The microbiota drives diurnal rhythms in tryptophan metabolism in the stressed gut.

Chronic stress disrupts microbiota-gut-brain axis function and is associated with altered tryptophan metabolism, impaired gut barrier function, and disrupted diurnal rhythms. However, little is known about the effects of acute stress on the gut and how it is influenced by diurnal physiology. Here, we used germ-free and antibiotic-depleted mice to understand how microbiota-dependent oscillations in tryptophan metabolism would alter gut barrier function at baseline and in response to an acute stressor. Cecal metabolomics identified tryptophan metabolism as most responsive to a 15-min acute stressor, while shotgun metagenomics revealed that most bacterial species exhibiting rhythmicity metabolize tryptophan. Our findings highlight that the gastrointestinal response to acute stress is dependent on the time of day and the microbiome, with a signature of stress-induced functional alterations in the ileum and altered tryptophan metabolism in the colon.

Do microbes play a role in Alzheimer's disease?

Alzheimer's disease is a complex and progressive condition that affects essential neurological functions such as memory and reasoning. In the brain, neuronal loss, synaptic dysfunction, proteinopathy, neurofibrillary tangles, and neuroinflammation are the hallmarks of Alzheimer's disease pathophysiology. In addition, recent evidence has highlighted that microbes, whether commensal or pathogenic, also have the ability to interact with their host and to regulate its immune system, therefore participating in the exchanges that lead to peripheral inflammation and neuropathology. Because of this intimate relationship, bacteria, viruses, fungi, and protozoa have been implicated in the development of Alzheimer's disease. Here, we bring together current and most recent evidence of the role of microbes in Alzheimer's disease, raising burning questions that need to be addressed to guide therapeutic approaches and potential prophylactic strategies.

Chronic immunosuppression across 12 months and high ability of acute and subacute CNS-injury biomarker concentrations to identify individuals with complicated mTBI on acute CT and MRI.

BACKGROUND: Identifying individuals with intracranial injuries following mild traumatic brain injury (mTBI), i.e. complicated mTBI cases, is important for follow-up and prognostication. The main aims of our study were (1) to assess the temporal evolution of blood biomarkers of CNS injury and inflammation in individuals with complicated mTBI determined on computer tomography (CT) and magnetic resonance imaging (MRI); (2) to assess the corresponding discriminability of both single- and multi-biomarker panels, from acute to chronic phases after injury. METHODS: Patients with mTBI (n = 207), defined as Glasgow Coma Scale score between 13 and 15, loss of consciousness < 30 min and post-traumatic amnesia < 24 h, were included. Complicated mTBI - i.e., presence of any traumatic intracranial injury on neuroimaging - was present in 8% (n = 16) on CT (CT+) and 12% (n = 25) on MRI (MRI+). Blood biomarkers were sampled at four timepoints following injury: admission (within 72 h), 2 weeks (± 3 days), 3 months (± 2 weeks) and 12 months (± 1 month). CNS biomarkers included were glial fibrillary acidic protein (GFAP), neurofilament light (NFL) and tau, along with 12 inflammation markers. RESULTS: The most discriminative single biomarkers of traumatic intracranial injury were GFAP at admission (CT+: AUC = 0.78; MRI+: AUC = 0.82), and NFL at 2 weeks (CT+: AUC = 0.81; MRI+: AUC = 0.89) and 3 months (MRI+: AUC = 0.86). MIP-1ß and IP-10 concentrations were significantly lower across follow-up period in individuals who were CT+ and MRI+. Eotaxin and IL-9 were significantly lower in individuals who were MRI+ only. FGF-basic concentrations increased over time in MRI- individuals and were significantly higher than MRI+ individuals at 3 and 12 months. Multi-biomarker panels improved discriminability over single biomarkers at all timepoints (AUCs > 0.85 for admission and 2-week models classifying CT+ and AUC ≈ 0.90 for admission, 2-week and 3-month models classifying MRI+). CONCLUSIONS: The CNS biomarkers GFAP and NFL were useful single diagnostic biomarkers of complicated mTBI, especially in acute and subacute phases after mTBI. Several inflammation markers were suppressed in patients with complicated versus uncomplicated mTBI and remained so even after 12 months. Multi-biomarker panels improved diagnostic accuracy at all timepoints, though at acute and 2-week timepoints, the single biomarkers GFAP and NFL, respectively, displayed similar accuracy compared to multi-biomarker panels.

Probiotic, prebiotic, synbiotic and fermented food supplementation in psychiatric disorders: A systematic review of clinical trials.

The use of probiotics, prebiotics, synbiotics or fermented foods can modulate the gut-brain axis and constitute a potentially therapeutic intervention in psychiatric disorders. This systematic review aims to identify current evidence regarding these interventions in the treatment of patients with DSM/ICD psychiatric diagnoses. Forty-seven articles from 42 studies met the inclusion criteria. Risk of bias was assessed in all included studies. Major depression was the most studied disorder (n = 19 studies). Studies frequently focused on schizophrenia (n = 11) and bipolar disorder (n = 5) and there were limited studies in anorexia nervosa (n = 4), ADHD (n = 3), Tourette (n = 1), insomnia (n = 1), PTSD (n = 1) and generalized anxiety disorder (n = 1). Except in MDD, current evidence does not clarify the role of probiotics and prebiotics in the treatment of mental illness. Several studies point to an improvement in the immune and inflammatory profile (e.g. CRP, IL6), which may be a relevant mechanism of action of the therapeutic response identified in these studies. Future research should consider lifestyle and dietary habits of patients as possible confounders that may influence inter-individual treatment response.

Longitudinal Associations Between Persistent Post-Concussion Symptoms and Blood Biomarkers of Inflammation and CNS-Injury After Mild Traumatic Brain Injury.

The aim of our study was to investigate the biological underpinnings of persistent post-concussion symptoms (PPCS) at 3 months following mild traumatic brain injury (mTBI). Patients (n = 192, age 16-60 years) with mTBI, defined as Glasgow Coma Scale (GCS) score between 13 and 15, loss of consciousness (LOC) <30 min, and post-traumatic amnesia (PTA) <24 h were included. Blood samples were collected at admission (within 72 h), 2 weeks, and 3 months. Concentrations of blood biomarkers associated with central nervous system (CNS) damage (glial fibrillary acidic protein [GFAP], neurofilament light [NFL], and tau) and inflammation (interferon gamma [IFNγ], interleukin [IL]-8, eotaxin, macrophage inflammatory protein-1-beta [MIP]-1ß, monocyte chemoattractant protein [MCP]-1, interferon-gamma-inducible protein [IP]-10, IL-17A, IL-9, tumor necrosis factor [TNF], basic fibroblast growth factor [FGF]-basic platelet-derived growth factor [PDGF], and IL-1 receptor antagonist [IL-1ra]) were obtained. Demographic and injury-related factors investigated were age, sex, GCS score, LOC, PTA duration, traumatic intracranial finding on magnetic resonance imaging (MRI; within 72 h), and extracranial injuries. Delta values, that is, time-point differences in biomarker concentrations between 2 weeks minus admission and 3 months minus admission, were also calculated. PPCS was assessed with the British Columbia Post-Concussion Symptom Inventory (BC-PSI). In single variable analyses, longer PTA duration and a higher proportion of intracranial findings on MRI were found in the PPCS group, but no single biomarker differentiated those with PPCS from those without. In multi-variable models, female sex, longer PTA duration, MRI findings, and lower GCS scores were associated with increased risk of PPCS. Inflammation markers, but not GFAP, NFL, or tau, were associated with PPCS. At admission, higher concentrations of IL-8 and IL-9 and lower concentrations of TNF, IL-17a, and MCP-1 were associated with greater likelihood of PPCS; at 2 weeks, higher IL-8 and lower IFNγ were associated with PPCS; at 3 months, higher PDGF was associated with PPCS. Higher delta values of PDGF, IL-17A, and FGF-basic at 2 weeks compared with admission, MCP-1 at 3 months compared with admission, and TNF at 2 weeks and 3 months compared with admission were associated with greater likelihood of PPCS. Higher IL-9 delta values at both time-point comparisons were negatively associated with PPCS. Discriminability of individual CNS-injury and inflammation biomarkers for PPCS was around chance level, whereas the optimal combination of biomarkers yielded areas under the curve (AUCs) between 0.62 and 0.73. We demonstrate a role of biological factors on PPCS, including both positive and negative effects of inflammation biomarkers that differed based on sampling time-point after mTBI. PPCS was associated more with acute inflammatory processes, rather than ongoing inflammation or CNS-injury biomarkers. However, the modest discriminative ability of the models suggests other factors are more important in the development of PPCS.

Social anxiety disorder-associated gut microbiota increases social fear.

Social anxiety disorder (SAD) is a crippling psychiatric disorder characterized by intense fear or anxiety in social situations and their avoidance. However, the underlying biology of SAD is unclear and better treatments are needed. Recently, the gut microbiota has emerged as a key regulator of both brain and behaviour, especially those related to social function. Moreover, increasing data supports a role for immune function and oxytocin signalling in social responses. To investigate whether the gut microbiota plays a causal role in modulating behaviours relevant to SAD, we transplanted the microbiota from SAD patients, which was identified by 16S rRNA sequencing to be of a differential composition compared to healthy controls, to mice. Although the mice that received the SAD microbiota had normal behaviours across a battery of tests designed to assess depression and general anxiety-like behaviours, they had a specific heightened sensitivity to social fear, a model of SAD. This distinct heightened social fear response was coupled with changes in central and peripheral immune function and oxytocin expression in the bed nucleus of the stria terminalis. This work demonstrates an interkingdom basis for social fear responses and posits the microbiome as a potential therapeutic target for SAD.

Microbiota-Gut-Brain Axis and Antidepressant Treatment.

In the treatment of depressive disorders, conventional antidepressant therapy has been the mainstay of clinical management, along with well-established nonpharmacological interventions such as various kinds of psychotherapy. Over the last 2 decades, there has been considerable interest in the role of the gastrointestinal system and its microbiota on brain function, behavior, and mental health. Components of what is referred to as the microbiota-gut-brain axis have been uncovered, and further research has elicited functional capabilities such as "gut-brain modules." Some studies have found associations with compositional alterations of gut microbiota in patients with depressive disorders and individuals experiencing symptoms of depression. Regarding the pathogenesis and neurobiology of depression itself, there appears to be a multifactorial contribution, in addition to the theories involving deficits in catecholaminergic and monoamine neurotransmission. Interestingly, there is evidence to suggest that antidepressants may play a role in modulating the gut microbiota, thereby possibly having an impact on the microbiota-gut-brain axis in this manner. The development of prebiotics, probiotics, and synbiotics has led to studies investigating not only their impact on the microbiota but also their therapeutic value in mental health. These psychobiotics have the potential to be used as therapeutic adjuncts in the treatment of depression. Regarding future directions, and in an attempt to further understand the role of the microbiota-gut-brain axis in depression, more studies such as those involving fecal microbiota transplantation will be required. In addition to recent findings, it is also suggested that more research will have to be undertaken to elicit whether specific strains of gut organisms are linked to depression. In terms of further investigation of the therapeutic potential of prebiotics, probiotics, and synbiotics as adjuncts to antidepressant treatment, we also expect there to be more research targeting specific microorganisms, as well as a strong focus on the effects of specific prebiotic fibers from an individualized (personalized) point of view.

The impact of acute and chronic stress on gastrointestinal physiology and function: a microbiota-gut-brain axis perspective.

The physiological consequences of stress often manifest in the gastrointestinal tract. Traumatic or chronic stress is associated with widespread maladaptive changes throughout the gut, although comparatively little is known about the effects of acute stress. Furthermore, these stress-induced changes in the gut may increase susceptibility to gastrointestinal disorders and infection, and impact critical features of the neural and behavioural consequences of the stress response by impairing gut-brain axis communication. Understanding the mechanisms behind changes in enteric nervous system circuitry, visceral sensitivity, gut barrier function, permeability, and the gut microbiota following stress is an important research objective with pathophysiological implications in both neurogastroenterology and psychiatry. Moreover, the gut microbiota has emerged as a key aspect of physiology sensitive to the effects of stress. In this review, we focus on different aspects of the gastrointestinal tract including gut barrier function as well as the immune, humoral and neuronal elements involved in gut-brain communication. Furthermore, we discuss the evidence for a role of stress in gastrointestinal disorders. Existing gaps in the current literature are highlighted, and possible avenues for future research with an integrated physiological perspective have been suggested. A more complete understanding of the spatial and temporal dynamics of the integrated host and microbial response to different kinds of stressors in the gastrointestinal tract will enable full exploitation of the diagnostic and therapeutic potential in the fast-evolving field of host-microbiome interactions.

AKT and MAPK signaling pathways in hippocampus reveals the pathogenesis of depression in four stress-induced models.

Major depressive disorder (MDD) is a highly heterogeneous psychiatric disorder. The pathogenesis of MDD remained unclear, and it may be associated with exposure to different stressors. Most previous studies have focused on molecular changes in a single stress-induced depression model, which limited the identification of the pathogenesis of MDD. The depressive-like behaviors were induced by four well-validated stress models in rats, including chronic unpredictable mild stress, learned helplessness stress, chronic restraint stress and social defeat stress. We applied proteomic and metabolomic to investigate molecular changes in the hippocampus of those four models and revealed 529 proteins and 98 metabolites. Ingenuity Pathways Analysis (IPA) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis identified differentially regulated canonical pathways, and then we presented a schematic model that simulates AKT and MAPK signaling pathways network and their interactions and revealed the cascade reactions. Further, the western blot confirmed that p-AKT, p-ERK12, GluA1, p-MEK1, p-MEK2, p-P38, Syn1, and TrkB, which were changed in at least one depression model. Importantly, p-AKT, p-ERK12, p-MEK1 and p-P38 were identified as common alterations in four depression models. The molecular level changes caused by different stressors may be dramatically different, and even opposite, between four depression models. However, the different molecular alterations converge on a common AKT and MAPK molecular pathway. Further studies of these pathways could contribute to a better understanding of the pathogenesis of depression, with the ultimate goal of helping to develop or select more effective treatment strategies for MDD.

Pesticide exposure and the microbiota-gut-brain axis.

The gut microbiota exist within a dynamic ecosystem shaped by various factors that includes exposure to xenobiotics such as pesticides. It is widely regarded that the gut microbiota plays an essential role in maintaining host health, including a major influence on the brain and behaviour. Given the widespread use of pesticides in modern agriculture practices, it is important to assess the long-term collateral effects these xenobiotic exposures have on gut microbiota composition and function. Indeed, exposure studies using animal models have shown that pesticides can induce negative impacts on the host gut microbiota, physiology and health. In tandem, there is a growing body of literature showing that the effects of pesticide exposure can be extended to the manifestation of behavioural impairments in the host. With the increasing appreciation of the microbiota-gut-brain axis, in this review we assess whether pesticide-induced changes in gut microbiota composition profiles and functions could be driving these behavioural alterations. Currently, the diversity of pesticide type, exposure dose and variation in experimental designs hinders direct comparisons of studies presented. Although many insights presented, the mechanistic connection between the gut microbiota and behavioural changes remains insufficiently explored. Future experiments should therefore focus on causal mechanisms to examine the gut microbiota as the mediator of the behavioural impairments observed in the host following pesticide exposure.

Machine learning classification of chronic traumatic brain injury using diffusion tensor imaging and NODDI: A replication and extension study.

Individuals with acute and chronic traumatic brain injury (TBI) are associated with unique white matter (WM) structural abnormalities, including fractional anisotropy (FA) differences. Our research group previously used FA as a feature in a linear support vector machine (SVM) pattern classifier, observing high classification between individuals with and without acute TBI (i.e., an area under the curve [AUC] value of 75.50%). However, it is not known whether FA could similarly classify between individuals with and without history of chronic TBI. Here, we attempted to replicate our previous work with a new sample, investigating whether FA could similarly classify between incarcerated men with (n = 80) and without (n = 80) self-reported history of chronic TBI. Additionally, given limitations associated with FA, including underestimation of FA values in WM tracts containing crossing fibers, we extended upon our previous study by incorporating neurite orientation dispersion and density imaging (NODDI) metrics, including orientation dispersion (ODI) and isotropic volume (Viso). A linear SVM based classification approach, similar to our previous study, was incorporated here to classify between individuals with and without self-reported chronic TBI using FA and NODDI metrics as separate features. Overall classification rates were similar when incorporating FA and NODDI ODI metrics as features (AUC: 82.50%). Additionally, NODDI-based metrics provided the highest sensitivity (ODI: 85.00%) and specificity (Viso: 82.50%) rates. The current study serves as a replication and extension of our previous study, observing that multiple diffusion MRI metrics can reliably classify between individuals with and without self-reported history of chronic TBI.

Beyond the symptom: the biology of fatigue.

A workshop titled "Beyond the Symptom: The Biology of Fatigue" was held virtually September 27-28, 2021. It was jointly organized by the Sleep Research Society and the Neurobiology of Fatigue Working Group of the NIH Blueprint Neuroscience Research Program. For access to the presentations and video recordings, see: https://neuroscienceblueprint.nih.gov/about/event/beyond-symptom-biology-fatigue. The goals of this workshop were to bring together clinicians and scientists who use a variety of research approaches to understand fatigue in multiple conditions and to identify key gaps in our understanding of the biology of fatigue. This workshop summary distills key issues discussed in this workshop and provides a list of promising directions for future research on this topic. We do not attempt to provide a comprehensive review of the state of our understanding of fatigue, nor to provide a comprehensive reprise of the many excellent presentations. Rather, our goal is to highlight key advances and to focus on questions and future approaches to answering them.

Compositional and Functional Alterations in Intestinal Microbiota in Patients with Psychosis or Schizophrenia: A Systematic Review and Meta-analysis.

BACKGROUND AND HYPOTHESIS: Intestinal microbiota is intrinsically linked to human health. Evidence suggests that the composition and function of the microbiome differs in those with schizophrenia compared with controls. It is not clear how these alterations functionally impact people with schizophrenia. We performed a systematic review and meta-analysis to combine and evaluate data on compositional and functional alterations in microbiota in patients with psychosis or schizophrenia. STUDY DESIGN: Original studies involving humans and animals were included. The electronic databases PsycINFO, EMBASE, Web of Science, PubMed/MEDLINE, and Cochrane were systematically searched and quantitative analysis performed. STUDY RESULTS: Sixteen original studies met inclusion criteria (1376 participants: 748 cases and 628 controls). Ten were included in the meta-analysis. Although observed species and Chao 1 show a decrease in diversity in people with schizophrenia compared with controls (SMD = -0.14 and -0.66 respectively), that did not reach statistical significance. We did not find evidence for variations in richness or evenness of microbiota between patients and controls overall. Differences in beta diversity and consistent patterns in microbial taxa were noted across studies. We found increases in Bifidobacterium, Lactobacillus, and Megasphaera in schizophrenia groups. Variations in brain structure, metabolic pathways, and symptom severity may be associated with compositional alterations in the microbiome. The heterogeneous design of studies complicates a similar evaluation of functional readouts. CONCLUSIONS: The microbiome may play a role in the etiology and symptomatology of schizophrenia. Understanding how the implications of alterations in microbial genes for symptomatic expression and clinical outcomes may contribute to the development of microbiome targeted interventions for psychosis.

Traumatic Brain Injury and Psychopathic Traits in Justice-Involved Adult Women.

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 (N = 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.

Disturbances of purine and lipid metabolism in the microbiota-gut-brain axis in male adolescent nonhuman primates with depressive-like behaviors.

INTRODUCTION: Major depressive disorder (MDD) in adolescents is a widespread and growing global public health concern with unique characteristics and pathophysiological mechanisms that are distinct from MDD in adults. OBJECTIVE: The purpose of our work was to address this knowledge gap about the unique characteristics and pathophysiological mechanisms of adolescent depression from a microbiota-gut-brain (MGB) axis perspective. METHOD: Ten healthy male cynomolgus macaques (Macaca fascicularis) were paired into five pairs based on age and body weight, and two cynomolgus macaques from each pair were randomly allocated to chronic unpredictable mild stress group, or unstressed control group. At endpoint, microbe composition from cecum, ascending colon, transverse colon, and descending colon were analyzed by metagenome sequencing, and the metabolite profiles of MGB axis including central (prefrontal cortex, hippocampus and amygdala) and peripheral (plasma, gut and feces of cecum, ascending colon, transverse colon and descending colon) samples were analyzed by metabolomic profiling. Then, we compare the gut microbiome and metabolic signatures in MGB axis between adolescent and adult depressed macaques. RESULTS: The microbial composition and gut-brain metabolic signatures were widely divergent between adolescent and adult depressed macaques, though the phylum Firmicutes and lipid metabolism pathways were persistently altered in both populations. Purine and arginine biosynthesis metabolism were a specific hallmark of adolescent depressed macaques, while fatty acyl metabolism was specially altered in adult. These differential metabolic pathways in adolescent and adult depressed macaques were mainly mapped into the prefrontal cortex and hippocampus, respectively. Notably, the genus Clostridium and Haemophilus, characteristically disturbed in adolescent depressed macaques but not in adult, were also significantly associated with the majority of purine metabolites in MGB axis. CONCLUSION: These findings provide a new framework describing divergent pathophysiological mechanisms between adolescent and adult depression, and may open new windows for more effective treatment strategies of adolescent depression.

Seeking the Psilocybiome: Psychedelics meet the microbiota-gut-brain axis

Moving towards a systems psychiatry paradigm embraces the inherent complex interactions across all levels from micro to macro and necessitates an integrated approach to treatment. Cortical 5-HT2A receptors are key primary targets for the effects of serotonergic psychedelics. However, the therapeutic mechanisms underlying psychedelic therapy are complex and traverse molecular, cellular, and network levels, under the influence of biofeedback signals from the periphery and the environment. At the interface between the individual and the environment, the gut microbiome, via the gut-brain axis, plays an important role in the unconscious parallel processing systems regulating host neurophysiology. While psychedelic and microbial signalling systems operate over different timescales, the microbiota-gut-brain (MGB) axis, as a convergence hub between multiple biofeedback systems may play a role in the preparatory phase, the acute administration phase, and the integration phase of psychedelic therapy. In keeping with an interconnected systems-based approach, this review will discuss the gut microbiome and mycobiome and pathways of the MGB axis, and then explore the potential interaction between psychedelic therapy and the MGB axis and how this might influence mechanism of action and treatment response. Finally, we will discuss the possible implications for a precision medicine-based psychedelic therapy paradigm. (AU)

Microbes, oxytocin and stress: Converging players regulating eating behavior.

Oxytocin is a peptide-hormone extensively studied for its multifaceted biological functions and has recently gained attention for its role in eating behavior, through its action as an anorexigenic neuropeptide. Moreover, the gut microbiota is involved in oxytocinergic signaling through the brain-gut axis, specifically in the regulation of social behavior. The gut microbiota is also implicated in appetite regulation and is postulated to play a role in central regulation of hedonic eating. In this review, we provide an overview on oxytocin and its individual links with the microbiome, the homeostatic and non-homeostatic regulation of eating behavior as well as social behavior and stress.

The gut microbiome in social anxiety disorder: evidence of altered composition and function.

The microbiome-gut-brain axis plays a role in anxiety, the stress response and social development, and is of growing interest in neuropsychiatric conditions. The gut microbiota shows compositional alterations in a variety of psychiatric disorders including depression, generalised anxiety disorder (GAD), autism spectrum disorder (ASD) and schizophrenia but studies investigating the gut microbiome in social anxiety disorder (SAD) are very limited. Using whole-genome shotgun analysis of 49 faecal samples (31 cases and 18 sex- and age-matched controls), we analysed compositional and functional differences in the gut microbiome of patients with SAD in comparison to healthy controls. Overall microbiota composition, as measured by beta-diversity, was found to be different between the SAD and control groups and several taxonomic differences were seen at a genus- and species-level. The relative abundance of the genera Anaeromassillibacillus and Gordonibacter were elevated in SAD, while Parasuterella was enriched in healthy controls. At a species-level, Anaeromassilibacillus sp An250 was found to be more abundant in SAD patients while Parasutterella excrementihominis was higher in controls. No differences were seen in alpha diversity. In relation to functional differences, the gut metabolic module 'aspartate degradation I' was elevated in SAD patients. In conclusion, the gut microbiome of patients with SAD differs in composition and function to that of healthy controls. Larger, longitudinal studies are warranted to validate these preliminary results and explore the clinical implications of these microbiome changes.

Beta 3-adrenoceptor agonism ameliorates early-life stress-induced visceral hypersensitivity in male rats.

Visceral hypersensitivity, a hallmark of disorders of the gut-brain axis, is associated with exposure to early-life stress (ELS). Activation of neuronal ß3-adrenoceptors (AR) has been shown to alter central and peripheral levels of tryptophan and reduce visceral hypersensitivity. In this study, we aimed to determine the potential of a ß3-AR agonist in reducing ELS-induced visceral hypersensitivity and possible underlying mechanisms. Here, ELS was induced using the maternal separation (MS) model, where Sprague Dawley rat pups were separated from their mother in early life (postnatal day 2-12). Visceral hypersensitivity was confirmed in adult offspring using colorectal distension (CRD). CL-316243, a ß3-AR agonist, was administered to determine anti-nociceptive effects against CRD. Distension-induced enteric neuronal activation as well as colonic secretomotor function were assessed. Tryptophan metabolism was determined both centrally and peripherally. For the first time, we showed that CL-316243 significantly ameliorated MS-induced visceral hypersensitivity. Furthermore, MS altered plasma tryptophan metabolism and colonic adrenergic tone, while CL-316243 reduced both central and peripheral levels of tryptophan and affected secretomotor activity in the presence of tetrodotoxin. This study supports the beneficial role of CL-316243 in reducing ELS-induced visceral hypersensitivity, and suggests that targeting the ß3-AR can significantly influence gut-brain axis activity through modulation of enteric neuronal activation, tryptophan metabolism, and colonic secretomotor activity which may synergistically contribute to offsetting the effects of ELS.

Age-associated deficits in social behaviour are microbiota-dependent.

Aging is associated with remodelling of immune and central nervous system responses resulting in behavioural impairments including social deficits. Growing evidence suggests that the gut microbiome is also impacted by aging, and we propose that strategies to reshape the aged gut microbiome may ameliorate some age-related effects on host physiology. Thus, we assessed the impact of gut microbiota depletion, using an antibiotic cocktail, on aging and its impact on social behavior and the immune system. Indeed, microbiota depletion in aged mice eliminated the age-dependent deficits in social recognition. We further demonstrate that although age and gut microbiota depletion differently shape the peripheral immune response, aging induces an accumulation of T cells in the choroid plexus, that is partially blunted following microbiota depletion. Moreover, an untargeted metabolomic analysis revealed age-dependent alterations of cecal metabolites that are reshaped by gut microbiota depletion. Together, our results suggest that the aged gut microbiota can be specifically targeted to affect social deficits. These studies propel the need for future investigations of other non-antibiotic microbiota targeted interventions on age-related social deficits both in animal models and humans.