receive dietary advice from their healthcare provider or to additionally receive a three session dietary intervention. Dietary data were collected at gestation weeks 26, 31, 36 and postnatal week 4. Outcome measures were diet quality, dietary variety, prebiotic and probiotic food intakes, energy, fibre, saturated fat and discretionary food intakes. Between-group differential changes from baseline before and after birth in these dietary measures were assessed using generalised estimating equations.

Setting: Melbourne, Australia.

Participants: Healthy pregnant women from gestation week 26.

Results: Forty-five women were randomised (twenty-two control, twenty-three intervention). Compared with the control group, the intervention group improved diet quality prior to birth (5·66 (95 % CI 1·65, 9·67), Cohen's d: 0·82 (se 0·33)). The intervention improved dietary variety (1·05 (95 % CI 0·17, 1·94), d: 0·66 (se 0·32)) and increased intakes of prebiotic (0·8 (95 % CI 0·27, 1·33), d: 0·91 (se 0·33)) and probiotic foods (1·05 (95 % CI 0·57, 1·53), d: 1·3(se 0·35)) over the whole study period compared with the control group.

Conclusion: A dietary intervention focused on 'eating for the gut microbiota' can improve aspects of perinatal diet quality during and after pregnancy.
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http://dx.doi.org/10.1017/S1368980020003511DOI Listing
April 2021

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.

EBioMedicine 2020 Sep 30;59:102968. Epub 2020 Aug 30.

Department of Physiology, School of Medicine, College of Medicine & Health, University College Cork, Cork, Ireland; APC Microbiome Ireland, University College Cork, Cork, Ireland. Electronic address:

Background: 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% O 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 by Science Foundation Ireland, through the Government's National Development Plan.
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http://dx.doi.org/10.1016/j.ebiom.2020.102968DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7475129PMC
September 2020

Up-Regulation of Nfat5 mRNA and Fzd4 mRNA as a Marker of Poor Outcome in Neonatal Hypoxic-Ischemic Encephalopathy.

J Pediatr 2021 01 20;228:74-81.e2. Epub 2020 Aug 20.

INFANT Research Centre, Ireland; Department of Paediatrics and Child Health, University College Cork, Cork, Ireland; National Children's Research Centre, Crumlin, Dublin, Ireland.

Objective: To evaluate umbilical cord messenger RNA (mRNA) expression as biomarkers for the grade of hypoxic-ischemic encephalopathy (HIE) and long-term neurodevelopment outcome.

Study Design: Infants were recruited from the BiHiVE1 study, Ireland (2009-2011), and the BiHiVE2 study, Ireland, and Sweden (2013-2015). Infants with HIE were assigned modified Sarnat scores at 24 hours and followed at 18-36 months. mRNA expression from cord blood was measured using quantitative real-time polymerase chain reaction.

Results: We studied 124 infants (controls, n = 37; perinatal asphyxia, n = 43; and HIE, n = 44). Fzd4 mRNA increased in severe HIE (median relative quantification, 2.98; IQR, 2.23-3.68) vs mild HIE (0.88; IQR, 0.46-1.37; P = .004), and in severe HIE vs moderate HIE (1.06; IQR, 0.81-1.20; P = .003). Fzd4 mRNA also increased in infants eligible for therapeutic hypothermia (1.20; IQR, 0.92-2.37) vs those who were ineligible for therapeutic hypothermia group (0.81; IQR, 0.46-1.53; P = .017). Neurodevelopmental outcome was analyzed for 56 infants. Nfat5 mRNA increased in infants with severely abnormal (1.26; IQR, 1.17-1.39) vs normal outcomes (0.97; IQR, 0.83-1.24; P = .036), and also in infants with severely abnormal vs mildly abnormal outcomes (0.96; IQR, 0.80-1.06; P = .013). Fzd4 mRNA increased in infants with severely abnormal (2.51; IQR, 1.60-3.56) vs normal outcomes (0.74; IQR, 0.48-1.49; P = .004) and in infants with severely abnormal vs mildly abnormal outcomes (0.97; IQR, 0.75-1.34; P = .026).

Conclusions: Increased Fzd4 mRNA expression was observed in cord blood of infants with severe HIE; Nfat5 mRNA and Fzd4 mRNA expression were increased in infants with severely abnormal long-term outcomes. These mRNA may augment current measures as early objective markers of HIE severity at delivery.
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http://dx.doi.org/10.1016/j.jpeds.2020.08.051DOI Listing
January 2021

Ethologically based behavioural and neurochemical characterisation of mice with isoform-specific loss of dysbindin-1A in the context of schizophrenia.

Neurosci Lett 2020 09 29;736:135218. Epub 2020 Jun 29.

School of Pharmacy and Biomolecular Sciences, Royal College of Surgeons in Ireland, Dublin, Ireland; Jiangsu Key Laboratory of Translational Research & Therapy for Neuro-Psychiatric Disorders and Department of Pharmacology, College of Pharmaceutical Sciences, Soochow University, Suzhou, China.

Dysbindin-1 is implicated in several aspects of schizophrenia, including cognition and both glutamatergic and dopaminergic neurotransmission. Targeted knockout of dysbindin-1A (Dys-1A KO), the most abundant and widely expressed isoform in the brain, is associated with deficits in delay/interference-dependent working memory. Using an ethologically based approach, the following behavioural phenotypes were examined in Dys-1A KO mice: exploratory activity, social interaction, anxiety and problem-solving ability. Levels of monoamines and their metabolites were measured in striatum, hippocampus and prefrontal cortex using high-performance liquid chromatography with electrochemical detection. The ethogram of initial exploration in Dys-1A KO mice was characterised by increased rearing from a seated position; over subsequent habituation, stillness was decreased relative to wildtype. In a test of dyadic social interaction with an unfamiliar conspecific in a novel environment, female KO mice showed an increase in investigative social behaviours. Marble burying behaviour was unchanged. Using the puzzle-box test to measure general problem-solving performance, no effect of genotype was observed across nine trials of increasing complexity. Dys-1A KO demonstrated lower levels of 5-HT in ratio to its metabolite 5-HIAA in the prefrontal cortex. These studies elaborate the behavioural and neurochemical phenotype of Dys-1A KO mice, revealing subtle genotype-related differences in non-social and social exploratory behaviours and habituation of exploration in a novel environment, as well as changes in 5-HT activity in brain areas related to schizophrenia.
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http://dx.doi.org/10.1016/j.neulet.2020.135218DOI Listing
September 2020

Distinct actions of the fermented beverage kefir on host behaviour, immunity and microbiome gut-brain modules in the mouse.

Microbiome 2020 05 18;8(1):67. Epub 2020 May 18.

APC Microbiome Ireland, University College Cork, Cork, Ireland.

Background: Mounting evidence suggests a role for the gut microbiota in modulating brain physiology and behaviour, through bi-directional communication, along the gut-brain axis. As such, the gut microbiota represents a potential therapeutic target for influencing centrally mediated events and host behaviour. It is thus notable that the fermented milk beverage kefir has recently been shown to modulate the composition of the gut microbiota in mice. It is unclear whether kefirs have differential effects on microbiota-gut-brain axis and whether they can modulate host behaviour per se.

Methods: To address this, two distinct kefirs (Fr1 and UK4), or unfermented milk control, were administered to mice that underwent a battery of tests to characterise their behavioural phenotype. In addition, shotgun metagenomic sequencing of ileal, caecal and faecal matter was performed, as was faecal metabolome analysis. Finally, systemic immunity measures and gut serotonin levels were assessed. Statistical analyses were performed by ANOVA followed by Dunnett's post hoc test or Kruskal-Wallis test followed by Mann-Whitney U test.

Results: Fr1 ameliorated the stress-induced decrease in serotonergic signalling in the colon and reward-seeking behaviour in the saccharin preference test. On the other hand, UK4 decreased repetitive behaviour and ameliorated stress-induced deficits in reward-seeking behaviour. Furthermore, UK4 increased fear-dependent contextual memory, yet decreased milk gavage-induced improvements in long-term spatial learning. In the peripheral immune system, UK4 increased the prevalence of Treg cells and interleukin 10 levels, whereas Fr1 ameliorated the milk gavage stress-induced elevation in neutrophil levels and CXCL1 levels. Analysis of the gut microbiota revealed that both kefirs significantly changed the composition and functional capacity of the host microbiota, where specific bacterial species were changed in a kefir-dependent manner. Furthermore, both kefirs increased the capacity of the gut microbiota to produce GABA, which was linked to an increased prevalence in Lactobacillus reuteri.

Conclusions: Altogether, these data show that kefir can signal through the microbiota-gut-immune-brain axis and modulate host behaviour. In addition, different kefirs may direct the microbiota toward distinct immunological and behavioural modulatory effects. These results indicate that kefir can positively modulate specific aspects of the microbiota-gut-brain axis and support the broadening of the definition of psychobiotic to include kefir fermented foods. Video abstract.
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http://dx.doi.org/10.1186/s40168-020-00846-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7236220PMC
May 2020

Gut-brain axis serotonergic responses to acute stress exposure are microbiome-dependent.

Neurogastroenterol Motil 2020 11 11;32(11):e13881. Epub 2020 May 11.

APC Microbiome Ireland, University College Cork, Cork, Ireland.

Background: Understanding the mechanisms underpinning the response to acute stress is critical for determining how this can be modulated in both health and disease and across sexes. Stress can markedly alter the microbiome and gut-brain axis signaling with the serotonergic system being particularly sensitive to acute stress. As the impact of acute stress on regional serotonergic dynamics in the gut-brain axis and the contribution of the microbiome to this are poorly appreciated, we used microbiota-deficient mice to assess whether the serotonergic response to acute stress exposure is microbiome dependent.

Methods: Adult male and female conventional, germ-free, and colonized germ-free mice underwent a single acute stressor and samples were harvested immediately or 45 minutes following stress. Serotonin and related metabolites and serotonergic gene expression were determined.

Key Results: Our data clearly show the microbiota influenced gastrointestinal serotonergic response to acute stress in a sex- and region-dependent manner. Male-specific poststress increases in colonic serotonin were absent in germ-free mice but normalized following colonization. mRNA serotonergic gene expression was differentially expressed in colon and ileum of germ-free mice on a sex-dependent basis. Within the frontal cortex, absence of the microbiome altered basal serotonin, its main metabolite 5-hydroxyindoleacetic acid, and prevented stress-induced increases in serotonin turnover.

Conclusions And Inferences: The gut microbiome influences the set points of the brain and gastrointestinal serotonergic systems and affected their response to acute stress in a sex- and region-dependent manner.
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http://dx.doi.org/10.1111/nmo.13881DOI Listing
November 2020

Gut microbiome-mediated modulation of hepatic cytochrome P450 and P-glycoprotein: impact of butyrate and fructo-oligosaccharide-inulin.

J Pharm Pharmacol 2020 Aug 26;72(8):1072-1081. Epub 2020 Apr 26.

APC Microbiome Ireland, University College Cork, Cork, Ireland.

Objectives: Our objective was to demonstrate microbial regulation of hepatic genes implicated in drug metabolism and transport using germ-free (GF) mice and to explore the impact of a microbial metabolite, butyrate, and a prebiotic dietary intervention on hepatic gene expression in mice.

Methods: Using reverse-transcriptase PCR, we investigated cytochrome P450 (CYP) and multidrug-resistance protein 1 (MDR1) expression in conventional, GF and colonised GF mice. To investigate the effects of butyrate, sodium butyrate (3 g/l) was administered for 21 days to conventional or GF mice. In the prebiotic study, young adult and middle-aged mice received diet enriched with 10% fructo-oligosaccharide (FOS)-inulin for 14 weeks.

Key Findings: Colonisation of GF animals normalised expression of Cyp3a11 and Mdr1b to conventional levels. Butyrate upregulated Cyp2b10 in conventional mice (P < 0.05) but overall did not induce widespread changes in hepatic genes. FOS-inulin increased Cyp3a13 expression and had the opposite effect on Mdr1a expression in young adult mice (P < 0.05). Age, on the other hand, influenced the prebiotic effect on Cyp2a4 expression (P < 0.01).

Conclusion: The expression of hepatic genes implicated in drug metabolism and transport displays sensitivity to the microbiome, microbiome-derived metabolites and a microbial-targeted intervention. Our study may provide the impetus to explore microbiota-targeted interventions in normalising host metabolic activity and reducing inter-individual variability in drug pharmacokinetics.
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http://dx.doi.org/10.1111/jphp.13276DOI Listing
August 2020

The role of the gut microbiome in the development of schizophrenia.

Schizophr Res 2020 Apr 23. Epub 2020 Apr 23.

Department of Psychiatry and Neurobehavioral Science, University College Cork, Ireland; APC Microbiome Ireland, University College Cork, Ireland. Electronic address:

Schizophrenia is a heterogeneous neurodevelopmental disorder involving the convergence of a complex and dynamic bidirectional interaction of genetic expression and the accumulation of prenatal and postnatal environmental risk factors. The development of the neural circuitry underlying social, cognitive and emotional domains requires precise regulation from molecular signalling pathways, especially during critical periods or "windows", when the brain is particularly sensitive to the influence of environmental input signalling. Many of the brain regions involved, and the molecular substrates sub-serving these domains are responsive to life-long microbiota-gut-brain (MGB) axis signalling. This intricate microbial signalling system communicates with the brain via the vagus nerve, immune system, enteric nervous system, enteroendocrine signalling and production of microbial metabolites, such as short-chain fatty acids. Preclinical data has demonstrated that MGB axis signalling influences neurotransmission, neurogenesis, myelination, dendrite formation and blood brain barrier development, and modulates cognitive function and behaviour patterns, such as, social interaction, stress management and locomotor activity. Furthermore, preliminary clinical studies suggest altered gut microbiota profiles in schizophrenia. Unravelling MGB axis signalling in the context of an evolving dimensional framework in schizophrenia may provide a more complete understanding of the neurobiological architecture of this complex condition and offers the possibility of translational interventions.
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http://dx.doi.org/10.1016/j.schres.2020.02.010DOI Listing
April 2020

Systemic Inflammation Persists the First Year after Mild Traumatic Brain Injury: Results from the Prospective Trondheim Mild Traumatic Brain Injury Study.

J Neurotrauma 2020 10 3;37(19):2120-2130. Epub 2020 Jun 3.

Department of Immunology, Oslo University Hospital and University of Oslo, Oslo, Norway.

Innate immune activation has been attributed a key role in traumatic brain injury (TBI) and successive morbidity. In mild TBI (mTBI), however, the extent and persistence of innate immune activation are unknown. We determined plasma cytokine level changes over 12 months after an mTBI in hospitalized and non-hospitalized patients compared with community controls; and examined their associations to injury-related and demographic variables at admission. Prospectively, 207 patients presenting to the emergency department (ED) or general practitioner with clinically confirmed mTBI and 82 matched community controls were included. Plasma samples were obtained at admission, after 2 weeks, 3 months, and 12 months. Cytokine levels were analysed with a 27-plex beads-based immunoassay. Brain magnetic resonance imaging (MRI) was performed on all participants. Twelve cytokines were reliably detected. Plasma levels of interferon gamma (IFN-γ), interleukin 8 (IL-8), eotaxin, macrophage inflammatory protein-1-beta (MIP-1β), monocyte chemoattractant protein 1 (MCP-1), IL-17A, IL-9, tumor necrosis factor (TNF), and basic fibroblast growth factor (FGF-basic) were significantly increased at all time-points in patients compared with controls, whereas IFN-γ-inducing protein 10 (IP-10), platelet-derived growth factor (PDGF), and IL-1ra were not. IL-17A and FGF-basic showed significant increases in patients from admission to follow-up at 3 months, and remained increased at 12 months compared with admission. Interestingly, MRI findings were negatively associated with four cytokines: eotaxin, MIP-1β, IL-9, and IP-10, whereas age was positively associated with nine cytokines: IL-8, eotaxin, MIP-1β, MCP-1, IL-17A, IL-9, TNF, FGF-basic, and IL-1ra. TNF was also increased in those with presence of other injuries. In conclusion, mTBI activated the innate immune system consistently and this is the first study to show that several inflammatory cytokines remain increased for up to 1 year post-injury.
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http://dx.doi.org/10.1089/neu.2019.6963DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7502683PMC
October 2020

Longitudinal relationship of amino acids and indole metabolites with long-term body mass index and cardiometabolic risk markers in young individuals.

Sci Rep 2020 04 14;10(1):6399. Epub 2020 Apr 14.

Nutritional Epidemiology, Department of Nutrition and Food Sciences, University of Bonn, Bonn, Germany.

Amino acid metabolites in biofluids are associated with high body mass index (BMI) and cardiometabolic abnormalities. However, prospective investigations regarding these associations are few, particularly among young individuals. Moreover, little is presently known about the impact of long-term high BMI. Using data from the DOrtmund Nutritional and Anthropometric Longitudinally Designed study (111 males and 107 females), we prospectively investigated relations between repeatedly measured urinary levels of 33 metabolites and (1) previously identified long-term BMI trajectory groups from childhood into late adolescence and (2) cardiometabolic risk markers in late adolescence-young adulthood, in sex-specific linear mixed regression models. Males with long-term overweight had lower indole-3-acetic acid when compared to others. Further, methionine, isoleucine, tryptophan, xanthurenic acid, and indole-3-carboxaldehyde were negatively associated with C-reactive protein (CRP), but 5-hydroxyindole-3-acetic acid was positively associated with CRP. No associations were observed in females. Long-term overweight from childhood into late adolescence is associated with decreased urinary levels of gut bacteria-derived indole-3-acetic acid, and several urinary amino acids, including gut bacteria-derived indole-3-carboxaldehyde are associated with elevated CRP later on in life. Taken together, our data suggest that indole metabolites, and their gut bacteria producers play potentially important roles in overweight-related inflammation.
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http://dx.doi.org/10.1038/s41598-020-63313-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7156759PMC
April 2020

The gut microbiome and depression: finding a way through troubled waters where the river meets the sea.

Authors:
Gerard Clarke

Expert Rev Gastroenterol Hepatol 2020 May 16;14(5):301-304. Epub 2020 Apr 16.

Department of Psychiatry and Neurobehavioural Science, University College Cork , Cork, Ireland.

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http://dx.doi.org/10.1080/17474124.2020.1754796DOI Listing
May 2020

Impact of host and environmental factors on β-glucuronidase enzymatic activity: implications for gastrointestinal serotonin.

Am J Physiol Gastrointest Liver Physiol 2020 04 9;318(4):G816-G826. Epub 2020 Mar 9.

APC Microbiome Ireland, University College Cork, Cork, Ireland.

The gastrointestinal tract houses a reservoir of bacterial-derived enzymes that can directly catalyze the metabolism of drugs, dietary elements and endogenous molecules. Both host and environmental factors may influence this enzymatic activity, with the potential to dictate the availability of the biologically-active form of endogenous molecules in the gut and influence inter-individual variation in drug metabolism. We aimed to investigate the influence of the microbiota, and the modulation of its composition, on fecal enzymatic activity. Intrinsic factors related to the host, including age, sex and genetic background, were also explored. Fecalase, a cell-free extract of feces, was prepared and used in a colorimetric-based assay to quantify enzymatic activity. To demonstrate the functional effects of fecal enzymatic activity, we examined β-glucuronidase-mediated cleavage of serotonin β-d-glucuronide (5-HT-GLU) and the resultant production of free 5-HT by HPLC. As expected, β-glucuronidase and β-glucosidase activity were absent in germ-free mice. Enzymatic activity was significantly influenced by mouse strain and animal species. Sex and age significantly altered metabolic activity with implications for free 5-HT. β-Glucuronidase and β-glucosidase activity remained at reduced levels for nearly two weeks after cessation of antibiotic administration. This effect on fecalase corresponded to significantly lower 5-HT levels as compared with incubation with pre-antibiotic fecalase from the same mice. Dietary targeting of the microbiota using prebiotics did not alter β-glucuronidase or β-glucosidase activity. Our data demonstrate that multiple factors influence the activity of bacterial-derived enzymes which may have potential clinical implications for drug metabolism and the deconjugation of host-produced glucuronides in the gut. This article explores a comprehensive range of host and environmental factors that introduce variability in the expression of bacterial-derived metabolic enzymes. Our results demonstrate that altered β-glucuronidase activity has implications for the bioavailability of luminal serotonin. The experimental approach employed, fecalase, provides a mechanistic basis and translational platform to further delineate the functional outputs of altered metabolic activity, and the associated physiological effects of microbiota-targeted interventions on host response to drugs and host-produced glucuronides.
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http://dx.doi.org/10.1152/ajpgi.00026.2020DOI Listing
April 2020

Resveratrol and metabolic health in COPD: A proof-of-concept randomized controlled trial.

Clin Nutr 2020 Oct 13;39(10):2989-2997. Epub 2020 Jan 13.

Department of Respiratory Medicine, NUTRIM School of Nutrition and Translational Research in Metabolism, Maastricht University Medical Centre+, Maastricht, the Netherlands.

Background: Patients with COPD are often characterized by disturbed metabolic health which is reflected in altered body composition. Current studies in healthy subjects suggest that resveratrol improves metabolic health by enhancing muscle mitochondrial function and adipose tissue morphology. The primary objective was to investigate the effect of four weeks resveratrol supplementation on muscle mitochondrial function in patients with COPD. Secondary objectives were to investigate the effect of resveratrol on adipose tissue inflammatory and metabolic gene expression, systemic inflammation and body composition in patients with COPD.

Methods: In a double-blind randomized placebo-controlled proof-of-concept study, 21 COPD patients (FEV: 53 ± 15% predicted; age: 67 ± 9 years and BMI: 24.5 ± 3.3 kg/m) received resveratrol (150 mg/day) or placebo for four weeks. Before and after intervention, blood samples, quadriceps muscle and subcutaneous abdominal fat biopsies were obtained for metabolic and inflammatory profiling. Body composition was assessed by dual energy X-ray absorptiometry.

Results: Muscle mitochondrial biogenesis regulators AMPK, SIRT1 and PGC-1α as well as mitochondrial respiration, Oxphos complexes, oxidative enzyme activities and kynurenine aminotransferases were not improved by resveratrol. Plasma high-sensitive C-reactive protein and kynurenine did not change after resveratrol supplementation. Adipose tissue inflammatory markers were unaffected by resveratrol, while markers of glycolysis and lipolysis were significantly increased compared to placebo supplementation. Body weight decreased after resveratrol supplementation (resveratrol -0.95 ± 1.01 kg vs placebo -0.16 ± 0.66 kg, p = 0.049) due to a reduction in lean mass (resveratrol -1.79 ± 1.67 kg vs 0.37 ± 0.86 kg, p = 0.026).

Conclusion: We do not confirm previously reported positive effects of resveratrol on skeletal muscle mitochondrial function in patients with COPD, but show an unexpected decline in lean mass.

Clinical Trial Registry: Clinicaltrials.gov NCT02245932.
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http://dx.doi.org/10.1016/j.clnu.2020.01.002DOI Listing
October 2020

Gutted! Unraveling the Role of the Microbiome in Major Depressive Disorder.

Harv Rev Psychiatry 2020 Jan/Feb;28(1):26-39

Microorganisms can be found in virtually any environment. In humans, the largest collection of microorganisms is found in the gut ecosystem. The adult gut microbiome consists of more genes than its human host and typically spans more than 60 genera from across the taxonomic tree. In addition, the gut contains the largest number of neurons in the body, after the brain. In recent years, it has become clear that the gut microbiome is in communication with the brain, through the gut-brain axis. A growing body of literature shows that the gut microbiome plays a shaping role in a variety of psychiatric disorders, including major depressive disorder (MDD). In this review, the interplay between the microbiome and MDD is discussed in three facets. First, we discuss factors that affect the onset/development of MDD that also greatly impinge on the composition of the gut microbiota-especially diet and stressful life events. We then examine the interplay between the microbiota and MDD. We examine evidence suggesting that the microbiota is altered in MDD, and we discuss why the microbiota should be considered during MDD treatment. Finally, we look toward the future and examine how the microbiota might become a therapeutic target for MDD. This review is intended to introduce those familiar with the neurological and psychiatric aspects of MDD to the microbiome and its potential role in the disorder. Although research is in its very early days, with much yet to be the understood, the microbiome is offering new avenues for developing potentially novel strategies for managing MDD.
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http://dx.doi.org/10.1097/HRP.0000000000000243DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7012351PMC
January 2020

The role of the microbiota in acute stress-induced myeloid immune cell trafficking.

Brain Behav Immun 2020 02 5;84:209-217. Epub 2019 Dec 5.

APC Microbiome Ireland, University College Cork, Cork, Ireland; Department of Anatomy and Neuroscience, University College Cork, Cork, Ireland. Electronic address:

There has been a growing recognition of the involvement of the gastrointestinal microbiota in the development of stress-related disorders. Acute stress leads to activation of neuroendocrine systems, which in turn orchestrate a large-scale redistribution of innate immune cells. Both these response systems are independently known to be primed by the microbiota, even though much is still unclear about the role of the gastrointestinal microbiota in acute stress-induced immune activation. In this study, we investigated whether the microbiota influences acute stress-induced changes in innate immunity using conventionally colonised mice, mice devoid of any microbiota (i.e. germ-free, GF), and colonised GF mice (CGF). We also explored the kinetics of stress-induced immune cell mobilisation in the blood, the spleen and mesenteric lymph nodes (MLNs). Mice were either euthanised prior to stress or underwent restraint stress and were then euthanised at various time points (i.e. 0, 45- and 240-minutes) post-stress. Plasma adrenaline and noradrenaline levels were analysed using ELISA and immune cell levels were quantified using flow cytometry. GF mice had increased baseline levels of adrenaline and noradrenaline, of which adrenaline was normalised in CGF mice. In tandem, GF mice had decreased circulating levels of LY6C and LY6C, CCR2+ monocytes, and granulocytes, but not LY6C-, CX3CR1+ monocytes. These deficits were normalised in CGF mice. Acute stress decreased blood LY6C and LY6C, CCR2+ monocytes while increasing granulocyte levels in all groups 45 min post-stress. However, only GF mice showed stress-induced changes in LY6C monocytes and granulocytes 240 min post-stress, indicating impairments in the recovery from acute stress-induced changes in levels of specific innate immune cell types. LY6C-, CX3CR1+ monocytes remained unaffected by stress, indicating that acute stress impacts systemic innate immunity in a cell-type-specific manner. Overall, these data reveal novel cell-type-specific changes in the innate immune system in response to acute stress, which in turn are impacted by the microbiota. In conclusion, the microbiota influences the priming and recovery of the innate immune system to an acute stressor and may inform future microbiota-targeted therapeutics aimed at modulating stress-induced immune activation in stress-related disorders.
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http://dx.doi.org/10.1016/j.bbi.2019.12.003DOI Listing
February 2020

Informal caregiving for dementia patients: the contribution of patient characteristics and behaviours to caregiver burden.

Age Ageing 2019 12;49(1):52-56

Centre for Gerontology & Rehabilitation, University College Cork, Cork, Ireland.

Objectives: The burden often associated with informal caregiving for patients with dementia is associated with negative effects on health, both physiologically and in terms of caregiver cognition. There is wide variation in the level of burden experienced by dementia caregivers. To better understand caregiver burden, it is thus important to understand the factors associated with level of burden.

Methods: In the current study, we collected carer burden and putative associated factors at baseline, 6 and 12 months. Hierarchical regression was used to assess the impact of these factors on caregiver burden. We assessed self-reported carer burden, patient behavioural and safety issues, and level of difficulty associated with providing assistance with activities of daily living (ADL). Patients' age was also recorded, and trained nurses assessed patient cognitive performance using the quick mild cognitive impairment screen.

Results: At baseline, patients' age, cognition and ADLs were associated with burden, and safety and challenging behaviour were both significantly associated with burden independent of the other factors. Change in burden was associated with change in carer-reported safety at 6-month follow-up, and with change in safety and change in carer-reported challenging behaviours at 12-month follow-up.

Conclusions: Safety issues and challenging behaviours are associated with carer burden, even after accounting for cognitive and functional impairment in the person with dementia. As dementia progresses, monitoring these factors may help to inform stress-management strategies for caregivers.
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http://dx.doi.org/10.1093/ageing/afz128DOI Listing
December 2019

Natural compulsive-like behaviour in the deer mouse (Peromyscus maniculatus bairdii) is associated with altered gut microbiota composition.

Eur J Neurosci 2020 03 21;51(6):1419-1427. Epub 2019 Nov 21.

Centre of Excellence for Pharmaceutical Sciences, North West-University, Potchefstroom, South Africa.

Obsessive-compulsive disorder (OCD) is a psychiatric illness that significantly impacts affected patients and available treatments yield suboptimal therapeutic response. Recently, the role of the gut-brain axis (GBA) in psychiatric illness has emerged as a potential target for therapeutic exploration. However, studies concerning the role of the GBA in OCD are limited. To investigate whether a naturally occurring obsessive-compulsive-like phenotype in a rodent model, that is large nest building in deer mice, is associated with perturbations in the gut microbiome, we investigated and characterised the gut microbiota in specific-pathogen-free bred and housed large (LNB) and normal (NNB) nest-building deer mice of both sexes (n = 11 per group, including three males and eight females). Following baseline characterisation of nest-building behaviour, a single faecal sample was collected from each animal and the gut microbiota analysed. Our results reveal the overall microbial composition of LNB animals to be distinctly different compared to controls (PERMANOVA p < .05). While no genera were found to be significantly differentially abundant after correcting for multiple comparisons, the normal phenotype showed a higher loading of Prevotella and Anaeroplasma, while the OC phenotype demonstrated a higher loading of Desulfovermiculus, Aestuariispira, Peptococcus and Holdemanella (cut-off threshold for loading at 0.2 in either the first or second component of the PCA). These findings not only provide proof-of-concept for continued investigation of the GBA in OCD, but also highlight a potential underlying aetiological association between alterations in the gut microbiota and the natural development of obsessive-compulsive-like behaviours.
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http://dx.doi.org/10.1111/ejn.14610DOI Listing
March 2020