Papers by Siobhain O'Mahony
CNS Neuroscience & Therapeutics, Dec 10, 2015
Visceral pain is a global term used to describe pain originating from the internal organs of the ... more Visceral pain is a global term used to describe pain originating from the internal organs of the body, which affects a significant proportion of the population and is a common feature of functional gastrointestinal disorders (FGIDs) such as irritable bowel syndrome (IBS). While IBS is multifactorial, with no single etiology to completely explain the disorder, many patients also experience comorbid behavioral disorders, such as anxiety or depression; thus, IBS is described as a disorder of the gut-brain axis. Stress is implicated in the development and exacerbation of visceral pain disorders. Chronic stress can modify central pain circuitry, as well as change motility and permeability throughout the gastrointestinal (GI) tract. More recently, the role of the gut microbiota in the bidirectional communication along the gutbrain axis, and subsequent changes in behavior, has emerged. Thus, stress and the gut microbiota can interact through complementary or opposing factors to influence visceral nociceptive behaviors. This review will highlight the evidence by which stress and the gut microbiota interact in the regulation of visceral nociception. We will focus on the influence of stress on the microbiota and the mechanisms by which microbiota can affect the stress response and behavioral outcomes with an emphasis on visceral pain.
Brain, Behavior, and Immunity, 2021
BACKGROUND The tryptophan-kynurenine pathway is of major interest in psychiatry and is altered in... more BACKGROUND The tryptophan-kynurenine pathway is of major interest in psychiatry and is altered in patients with depression, schizophrenia and panic disorder. Stress and immune alterations can impact this system, through cortisol- and cytokine-induced activation. In addition, there is emerging evidence that the kynurenine pathway is associated with suicidality. There have been no studies to date exploring the immune-kynurenine system in social anxiety disorder (SAD), and indeed very limited human studies on the kynurenine pathway in any clinical anxiety disorder. METHODS We investigated plasma levels of several kynurenine pathway markers, including kynurenine (KYN), tryptophan (TRYP) and kynurenic acid (KYNA), along with the KYN/TRYP and KYNA/KYN ratios, in a cohort of 32 patients with SAD and 36 healthy controls. We also investigated a broad array of both basal and lipopolysaccharide (LPS)-stimulated blood cytokine levels including IFN-γ, interleukin (IL)-10, IL-1β, IL-2, IL-4, IL-6, IL-8 and tumor necrosis factor (TNF)-α. RESULTS SAD patients had elevated plasma KYNA levels and an increased KYNA/KYN ratio compared to healthy controls. No differences in KYN, TRYP or the KYN/TRYP ratio were seen between the two groups. SAD patients with a history of past suicide attempt showed elevated plasma KYN levels and a higher KYN/TRYP ratio compared to patients without a history of suicide attempt. No differences were seen in basal or LPS-stimulated pro-inflammatory cytokine levels between the patients and controls. However, unstimulated IL-10, an anti-inflammatory cytokine, was significantly lower in the SAD group. A significant sex influence was evident with SAD males having lower levels of IL-10 compared to healthy males but no difference seen between SAD females and healthy females. CONCLUSIONS The peripheral kynurenine pathway is altered in SAD and preferentially directed towards KYNA synthesis. Additionally, kynurenine pathway activation, as evidenced by elevated KYN and KYN/TRYP ratio, is evident in SAD patients with a history of past suicide attempt. While no differences in pro-inflammatory cytokines is apparent in SAD patients, lower anti-inflammatory IL-10 levels are seen in SAD males. Further investigation of the role of the immune-kynurenine pathway in SAD and other clinical anxiety disorders is warranted.
Neuronal Signaling, 2020
Visceral hypersensitivity is a hallmark of many functional and stress-related gastrointestinal di... more Visceral hypersensitivity is a hallmark of many functional and stress-related gastrointestinal disorders, and there is growing evidence that the gut microbiota may play a role in its pathophysiology. It has previously been shown that early life stress-induced visceral sensitivity is reduced by various probiotic strains of bacteria (including Lactobacillus rhamnosus GG (LGG)) alone or in combination with prebiotic fibres in rat models. However, the exact mechanisms underpinning such effects remain unresolved. Here, we investigated if soluble mediators derived from LGG can mimic the bacteria’s effects on visceral hypersensitivity and the microbiota–gut–brain axis. Rats were exposed to maternal separation (MS) from postnatal days 2–12. From weaning onwards both non-separated (NS) and MS offspring were provided drinking water with or without supplementation of standardized preparations of the LGG soluble mediators (LSM). Our results show that MS led to increased visceral sensitivity and...
Background. Recent findings linked gastrointestinal disorders characterized by abdominal pain to ... more Background. Recent findings linked gastrointestinal disorders characterized by abdominal pain to gut microbiota composition. The present work aimed to evaluate the power of gut microbiota as a visceral pain modulator and, consequently, the relevance of its manipulation as a therapeutic option in reversing the persistence of visceral hypersensitivity consequent to colitis induced by the intra-rectal injection of 2,4-dinitrobezenesulfonic acid (DNBS) in rats. Results: The effect of faecal microbiota transfer (FMT) from viscerally hypersensitive DNBS and naïve donors was evaluated in control rats after an antibiotic-mediated microbiota depletion. FMT from DNBS donors induced a long-lasting visceral hypersensitivity in control rats. Pain threshold trend correlated with major modifications in the composition and structure of the gut microbiota at phylum (Proteobacteria and Firmicutes to Bacteroides ratio) and family levels (Enterobacteriaceae, Akkermansiaceae and Lachnospiraceae). Acetic...
Current Opinion in Physiology, 2019
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Brain, Behavior, and Immunity, 2019
Nutritional neuroscience, Jan 27, 2017
Early life is a period of significant brain development when the brain is at its most plastic and... more Early life is a period of significant brain development when the brain is at its most plastic and vulnerable. Stressful episodes during this window of development have long-lasting effects on the central nervous system. Rodent maternal separation (MS) is a reliable model of early-life stress and induces alterations in both physiology and behaviour. Intriguingly, the gut microbiota of MS offspring differ from that of non-separated offspring, suggesting a mechanistic role for the microbiota-gut-brain axis. Hence, we tested whether dietary factors known to affect the gut microbiota alter the neurobehavioural effects of MS. The impact of consuming diet containing prebiotics polydextrose (PDX) and galactooligosaccharide (GOS) alone or in combination with live bacteria Lactobacillus rhamnosus GG (LGG) from weaning onwards in rats subjected to early-life MS was assessed. Adult offspring were assessed for anxiety-like behaviour in the open field test, spatial memory using the Morris water m...
Handbook of experimental pharmacology, 2017
Irritable bowel syndrome is a functional gastrointestinal disorder, with stress playing a major r... more Irritable bowel syndrome is a functional gastrointestinal disorder, with stress playing a major role in onset and exacerbation of symptoms such as abdominal pain and altered bowel movements. Stress-related disorders including anxiety and depression often precede the development of irritable bowel syndrome and vice versa. Stressor exposure during early life has the potential to increase an individual's susceptibility to both irritable bowel syndrome and psychiatric disease indicating that there may be a common origin for these disorders. Moreover, adverse early life events significantly impact upon many of the communication pathways within the brain-gut-microbiota axis, which allows bidirectional interaction between the central nervous system and the gastrointestinal tract. This axis is proposed to be perturbed in irritable bowel syndrome and studies now indicate that dysfunction of this axis is also seen in psychiatric disease. Here we review the co-morbidity of irritable bowel ...
Gastrointestinal Pharmacology, 2016
A growing body of preclinical and clinical evidence supports a relationship between the complexit... more A growing body of preclinical and clinical evidence supports a relationship between the complexity and diversity of the microorganisms that inhabit our gut (human gastrointestinal microbiota) and health status. Under normal homeostatic conditions this microbial population helps maintain intestinal peristalsis, mucosal integrity, pH balance, immune priming and protection against invading pathogens. Furthermore, these microbes can influence centrally regulated emotional behaviour through mechanisms including microbially derived bioactive molecules (amino acid metabolites, short-chain fatty acids, neuropeptides and neurotransmitters), mucosal immune and enteroendocrine cell activation, as well as vagal nerve stimulation.The microbiota-gut-brain axis comprises a dynamic matrix of tissues and organs including the brain, autonomic nervous system, glands, gut, immune cells and gastrointestinal microbiota that communicate in a complex multidirectional manner to maintain homeostasis and resist perturbation to the system. Changes to the microbial environment, as a consequence of illness, stress or injury, can lead to a broad spectrum of physiological and behavioural effects locally including a decrease in gut barrier integrity, altered gut motility, inflammatory mediator release as well as nociceptive and distension receptor sensitisation. Centrally mediated events including hypothalamic-pituitary-adrenal (HPA) axis, neuroinflammatory events and neurotransmitter systems are concomitantly altered. Thus, both central and peripheral pathways associated with pain manifestation and perception are altered as a consequence of the microbiota-gut-brain axis imbalance.In this chapter the involvement of the gastrointestinal microbiota in visceral pain is reviewed. We focus on the anatomical and physiological nodes whereby microbiota may be mediating pain response, and address the potential for manipulating gastrointestinal microbiota as a therapeutic target for visceral pain.
Perspectives on Medical Education, 2016
Introduction Against a backdrop of ever-changing diagnostic and treatment modalities, stakeholder... more Introduction Against a backdrop of ever-changing diagnostic and treatment modalities, stakeholder perceptions (medical students, clinicians, anatomy educators) are crucial for the design of an anatomy curriculum which fulfils the criteria required for safe medical practice. This study compared perceptions of students, practising clinicians, and anatomy educators with respect to the relevance of anatomy education to medicine. Methods A quantitative survey was administered to undergraduate entry (n = 352) and graduate entry students (n = 219) at two Irish medical schools, recently graduated Irish clinicians (n = 146), and anatomy educators based in Irish and British medical schools (n = 30). Areas addressed included the association of anatomy with medical education and clinical practice, mode of instruction, and curriculum duration. Results Graduate-entry students were less likely to associate anatomy with the development of professionalism, teamwork skills, or improved awareness of e...
Brain, behavior, and immunity, Jan 4, 2016
The dopaminergic system is involved in motivation, reward and the associated motor activities. Me... more The dopaminergic system is involved in motivation, reward and the associated motor activities. Mesodiencephalic dopaminergic neurons in the ventral tegmental area (VTA) regulate motivation and reward, whereas those in the substantia nigra (SN) are essential for motor control. Defective VTA dopaminergic transmission has been implicated in schizophrenia, drug addiction and depression whereas dopaminergic neurons in the SN are lost in Parkinson's disease. Maternal immune activation (MIA) leading to in utero inflammation has been proposed to be a risk factor for these disorders, yet it is unclear how this stimulus can lead to the diverse disturbances in dopaminergic-driven behaviors that emerge at different stages of life in affected offspring. Here we report that gestational age is a critical determinant of the subsequent alterations in dopaminergic-driven behavior in rat offspring exposed to lipopolysaccharide (LPS)-induced MIA. Behavioral analysis revealed that MIA on gestational...
Anatomical Sciences Education, 2016
Utilizing reality anatomy such as dissection and demonstrating using cadavers has been described ... more Utilizing reality anatomy such as dissection and demonstrating using cadavers has been described as a superior way to create meaning. The chemicals used to embalm cadavers differentially alter the tissue of the human body, which has led to the usage of different processes along the hard to soft-fixed spectrum of preserved cadavers. A questionnaire based approach was used to gain a better insight into the opinion of anatomists on the use of preserved cadavers for the teaching of human anatomy. This study focused on anatomy teachers in the United Kingdom and Ireland. From the 125 participating anatomists, 34.4% were medically qualified, 30.4% had a PhD in a non-anatomical science and 22.4% had a PhD in an anatomical science, these figures include ten anatomists who had combinations of MD with the two other PhD qualifications. The main findings from the questionnaire were that 61.6% of participants agreed that hard-fixed formalin cadavers accurately resemble features of a human body whereas 21.6% disagreed. Moreover, anatomists rated the teaching aids on how accurately they resemble features of the human body as follows: plastic models the least accurate followed by plastinated specimens, hard fixed cadavers; soft preserved cadavers were considered to be the most accurate when it comes to resembling features of the human body. Though anatomists considered soft preserved cadavers as the most accurate tool, further research is required in order to investigate which techniques or methods provide better teaching tool for a range of anatomical teaching levels and for surgical training. Anat Sci Educ. © 2016 American Association of Anatomists.
Parkinsonism & Related Disorders, 2016
Parkinson's disease is the second most common neurodegenerative disorder, affecting 1-2% of the p... more Parkinson's disease is the second most common neurodegenerative disorder, affecting 1-2% of the population over 65 years of age. The primary neuropathology is the loss of midbrain dopaminergic neurons, resulting in characteristic motor deficits, upon which the clinical diagnosis is based. However a number of significant non-motor symptoms (NMS) are also apparent that appear to have a greater impact on the quality of life of these patients. In recent years, it has become increasingly apparent that neurobiological processes can be modified by the bi-directional communication that occurs along the brain-gut axis. The microbiota plays a key role in this communication throughout different routes in both physiological and pathological conditions. Thus, there has been an increasing interest in investigating how microbiota changes within the gastrointestinal tract may be implicated in health and disease including PD. Interestingly α-synuclein-aggregates, the cardinal neuropathological feature in PD,are present in both the submucosal and myenteric plexuses of the enteric nervous system, prior to their appearance in the brain, indicating a possible gut to brain route of "prion-like" spread. In this review we highlight the potential importance of gut to brain signalling in PD with particular focus on the role of the microbiota as major player in this communication.
Anatomical Sciences Education, 2016
An improved understanding of the relationship between anatomy learning performance and approaches... more An improved understanding of the relationship between anatomy learning performance and approaches to learning can lead to the development of a more tailored approach to delivering anatomy teaching to medical students. This study investigated the relationship between learning style preferences, as measured by Visual, Aural, Read/write, and Kinesthetic (VARK) inventory style questionnaire and Honey and Mumford's learning style questionnaire (LSQ), and anatomy and clinical skills assessment performance at an Irish medical school. Additionally, mode of entry to medical school [undergraduate/direct-entry (DEM) vs. graduate-entry (GEM)], was examined in relation to individual learning style, and assessment results. The VARK and LSQ were distributed to first and second year DEM, and first year GEM students. DEM students achieved higher clinical skills marks than GEM students, but anatomy marks did not differ between each group. Several LSQ style preferences were shown to be weakly correlated with anatomy assessment performance in a program-and year-specific manner. Specifically, the "Activist" style was negatively correlated with anatomy scores in DEM Year 2 students (r s 5 20.45, P 5 0.002). The "Theorist" style demonstrated a weak correlation with anatomy performance in DEM Year 2 (r s 5 0.18, P 5 0.003). Regression analysis revealed that, among the LSQ styles, the "Activist" was associated with poorer anatomy assessment performance (P < 0.05), while improved scores were associated with students who scored highly on the VARK "Aural" modality (P < 0.05). These data support the contention that individual student learning styles contribute little to variation in academic performance in medical students.
Journal of Neuroscience Methods
The amino acid neurotransmitters gamma-aminobutyric acid (GABA) and glutamate have been implicate... more The amino acid neurotransmitters gamma-aminobutyric acid (GABA) and glutamate have been implicated in mood disorders and high performance liquid chromatography (HPLC) is an important method in their quantitation. This paper describes a method which employs either electrochemical or fluorescent detection of the amino acid derivatives formed by a reaction with naphthalene-2,3-dicarboxaldehyde (NDA) in the presence of cyanide ions. Elution is based on an isocratic protocol and is achieved in 20 min or less. The method is reproducible, shows excellent linearity and generates derivatives which are stable for up to 16 h. Successful application of the method to a maternal deprivation study has identified the hippocampus and the brainstem as possible sites of long-term alteration in this paradigm.
Clinical anatomy (New York, N.Y.), Jan 28, 2015
Anatomy is the cornerstone of education for healthcare professionals with the use of human materi... more Anatomy is the cornerstone of education for healthcare professionals with the use of human material providing an excellent teaching tool in the modern curricula. The ability and quality of preservation of human remains has enabled such use. The introduction of formaldehyde as a preservative in 1893 was an important step in the history of preservation. With the European Union directive on the use of formaldehyde and its expected banning, anatomists are trying to find a more convenient and safe substitute. In this review, we compare the different techniques used based on the need for embalming, fixative used, period of preservation and the features of the embalmed specimen. The fact that embalming is used in different disciplines, multiple purposes and described in different languages has led to the development of ambiguous interchangeable terminology. Overall, there is a lack of information specifically classifying, listing and comparing different embalming techniques, and this may b...
Neuroscience, Oct 25, 2016
Females are more likely to experience visceral pain than males, yet mechanisms underlying this se... more Females are more likely to experience visceral pain than males, yet mechanisms underlying this sex bias are not fully elucidated. Moreover, pain sensitivity can change throughout the menstrual cycle. Alterations in the glutamatergic system have been implicated in several pain-disorders; however, whether these are sex-dependent is unclear. Thus, we aimed to investigate sex differences in the spinal cord glutamate uptake and how it varies across the estrous cycle. The activity of the glutamate transporters, excitatory amino acid transporters (EAATs) was assessed using an ex vivo aspartate radioactive uptake assay in the lumbosacral spinal cord in Sprague-Dawley male and female rats. The gene expression of EAATs, glutamate receptor subunits NR1 and NR2B and the estrogen receptors ERα & ERβ in the spinal cord were also analyzed. EAAT activity was lower in females, particularly during the estrus phase, and this was the only cycle stage that was responsive to the pharmacological effects o...
International Journal of Molecular Sciences, 2021
Steroid hormones are essential biomolecules for human physiology as they modulate the endocrine s... more Steroid hormones are essential biomolecules for human physiology as they modulate the endocrine system, nervous function and behaviour. Recent studies have shown that the gut microbiota is directly involved in the production and metabolism of steroid hormones in the periphery. However, the influence of the gut microbiota on levels of steroids acting and present in the brain (i.e., neuroactive steroids) is not fully understood. Therefore, using liquid chromatography–tandem mass spectrometry, we assessed the levels of several neuroactive steroids in various brain areas and the plasma of germ-free (GF) male mice and conventionally colonized controls. The data obtained indicate an increase in allopregnanolone levels associated with a decrease in those of 5α-androstane-3α, 17β-diol (3α-diol) in the plasma of GF mice. Moreover, an increase of dihydroprogesterone and isoallopregnanolone in the hippocampus, cerebellum, and cerebral cortex was also reported. Changes in dihydrotestosterone an...
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Papers by Siobhain O'Mahony