Publications by authors named "Marcel van de Wouw"

21 Publications

  • Page 1 of 1

Associations Between the Gut Microbiota and Internalizing Behaviors in Preschool Children.

Psychosom Med 2021 Oct 12. Epub 2021 Oct 12.

Department of Pediatrics, University of Calgary, Calgary, Alberta, Canada Department of Psychology, University of Calgary, Calgary, Alberta, Canada Alberta Children's Hospital Research Institute (ACHRI), Calgary, Alberta, Canada Department of Community Health Sciences, University of Calgary, Calgary, Alberta, Canada UCVM Bioinformatics, Faculty of Veterinary Medicine, University of Calgary, Calgary, Alberta, Canada Faculty of Kinesiology, University of Calgary, Calgary, Alberta, Canada Department of Biochemistry and Molecular Biology, Cumming School of Medicine, University of Calgary, Alberta, Canada.

Objective: Emerging evidence points toward a connection between mental health and the gut microbiota and its metabolites (e.g., short-chain fatty acids - SCFAs). It is unknown whether gut microbiota levels are associated with the development of mental health problems (e.g., internalizing or externalizing behaviors) in preschool children. The objective of this study was to evaluate associations between the gut microbiota and internalizing and externalizing behaviors in preschool-aged children.

Methods: A community sample of 248 typically developing children (3-5 years) provided a stool sample for gut microbiota and SCFA analysis. Parents reported child internalizing and externalizing behaviors using the Child Behavior Checklist. Associations between child behaviors and gut microbiota measures were analyzed using Spearman correlations followed by an adjustment for multiple testing, with subanalysis conducted in children clinically "at risk" for behavioral problems compared to those who were not using Mann-Whitney U tests.

Results: There was a correlation between Shannon alpha diversity with internalizing behaviors (rs = -0.134, p = 0.035), and its subscale somatic complaints (rs = -0.144, p = 0.023), while children clinically "at risk" for internalizing problems had decreased alpha diversity (U = 551, p = 0.017). Internalizing behaviors correlated with valerate and isobutyrate (rs = -0.147, p = 0.021; rs = -0.140, p = 0.028, respectively), while the somatic complaints subscale additionally correlated with acetate and butyrate (rs = -0.219, p = 0.001; rs = -0.241, p < 0.001, respectively). These findings were also present in children "at risk" for internalizing problems (U = 569, p = 0.026; U = 571, p = 0.028), and somatic complaints (U = 164, p = 0.004; U = 145, p = 0.001).

Conclusions: These analyses reveal novel associations between internalizing behaviors and the gut microbiota in preschool children. Furthermore, a relationship between somatic complaints and acetate and butyrate was identified, indicating that interventions that increase SCFA production warrant future investigation.
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http://dx.doi.org/10.1097/PSY.0000000000001026DOI Listing
October 2021

Kefir ameliorates specific microbiota-gut-brain axis impairments in a mouse model relevant to autism spectrum disorder.

Brain Behav Immun 2021 10 9;97:119-134. Epub 2021 Jul 9.

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

Autism spectrum disorder (ASD) is one of the most severe developmental disorders, affecting on average 1 in 150 children worldwide. There is a great need for more effective strategies to improve quality of life in ASD subjects. The gut microbiome has emerged as a potential therapeutic target in ASD. A novel modulator of the gut microbiome, the traditionally fermented milk drink kefir, has recently been shown to modulate the microbiota and decrease repetitive behaviour, one of the hallmarks of ASD, in mice. As such, we hypothesized that kefir could ameliorate behavioural deficits in a mouse model relevant to ASD; the BTBR T Itpr3/J mouse strain. To this end, adult mice were administered either kefir (UK4) or a milk control for three weeks as treatment lead-in, after which they were assessed for their behavioural phenotype using a battery of tests. In addition, we assessed systemic immunity by flow cytometry and the gut microbiome using shotgun metagenomic sequencing. We found that indeed kefir decreased repetitive behaviour in this mouse model. Furthermore, kefir prolonged stress-induced increases in corticosterone 60 min post-stress, which was accompanied by an ameliorated innate immune response as measured by LY6C monocyte levels. In addition, kefir increased the levels of anti-inflammatory Treg cells in mesenteric lymph nodes (MLNs). Kefir also increased the relative abundance of Lachnospiraceae bacterium A2, which correlated with reduced repetitive behaviour and increased Treg cells in MLNs. Functionally, kefir modulated various predicted gut microbial pathways, including the gut-brain module S-Adenosylmethionine (SAM) synthesis, as well as L-valine biosynthesis and pyruvate fermentation to isobutanol, which all correlated with repetitive behaviour. Taken together our data show that kefir modulates peripheral immunoregulation, can ameliorate specific ASD behavioural dysfunctions and modulates selective aspects of the composition and function of the gut microbiome, indicating that kefir supplementation might prove a viable strategy in improving quality of life in ASD subjects.
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http://dx.doi.org/10.1016/j.bbi.2021.07.004DOI Listing
October 2021

Protocol for the Pregnancy During the COVID-19 Pandemic (PdP) Study: A Longitudinal Cohort Study of Mental Health Among Pregnant Canadians During the COVID-19 Pandemic and Developmental Outcomes in Their Children.

JMIR Res Protoc 2021 Apr 28;10(4):e25407. Epub 2021 Apr 28.

Department of Pediatrics, University of Calgary, Calgary, AB, Canada.

Background: The COVID-19 pandemic and countermeasures implemented by governments around the world have led to dramatically increased symptoms of depression and anxiety. Pregnant individuals may be particularly vulnerable to the negative psychological effects of COVID-19 public health measures because they represent a demographic that is most affected by disasters and because pregnancy itself entails significant life changes that require major psychosocial and emotional adjustments.

Objective: The PdP study was designed to investigate the associations among exposure to objective hardship caused by the pandemic, perceived stress and psychological distress in pregnant individuals, and developmental outcomes in their offspring.

Methods: The PdP study comprises a prospective longitudinal cohort of individuals who were pregnant at enrollment, with repeated follow-ups during pregnancy and the postpartum period. Participants were eligible if they were pregnant, ≥17 years old, at ≤35 weeks of gestation at study enrollment, living in Canada, and able to read and write in English or French. At enrollment, participants completed an initial survey that assessed demographic and socioeconomic characteristics, previous pregnancies and births, prepregnancy health, health conditions during pregnancy, medications, psychological distress, social support, and hardships experienced because of the COVID-19 pandemic (eg, lost employment or a loved one dying). For the first three months following the initial survey, participants received a monthly email link to complete a follow-up survey that asked about their experiences since the previous survey. After three months, follow-up surveys were sent every other month to reduce participant burden. For each of these surveys, participants were first asked if they were still pregnant and then routed either to the next prenatal survey or to the delivery survey. In the postpartum period, surveys were sent at 3, 6, and 12 months of infant age to assess maternal stress, psychological distress, and infant development.

Results: Participant recruitment via social media (Facebook and Instagram) began on April 5, 2020, and is ongoing. As of April 2021, more than 11,000 individuals have started the initial survey. Follow-up data collection is ongoing.

Conclusions: This longitudinal investigation seeks to elucidate the associations among hardships, maternal psychological distress, child development during the COVID-19 pandemic, and risk and resilience factors that amplify or ameliorate these associations. The findings of this study are intended to generate knowledge about the psychological consequences of pandemics on pregnant individuals and point toward prevention and intervention targets.

International Registered Report Identifier (irrid): DERR1-10.2196/25407.
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http://dx.doi.org/10.2196/25407DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8080963PMC
April 2021

Acute stress increases monocyte levels and modulates receptor expression in healthy females.

Brain Behav Immun 2021 05 9;94:463-468. Epub 2021 Mar 9.

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 immune system in stress-related disorders. Acute stress leads to the activation of neuroendocrine systems, which in turn orchestrate a large-scale redistribution of innate immune cells, such as monocytes. Even though acute stress/monocyte interactions have been well-characterized in mice, this is not the case for humans. As such, this study aimed to investigate whether acute stress modulates blood monocyte levels in a subtype-dependent manner and whether the receptor expression of stress-related receptors is affected in humans. Blood was collected from healthy female volunteers at baseline and 1 h after the socially evaluated cold pressor test, after which blood monocyte levels and receptor expression were assessed by flow cytometry. Our results reveal a stress-induced increase in blood monocyte levels, which was independent of monocyte subtypes. Furthermore, colony stimulating factor 1 receptor (CSF-1R) and CD29 receptor expression was increased, while CD62L showed a trend towards increased expression. These results provide novel insights into how acute stress affects the innate immune system.
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http://dx.doi.org/10.1016/j.bbi.2021.03.005DOI Listing
May 2021

Bifidobacterium longum counters the effects of obesity: Partial successful translation from rodent to human.

EBioMedicine 2021 Jan 18;63:103176. Epub 2020 Dec 18.

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

Background: The human gut microbiota has emerged as a key factor in the development of obesity. Certain probiotic strains have shown anti-obesity effects. The objective of this study was to investigate whether Bifidobacterium longum APC1472 has anti-obesity effects in high-fat diet (HFD)-induced obese mice and whether B. longum APC1472 supplementation reduces body-mass index (BMI) in healthy overweight/obese individuals as the primary outcome. B. longum APC1472 effects on waist-to-hip ratio (W/H ratio) and on obesity-associated plasma biomarkers were analysed as secondary outcomes.

Methods: B. longum APC1472 was administered to HFD-fed C57BL/6 mice in drinking water for 16 weeks. In the human intervention trial, participants received B. longum APC1472 or placebo supplementation for 12 weeks, during which primary and secondary outcomes were measured at the beginning and end of the intervention.

Findings: B. longum APC1472 supplementation was associated with decreased bodyweight, fat depots accumulation and increased glucose tolerance in HFD-fed mice. While, in healthy overweight/obese adults, the supplementation of B. longum APC1472 strain did not change primary outcomes of BMI (0.03, 95% CI [-0.4, 0.3]) or W/H ratio (0.003, 95% CI [-0.01, 0.01]), a positive effect on the secondary outcome of fasting blood glucose levels was found (-0.299, 95% CI [-0.44, -0.09]).

Interpretation: This study shows a positive translational effect of B. longum APC1472 on fasting blood glucose from a preclinical mouse model of obesity to a human intervention study in otherwise healthy overweight and obese individuals. This highlights the promising potential of B. longum APC1472 to be developed as a valuable supplement in reducing specific markers of obesity.

Funding: This research was funded in part by Science Foundation Ireland in the form of a Research Centre grant (SFI/12/RC/2273) to APC Microbiome Ireland and by a research grant from Cremo S.A.
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http://dx.doi.org/10.1016/j.ebiom.2020.103176DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7838052PMC
January 2021

Volatility as a Concept to Understand the Impact of Stress on the Microbiome.

Psychoneuroendocrinology 2021 02 8;124:105047. Epub 2020 Dec 8.

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

The microbiome-gut-brain-axis is a complex phenomenon spanning several dynamic systems in the body which can be parsed at a molecular, cellular, physiological and ecological level. A growing body of evidence indicates that this axis is particularly sensitive to the effects of stress and that it may be relevant to stress resilience and susceptibility. Although stress-induced changes in the composition of the microbiome have been reported, the degree of compositional change over time, which we define as volatility, has not been the subject of in-depth scrutiny. Using a chronic psychosocial stress paradigm in male mice, we report that the volatility of the microbiome significantly correlated with several readouts of the stress response, including behaviour and corticosterone response. We then validated these findings in a second independent group of stressed mice. Additionally, we assessed the relationship between volatility and stress parameters in a cohort of health volunteers who were undergoing academic exams and report similar observations. Finally, we found inter-species similarities in the microbiome stress response on a functional level. Our research highlights the effects of stress on the dynamic microbiome and underscores the informative value of volatility as a parameter that should be considered in all future analyses of the microbiome.
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http://dx.doi.org/10.1016/j.psyneuen.2020.105047DOI Listing
February 2021

Strain differences in behaviour and immunity in aged mice: Relevance to Autism.

Behav Brain Res 2021 02 20;399:113020. Epub 2020 Nov 20.

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

The BTBR mouse model has been shown to be associated with deficits in social interaction and a pronounced engagement in repetitive behaviours. Autism spectrum disorder (ASD) is the most prevalent neurodevelopmental condition globally. Despite its ubiquity, most research into the disorder remains focused on childhood, with studies in adulthood and old age relatively rare. To this end, we explored the differences in behaviour and immune function in an aged BTBR T + Itpr3tf/J mouse model of the disease compared to a similarly aged C57bl/6 control. We show that while many of the alterations in behaviour that are observed in young animals are maintained (repetitive behaviours, antidepressant-sensitive behaviours, social deficits & cognition) there are more nuanced effects in terms of anxiety in older animals of the BTBR strain compared to C57bl/6 controls. Furthermore, BTBR animals also exhibit an activated T-cell system. As such, these results represent confirmation that ASD-associated behavioural deficits are maintained in ageing, and that that there may be need for differential interventional approaches to counter these impairments, potentially through targeting the immune system.
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http://dx.doi.org/10.1016/j.bbr.2020.113020DOI Listing
February 2021

A specific dietary fibre supplementation improves cognitive performance-an exploratory randomised, placebo-controlled, crossover study.

Psychopharmacology (Berl) 2021 Jan 20;238(1):149-163. Epub 2020 Sep 20.

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

Rationale: The impact of the microbiota on the gut-brain axis is increasingly appreciated. A growing body of literature demonstrates that use of dietary fibre and prebiotics can manipulate the microbiota and affect host health. However, the influence on cognition and acute stress response is less well understood.

Objectives: The objective of this study was to investigate the efficacy of a dietary fibre, polydextrose (PDX), in improving cognitive performance and acute stress responses through manipulation of the gut microbiota in a healthy population.

Methods: In this double-blind, randomised, placebo-controlled, crossover design study, 18 healthy female participants received 12.5 g Litesse®Ultra (> 90% PDX polymer) or maltodextrin for 4 weeks. Cognitive performance, mood, acute stress responses, microbiota composition, and inflammatory markers were assessed pre- and post-intervention.

Results: PDX improved cognitive flexibility as evidenced by the decrease in the number of errors made in the Intra-Extra Dimensional Set Shift (IED) task. A better performance in sustained attention was observed through higher number of correct responses and rejections in the Rapid Visual Information Processing (RVP) task. Although there was no change in microbial diversity, abundance of Ruminiclostridium 5 significantly increased after PDX supplementation compared with placebo. PDX supplementation attenuated the increase of adhesion receptor CD62L on classical monocytes observed in the placebo group.

Conclusions: Supplementation with the PDX resulted in a modest improvement in cognitive performance. The results indicate that PDX could benefit gut-to-brain communication and modulate behavioural responses.
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http://dx.doi.org/10.1007/s00213-020-05665-yDOI Listing
January 2021

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 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 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

The Microbiota-Gut-Brain Axis.

Physiol Rev 2019 10;99(4):1877-2013

APC Microbiome Ireland, University College Cork, Cork, Ireland; Department of Anatomy and Neuroscience, University College Cork, Cork, Ireland; Department of Psychiatry and Neurobehavioural Science, University College Cork, Cork, Ireland; and Department of Physiology, University College Cork, Cork, Ireland.

The importance of the gut-brain axis in maintaining homeostasis has long been appreciated. However, the past 15 yr have seen the emergence of the microbiota (the trillions of microorganisms within and on our bodies) as one of the key regulators of gut-brain function and has led to the appreciation of the importance of a distinct microbiota-gut-brain axis. This axis is gaining ever more traction in fields investigating the biological and physiological basis of psychiatric, neurodevelopmental, age-related, and neurodegenerative disorders. The microbiota and the brain communicate with each other via various routes including the immune system, tryptophan metabolism, the vagus nerve and the enteric nervous system, involving microbial metabolites such as short-chain fatty acids, branched chain amino acids, and peptidoglycans. Many factors can influence microbiota composition in early life, including infection, mode of birth delivery, use of antibiotic medications, the nature of nutritional provision, environmental stressors, and host genetics. At the other extreme of life, microbial diversity diminishes with aging. Stress, in particular, can significantly impact the microbiota-gut-brain axis at all stages of life. Much recent work has implicated the gut microbiota in many conditions including autism, anxiety, obesity, schizophrenia, Parkinson's disease, and Alzheimer's disease. Animal models have been paramount in linking the regulation of fundamental neural processes, such as neurogenesis and myelination, to microbiome activation of microglia. Moreover, translational human studies are ongoing and will greatly enhance the field. Future studies will focus on understanding the mechanisms underlying the microbiota-gut-brain axis and attempt to elucidate microbial-based intervention and therapeutic strategies for neuropsychiatric disorders.
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http://dx.doi.org/10.1152/physrev.00018.2018DOI Listing
October 2019

Host Microbiota Regulates Central Nervous System Serotonin Receptor 2C Editing in Rodents.

ACS Chem Neurosci 2019 09 19;10(9):3953-3960. Epub 2019 Aug 19.

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

Microbial colonization of the gastrointestinal tract plays a crucial role in the development of enteric and central nervous system functionality. The serotonergic system has been heavily implicated in microbiota-gut-brain axis signaling, particularly in proof-of-principle studies in germ-free (GF) animals. One aspect of the serotonergic system that has been left unexplored in relation to the microbiota is the unique ability of the serotonin receptor 2C (5-HT) to undergo post-transcriptional editing, which has been implicated in decreased receptor functionality. We investigated whether GF mice, with absent microbiota from birth, have altered 5-HT receptor expression and editing in the brain, and if colonization of the microbiota is able to restore editing patterns. Next, we investigated whether microbiota depletion later in life using a chronic antibiotic treatment could affect 5-HT receptor editing patterns in rats. We found that GF mice have an increased prevalence of the edited 5-HT receptor isoforms in the amygdala, hypothalamus, prefrontal cortex, and striatum, which was partially normalized upon colonization post-weaning. However, no alterations were observed in the hypothalamus after microbiota depletion using an antibiotic treatment in adult rats. This suggests that alterations in the microbiome during development, but not later in life, could influence 5-HT receptor editing patterns. Overall, these results demonstrate that the microbiota affects 5-HT receptor editing in the brain and may inform novel therapeutic strategies in conditions in which 5-HT receptor editing is altered, such as depression.
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http://dx.doi.org/10.1021/acschemneuro.9b00414DOI Listing
September 2019

Monocyte mobilisation, microbiota & mental illness.

Brain Behav Immun 2019 10 19;81:74-91. Epub 2019 Jul 19.

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

The gastrointestinal microbiome has emerged as a key player in regulating brain and behaviour. This has led to the strategy of targeting the gut microbiota to ameliorate disorders of the central nervous system. Understanding the underlying signalling pathways in which the microbiota impacts these disorders is crucial for the development of future therapeutics for improving CNS functionality. One of the major pathways through which the microbiota influences the brain is the immune system, where there is an increasing appreciation for the role of monocyte trafficking in regulating brain homeostasis. In this review, we will shed light on the role of monocyte trafficking as a relay of microbiota signals in conditions where the central nervous system is in disorder, such as stress, peripheral inflammation, ageing, traumatic brain injury, stroke, multiple sclerosis, Alzheimer's disease and Parkinson's disease. We also cover how the gastrointestinal microbiota is implicated in these mental illnesses. In addition, we aim to discuss how the monocyte system can be modulated by the gut microbiota to mitigate disorders of the central nervous system, which will lead to novel microbiota-targeted strategies.
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http://dx.doi.org/10.1016/j.bbi.2019.07.019DOI Listing
October 2019

Mid-life microbiota crises: middle age is associated with pervasive neuroimmune alterations that are reversed by targeting the gut microbiome.

Mol Psychiatry 2020 10 16;25(10):2567-2583. Epub 2019 May 16.

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

Male middle age is a transitional period where many physiological and psychological changes occur leading to cognitive and behavioural alterations, and a deterioration of brain function. However, the mechanisms underpinning such changes are unclear. The gut microbiome has been implicated as a key mediator in the communication between the gut and the brain, and in the regulation of brain homeostasis, including brain immune cell function. Thus, we tested whether targeting the gut microbiome by prebiotic supplementation may alter microglia activation and brain function in ageing. Male young adult (8 weeks) and middle-aged (10 months) C57BL/6 mice received diet enriched with a prebiotic (10% oligofructose-enriched inulin) or control chow for 14 weeks. Prebiotic supplementation differentially altered the gut microbiota profile in young and middle-aged mice with changes correlating with faecal metabolites. Functionally, this translated into a reversal of stress-induced immune priming in middle-aged mice. In addition, a reduction in ageing-induced infiltration of Ly-6C monocytes into the brain coupled with a reversal in ageing-related increases in a subset of activated microglia (Ly-6C) was observed. Taken together, these data highlight a potential pathway by which targeting the gut microbiome with prebiotics can modulate the peripheral immune response and alter neuroinflammation in middle age. Our data highlight a novel strategy for the amelioration of age-related neuroinflammatory pathologies and brain function.
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http://dx.doi.org/10.1038/s41380-019-0425-1DOI Listing
October 2020

Resilience to chronic stress is associated with specific neurobiological, neuroendocrine and immune responses.

Brain Behav Immun 2019 08 3;80:583-594. Epub 2019 May 3.

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

Research into the molecular basis of stress resilience is a novel strategy to identify potential therapeutic strategies to treat stress-induced psychopathologies such as anxiety and depression. Stress resilience is a phenomenon which is not solely driven by effects within the central nervous system (CNS) but involves multiple systems, central and peripheral, which interact with and influence each other. Accordingly, we used the chronic social defeat stress paradigm and investigated specific CNS, endocrine and immune responses to identify signatures of stress-resilience and stress susceptibility in mice. Our results showed that mice behaviourally susceptible to stress (indexed by a reduction in social interaction behaviour) had higher plasma corticosterone levels and adrenal hypertrophy. An increase in inflammatory circulating monocytes was another hallmark of stress susceptibility. Furthermore, prefrontal cortex mRNA expression of corticotrophin-releasing factor (Crf) was increased in susceptible mice relative to resilient mice. We also report differences in hippocampal synaptic plasticity between resilient and susceptible mice. Ongoing studies will interpret the functional relevance of these signatures which could potentially inform the development of novel psychotherapeutic strategies.
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http://dx.doi.org/10.1016/j.bbi.2019.05.004DOI Listing
August 2019

Differential gene expression in the mesocorticolimbic system of innately high- and low-impulsive rats.

Behav Brain Res 2019 05 6;364:193-204. Epub 2019 Feb 6.

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

Impulsivity is an important component of many psychiatric illnesses and has been associated with a number of psychiatric disorders such as bipolar disorder and attention deficit / hyperactivity disorder (ADHD). Exploring the different aspects of impulsive behaviour and assigning these to specific neurobiological pathways would advance our interpretation of disorders for which impulsivity is key. Pharmacological studies have implicated a number of neurotransmitters in impulsivity, which in turn have been shown to be affected by several genes in both rodent and human studies of impulsivity. Here, we examine impulsivity-related differences in gene expression in finer detail, using the 2-choice serial reaction time task (2-CSRTT) to assess the molecular signature of impulsivity in brain regions previously linked to impulsive behaviour. Wistar rats were rated as high, (n = 6), intermediate, (n = 12) or low impulsive (n = 6), based on premature responses in the 2-CSRTT, after which RNA was extracted from the nucleus accumbens core (NAcc) and ventral prefrontal cortex (vPFC). RNA from the NAcc and vPFC of high and low impulsivity rats (n = 6 per group) was analysed for differential gene expression patterns and exon usage using RNA poly-A tail sequencing. Pnisr, Mal, and Tspan2 were significantly increased in the NAcc of highly impulsive rats, whereas Ube3a was significantly decreased. No differences were seen in the vPFC. In addition to changes in gene expression, Tspan2 displayed differential exon usage in impulsive rats, while functionally, gene expression changes were related to membrane depolarisation and changes in exon usage were linked to sphingolipid breakdown. The changes in gene expression and exon usage observed in this study represent an important step towards defining the molecular architecture of impulsivity. This study therefore represents an important starting point for analysis of the biological role of impulsivity in addiction and other neurological conditions associated with impulsive phenotypes.
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http://dx.doi.org/10.1016/j.bbr.2019.01.022DOI Listing
May 2019

Short-chain fatty acids: microbial metabolites that alleviate stress-induced brain-gut axis alterations.

J Physiol 2018 10 28;596(20):4923-4944. Epub 2018 Aug 28.

Department of Anatomy and Neuroscience, University College Cork, Cork, Ireland.

Key Points: Chronic (psychosocial) stress changes gut microbiota composition, as well as inducing behavioural and physiological deficits. The microbial metabolites short-chain fatty acids (SCFAs) have been implicated in gastrointestinal functional, (neuro)immune regulation and host metabolism, but their role in stress-induced behavioural and physiological alterations is poorly understood. Administration of SCFAs to mice undergoing psychosocial stress alleviates enduring alterations in anhedonia and heightened stress-responsiveness, as well as stress-induced increases in intestinal permeability. In contrast, chronic stress-induced alterations in body weight gain, faecal SCFAs and the gene expression of the SCFA receptors FFAR2 and FFAR3 remained unaffected by SCFA supplementation. These results present novel insights into mechanisms underpinning the influence of the gut microbiota on brain homeostasis, behaviour and host metabolism, informing the development of microbiota-targeted therapies for stress-related disorders.

Abstract: There is a growing recognition of the involvement of the gastrointestinal microbiota in the regulation of physiology and behaviour. Microbiota-derived metabolites play a central role in the communication between microbes and their host, with short-chain fatty acids (SCFAs) being perhaps the most studied. SCFAs are primarily derived from fermentation of dietary fibres and play a pivotal role in host gut, metabolic and immune function. All these factors have previously been demonstrated to be adversely affected by stress. Therefore, we sought to assess whether SCFA supplementation could counteract the enduring effects of chronic psychosocial stress. C57BL/6J male mice received oral supplementation of a mixture of the three principle SCFAs (acetate, propionate and butyrate). One week later, mice underwent 3 weeks of repeated psychosocial stress, followed by a comprehensive behavioural analysis. Finally, plasma corticosterone, faecal SCFAs and caecal microbiota composition were assessed. SCFA treatment alleviated psychosocial stress-induced alterations in reward-seeking behaviour, and increased responsiveness to an acute stressor and in vivo intestinal permeability. In addition, SCFAs exhibited behavioural test-specific antidepressant and anxiolytic effects, which were not present when mice had also undergone psychosocial stress. Stress-induced increases in body weight gain, faecal SCFAs and the colonic gene expression of the SCFA receptors free fatty acid receptors 2 and 3 remained unaffected by SCFA supplementation. Moreover, there were no collateral effects on caecal microbiota composition. Taken together, these data show that SCFA supplementation alleviates selective and enduring alterations induced by repeated psychosocial stress and these data may inform future research into microbiota-targeted therapies for stress-related disorders.
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http://dx.doi.org/10.1113/JP276431DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6187046PMC
October 2018

Differential functional selectivity and downstream signaling bias of ghrelin receptor antagonists and inverse agonists.

FASEB J 2019 01 18;33(1):518-531. Epub 2018 Jul 18.

Alimentary Pharmabiotic Centre (APC) Microbiome Ireland, University College Cork, Cork, Ireland.

The ghrelin receptor [growth hormone secretagogue receptor (GHSR)-1a] represents a promising pharmacologic target for the treatment of metabolic disorders, including obesity and cachexia, via central appetite modulation. The GHSR-1a has a complex pharmacology, highlighted by G-protein-dependent and -independent downstream signaling pathways and high basal constitutive activity. The functional selectivity and signaling bias of many GHSR-1a-specific ligands has not been fully characterized. In this study, we investigated the pharmacologic properties of ghrelin, MK-0677, L692,585, and [d-Lys3]-growth hormone-releasing peptide-6 (Dlys), JMV2959, and [d-Arg(1),d-Phe(5),d-Trp(7, 9),Leu(11)]-substance P (SP-analog). We investigated their effect on basal GHSR-1a constitutive signaling, ligand-directed downstream GHSR-1a signaling, functional selectivity, and signaling bias. Dlys behaved as a partial antagonist with a strong bias toward GHSR-1a-β-arrestin signaling, whereas JMV2959 acted as a full unbiased GHSR-1a antagonist. Moreover, the SP-analog behaved as an inverse agonist increasing G-protein-dependent signaling, but only at high concentrations, whereas, at low concentrations, the SP-analog attenuated β-arrestin-dependent signaling. Considering the limited success in the clinical development of GHSR-1a-targeted drugs so far, these findings provide a novel insight into the pharmacologic characteristics of GHSR-1a ligands and their signaling bias, which has important implications in the design of novel, more selective GHSR-1a ligands with predictable functional outcome and selectivity for preclinical and clinical drug development.-Ramirez, V. T., van Oeffelen, W. E. P. A., Torres-Fuentes, C., Chruścicka, B., Druelle, C., Golubeva, A. V., van de Wouw, M., Dinan, T. G., Cryan, J. F., Schellekens, H. Differential functional selectivity and downstream signaling bias of ghrelin receptor antagonists and inverse agonists.
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http://dx.doi.org/10.1096/fj.201800655RDOI Listing
January 2019

Microbiota-Gut-Brain Axis: Modulator of Host Metabolism and Appetite.

J Nutr 2017 05 29;147(5):727-745. Epub 2017 Mar 29.

Department of Anatomy and Neuroscience,

The gut harbors an enormous diversity of microbes that are essential for the maintenance of homeostasis in health and disease. A growing body of evidence supports the role of this microbiota in influencing host appetite and food intake. Individual species within the gut microbiota are under selective pressure arising from nutrients available and other bacterial species present. Each bacterial species within the gut aims to increase its own fitness, habitat, and survival via specific fermentation of dietary nutrients and secretion of metabolites, many of which can influence host appetite and eating behavior by directly affecting nutrient sensing and appetite and satiety-regulating systems. These include microbiota-produced neuroactives and short-chain fatty acids. In addition, the gut microbiota is able to manipulate intestinal barrier function, interact with bile acid metabolism, modulate the immune system, and influence host antigen production, thus indirectly affecting eating behavior. A growing body of evidence indicates that there is a crucial role for the microbiota in regulating different aspects of eating-related behavior, as well as behavioral comorbidities of eating and metabolic disorders. The importance of intestinal microbiota composition has now been shown in obesity, anorexia nervosa, and forms of severe acute malnutrition. Understanding the mechanisms in which the gut microbiota can influence host appetite and metabolism will provide a better understanding of conditions wherein appetite is dysregulated, such as obesity and other metabolic or eating disorders, leading to novel biotherapeutic strategies.
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http://dx.doi.org/10.3945/jn.116.240481DOI Listing
May 2017

The neuropharmacology of butyrate: The bread and butter of the microbiota-gut-brain axis?

Neurochem Int 2016 10 23;99:110-132. Epub 2016 Jun 23.

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

Several lines of evidence suggest that brain function and behaviour are influenced by microbial metabolites. Key products of the microbiota are short-chain fatty acids (SCFAs), including butyric acid. Butyrate is a functionally versatile molecule that is produced in the mammalian gut by fermentation of dietary fibre and is enriched in butter and other dairy products. Butyrate along with other fermentation-derived SCFAs (e.g. acetate, propionate) and the structurally related ketone bodies (e.g. acetoacetate and d-β-hydroxybutyrate) show promising effects in various diseases including obesity, diabetes, inflammatory (bowel) diseases, and colorectal cancer as well as neurological disorders. Indeed, it is clear that host energy metabolism and immune functions critically depend on butyrate as a potent regulator, highlighting butyrate as a key mediator of host-microbe crosstalk. In addition to specific receptors (GPR43/FFAR2; GPR41/FFAR3; GPR109a/HCAR2) and transporters (MCT1/SLC16A1; SMCT1/SLC5A8), its effects are mediated by utilisation as an energy source via the β-oxidation pathway and as an inhibitor of histone deacetylases (HDACs), promoting histone acetylation and stimulation of gene expression in host cells. The latter has also led to the use of butyrate as an experimental drug in models for neurological disorders ranging from depression to neurodegenerative diseases and cognitive impairment. Here we provide a critical review of the literature on butyrate and its effects on multiple aspects of host physiology with a focus on brain function and behaviour. We find fundamental differences in natural butyrate at physiological concentrations and its use as a neuropharmacological agent at rather high, supraphysiological doses in brain research. Finally, we hypothesise that butyrate and other volatile SCFAs produced by microbes may be involved in regulating the impact of the microbiome on behaviour including social communication.
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http://dx.doi.org/10.1016/j.neuint.2016.06.011DOI Listing
October 2016
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