T.G. Dinan

Microbial genes, brain & behaviour – epigenetic regulation of the gut–brain axis

To date, there is rapidly increasing evidence for host–microbe interaction at virtually all levels of complexity, ranging from direct cell‐to‐cell communication to extensive systemic signalling, and involving various organs and organ systems, including the central nervous system. As such, the discovery that differential microbial composition is associated with alterations in behaviour and cognition has significantly contributed to establishing the microbiota–gut–brain axis as an extension of the well‐accepted gut–brain axis concept. Many efforts have been focused on delineating a role for this axis in health and disease, ranging from stress‐related disorders such as depression, anxiety and irritable bowel syndrome to neurodevelopmental disorders such as autism. There is also a growing appreciation of the role of epigenetic mechanisms in shaping brain and behaviour. However, the role of epigenetics in informing host–microbe interactions has received little attention to date. This is despite the fact that there are many plausible routes of interaction between epigenetic mechanisms and the host‐microbiota dialogue. From this new perspective we put forward novel, yet testable, hypotheses. Firstly, we suggest that gut‐microbial products can affect chromatin plasticity within their hosts brain that in turn leads to changes in neuronal transcription and eventually alters host behaviour. Secondly, we argue that the microbiota is an important mediator of gene‐environment interactions. Finally, we reason that the microbiota itself may be viewed as an epigenetic entity. In conclusion, the fields of (neuro)epigenetics and microbiology are converging at many levels and more interdisciplinary studies are necessary to unravel the full range of this interaction.

The intestinal microbiome, probiotics and prebiotics in neurogastroenterology

The brain-gut axis allows bidirectional communication between the central nervous system (CNS) and the enteric nervous system (ENS), linking emotional and cognitive centers of the brain with peripheral intestinal functions. Recent experimental work suggests that the gut microbiota have an impact on the brain-gut axis. A group of experts convened by the International Scientific Association for Probiotics and Prebiotics (ISAPP) discussed the role of gut bacteria on brain functions and the implications for probiotic and prebiotic science. The experts reviewed and discussed current available data on the role of gut microbiota on epithelial cell function, gastrointestinal motility, visceral sensitivity, perception and behavior. Data, mostly gathered from animal studies, suggest interactions of gut microbiota not only with the enteric nervous system but also with the central nervous system via neural, neuroendocrine, neuroimmune and humoral links. Microbial colonization impacts mammalian brain development in early life and subsequent adult behavior. These findings provide novel insights for improved understanding of the potential role of gut microbial communities on psychological disorders, most particularly in the field of psychological comorbidities associated with functional bowel disorders like irritable bowel syndrome (IBS) and should present new opportunity for interventions with pro- and prebiotics.

Altered peripheral toll-like receptor responses in the irritable bowel syndrome

Aliment Pharmacol Ther 2011; 33: 1045–1052

Changes in Hypothalamic–Pituitary–Adrenal Axis Measures After Vagus Nerve Stimulation Therapy in Chronic Depression

BACKGROUND Little is known about the hypothalamic-pituitary-adrenal (HPA) axis stress system in chronic depression. This study examined the corticotropin-releasing hormone (CRH) challenge test in a group of patients with chronic depression, before and after 3 months of treatment with vagus nerve stimulation (VNS) therapy, and a matched group of healthy control subjects. METHODS Key inclusion criteria were DSM-IV-defined major depressive disorder, a history of a current episode lasting for at least 2 years, and unresponsiveness to at least two classes of antidepressant medications. Eleven test subjects and 11 matched control subjects underwent a CRH challenge. RESULTS There were significant reductions in depression scores over the study period. The CRH/ACTH (adrenocorticotropic hormone) responses in the depressed group before VNS implantation were significantly higher than in the healthy group and were reduced to normal values after VNS treatment. Some measures of cortisol response were elevated before treatment and were reduced to normal over the study period. The only clinical measure correlated with HPA axis alterations was reduction in atypical depressive symptom scores. CONCLUSIONS These preliminary results suggest that chronic depression, in contrast to acute melancholic depression, might be characterized by increased ACTH response to CRH challenge. Short-term treatment with VNS therapy was associated with normalization of this response.

Irritable bowel syndrome: role of food in pathogenesis and management.

Patients with the irritable bowel syndrome (IBS) commonly report the precipitation of symptoms on food ingestion. Though the role of dietary constituents in IBS has not been extensively studied, food could contribute to symptom onset or even the causation of IBS through a number of mechanisms. First, the physiological response of the intestine to food ingestion could precipitate symptoms in predisposed individuals; second, there is some evidence that allergy or intolerance to a particular food can produce IBS‐like symptoms, third, certain foods may alter the composition of the luminal milieu, either directly or indirectly through effects on bacterial metabolism, and thus induce symptoms and, finally, IBS may develop following exposure to food‐borne pathogens. Anticipatory, psychological factors generated by previous negative experiences with food ingestion or other factors may also contribute though their contribution has been scarcely quantified. Not surprisingly, there is considerable interest in the potential roles of diet and food supplements in the therapy of IBS; for the most part, the evidence base for such recommendations remains slim though certain probiotics show considerable promise.

Genetic vs. pharmacological inactivation of COMT influences cannabinoid-induced expression of schizophrenia-related phenotypes

Catechol-O-methyltransferase (COMT) is an important enzyme in the metabolism of dopamine and disturbance in dopamine function is proposed to be central to the pathogenesis of schizophrenia. Clinical epidemiological studies have indicated cannabis use to confer a 2-fold increase in risk for subsequent onset of psychosis, with adolescent-onset use conveying even higher risk. There is evidence that a high activity COMT polymorphism moderates the effects of adolescent exposure to cannabis on risk for adult psychosis. In this paper we compared the effect of chronic adolescent exposure to the cannabinoid WIN 55212 on sensorimotor gating, behaviours related to the negative symptoms of schizophrenia, anxiety- and stress-related behaviours, as well as ex-vivo brain dopamine and serotonin levels, in COMT KO vs. wild-type (WT) mice. Additionally, we examined the effect of pretreatment with the COMT inhibitor tolcapone on acute effects of this cannabinoid on sensorimotor gating in C57BL/6 mice. COMT KO mice were shown to be more vulnerable than WT to the disruptive effects of adolescent cannabinoid treatment on prepulse inhibition (PPI). Acute pharmacological inhibition of COMT in C57BL/6 mice also modified acute cannabinoid effects on startle reactivity, as well as PPI, indicating that chronic and acute loss of COMT can produce dissociable effects on the behavioural effects of cannabinoids. COMT KO mice also demonstrated differential effects of adolescent cannabinoid administration on sociability and anxiety-related behaviour, both confirming and extending earlier reports of COMT×cannabinoid effects on the expression of schizophrenia-related endophenotypes.

Downregulation of Umbilical Cord Blood Levels of miR-374a in Neonatal Hypoxic Ischemic Encephalopathy

OBJECTIVE To investigate the expression profile of microRNA (miRNA) in umbilical cord blood from infants with hypoxic ischemic encephalopathy (HIE). STUDY DESIGN Full-term infants with perinatal asphyxia were identified under strict enrollment criteria. Degree of encephalopathy was defined using both continuous multichannel electroencephalogram in the first 24 hours of life and modified Sarnat score. Seventy infants (18 controls, 33 with perinatal asphyxia without HIE, and 19 infants with HIE [further graded as 13 mild, 2 moderate, and 4 severe]) were included in the study. MiRNA expression profiles were determined using a microarray assay and confirmed using quantitative real-time polymerase chain reaction. RESULTS Seventy miRNAs were differentially expressed between case and control groups. Of these hsa-miR-374a was the most significantly downregulated in infants with HIE vs controls. Validation of hsa-miR-374a expression using quantitative real-time polymerase chain reaction confirmed a significant reduction in expression among infants with HIE compared with those with perinatal asphyxia and healthy controls (mean relative quantification [SD] = 0.52 [0.37] vs 1.10 [1.52] vs 1.76 [1.69], P < .02). CONCLUSIONS We have shown a significant step-wise downregulation of hsa-miR-374a expression in cord blood of infants with perinatal asphyxia and subsequent HIE.

The microbiota-gut-brain axis as a key regulator of neural function and the stress response: Implications for human and animal health,

The brain-gut-microbiota axis comprises an extensive communication network between the brain, the gut, and the microbiota residing there. Development of a diverse gut microbiota is vital for multiple features of behavior and physiology, as well as many fundamental aspects of brain structure and function. Appropriate early-life assembly of the gut microbiota is also believed to play a role in subsequent emotional and cognitive development. If the composition, diversity, or assembly of the gut microbiota is impaired, this impairment can have a negative impact on host health and lead to disorders such as obesity, diabetes, inflammatory diseases, and even potentially neuropsychiatric illnesses, including anxiety and depression. Therefore, much research effort in recent years has focused on understanding the potential of targeting the intestinal microbiota to prevent and treat such disorders. This review aims to explore the influence of the gut microbiota on host neural function and behavior, particularly those of relevance to stress-related disorders. The involvement of microbiota in diverse neural functions such as myelination, microglia function, neuronal morphology, and blood-brain barrier integrity across the life span, from early life to adolescence to old age, will also be discussed. Nurturing an optimal gut microbiome may also prove beneficial in animal science as a means to manage stressful situations and to increase productivity of farm animals. The implications of these observations are manifold, and researchers are hopeful that this promising body of preclinical work can be successfully translated to the clinic and beyond.

Towards microbiome-informed dietary recommendations for promoting metabolic and mental health: Opinion papers of the MyNewGut project

The gut microbiota coexists in partnership with the human host through adaptations to environmental and physiological changes that help maintain dynamic homeostatic healthy states. Break-down of this delicate balance under sustained exposure to stressors (e.g. unhealthy diets) can, however, contribute to the onset of disease. Diet is a key modifiable environmental factor that modulates the gut microbiota and its metabolic capacities that, in turn, could impact human physiology. On this basis, the diet and the gut microbiota could act as synergistic forces that provide resilience against disease or that speed the progress from health to disease states. Associations between unhealthy dietary patterns, non-communicable diseases and intestinal dysbiosis can be explained by this hypothesis. Translational studies showing that dietary-induced alterations in microbial communities recapitulate some of the pathological features of the original host further support this notion. In this introductory paper by the European project MyNewGut, we briefly summarize the investigations conducted to better understand the role of dietary patterns and food components in metabolic and mental health and the specificities of the microbiome-mediating mechanisms. We also discuss how advances in the understanding of the microbiomes role in dietary health effects can help to provide acceptable scientific grounds on which to base dietary advice for promoting healthy living.

Differential effects of perturbations of the microbiome during the adolescent period induces long lasting behavioural effects in adult mice

It has become clear that the gut microbiota plays a key role in all aspects of health including mental health. The concept of the microbiota-gut-brain axis focuses on the ability of the microbiota to influence CNS function and modulate brain development and behaviour [1]. Microbiota composition can be affected by many different environmental factors such as stress, diet, exercise, illness and antibiotic treatment. Recent hypothesis suggests that neurodevelopment runs in parallel with establishment of an adult microbial profile and that disturbance or the lack thereof influences behaviour and brain function in adulthood [2]. Many different strategies can be utilized to investigate the role of the intestinal microbiota in host brain and behaviour. Here, we aimed to investigate whether exposure to antibiotic treatment or suboptimal diet both of which significantly affect microbiota composition resulted in long lasting effects on behaviour. Methods Male C57BL/6 mice were either exposed to high fat, a cafeteria diet or antibiotic treatment [3] for 21 days during the adolescence. We next assessed whether exposure to these known microbial interventions resulted in long lasting changes in gene expression and a variety of behaviours, in adulthood. Mice were tested for -like behaviour in the elevated plus maze and open field, memory in the novel object recognition task and fear in the fear conditioning paradigm. A T-test was used to compare antibiotic treatment with controls and ANOVA to compare controls and duet intervention, repeated measures were used when applicable. Results Both, diet and antibiotic treatment resulted in specific behavioural alterations. Antibiotic treatment alone resulted in increased anxiety-like behaviour in the elevated plus maze for the % time spend in the open arm (unpaired t-test, control M=17.64 SEM=±2.78 , antibiotic M=7.90 SEM=±1.99; t(17)=2.79 p=0.013), the % of entries into the open arm (unpaired t-test, control M=30.61 SEM=±2.95, antibiotic M=20.17 SEM=±2.86; t(17)=2.53 p=0.022) and head dips (unpaired t-test with Welch’s correction, control M=10.30 SEM=±1.76, antibiotic M=4.67 SEM=±0.80; t(12)=2.91 p=0.013), high fat diet induced increased contextual fear memory (two-way repeated measure ANOVA F(4, 54)=1.23, followed by Newman-Keuls multiple comparison test p Conclusion We demonstrate that short term exposure to known microbial altering factors during the adolescent period, a critical window of neurodevelopment, can induce long lasting changes on brain and behaviour. Further research needs to be done to investigate the mechanisms underlying the effects of altered microbiota on behaviour and brain circuits during this critical period.