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Background: Alcohol use disorder (AUD) is commonly associated with distressing psychological symptoms. Pathologic changes associated with AUD have been described in both the gut microbiome and brain, but the mechanisms underlying gut‐brain signaling in individuals with AUD are unknown. This study examined associations among the gut microbiome, brain morphometry, and clinical symptoms in treatment‐seeking individuals with AUD. Methods: We performed a secondary analysis of data collected during inpatient treatment for AUD in subjects who provided gut microbiome samples and had structural brain magnetic resonance imaging (MRI; n = 16). Shotgun metagenomics sequencing was performed, and the morphometry of brain regions of interest was calculated. Clinical symptom severity was quantified using validated instruments. Gut‐brain modules (GBMs) used to infer neuroactive signaling potential from the gut microbiome were generated in addition to microbiome features (e.g., alpha diversity and bacterial taxa abundance). Bivariate correlations were performed between MRI and clinical features, microbiome and clinical features, and MRI and microbiome features. Results: Amygdala volume was significantly associated with alpha diversity and the abundance of several bacteria including taxa classified to Blautia,Ruminococcus, Bacteroides, and Phocaeicola. There were moderate associations between amygdala volume and GBMs, including butyrate synthesis I, glutamate synthesis I, and GABA synthesis I & II, but these relationships were not significant after false discovery rate (FDR) correction. Other bacterial taxa with shared associations to MRI features and clinical symptoms included Escherichia coli and Prevotella copri. Conclusions: We identified gut microbiome features associated with MRI morphometry and AUD‐associated symptom severity. Given the small sample size and bivariate associations performed, these results require confirmation in larger samples and controls to provide meaningful clinical inferences. Nevertheless, these results will inform targeted future research on the role of the gut microbiome in gut‐brain communication and how signaling may be altered in patients with AUD. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

The bed nucleus of the stria terminalis (BNST) is a focal point for the convergence of inputs from canonical stress‐sensitive structures to fine‐tune the response to stress. However, its role in mediating phenotypes of stress resilience or susceptibility is yet to be fully defined. In this study, we carried out unbiased RNA‐sequencing to analyse the BNST transcriptomes of adult male mice, which were classified as resilient or susceptible following a 10‐day chronic psychosocial defeat stress paradigm. Pairwise comparisons revealed 20 differentially expressed genes in resilience (6) and susceptible (14) mice compared with controls. An in silico validation of our data against an earlier study revealed significant concordance in gene expression profiles associated with resilience to chronic stress. Enrichment analysis revealed that resilience is linked to functions including retinoic acid hydrolase activity, phospholipase inhibitor and tumour necrosis factor (TNF)‐receptor activities, whereas susceptibility is linked to alterations in amino acid transporter activity. We also identified differential usage of 134 exons across 103 genes associated with resilience and susceptibility; enrichment analysis for genes with differential exon usage in resilient mice was linked to functions including adrenergic receptor binding mice and oxysterol binding in susceptible mice. Our findings highlight the important and underappreciated role of the BNST in stress resilience and susceptibility and reveal research avenues for follow‐up investigations. [ABSTRACT FROM AUTHOR]

Obsessive–compulsive disorder (OCD) is a psychiatric illness that significantly impacts affected patients and available treatments yield suboptimal therapeutic response. Recently, the role of the gut–brain axis (GBA) in psychiatric illness has emerged as a potential target for therapeutic exploration. However, studies concerning the role of the GBA in OCD are limited. To investigate whether a naturally occurring obsessive–compulsive‐like phenotype in a rodent model, that is large nest building in deer mice, is associated with perturbations in the gut microbiome, we investigated and characterised the gut microbiota in specific‐pathogen‐free bred and housed large (LNB) and normal (NNB) nest‐building deer mice of both sexes (n = 11 per group, including three males and eight females). Following baseline characterisation of nest‐building behaviour, a single faecal sample was collected from each animal and the gut microbiota analysed. Our results reveal the overall microbial composition of LNB animals to be distinctly different compared to controls (PERMANOVA p <.05). While no genera were found to be significantly differentially abundant after correcting for multiple comparisons, the normal phenotype showed a higher loading of Prevotella and Anaeroplasma, while the OC phenotype demonstrated a higher loading of Desulfovermiculus, Aestuariispira, Peptococcus and Holdemanella (cut‐off threshold for loading at 0.2 in either the first or second component of the PCA). These findings not only provide proof‐of‐concept for continued investigation of the GBA in OCD, but also highlight a potential underlying aetiological association between alterations in the gut microbiota and the natural development of obsessive–compulsive‐like behaviours. [ABSTRACT FROM AUTHOR]

Microorganisms can be found almost anywhere, including in and on the human body. The collection of microorganisms associated with a certain location is called a microbiota, with its collective genetic material referred to as the microbiome. The largest population of microorganisms on the human body resides in the gastrointestinal tract; thus, it is not surprising that the most investigated human microbiome is the human gut microbiome. On average, the gut hosts microbes from more than 60 genera and contains more cells than the human body. The human gut microbiome has been shown to influence many aspects of host health, including more recently the brain. Several modes of interaction between the gut and the brain have been discovered, including via the synthesis of metabolites and neurotransmitters, activation of the vagus nerve, and activation of the immune system. A growing body of work is implicating the microbiome in a variety of psychological processes and neuropsychiatric disorders. These include mood and anxiety disorders, neurodevelopmental disorders such as autism spectrum disorder and schizophrenia, and even neurodegenerative disorders such as Alzheimer's and Parkinson's diseases. Moreover, it is probable that most psychotropic medications have an impact on the microbiome. Here, an overview will be provided for the bidirectional role of the microbiome in brain health, age-associated cognitive decline, and neurological and psychiatric disorders. Furthermore, a primer on the common microbiological and bioinformatics techniques used to interrogate the microbiome will be provided. This review is meant to equip the reader with a primer to this exciting research area that is permeating all areas of biological psychiatry research. [ABSTRACT FROM AUTHOR]

O2 PLIM microscopy was employed in various studies, however current platforms have limitations in sensitivity, image acquisition speed, accuracy and general usability. We describe a new PLIM imager based on the Timepix3 camera (Tpx3cam) and its application for imaging of O2 concentration in various tissue samples stained with a nanoparticle based probe, NanO2-IR. Upon passive staining of mouse brain, lung or intestinal tissue surface with minute quantities of NanO2-IR or by microinjecting the probe into the lumen of small or large intestine fragments, robust phosphorescence intensity and lifetime signals were produced, which allow mapping of O2 in the tissue within 20 s. Inhibition of tissue respiration or limitation of O2 diffusion to tissue produced the anticipated increases or decreases in O2 levels, respectively. The difference in O2 concentration between the colonic lumen and air-exposed serosal surface was around 140 µM. Furthermore, subcutaneous injection of 5 µg of the probe in intact organs (a paw or tail of sacrificed mice) enabled efficient O2 imaging at tissue depths of up to 0.5 mm. Overall, the PLIM imager holds promise for metabolic imaging studies with various ex vivo models of animal tissue, and also for use in live animals. [ABSTRACT FROM AUTHOR]

Stress and circadian systems are interconnected through the hypothalamic-pituitary-adrenal (HPA) axis to maintain responses to external stimuli. Yet, the mechanisms of how such signals are orchestrated remain unknown. Here, we uncover the gut microbiota as a regulator of HPA-axis rhythmicity. Microbial depletion disturbs the brain transcriptome and metabolome in stress-responding pathways in the hippocampus and amygdala across the day. This is coupled with a dysregulation of the circadian pacemaker in the brain that results in perturbed glucocorticoid rhythmicity. The resulting hyper-activation of the HPA axis at the sleep/wake transition drives time-of-day-specific impairments of the stress response and stress-sensitive behaviors. Finally, microbiota transplantation confirmed that diurnal oscillations of gut microbes underlie altered glucocorticoid secretion and that L. reuteri is a candidate strain for such effects. Our data offer compelling evidence that the microbiota regulates stress responsiveness in a circadian manner and is necessary to respond adaptively to stressors throughout the day., Competing Interests: Declaration of interests J.F.C. has been an invited speaker at conferences organized by Bromotech and Nestle and has received research funding from Nutricia, Dupont/IFF, and Nestle. G.C. has received honoraria from Janssen, Probi, and Apsen as an invited speaker; is in receipt of research funding from Pharmavite, Fonterra, Reckitt, Nestle, Tate, and Lyle; and is a paid consultant for Yakult, Zentiva, and Heel Pharmaceuticals. This support neither influenced nor constrained the contents of this article., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Background: Alterations in gut-brain axis communication pathways and the gut microbiota ecosystem caused by early life stress have been extensively described as critical players in the pathophysiology of stress-induced disorders. However, the extent to which stress-induced gut microbiota alterations manifest in early life and contribute to the sex-specific susceptibility to distinct gut-brain phenotypes in adulthood has yet to be defined., Methods: Male and female Sprague-Dawley rat offspring underwent maternal separation (3h/day from postnatal day 2-12). Faecal samples were collected before weaning for gut microbiota 16S rRNA sequencing and metabolomic analysis. Visceral pain sensitivity and negative valence behaviours were assessed in adulthood using colorectal distension and the forced swim test respectively. Behavioural data were processed in a two-step cluster analysis to identify groupings within the dataset. Multi-omics analysis was carried out to investigate if the microbial signatures following early life stress were already defined according to the membership of the adult behavioural phenotypes., Results: Maternal separation resulted in increased visceral hypersensitivity while showing a trend for a sex-dependent increase in negative valence behaviour in adulthood. The cluster analysis revealed four clusters within the dataset representing distinct pathophysiological domains reminiscent of the behavioural consequences of early-life stress: 1. resilient, 2. pain, 3. immobile and 4. comorbid. The early life gut microbiota of each of these clusters show distinct alterations in terms of diversity, genus level differential abundance, and functional modules. Multi-omic integrations points towards a role for different metabolic pathways underlying each cluster-specific phenotype., Conclusion: Our study is the first to identify distinct phenotypes defined by susceptibility or resilience to gut-brain dysfunction induced by early life stress. The gut microbiota in early life shows sex-dependent alterations in each cluster that precede specific behavioural phenotypes in adulthood. Future research is warranted to determine the causal relationship between early-life stress-induced changes in the gut microbiota and to understand the trajectory leading to the manifestation of different behavioural phenotypes in adulthood., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. SMO’M has received funding from 10.13039/100006628Mead Johnson. JFC has spoken at conferences organised by Mead Johnson, Ordesa, and Yakult and has received research funding from Reckitt, Nutricia, Dupont/IFF, and Nestle. G.C. received honoraria from Janssen, Probi, and Apsen and research funding from Pharmavite and 10.13039/501100003144Fonterra and is a paid consultant for Yakult and Zentiva., (© 2024 The Authors.)

Recent research highlights the pivotal role of the maternal gut microbiome during pregnancy in shaping offspring neurodevelopment. In this study, we investigated the impact of maternal intake of a multispecies probiotic formulation during a critical prenatal window (from gestational day 6 until birth) on neurodevelopmental trajectories in mice. Our findings demonstrate significant and persistent benefits in emotional behavior, gut microbiota composition, and expression of tight junction-related genes, particularly in male offspring, who exhibited heightened sensitivity to the probiotic intervention compared to females. Additionally, we observed elevated gene expression levels of the anti-inflammatory cytokine IL-10 and the oxytocin receptor (Oxtr) in the prefrontal cortex (PFC) of exposed juvenile offspring; however, these changes persisted only in the adult male offspring. Furthermore, the sustained increase in the expression of the proton-coupled oligopeptide transporter 1 (PepT1), which is involved in the transport of bacterial peptidoglycan motifs, in the PFC of exposed male offspring suggests a potential mechanistic pathway underlying the observed sex-dependent effects on behavior and gene expression. These results underscore the potential of prenatal multispecies probiotic interventions to promote long-term neurodevelopmental outcomes, with implications for precision microbial reconstitution aimed at promoting healthy neurodevelopment and behavior., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Social anxiety disorder is a common psychiatric condition that severely affects quality of life of individuals and is a significant societal burden. Although many risk factors for social anxiety exist, it is currently unknown how social fear sensitivity manifests biologically. Furthermore, since some individuals are resilient and others are susceptible to social fear, it is important to interrogate the mechanisms underpinning individual response to social fear situations. The microbiota-gut-brain axis has been associated with social behaviour, has recently been linked with social anxiety disorder, and may serve as a therapeutic target for modulation. Here, we assess the potential of this axis to be linked with social fear extinction processes in a murine model of social anxiety disorder. To this end, we correlated differential social fear responses with microbiota composition, central gene expression, and immune responses. Our data provide evidence that microbiota variability is strongly correlated with alterations in social fear behaviour. Moreover, we identified altered gene candidates by amygdalar transcriptomics that are linked with social fear sensitivity. These include genes associated with social behaviour (Armcx1, Fam69b, Kcnj9, Maoa, Serinc5, Slc6a17, Spata2, and Syngr1), inflammation and immunity (Cars, Ckmt1, Klf5, Maoa, Map3k12, Pex5, Serinc5, Sidt1, Spata2), and microbe-host interaction (Klf5, Map3k12, Serinc5, Sidt1). Together, these data provide further evidence for a role of the microbiota-gut-brain axis in social fear responses., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

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., Competing Interests: Declaration of interests J.F.C. has spoken at conferences organized by Mead Johnson, Ordesa, and Yakult and has received research funding from Reckitt, Nutricia, Dupont/IFF, and Nestle. G.C. received honoraria from Janssen, Probi, and Apsen and research funding from Pharmavite and Fonterra and is a paid consultant for Yakult and Zentiva. This support did not influence or constrain this preview. The authors’ views do not reflect the official guidance or position of the United States Government, the Department of Defense, or the United States Air Force. Approved for public release; distribution is unlimited. Case no. AFRL-2022-5638, December 2, 2022., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

In this study, rapid respirometric microbial testing was combined with 16S rRNA amplicon sequencing, to assess the composition of microbiota in a total of 64 samples of commercial beef, turkey, lamb and pork mince. The O 2 sensor-based respirometry system, while producing the anticipated total aerobic viable counts (TVC) data and patterns for most samples, also revealed unusual (linear) respiration profiles for some samples, mostly lamb and pork mince. The TVC values for beef mince, produced by respirometry and calculated using the available calibration equation, correlated well with the conventional plate counting method, ISO 4833-1:2013, 2013, while for the other species the correlation was less good. These effects, not observed in previous studies employing various food matrices, require further investigation. Using the same samples (crude homogenates) as in respirometry, the whole microbiome was also analysed by 16S rRNA amplicon sequencing for each mince-type. The sequencing showed an overall decrease in alpha diversity over shelf-life, with lamb and pork mince maintaining a proportion of rare taxa. Some taxa exhibited significant changes in abundance over shelf-life and after the respirometric analysis, with beef mince exhibiting a decrease in aerobic bacteria and an increase in facultative anaerobes. Beta diversity was also seen to depend on mince-type. Thus, the combined use of respirometry and sequencing techniques shows promise as a useful and unique analytical approach for food quality and safety evaluation, However, more data points and in-depth analysis are required to back up the findings of this initial study., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.)