There is growing evidence for a role of the gut microbiome in shaping behaviour relevant to many psychiatric and neurological disorders. Preclinical studies using germ-free (GF) animals have been ...essential in contributing to our current understanding of the potential importance of the host microbiome for neurodevelopment and behaviour. In particular, it has been repeatedly demonstrated that manipulation of the gut microbiome modulates anxiety-like behaviours. The neural circuits that underlie anxiety- and fear-related behaviours are complex and heavily depend on functional communication between the amygdala and prefrontal cortex (PFC). Previously, we have shown that the transcriptional networks within the amygdala and PFC of GF mice are altered. MicroRNAs (miRNAs) act through translational repression to control gene translation and have also been implicated in anxiety-like behaviours. However, it is unknown whether these features of host post-transcriptional machinery are also recruited by the gut microbiome to exert control over CNS transcriptional networks.
We conducted Illumina® next-generation sequencing (NGS) in the amygdala and PFC of conventional, GF and germ-free colonized mice (exGF). We found a large proportion of miRNAs to be dysregulated in GF animals in both brain regions (103 in the amygdala and 31 in the PFC). Additionally, colonization of GF mice normalized some of the noted alterations. Next, we used a complementary approach to GF by manipulating the adult rat microbiome with an antibiotic cocktail to deplete the gut microbiota and found that this strategy also impacted the expression of relevant miRNAs.
These results suggest that the microbiome is necessary for appropriate regulation of miRNA expression in brain regions implicated in anxiety-like behaviours.
Irritable bowel syndrome (IBS) is a heterogeneous functional disorder with a multifactorial etiology that involves the interplay of both host and environmental factors. Among environmental factors ...relevant for IBS etiology, the diet stands out given that the majority of IBS patients report their symptoms to be triggered by meals or specific foods. The diet provides substrates for microbial fermentation, and, as the composition of the intestinal microbiota is disturbed in IBS patients, the link between diet, microbiota composition, and microbial fermentation products might have an essential role in IBS etiology. In this review, we summarize current evidence regarding the impact of diet and the intestinal microbiota on IBS symptoms, as well as the reported interactions between diet and the microbiota composition. On the basis of the existing data, we suggest pathways (mechanisms) by which diet components, via the microbial fermentation, could trigger IBS symptoms. Finally, this review provides recommendations for future studies that would enable elucidation of the role of diet and microbiota and how these factors may be (inter)related in the pathophysiology of IBS.
Despite extensive evidence implicating the microbiota in regulating the immune system, the precise mechanisms underlying microbial control of microglial maturation remain unclear. In a methodological ...tour de force, Erny et al. (2021) identify acetate as an essential microbiota-derived molecule driving microglial metabolic pathways and functions during healthy and diseased states.
Despite extensive evidence implicating the microbiota in regulating the immune system, the precise mechanisms underlying microbial control of microglial maturation remain unclear. In a methodological tour de force, Erny et al. identify acetate as an essential microbiota-derived molecule driving microglial metabolic pathways and functions during healthy and diseased states.
Researchers interested in the neurobiology of the acute stress response in humans require a valid and reliable acute stressor that can be used under experimental conditions. The Trier Social Stress ...Test (TSST) provides such a testing platform. It induces stress by requiring participants to make an interview-style presentation, followed by a surprise mental arithmetic test, in front of an interview panel who do not provide feedback or encouragement. In this review, we outline the methodology of the TSST, and discuss key findings under conditions of health and stress-related disorder. The TSST has unveiled differences in males and females, as well as different age groups, in their neurobiological response to acute stress. The TSST has also deepened our understanding of how genotype may moderate the cognitive neurobiology of acute stress, and exciting new inroads have been made in understanding epigenetic contributions to the biological regulation of the acute stress response using the TSST. A number of innovative adaptations have been developed which allow for the TSST to be used in group settings, with children, in combination with brain imaging, and with virtual committees. Future applications may incorporate the emerging links between the gut microbiome and the stress response. Future research should also maximise use of behavioural data generated by the TSST. Alternative acute stress paradigms may have utility over the TSST in certain situations, such as those that require repeat testing. Nonetheless, we expect that the TSST remains the gold standard for examining the cognitive neurobiology of acute stress in humans.
•The TSST is the human experimental gold standard for evaluating the neurobiology of acute stress.•The HPA axis response to the TSST is higher in males and lower in older adults.•Genotype and epigenetic factors moderate the neurobiological response to the TSST.•Multiple adaptations of the TSST are available for different testing contexts.
The amygdala is a key brain area regulating responses to stress and emotional stimuli, so improving our understanding of how it is regulated could offer novel strategies for treating disturbances in ...emotion regulation. As we review here, a growing body of evidence indicates that the gut microbiota may contribute to a range of amygdala‐dependent brain functions from pain sensitivity to social behavior, emotion regulation, and therefore, psychiatric health. In addition, it appears that the microbiota is necessary for normal development of the amygdala at both the structural and functional levels. While further investigations are needed to elucidate the exact mechanisms of microbiota‐to‐amygdala communication, ultimately, this work raises the intriguing possibility that the gut microbiota may become a viable treatment target in disorders associated with amygdala dysregulation, including visceral pain, post‐traumatic stress disorder, and beyond. Also see the video here: https://youtu.be/O5gvxVJjX18
The amygdala plays a central role in regulating many aspects of behavior in rodents and humans, from pain responding to social interaction and psychiatric function. Accumulating evidence suggests microbiota‐to‐amygdala communication along the gut‐brain axis is a key modulator of these amygdala‐dependent behaviors, with critical implications for health and disease.
Studies have documented associations between traumatic brain injury (TBI) and mental disorders. The relationship between psychopathic personality and TBI remains poorly understood, though both are ...associated with similar characteristics (e.g., low empathy, aggression, disturbances in social/moral behavior). Yet, it is not clear whether assessment of psychopathic features is influenced by presence versus absence of TBI, and which aspects of TBI may be associated with psychopathic traits. This study examined the psychopathy-TBI association in justice-involved women (
= 341) with structural equation modeling. We tested if measurement invariance of psychopathic traits was evident among those with versus without TBI and which TBI variables (number, severity, age at first TBI) predicted psychopathic features in conjunction with symptoms of psychopathology, IQ, and age. Results provided evidence of measurement invariance, and more women with TBI, compared to those without, met criteria for psychopathy. Younger age of TBI and TBI severity predicted interpersonal-affective psychopathic features.
Autism spectrum disorder (ASD) is one of the most prevalent neurodevelopmental conditions worldwide. There is growing awareness that ASD is highly comorbid with gastrointestinal distress and altered ...intestinal microbiome, and that host-microbiome interactions may contribute to the disease symptoms. However, the paucity of knowledge on gut-brain axis signaling in autism constitutes an obstacle to the development of precision microbiota-based therapeutics in ASD. To this end, we explored the interactions between intestinal microbiota, gut physiology and social behavior in a BTBR T+Itpr3tf/J mouse model of ASD. Here we show that a reduction in the relative abundance of very particular bacterial taxa in the BTBR gut – namely, bile-metabolizing Bifidobacterium and Blautia species, - is associated with deficient bile acid and tryptophan metabolism in the intestine, marked gastrointestinal dysfunction, as well as impaired social interactions in BTBR mice. Together these data support the concept of targeted manipulation of the gut microbiota for reversing gastrointestinal and behavioral symptomatology in ASD, and offer specific plausible targets in this endeavor.
•BTBR mice display a reduced abundance of bile-metabolizing Bifidobacterium and Blautia bacterial species in the intestine.•BTBR mice demonstrate deficient bacterial metabolism of bile moieties in the gut.•Changes in the gut microbiota are associated with marked gastrointestinal distress and reduced sociability in BTBR mice.
There is growing awareness that the gut microbiome may contribute to gastrointestinal and behavioral symptomatology of autism spectrum disorder (ASD). However, the exact mechanisms by which intestinal bacteria can affect gut-brain axis signaling in autism are as yet poorly understood. Here we explore interactions between intestinal microbiota, gut physiology and behavior in a mouse model of ASD. We show that a reduction in the abundance of particular intestinal bacteria in “autistic” mice is associated with gastrointestinal distress and social behavior deficits. This work supports the concept of targeting the gut microbiota for reversing gastrointestinal symptoms in ASD, and identifies specific plausible targets for microbiota-based interventions.
Abstract Introduction Recent research has seen low-dose ketamine emerge as a novel, rapid-acting antidepressant. Ketamine, an N -methy- d -aspartate (NMDA) receptor antagonist, leads to effects on ...the glutamatergic system and abnormalities in this neurotransmittor system are present in depression. This article aims to (1) review the clinical literature on low-dose ketamine as a rapid-acting antidepressant in affective disorders, (2) provide a critical overview of the limitations of ketamine and research attempts to overcome these (3) discuss the proposed mechanisms of action of ketamine and (4) point towards future research directions. Method The electronic database Pubmed, Web of Science and sciencedirect were searched using the keywords: ketamine, N -methyl- d -aspartate receptor antagonist, rapid-acting antidepressant, depression, treatment-resistant depression, bipolar depression, suicidal ideation, electroconvulsive therapy, mechanism of action. Result The literature demonstrates evidence supporting a rapid-acting antidepressant effect of low-dose intravenous ketamine in major depressive disorder, in bipolar depression and in depression with suicidal ideation. There are mixed results as to whether ketamine leads to a reduction in time to remission in patients undergoing electroconvulsive therapy (ECT). Efforts to unravel ketamine′s therapeutic mechanism of action have implicated the mammalian target of rapamycin (mTOR)-dependent synapse formation in the rat prefrontal cortex, eukaryotic elongation factor 2 phosphorylation (p-eEF2) and glycogen synthase kinase (GSK-3). Ketamine′s limiting factors are the transient nature of its antidepressant effect and concerns regarding abuse, and research efforts to overcome these are reviewed. Conclusion Current and future research studies are using ketamine as a promising tool to evaluate the glutamatergic neurotransmittor system to learn more about the pathophysiology of depression and develop more specific rapid-acting antidepressant treatments.
Temporal lobe epilepsy (TLE) is a neurological disorder affecting millions of people worldwide and currently represents the most common form of focal epilepsy. Thus, the search for aetiological and ...pathophysiological parameters of TLE is ongoing.
Preclinical work and post-mortem human studies suggest adult hippocampal neurogenesis as a potentially relevant factor in TLE pathogenesis. Although progress has been made in elucidating the molecular links between TLE and hippocampal neurogenesis, recent evidence suggests that additional peripheral mediators may be involved.
The microbiota-gut-brain axis mediates bidirectional communication between the gut and the brain and could comprise a link between neurogenesis and TLE. In this review, we discuss emerging evidence highlighting a potential role for the gut microbiome in connecting TLE pathogenesis and hippocampal neurogenesis. We focus in particular on mechanisms associated with neuronal excitability, neuroinflammation and gut microbial metabolites. As the evidence does not yet support a direct link between gut microbiota-regulated hippocampal neurogenesis and TLE aetiology or pathophysiology, future studies are needed to establish whether current findings comprise circumstantial links or a potentially novel avenue for clinically relevant research.
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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.
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